Prostaglandin E2 (PGE2) EP4 receptor antagonist

Abstract

The present invention relates to novel compounds of formula (I) and pharmaceutical compositions containing these compounds.The compounds provided herein can act as prostaglandin E2 (PGE2) EP4 receptor antagonists, and therefore the compounds are highly advantageous for use in therapy, particularly in the treatment or prevention of cancer, angiogenic eye disease, inflammatory pain, or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, or endometriosis. TIFF2022552797000523.tif6475

Description

[Technical Field]

[0001] The present invention relates to novel compounds of formula (I) and pharmaceutical compositions containing these compounds.The compounds provided herein can act as prostaglandin E2 (PGE2) EP4 receptor antagonists, and therefore the compounds are highly advantageous for use in therapy, particularly in the treatment or prevention of cancer, angiogenic eye disease, inflammatory pain, or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, or endometriosis. [Background technology]

[0002] Prostaglandin E2 (PGE2) is an eicosanoid described as a major mediator of inflammation, exhibiting pro- and anti-inflammatory effects depending on the context. This bioactive lipid is the most widely produced prostanoid in animal species and humans and is synthesized from arachidonic acid by cyclooxygenases COX-1 or COX-2 and specific prostanoid synthases cPGES-1, m-PGES-1, and m-PGES-2. PGE2 is involved in a wide variety of physiological effects, including pain, fever, inflammation, regulation of vascular tone, mucosal integrity, fracture healing, renal function, angiogenesis, and tumor growth. PGE2 signaling is mediated by four G protein-coupled receptors (GPCRs): EP1, EP2, EP3, and EP4. The EP4 receptor mediates G αS Proteins are primarily coupled to EP4 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels upon PGE2 activation (Konya V. et al., Pharmacology & Therapeutics, 2013, 485; Yokoyama U. et al., Pharmacological reviews, 2013, 1010). In addition, the EP4 receptor is also G αi It can signal via other pathways involving proteins or β-arrestins.

[0003] Interfering with PGE2 signaling provides a tool for modulating immune patterns in a wide range of diseases, from autoimmunity to cancer (Kalinski P., The Journal of Immunology, 2012, 21). Indeed, sustained levels of PGE2 in the tumor microenvironment promote immunosuppression across a diverse range of immune cells, leading to subsequent cancer immune evasion. Notably, this immunosuppression results in a shift from Th1 to Th2 immune responses, altered antigen-presenting cell infiltration and function, and altered CD8 + This mechanism operates via aberrant cytotoxic activity of T cells and natural killer cells, as well as enhanced immune suppressor cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Elevated COX-2 expression and resulting elevated PGE2 levels are observed in numerous cancers and are associated with tumor development and progression (O'Callaghan G. et al., British Journal of Pharmacology, 2015, 5239). Notably, COX-2 overexpression has been reported to promote breast cancer progression and metastasis (Majumder M. et al., Cancer Science, 2014, 1142). PGE2 produced by host tissues has also been shown to be crucial for B16 melanoma growth, angiogenesis, and metastasis to bone and soft tissues (Inada M. et al., The Journal of Biological Chemistry, 2015, 29781). Alternatively, the crucial role of the PGE2 / EP4 signaling pathway was highlighted in promoting oxaliplatin resistance in human colorectal cancer cells (Huang H. et al., Scientific Reports, 2019, 4954). PGE2 has also been shown to be involved in regulating PD-L1 expression in tumor-infiltrating myeloid cells, thus mediating tumor evasion from the immune system (Prima et al., Proceedings of the National Academy of Sciences, 2017, 1117).

[0004] Previous studies support the primary role of the EP4 receptor in mediating the immunosuppressive effects of PGE2. Selective EP4 antagonism has previously been shown to prevent lung and breast cancer metastasis (Yang L., Cancer Research, 2006, 9665; Ma X. et al., Cancer Research, 2006, 2923). Metastatic tumor growth and angiogenesis in soft tissues were inhibited by an EP4 receptor antagonist in a B16 melanoma model (Inada M. et al., The Journal of Biological Chemistry, 2015, 29781). EP4 receptor antagonists have also been shown to disrupt tumor growth, lymphangiogenesis, and metastasis to lymph nodes and lungs in a breast cancer model (Majumder M. et al., Cancer Science, 2014, 1142). EP4 blockade has been shown to prevent tumor-mediated NK cell immunosuppression and reduce immune tolerance caused by myeloid-derived suppressor cells and tumor-associated macrophages (Ma X. et al., Oncoimmunology, 2013, e22647; Albu D. et al., Oncoimmunology, 2017, e1338239). Successful combination therapy of EP4 antagonists with immune checkpoint inhibitors has been reported (Bao X. et al., Journal for ImmunoTherapy of Cancer, 2015, 350). Notably, concomitant blockade of the EP4 receptor and the use of anti-PD-1 antibodies provides effective antitumor responses. Summary of the Invention [Problem to be solved by the invention]

[0005] Although various antagonists of the EP4 receptor have already been reported in the literature (as mentioned above), there remains a continuing need for new and / or improved EP4 receptor antagonists, particularly for the therapy of cancer and other EP4-related pathologies. [Means for solving the problem]

[0006] The present invention addresses this need and solves the problem of providing novel and highly potent EP4 receptor antagonists.In particular, it has been surprisingly found that the compounds provided herein have strong EP4 antagonistic activity and also exhibit outstanding therapeutic efficacy against cancer, as reflected by the substantial tumor growth inhibition and even complete tumor regression achieved in a high percentage of cases in xenograft mouse models (as further described in the Examples section).

[0007] Therefore, the present invention provides a compound of formula (I)

[0008] [ka]

[0009] or a pharmaceutically acceptable salt thereof. In formula (I), the group A 1 and A 2 are each independently 1~5 alkyl or a group A 1 and A 2 are joined to each other and together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is bound to one or more groups R 1 The carbocyclic or heterocyclic group (A 1 , A 2 , and A 1 and A 2 ) is also referred to herein as "Ring A."

[0010] In the context of the present invention, surprisingly, A 1 and A 2 The presence of two alkyl groups (especially two methyl groups) as A 1 and A 2It has been found that the presence of a carbocyclic or heterocyclic group (ring A) formed from is highly advantageous with regard to the antagonistic activity of the compounds of formula (I) towards the prostaglandin E2 (PGE2) EP4 receptor.

[0011] Ring B is a carbocyclic or heterocyclic group. Ring D is carbocyclyl or heterocyclyl. L is C 1~6 alkylene or a covalent bond, 1~6 One or more -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)-, -C(C 1~5 Alkyl)(C 1~5 alkyl), carbocyclylene and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally replaced by one or more groups -L A -R A may be substituted with each of the following:

[0012] m is an integer from 0 to 4. p is an integer from 0 to 4. Each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A are independently selected from

[0013] R 2 is hydrogen, C 1~5 Alkyl and -CO(C 1~5 alkyl). X is C(R 3a )(R 3b ) or N(R 3c ) Therefore, X is a substituent R 3a and R 3b or X is a carbon atom bearing a substituent R 3c is a nitrogen atom having the formula:

[0014] R 3a and R3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl, or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is selected from the group consisting of one or more groups R 31 or R 3a is a linear C 2~4 Alkylene and Linear C 2~4 alkenylene, wherein the divalent group is connected via one end to R 3b and is bonded through its other end to a ring atom of ring B adjacent to the ring atom bearing group X, wherein said alkylene or said alkenylene is bonded through one or more groups R 31 wherein one —CH2— unit in said alkylene or said alkenylene is substituted with —O—, —S—, —NH— or —N(C 1~5 alkyl)-, and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl.

[0015] R 3c is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Each R 31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), and -SO2-(C 1~5 alkyl).

[0016] Each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A are independently selected from

[0017] R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C1~5 alkyl), -S(=O)(=NH)-(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -CN, hydrogen, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more groups -L A -R A may be substituted with.

[0018] Each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~6 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 are independently selected from

[0019] L 1 is C 1~6 alkylene or a covalent bond, 1~6 One or more -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 and each may be replaced by a group independently selected from:

[0020] R 61 is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more groups R 62 may be substituted with. Each R 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 alkylene)-heterocycloalkyl.

[0021] Each L A is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 Each of the alkylene, alkenylene, and alkynylene groups may be substituted with one or more groups independently selected from the group consisting of -O-, -NH-, -N(C 1~5Each of the alkyl groups may be replaced by a group independently selected from -CO-, -S-, -SO-, and -SO2-.

[0022] Each R A -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0023] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient. Accordingly, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of the aforementioned entities and a pharmaceutically acceptable excipient, for use as a medicament.

[0024] The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of the aforementioned entities and a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, inflammatory pain, inflammatory diseases, or angiogenic eye diseases. Thus, the present invention particularly provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, inflammatory pain, inflammatory diseases, or angiogenic eye diseases.

[0025] Furthermore, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of cancer, inflammatory pain, inflammatory diseases or angiogenic eye diseases.

[0026] The present invention also relates to a method of treating or preventing cancer, inflammatory pain, inflammatory diseases or neovascular eye diseases, comprising administering to a subject (preferably a human) in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient. It will be understood that a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (or pharmaceutical composition) will be administered in accordance with this method.

[0027] As explained above, diseases / disorders to be treated or prevented with the compound of formula (I) or a pharmaceutically acceptable salt thereof (or the corresponding pharmaceutical composition) according to the present invention include, in particular, cancer, inflammatory pain, inflammatory disease, or angiogenic eye disease. It is particularly preferred that the disease / disorder to be treated or prevented according to the present invention is cancer.

[0028] The cancer to be treated or prevented in accordance with the present invention may be a solid cancer or a blood cancer, and is preferably lung cancer (e.g., small cell lung cancer or non-small cell lung cancer; in particular, non-small cell lung cancer), kidney cancer, gastrointestinal cancer, stomach cancer, colorectal cancer, colon cancer, anal cancer, genitourinary cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, prostate cancer (e.g., hormone-refractory prostate cancer), testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, brain cancer (e.g., glioblastoma), breast cancer (e.g., COX-2 expressing triple negative cancer), The cancer may be selected from: triple-negative breast cancer, including idiopathic breast cancer), head and / or neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkel cell carcinoma, squamous cell carcinoma, squamous cell carcinoma (e.g., oral squamous cell carcinoma), bone cancer (or osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, mouth cancer, thymoma, neuroendocrine cancer, blood cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia; in particular, acute myeloid leukemia), lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma), and multiple myeloma. Moreover, the cancer to be treated or prevented (including any one of the aforementioned specific types of cancer) may be metastatic cancer.

[0029] As explained above, the cancer to be treated or prevented according to the present invention may be a blood cancer. In this case, the blood cancer may be, for example, Hodgkin's lymphoma, including the nodular sclerosis subtype of Hodgkin's lymphoma, the mixed cell type subtype of Hodgkin's lymphoma, the lymphocyte-rich subtype of Hodgkin's lymphoma, or the lymphocyte-depleted subtype of Hodgkin's lymphoma; non-Hodgkin's lymphoma, including, for example, follicular non-Hodgkin's lymphoma, mantle cell lymphoma, or diffuse non-Hodgkin's lymphoma (e.g., diffuse large B-cell lymphoma or Burkitt's lymphoma); nodular lymphocyte-predominant Hodgkin's lymphoma; for example, peripheral / cutaneous T-cell lymphoma, including mycosis fungoides, Sézary's disease, T-zone lymphoma, lymphoepithelial lymphoma (e.g., Lennert's lymphoma), or peripheral T-cell lymphoma; lymphosarcoma; malignant immunoproliferative disorders, including, for example, Waldenstrom's macroglobulinemia, alpha heavy chain disease, gamma heavy chain disease (e.g., Franklin's disease), or immunoproliferative small intestinal disease (e.g., Mediterranean disease); multiple myeloma, including, for example, Kahler's disease or myelomatosis; plasma cell leukemia; for example, acute lymphoblastic leukemia lymphocytic leukemia, including chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g., leukemic reticuloendotheliosis), or adult T-cell leukemia; myeloid leukemia, including acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myeloid sarcoma (e.g., chloroma or granulocytic sarcoma), acute promyelocytic leukemia, or acute myelomonocytic leukemia; e.g., polycythemia vera myeloproliferative neoplastic disorders, including, for example, acute myelopathy, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute erythrombocytosis or erythroleukemia, including, for example, acute erythraemic myelopathy or Di Guglielmo disease; chronic erythrombocytosis, including, for example, Heilmeyer-Schonell disease; acute megakaryoblastic leukemia; mast cell leukemia; acute panmyelosis; acute myelofibrosis; and Letterer-Seewe disease.

[0030] The inflammatory pain treated or prevented in accordance with the present invention may be acute inflammatory pain or chronic inflammatory pain, in particular osteoarthritic pain, inflammatory pain associated with rheumatoid arthritis, or inflammatory post-operative pain.

[0031] The inflammatory disease to be treated or prevented in accordance with the present invention may be an acute inflammatory disease or a chronic inflammatory disease, and is preferably selected from multiple sclerosis, rheumatoid arthritis, endometriosis and osteoarthritis.

[0032] The neovascular eye disease to be treated or prevented in accordance with the present invention is preferably selected from neovascular macular degeneration (or "wet" macular degeneration), proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity.

[0033] The present invention further relates to the use of the compound of formula (I) or its pharmaceutically acceptable salt as an antagonist of prostaglandin E2 receptor subtype 4 (EP4) in research, particularly as a research tool compound for antagonizing EP4 receptor.Therefore, the present invention refers to the in vitro use of the compound of formula (I) or its pharmaceutically acceptable salt as an EP4 receptor antagonist, and particularly to the in vitro use of the compound of formula (I) or its pharmaceutically acceptable salt as a research tool compound that acts as an EP4 receptor antagonist.The present invention also relates to a method for antagonizing EP4 receptor, particularly an in vitro method, which comprises applying the compound of formula (I) or its pharmaceutically acceptable salt.The present invention further relates to a method for antagonizing EP4 receptor, which comprises applying the compound of formula (I) or its pharmaceutically acceptable salt to test sample (for example, biological sample) or test animal (i.e., non-human test animal). The present invention also refers to a method for antagonizing EP4 receptor in a sample (e.g., biological sample), particularly an in vitro method, comprising applying a compound of formula (I) or a pharmaceutically acceptable salt thereof to the sample.The present invention further provides a method for antagonizing EP4 receptor, comprising contacting a test sample (e.g., biological sample) or a test animal (i.e., a non-human test animal) with a compound of formula (I) or a pharmaceutically acceptable salt thereof.The terms "sample", "test sample" and "biological sample" include but are not limited to cells, cell cultures, or cellular or intracellular extracts; biopsies obtained from animals (e.g., humans) or their extracts; or blood, serum, plasma, saliva, urine, feces, or any other body fluids or their extracts. The term "in vitro" is used in this specific context to mean "outside the living human or animal body" and is understood to include, in particular, experiments carried out with cells, cellular or subcellular extracts and / or biomolecules in an artificial environment such as an aqueous solution or culture medium that may be provided, e.g., in a flask, test tube, Petri dish, microtiter plate, etc.

[0034] The compounds of formula (I) and pharmaceutically acceptable salts thereof are described in more detail below.

[0035] [ka]

[0036] In formula (I), the group A 1 and A 2 are each independently 1~5 alkyl (e.g., methyl or ethyl) or a group A 1 and A 2 are joined to each other and together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is bound to one or more (e.g., 1, 2, 3, or 4) groups R 1 The carbocyclic or heterocyclic group (A 1 , A 2 , and A 1 and A 2 ) is also referred to herein as "ring A." 1 and A 2 are each independently 1~5 Preferably it is alkyl (eg methyl).

[0037] In the context of the present invention, surprisingly, A 1 and A 2 The presence of two alkyl groups (especially two methyl groups) as A 1 and A 2 It has been found that the presence of a carbocyclic or heterocyclic group (ring A) formed from is highly advantageous with regard to the antagonistic activity of the compounds of formula (I) towards the prostaglandin E2 (PGE2) EP4 receptor.

[0038] Preferably, A 1 and A 2 are each independently 1~5 More preferably, A is alkyl.1 and A 2 are each independently methyl or ethyl. Even more preferably, A 1 and A 2 are methyl, respectively.

[0039] As mentioned above, group A 1 and A 2 may be joined to each other and, together with the carbon atoms to which they are attached, form a carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is bound to one or more (e.g., 1, 2, 3, or 4) groups R 1 In this case, the compound of formula (I) may be substituted with a compound having the following formula (Ia): or a pharmaceutically acceptable salt thereof:

[0040] [ka]

[0041] wherein ring A in formula (Ia) is a carbocyclic or heterocyclic group, n is an integer from 0 to 4, and further groups / variables in formula (Ia) (particularly rings B, D, R 1 , R 2 , R 4 , R 5 , R 6 , X, L, m and p) have the same meanings, including the same preferred meanings as described and defined in connection with formula (I).

[0042] As depicted in formula (Ia), the moiety -CO-N(R 2 )-XB[(-R 4 ) m ]-R 5 and the part -LD[(-R 6 ) p ] are all attached to the same ring carbon atom of ring A, and therefore ring A is a divalent carbocyclic or heterocyclic group. The following description of ring A refers to A in formula (I), as depicted in formula (Ia). 1 and A 2(and the carbon atoms to which they are attached), wherein said carbocyclic or heterocyclic group is substituted by one or more groups R 1 It will be understood that it may be substituted with

[0043] Ring A is preferably saturated. Therefore, ring A is preferably cycloalkylene or heterocycloalkylene. The cycloalkylene or heterocycloalkylene is preferably monocyclic or bicyclic. More preferably, A is a monocyclic cycloalkylene or monocyclic heterocycloalkylene. Even more preferably, A is a monocyclic C 3~9 It is a cycloalkylene or a monocyclic 4- to 9-membered heterocycloalkylene.

[0044] Preferred examples of ring A include, in particular, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g., tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothiophenylene (e.g., tetrahydrothiophene-2,2-diyl or tetrahydrothiophene-3,3-diyl), tetrahydropyranylene (e.g., tetrahydropyran-2,2-diyl, tetrahydropyran-3,3-diyl or tetrahydropyran-4,4-diyl) or thianylene (e.g., thian-2,2-diyl, thian-3,3-diyl or thian-4,4-diyl). It is particularly preferred that ring A is tetrahydrofuranylene (preferably tetrahydrofuran-3,3-diyl), tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl), cyclopropylene (i.e., cyclopropane-1,1-diyl), cyclobutylene (i.e., cyclobutane-1,1-diyl), cyclopentylene (i.e., cyclopentane-1,1-diyl) or cyclohexylene (i.e., cyclohexane-1,1-diyl), and it is even more preferred that ring A is cyclopropylene (i.e., cyclopropane-1,1-diyl).

[0045] Ring B is a carbocyclic or heterocyclic group. As depicted in formula (I), ring B is bonded to X and has a group R 5 is a divalent group further bonded to

[0046] Preferably, Ring B is selected from arylene, heteroarylene (e.g., pyridinylene; especially including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. More preferably, Ring B is arylene or cycloalkylene. Even more preferably, Ring B is phenylene or C 3~9 It is cycloalkylene (e.g., cyclopentylene, cyclohexylene, cycloheptylene, spiro[3.3]heptylene (e.g., spiro[3.3]hepta-2,6-diyl), or bicyclo[1.1.1]pentylene, etc.). Even more preferably, ring B is phenylene (e.g., phen-1,4-diyl) or cyclohexylene (e.g., cyclohexane-1,4-diyl). Even more preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phen-1,4-diyl.

[0047] Ring D is carbocyclyl or heterocyclyl. Preferably, ring D is selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl. More preferably, ring D is selected from phenyl, monocyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycloalkyl. Even more preferably, ring D is selected from phenyl, pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl or pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl) and cyclohexyl. Even more preferably, ring D is phenyl or pyridinyl. Even more preferably, ring D is phenyl.

[0048] L is C 1~6 alkylene or a covalent bond, 1~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)-, -C(C 1~5 Alkyl)(C 1~5 alkyl)-, carbocyclylene, and heterocyclylene, wherein said carbocyclylene and said heterocyclylene are each optionally replaced by one or more (e.g., 1, 2, or 3) groups -L A -R A may be substituted with each of the following:

[0049] Said C 1~6At most one -CH2- unit contained in the alkylene may be replaced by a carbocyclylene (e.g., cycloalkylene or arylene) or heterocyclylene (e.g., heterocycloalkylene or heteroarylene), preferably by a heterocyclylene, more preferably by a heterocycloalkylene, wherein said carbocyclylene or said heterocyclylene (or said heterocycloalkylene) may be replaced by one or more groups -L A -R A Preferably, the carbocyclylene or heterocyclylene (or the heterocycloalkylene) is preferably attached in the 1,3-orientation (e.g., as in the compounds of Example 134 or Example 138). Corresponding preferred examples include, in particular, pyrrolidine-1,3-diyl or piperidine-1,3-diyl.

[0050] Preferably, L is C 3~6 alkylene (e.g., propylene, butylene, or pentylene), wherein 3~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 In particular, by groups independently selected from -O-, -CO-, -NH-, -N(C alkyl)- 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]-(e.g., -N[-(C 0~4 alkylene)-cyclopropyl]-), -CH(C 1~5 alkyl)- and -C(C 1~5Alkyl)(C 1~5 More preferably, by groups independently selected from —O—, —NH— and —N(C alkyl)- 1~5 Alternatively, L may each be replaced by a group independently selected from -N(-CH3)- or -N(-CH2CH3)-; 2~4 alkylene (e.g., ethylene, n-propylene, or n-butylene), 2~4 One -CH2- unit in the alkylene (preferably ring A or A 1 and A 2 is replaced by a carbocyclylene or heterocyclylene (preferably by a heterocyclylene), wherein the C 2~4 One additional —CH2— unit contained in the alkylene (preferably the —CH2— unit bonded to ring D) may be selected from —O—, —CO—, —NH—, —N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO- and -SO2- (preferably -O-, -NH- and -N(C 1~5 and optionally, by a group selected from the group consisting of -alkyl)-, more preferably by a group -O-), wherein said carbocyclylene or said heterocyclylene is preferably attached in a 1,3-orientation, and further wherein said carbocyclylene or said heterocyclylene is optionally replaced by one or more groups -L A -R A may be substituted with.

[0051] More preferably, L is -(CH2) 3~5 -, wherein said -(CH) 3~5 One or more (e.g., 1, 2, or 3) —CH2— units in — are selected from —O—, —CO—, —NH—, —N(C 1~5alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]- (e.g., -N(-CH2-cyclopropyl)-), -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 alkyl)-, in particular -O-, -NH- and -N(C 1~5 or L is optionally replaced by a group independently selected from -heterocyclylene-(CH) 1~2 -heterocyclylene-(CH2) 1~2 -One -CH2- unit contained in - is -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (especially -O-, -NH- and -N(C 1~5 and -heterocyclylene-(CH) 1~2 The heterocyclylene in - is substituted with one or more groups -L A -R A and further, the -heterocyclylene-(CH2) 1~2 The heterocyclylene in - is preferably attached in a 1,3-orientation.

[0052] Even more preferably, L is -CH-CH-CH-CH-, wherein one or more (e.g., 1, 2 or 3) -CH- units in said -CH-CH-CH-CH- are -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]- (e.g., -N(-CH2-cyclopropyl)-), -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5alkyl)-, in particular -O-, -NH- and -N(C 1~5 or L is -heterocycloalkylene-CH-, wherein the -CH- units in said -heterocycloalkylene-CH- are selected from -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (in particular -O-, -NH- and -N(C 1~5 Preferably, the heterocycloalkylene in said -heterocycloalkylene-CH- is bonded in a 1,3-orientation. It is further preferred that said -heterocycloalkylene-CH- is bonded to Ring D via the -CH- unit in said -heterocycloalkylene-CH- (which may be replaced as described above).

[0053] In accordance with the above general and preferred definitions of L, it is particularly preferred that in any one of these definitions of L, each group L is linked to ring D via -CH2- or via -O-, even more preferably via -O- (i.e. each group L contains a -CH2- unit replaced by -O-, and group L is connected to ring D via said -O-).

[0054] Even more preferably, L is -CH-CH-CH-O-, and -CH-CH-CH-O- is bonded to ring D via an oxygen atom (-O-) in the group -CH-CH-CH-O-, wherein one or more (e.g., one or two) -CH- units contained in the -CH-CH-CH-O- are -O-, -CO-, -NH-, -N(C 1~4 alkyl)-, -N[-CO-(C 1~4 alkyl)]-, -N[-(C 1~3 alkylene)-cyclopropyl]-, -CH(C 1~4 alkyl)- and -C(C 1~4Alkyl)(C 1~4 alkyl)-, in particular -O-, -NH- and -N(C 1~4 and each -CH2- unit (furthest from the oxygen atom in -CH2-CH2-CH2-O-) may be replaced by a group as defined above (e.g., -N(C 1~4 or L is -heterocycloalkylene-O-, which is attached to ring D via an oxygen atom in the group -heterocycloalkylene-O-, wherein it is further preferred that the heterocycloalkylene in said -heterocycloalkylene-O- is attached in a 1,3-orientation. The heterocycloalkylene in said -heterocycloalkylene-O- is preferably a monocyclic 4- to 9-membered (more preferably a monocyclic 5-, 6-, or 7-membered) heterocycloalkylene, which is attached to ring A (or A) via a nitrogen ring atom. 1 and A 2 and is bonded to the oxygen (—O—) in said -heterocycloalkylene-O— through a carbon ring atom, where said nitrogen ring atom and said carbon ring atom are separated by one carbon ring atom. Thus, L can be, for example, a group

[0055] [ka]

[0056] wherein the group is attached to ring D through an oxygen atom (—O—), and wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected through a single bond, wherein one or two of said ring atoms (Z) are each independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z), if any, are all carbon atoms. In particular, L is a group

[0057] [ka]

[0058] which is attached to Ring D via an oxygen atom (—O—), where y is 1, 2, 3, 4, or 5, where y is preferably 2, 3, or 4 (so that the heterocycloalkylene ring preferably has a total of 5, 6, or 7 ring members).

[0059] Corresponding preferred examples of L are, in particular, -CH2-CH2-CH2-O-, -NH-CH2-CH2-O-, -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(isopropyl)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -N(-CO-CH3)-CH2-CH2-O-, -NH-CO-CH2-O-, -O-CH2-CH2-O-,

[0060] [ka]

[0061] each of these groups is attached to Ring D via a terminal oxygen atom (—O—) contained therein. Further examples of L include any one of the groups listed in the preceding paragraph, wherein the terminal oxygen atom (via which these groups are attached to ring D) is replaced by methylene (—CH2)—.

[0062] Particularly preferred examples of L include -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -O-CH2-CH2-O-,

[0063] [ka]

[0064] Each of these groups is bonded to ring D via a terminal oxygen atom contained therein. Even more preferred examples of L include -N(-CH3)-CH2-CH2-O-,

[0065] [ka]

[0066] each of these groups is attached to Ring D via a terminal oxygen atom contained therein. L is the base

[0067] [ka]

[0068] When this group is present in the compound of formula (I) in the following stereochemical configuration:

[0069] [ka]

[0070] It is more preferred that the hydroxyl group is present in the range of 0.1 to 1.0. L is the base

[0071] [ka]

[0072] When this group is present in the compound of formula (I) in the following stereochemical configuration:

[0073] [ka]

[0074] It is more preferred that the hydroxyl group is present in the range of 0.1 to 1.0. Group A in formula (I) 1 and A 2 But, respectively, C 1~5When L is alkyl (e.g., methyl),

[0075] [ka]

[0076] and each of these groups is particularly preferably attached to Ring D via a terminal oxygen atom contained therein. n is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4). Preferably, n is 0, 1, or 2. More preferably, n is 0 or 1. Even more preferably, n is 0.

[0077] m is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4). Preferably, m is 0, 1, or 2. More preferably, m is 0 or 1. Even more preferably, m is 0.

[0078] p is an integer from 0 to 4 (i.e., 0, 1, 2, 3, or 4). Preferably, p is 0, 1, or 2. More preferably, p is 1. m is a substituent R bonded to ring B in the compound of formula (I) or (Ia). 4 It is to be understood that when m is 0, ring B is free from any group R 4 is not substituted, i.e., R 4 Furthermore, p is substituted with hydrogen instead of the substituent R bonded to ring D in the compound of formula (I) or (Ia). 6 When p is 0, ring D is free from any group R 6 is not substituted, i.e., R 6 Similarly, n is substituted with hydrogen instead of the substituent R bonded to ring A in the compound of formula (Ia). 1 When n is 0, ring A is free from any group R 1 is not substituted, i.e., R 1 is substituted with hydrogen instead of the substituent R 1 , R 4and R 6 It will further be understood that the maximum number of is limited by the number of bonding sites available on each ring group, ie, on Ring A, Ring B and Ring D, respectively.

[0079] Each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3alkylene)-heterocycloalkyl and -L A -R A are independently selected from

[0080] Preferably, each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl (e.g., -CH2-cyclopropyl), -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 1 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 1 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0081] Two groups R 1 A preferred example of ring A substituted with is 4,4-difluoro-cyclohexane-1,1-diyl, i.e., two fluoro atoms (R 1 and cyclohexylene (as ring A) substituted with cyclohexylene (as ring B).

[0082] R 2 is hydrogen, C 1~5 Alkyl and -CO(C 1~5 alkyl). Preferably, R 2 is hydrogen or C 1~5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 is hydrogen.

[0083] X is C(R 3a )(R 3b ) or N(R 3c ) Therefore, X is a substituent R 3a and R 3b or X is a carbon atom bearing a substituent R 3c Preferably, X is a nitrogen atom having the formula C(R 3a )(R 3b )

[0084] R 3a and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl; or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) groups R 31 or R 3a is a linear C 2~4 Alkylene and Linear C 2~4 alkenylene, wherein the divalent group is connected via one end to R 3b and is bonded through its other end to a ring atom of ring B adjacent to the ring atom (of ring B) bearing group X, wherein said alkylene or said alkenylene is bonded through one or more (e.g., 1, 2 or 3) groups R 31wherein one —CH2— unit in said alkylene or said alkenylene is substituted with —O—, —S—, —NH— or —N(C 1~5 alkyl)-, and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl.

[0085] As indicated above, R 3a is a linear C 2~4 Alkylene (e.g., -CH2CH2- or -CH2CH2CH2-) and linear C 2~4 may be a divalent group selected from alkenylene (e.g., -CH=CH-, -CH=CH-CH-, or -CH-CH=CH-), wherein the divalent group is joined via one end by R 3b and through its other end is attached to a ring atom of ring B adjacent to the ring atom (of ring B) bearing group X, wherein said alkylene or said alkenylene is linked to one or more groups R 31 wherein one —CH2— unit in said alkylene or said alkenylene is substituted with —O—, —S—, —NH— or —N(C 1~5 alkyl)-, and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. In particular, R 3a may be a divalent group selected from -CH2CH2- and -CH2CH2CH2-, wherein said divalent group is connected through one end to R 3b and via its other end is attached to a ring atom of ring B adjacent to the ring atom (of ring B) bearing group X, wherein said divalent group is selected from one or more groups R 31 and R 3b is hydrogen, C 1~5 Alkyl or C 2~5 It may also be alkenyl, in particular hydrogen.

[0086] [ka]

[0087] is the base

[0088] [ka]

[0089] (especially,

[0090] [ka]

[0091] ), where the group is attached to two adjacent ring atoms of ring B via two bonds marked with an asterisk (*), and the group can be selected from one or more (e.g., 1, 2, or 3) R 31 may be substituted with.

[0092] Moreover, as indicated above, R 3a and R 3b may be linked together to form, together with the carbon atoms to which they are attached, a cycloalkyl or a heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is selected from one or more groups R 31 may be substituted with R 3a and R 3b The cycloalkyl or heterocycloalkyl formed from R 3a and R 3b It will be understood that the cycloalkyl or heterocycloalkyl is attached to the remainder of the compound of formula (I) via the carbon atom bearing the group R. Thus, said cycloalkyl or heterocycloalkyl is attached to ring B and to ring R via the same ring carbon atom. 2 is a divalent group bonded to a nitrogen atom having the formula: 3a and R 3bare linked together with the carbon atoms to which they are attached to form a cyclopropyl, said cyclopropyl is a cyclopropa-1,1-diyl group, i.e., the group

[0093] [ka]

[0094] is. Furthermore, as indicated above, R 3a and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. For example, R 3a is C 1~5 Alkyl or C 2~5 may be alkenyl, and R 3b is hydrogen, C 1~5 Alkyl or C 2~5 In particular, R 3a is C 1~5 may be alkyl, R 3b is hydrogen or C 1~5 It may also be alkyl.

[0095] Preferably, R 3a and R 3b is hydrogen and C 1~5 alkyl, or R 3a and R 3b are linked together with the carbon atoms to which they are attached, forming C 3~5 form a cycloalkyl or a 3 to 5 membered heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is substituted with one or more (e.g., one or two) groups R 31 More preferably, R 3a and R 3b is hydrogen and C 1~5 alkyl (e.g., methyl or ethyl), or R 3a and R 3bare linked together with the carbon atoms to which they are attached to form a cyclopropyl. Even more preferably, R 3a is C 1~5 alkyl (e.g., methyl or ethyl), and R 3b is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl), or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cyclopropyl. And even more preferably, R 3a is methyl and R 3b is hydrogen or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cyclopropyl.

[0096] R 3c is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Preferably, R 3c is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl). More preferably, R 3c is hydrogen or methyl. Even more preferably, R 3c is methyl.

[0097] X, R 3a and R 3b In accordance with the above definition of the moiety in formula (I) or (Ia)

[0098] [ka]

[0099] teeth,

[0100] [ka]

[0101] (e.g., similar to the compound of Example 1) or

[0102] [ka]

[0103] It is particularly preferred that: Each R 31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), and -SO2-(C 1~5 alkyl). Preferably, each R 31 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Independently selected from haloalkyl (eg, —CF 3 ) and —CN.

[0104] Each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A are independently selected from

[0105] Preferably, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 4 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 4 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0106] R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), halogen (e.g., -F or -Cl), C 1~5 Haloalkyl (e.g., -CF3), -CN, hydrogen, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl (e.g., aryl or cycloalkyl), and heterocyclyl (e.g., heteroaryl or heterocycloalkyl), wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2, or 3) groups -L A -R A may be substituted with.

[0107] Preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -CN, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more groups -L A -R A More preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), -CN, -O(C 1~4 alkyl) (e.g., —OCH) and heteroaryl (e.g., tetrazolyl). More preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 More preferably, R is selected from -alkyl, -CN, and heteroaryl (e.g., tetrazolyl). 5 are -COOH, -CO-NH2, -CO-NH(C1~5 alkyl) (e.g., -CO-NH-CH3), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., -CO-N(CH3)-CH3), -SO2-(C 1~5 alkyl) (e.g., -SO2-CH3), -S(=O)(=NH)-(C 1~5 alkyl) (e.g., —S(═O)(═NH)—CH) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH or tetrazolyl (especially 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is —COOH or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH.

[0108] Ring B, X, R 2 , R 3a , R 3b , R 4 , R 5 and according to the above definition of m, the part

[0109] [ka]

[0110] has the following structure:

[0111] [ka]

[0112] It is particularly preferred that Furthermore, when ring B is cyclohexylene, the moiety

[0113] [ka]

[0114] For example, the following structure:

[0115] [ka]

[0116] ,especially

[0117] [ka]

[0118] may have Each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~6 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 are independently selected from

[0119] Preferably, each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 More preferably, each R 6 is C 1~5 Alkyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., -CF3), -O-(C 1~5 haloalkyl) (e.g., -OCF3), -CN and -L 1 -R 61 Even more preferably, each R 6 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4alkyl) (e.g., -N(CH3)2), halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, -CF and -OCF. Even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, and -CF. 6 is particularly preferably independently —Cl or —CF 3 .

[0120] If p is 1, then R 6 is attached to ring D in a 1,2-, 1,3-, or 1,4-orientation relative to the attachment point of group L to ring D, and more preferably, R 6 is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D. In this regard, it will be understood that the point of attachment of group L on ring D (i.e., the ring atom of ring D that is attached to L) is numbered as position 1, and any one of the two immediately adjacent ring atoms is numbered as position 2, etc. Thus, when p is 1 and ring D is phenyl, R 6 is preferably attached to ring D meta (corresponding to a 1,3-orientation) relative to the point of attachment of group L to ring D. Similarly, when p is greater than 1 (e.g., 2, 3, or 4), group R 6 is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D; for example, when p is 2 and ring D is phenyl, two groups R 6 is a group R at the meta position (i.e., the 3-position) relative to the point of attachment of the group L to the phenyl; 6 and another group R in the 5-position 6) may be bonded to each other.

[0121] p and R 6 According to the above definition of p is 1 and the group R 6 is attached to ring D (which may be, for example, phenyl) in a 1,3-orientation relative to the point of attachment of group L to ring D, and said group R 6 is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 More preferably, the group R 6 is selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3, even more preferably said group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, even more preferably said group R 6 is particularly preferably selected from -Cl and -CF3.

[0122] L 1 is C 1~6 alkylene or a covalent bond, 1~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 and each may be replaced by a group independently selected from:

[0123] Preferably, L 1 is C 1~4 alkylene, wherein C 1~4 One or more (for example, one or two) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 The alkylene is preferably replaced by a group independently selected from C 2~4 It is an alkylene (e.g., ethylene, propylene, or butylene), more preferably -(CH2)2-, -(CH2)3-, or -(CH2)4-, and even more preferably -(CH2)2-. Furthermore, the one or more -CH2- units are selected from -O-, -S-, -NH-, and -N(C 1~5 Preferably, each of L may be replaced by a group independently selected from -alkyl), in particular by -O-. 1 is bonded to ring D via -O- (i.e., L 1 contains a terminal -CH2- unit replaced by -O-, and L 1 is more preferably connected to ring D via the —O—.

[0124] More preferably, L 1 is -(CH2) 2~4 -, wherein said -(CH) 2~4 -One -CH2- unit contained in - is -O-, -S-, -NH- and -N(C 1~5 It may be replaced by a group selected from the group -alkyl)-, in particular by the group -O-. Even more preferably, L 1 is -O-(CH2) 1~3 -, where L 1 In ring D, the -O-(CH2) 1~3 More preferably, L 1 is -O-CH2- or -O-CH2-CH2-, where L 1 is bonded to ring D via the oxygen atom in said —O—CH— or said —O—CH—CH—. Even more preferably, L 1is —O—CH 2 — and is bonded to ring D via the oxygen atom (—O—) contained in —O—CH 2 —.

[0125] R 61 is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2 or 3) groups R 62 may be substituted with.

[0126] Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and heteroaryl (e.g., pyridinyl), wherein said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl are each independently selected from one or more (e.g., 1, 2, or 3) groups R 62 More preferably, R 61 is a cycloalkyl or aryl, wherein said cycloalkyl or said aryl is selected from one or more R 62 Even more preferably, R 61 is C 3~9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein said C 3~9 The cycloalkyl or the phenyl may be one or more R 62 and even more preferably, R 61 is C 5~9 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl), wherein the cycloalkyl is selected from one or more R 62 and even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein said cyclohexyl or said cycloheptyl is selected from one or more R 62Even more preferably, R 61 is cyclohexyl, and the cyclohexyl is selected from one or more R 62 The cyclic group (R 61 ) is not a group R 62 More preferably, it is unsubstituted.

[0127] Each R 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 alkylene)-heterocycloalkyl.

[0128] Preferably, each R 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 More preferably, each R 62 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 62 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0129] Each L A is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 Each of the alkylene, alkenylene, and alkynylene groups may be substituted with one or more (e.g., 1, 2, or 3) groups independently selected from -O-, -NH-, -N(C 1~5 Each of the alkyl groups may be replaced by a group independently selected from -CO-, -S-, -SO-, and -SO2-.

[0130] Each R A -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0131] It is particularly preferred that the compound of formula (I) is any one of the specific compounds of formula (I) described in the Examples section herein, including any one of Examples 1 to 210 described further below, either in the non-salt form or as a pharmaceutically acceptable salt of the respective compound.

[0132] Thus, the compound of formula (I) 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; N-[(1S)-1-(4-carbamoylphenyl)ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; N-[(1S)-1-[4-(methylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; N-[(1S)-1-[4-(dimethylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; 4-[(1S)-1-[[4-[acetyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[(2-phenoxyacetyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-ethyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(4-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-[3-(trifluoromethyl)phenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-[3-methoxyphenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-methylphenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(4-cyanophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3,5-difluorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3,4-dichlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-phenylpropylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(2-phenylethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[(3-fluorophenyl)methylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(cyclohexylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-pyridylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(2-pyridylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[propyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[cyclopropylmethyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 2-Fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 3-Fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 2-chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 3-chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 5-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-2-carboxylic acid; 6-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-3-carboxylic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-methylphenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[methyl-[2-(3-methylphenoxy)ethyl]amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-methoxyphenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[methyl(2-phenoxyethyl)amino]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 3-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]bicyclo[1.1.1]pentane-1-carboxylic acid; 4-[(1S)-1-[[4,4-difluoro-1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydrothiopyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1,1-dioxo-4-(2-phenoxyethylamino)thiane-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-(2-phenoxyethylamino)spiro[3.3]heptane-2-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclobutanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[8,8-dimethyl-7-(2-phenoxyethylamino)-2-oxabicyclo[4.2.0]octane-7-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2,2-dimethyl-4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2,2-dimethyl-4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydropyran-3-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[1-methyl-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-methoxyethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(cyclopropylmethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-phenoxypropyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethoxy]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-(3-fluorophenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(2-methylpentoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(4-methoxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-isopropoxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(2,2,2-trifluoroethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(4-benzyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(tetrahydropyran-4-ylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(2,2,2-trifluoroethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(3-phenylpropoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(2-tetrahydropyran-4-ylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(3-phenylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(2-cyclohexylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(3-pyridylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(cyclohexylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(tetrahydropyran-4-ylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-benzyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(cyclohexoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(cyclopropylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(cyclopentylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(cycloheptylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-isopentyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-(2-cyclohexylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-[[(3S)-tetrahydrofuran-3-yl]methoxy]phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[3-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[4-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(4-benzyloxyphenyl)cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[4-(2-cyclohexylethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[4-(2-cyclohexylethoxy)phenyl]cyclopentanecarbonyl]-methyl-amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[3-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(3-benzyloxyphenyl)cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(cyclohexylmethoxy)-4-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[5-(2-cyclohexylethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[6-(2-cyclohexylethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(cyclohexylmethoxy)-4-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[4-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[5-(2-cyclohexylethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[6-(2-cyclohexylethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(cyclohexyloxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]methylamino]ethyl]benzamide; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]dimethylamino]ethyl]benzamide; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide; N-((S)-1-(4-(2H-tetrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(1H-pyrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-sulfamoylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((1S)-1-(4-(S-methylsulfonimidoyl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-hydroxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-cyanophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-phenylethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(pyridin-4-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(pyridin-3-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(pyridin-2-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-bromophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; (R)-2-methyl-4-(1-(4-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)cyclopropyl)benzoic acid; (R)-6-(4-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide)spiro[3.3]heptane-2-carboxylic acid; (1R,4R)-4-((4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)methyl)cyclohexane-1-carboxylic acid; (1R,4R)-4-((2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamido)methyl)cyclohexane-1-carboxylic acid; (1R,4R)-4-((2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamido)methyl)cyclohexane-1-carboxamide; 2-methyl-N-((S)-1-(4-sulfamoylphenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 2-methyl-N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 2-methyl-N-((1S)-1-(4-(S-methylsulfonimidoyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4-oxadiazol-3-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4-oxadiazol-5-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 4-((1S)-1-(2-(3-benzylpyrrolidin-1-yl)-2-methylpropanamido)ethyl)benzoic acid; 4-((S)-1-(2-((R)-3-((3-chlorophenoxy)methyl)pyrrolidin-1-yl)-2-methylpropanamido)ethyl)benzoic acid; 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-ethylbutane-carbonyl]amino]ethyl]benzoic acid; and a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

[0133] The present invention also relates to each of the intermediates further described below in the Examples section of this specification, including any one of these intermediates in the form of a non-salt or a salt (e.g., a pharmaceutically acceptable salt) of the respective compound. Such intermediates may be used, inter alia, in the synthesis of compounds of formula (I).

[0134] In a first specific embodiment, the compound of formula (I) has the formula:

[0135] [ka]

[0136] or a pharmaceutically acceptable salt thereof. In this first specific embodiment, A 1 and A 2 are each independently 1~5 More preferably, A is alkyl. 1 and A 2 are each independently methyl or ethyl. Even more preferably, A 1 and A 2 are methyl, respectively.

[0137] In this first specific embodiment, ring B is a carbocyclic group or a heterocyclic group. Preferably, ring B is selected from arylene, heteroarylene (e.g., pyridinylene; particularly, including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is further preferred that ring B is monocyclic. More preferably, ring B is arylene or cycloalkylene. Even more preferably, ring B is phenylene or C 3~9 More preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phen-1,4-diyl.

[0138] In this first specific embodiment, ring D is phenyl. In this first specific embodiment, L is C 2~4 alkylene (e.g., ethylene, n-propylene, or n-butylene), 2~4 One -CH2- unit contained in the alkylene (preferably, A 1 and A 2is replaced by a carbocyclylene or heterocyclylene (preferably by a heterocyclylene), wherein the C 2~4 One additional —CH2— unit contained in the alkylene (preferably the —CH2— unit bonded to ring D) may be selected from —O—, —CO—, —NH—, —N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO- and -SO2- (preferably -O-, -NH- and -N(C 1~5 and optionally, by a group selected from the group consisting of -alkyl)-, more preferably by a group -O-), wherein said carbocyclylene or said heterocyclylene is preferably attached in a 1,3-orientation, and further wherein said carbocyclylene or said heterocyclylene is optionally replaced by one or more groups -L A -R A Preferably, L is -heterocyclylene-(CH2) 1~2 -heterocyclylene-(CH2) 1~2 -One -CH2- unit contained in - is -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (especially -O-, -NH- and -N(C 1~5 and -heterocyclylene-(CH) 1~2 The heterocyclylene in - is substituted with one or more groups -L A -R A and further, the -heterocyclylene-(CH2) 1~2The heterocyclylene in - is preferably bonded in a 1,3-orientation. More preferably, L is -heterocycloalkylene-CH-, wherein the -CH- units in said -heterocycloalkylene-CH- are not -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (in particular -O-, -NH- and -N(C 1~5 and the heterocycloalkylene in said -heterocycloalkylene-CH- is preferably bonded in a 1,3-orientation; and further preferably said -heterocycloalkylene-CH- is bonded to ring D via an -CH- unit in said -heterocycloalkylene-CH- (optionally exchanged as described above). Even more preferably, L is -heterocycloalkylene-O-, which -heterocycloalkylene-O- is bonded to ring D via an oxygen atom in said group -heterocycloalkylene-O-, and the heterocycloalkylene in said -heterocycloalkylene-O- is bonded in a 1,3-orientation; and the heterocycloalkylene in said -heterocycloalkylene-O- is preferably a monocyclic 4- to 9-membered (more preferably a monocyclic 5-, 6-, or 7-membered) heterocycloalkylene, which is bonded to ring D via a nitrogen ring atom. 1 and A 2 and is bonded through a carbon ring atom to the oxygen (—O—) in said -heterocycloalkylene-O—, wherein said nitrogen ring atom and said carbon ring atom are separated by one carbon ring atom. Thus, L can be, for example, a group

[0139] [ka]

[0140] wherein the group is attached to ring D through an oxygen atom (—O—), and wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected through a single bond, wherein one or two of said ring atoms (Z) are each independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z), if any, are all carbon atoms. In particular, L is a group

[0141] [ka]

[0142] wherein the group is attached to ring D via an oxygen atom (—O—), where y is 1, 2, 3, 4, or 5, where y is preferably 2, 3, or 4 (so that the heterocycloalkylene ring preferably has a total of 5, 6, or 7 ring members). Particularly preferred examples of L are:

[0143] [ka]

[0144] and each of these groups is bonded to ring D through a terminal oxygen atom contained therein.

[0145] [ka]

[0146] is, the corresponding group L has the following stereochemical configuration:

[0147] [ka]

[0148] It is more preferred that the hydroxyl group is present in the range of 0.1 to 1.0. In this first specific embodiment, m is 0, 1, 2, 3, or 4. Preferably, m is 0, 1, or 2. More preferably, m is 0 or 1. Even more preferably, m is 0.

[0149] In this first specific embodiment, p is 0, 1, 2, 3 or 4. Preferably, p is 0, 1 or 2. More preferably, p is 1. In this first specific embodiment, R 2 is hydrogen, C 1~5 Alkyl and -CO(C 1~5 alkyl). Preferably, R 2 is hydrogen or C 1~5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 is hydrogen.

[0150] In this first specific embodiment, X is C(R 3a )(R 3b ) Therefore, X is a substituent R 3a and R 3b is a carbon atom having the formula: In this first specific embodiment, R 3a and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Preferably, R 3a and R 3b is hydrogen and C 1~5 alkyl (e.g., methyl or ethyl). More preferably, R 3a is C 1~5 alkyl (e.g., methyl or ethyl), and R 3b is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl). Even more preferably, R 3a is methyl and R 3b is hydrogen.

[0151] X, R 3a and R 3b According to the above definition of

[0152] [ka]

[0153] teeth,

[0154] [ka]

[0155] It is particularly preferred that: In this first specific embodiment, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A Preferably, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 4 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 4 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0156] In this first specific embodiment, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), halogen (e.g., -F or -Cl), C 1~5 Haloalkyl (e.g., -CF3), -CN, hydrogen, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl (e.g., aryl or cycloalkyl), and heterocyclyl (e.g., heteroaryl or heterocycloalkyl), wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2, or 3) groups -L A -R A Preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), -CN, -O(C 1~4 alkyl) (e.g., —OCH) and heteroaryl (e.g., tetrazolyl). More preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5alkyl) (e.g., -CO-NH-CH3), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., -CO-N(CH3)-CH3), -SO2-(C 1~5 alkyl) (e.g., -SO2-CH3), -S(=O)(=NH)-(C 1~5 alkyl) (e.g., —S(═O)(═NH)—CH) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH or tetrazolyl (especially 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is —COOH or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH.

[0157] In this first specific embodiment, each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~6 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 Preferably, each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 More preferably, each R 6 is C 1~5 Alkyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., -CF3), -O-(C 1~5 haloalkyl) (e.g., -OCF3), -CN and -L 1 -R 61 Even more preferably, each R 6 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., -N(CH3)2), halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, -CF and -OCF. Even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, and -CF. 6 is particularly preferably independently —Cl or —CF 3 .

[0158] In this first specific embodiment, when p is 1, R 6 is attached to ring D in a 1,2-, 1,3-, or 1,4-orientation relative to the attachment point of group L to ring D, and more preferably, R 6 is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D. Furthermore, when p is greater than 1 (e.g., 2, 3, or 4), group R 6 is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D.

[0159] In this first specific embodiment, p and R 6 According to the above definition of p is 1 and the group R 6 is attached to ring D in a 1,3-orientation relative to the attachment point of group L to ring D, and said group R 6is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 More preferably, the group R 6 is selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3, even more preferably said group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, even more preferably said group R 6 is particularly preferably selected from -Cl and -CF3.

[0160] In this first specific embodiment, L 1 is C 1~6 alkylene or a covalent bond, 1~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 and each of L is independently replaced by a group selected from the group consisting of alkyl, methyl ... 1 is C 1~4 alkylene, wherein C 1~4 One or more (for example, one or two) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 The alkylene is preferably replaced by a group independently selected from C 2~4It is an alkylene (e.g., ethylene, propylene, or butylene), more preferably -(CH2)2-, -(CH2)3-, or -(CH2)4-, and even more preferably -(CH2)2-. Furthermore, the one or more -CH2- units are selected from -O-, -S-, -NH-, and -N(C 1~5 Preferably, each of L may be replaced by a group independently selected from -alkyl), in particular by -O-. 1 is bonded to ring D via -O- (i.e., L 1 contains a terminal -CH2- unit replaced by -O-, and L 1 is connected to ring D via the —O—. 1 is -(CH2) 2~4 -, wherein said -(CH) 2~4 -One -CH2- unit contained in - is -O-, -S-, -NH- and -N(C 1~5 It may be replaced by a group selected from the group -alkyl)-, in particular by the group -O-. Even more preferably, L 1 is -O-(CH2) 1~3 -, where L 1 In ring D, the -O-(CH2) 1~3 More preferably, L 1 is -O-CH2- or -O-CH2-CH2-, where L 1 is bonded to ring D via the oxygen atom in said —O—CH— or said —O—CH—CH—. Even more preferably, L 1 is —O—CH 2 — and is bonded to ring D via the oxygen atom (—O—) contained in —O—CH 2 —.

[0161] In this first specific embodiment, R 61 is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2 or 3) groups R 62Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and heteroaryl (e.g., pyridinyl), wherein said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl are each independently selected from one or more (e.g., 1, 2, or 3) groups R 62 More preferably, R 61 is a cycloalkyl or aryl, wherein said cycloalkyl or said aryl is selected from one or more R 62 Even more preferably, R 61 is C 3~9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein said C 3~9 The cycloalkyl or the phenyl may be one or more R 62 and even more preferably, R 61 is C 5~9 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl), wherein the cycloalkyl is selected from one or more R 62 and even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein said cyclohexyl or said cycloheptyl is selected from one or more R 62 Even more preferably, R 61 is cyclohexyl, and the cyclohexyl is selected from one or more R 62 The cyclic group (R 61 ) is not a group R 62 More preferably, it is unsubstituted.

[0162] In this first specific embodiment, each R 62 is C 1~5 Alkyl, C2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 Preferably, each R is independently selected from the group consisting of alkylene-heterocycloalkyl. 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 More preferably, each R 62 is C 1~5Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 62 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0163] In this first specific embodiment, each L A is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 Each of the alkylene, alkenylene, and alkynylene groups may be substituted with one or more (e.g., 1, 2, or 3) groups independently selected from -O-, -NH-, -N(C 1~5Each of the alkyl groups may be replaced by a group independently selected from -CO-, -S-, -SO-, and -SO2-.

[0164] In this first specific embodiment, each R A -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0165] In a second specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) groups R 31 As defined in the first specific embodiment, except that it may be substituted with

[0166] In this second specific embodiment, R 3a and R 3b are linked together with the carbon atoms to which they are attached, forming C 3~5 form a cycloalkyl or a 3 to 5 membered heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is substituted with one or more (e.g., one or two) groups R 31 Preferably, R 3a and R 3bare linked together with the carbon atoms to which they are attached to form a cyclopropyl.

[0167] In this second specific embodiment, therefore, the moiety

[0168] [ka]

[0169] but,

[0170] [ka]

[0171] It is particularly preferred that: In this second specific embodiment, each R 31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), and -SO2-(C 1~5 alkyl). Preferably, each R 31 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Independently selected from haloalkyl (eg, —CF 3 ) and —CN.

[0172] In a third specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the first specific embodiment, except that Ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl.

[0173] In this third specific embodiment, ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0174] In a fourth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the second specific embodiment, except that Ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl.

[0175] In this fourth specific embodiment, ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0176] In a fifth specific embodiment, the compound of formula (I) has the formula:

[0177] [ka]

[0178] or a pharmaceutically acceptable salt thereof. In this fifth specific embodiment, ring A is a carbocyclic or heterocyclic group. As depicted in the formula above, the moiety —CO—N(R 2 )-XB[(-R 4 )m ]-R 5 and the part -LD[(-R 6 ) p

[0033] are all bonded to the same ring carbon atom of ring A, and therefore ring A is a divalent carbocyclic or heterocyclic group. Ring A is preferably saturated. Thus, ring A is preferably a cycloalkylene or heterocycloalkylene; said cycloalkylene or said heterocycloalkylene is preferably monocyclic or bicyclic. More preferably, A is a monocyclic cycloalkylene or monocyclic heterocycloalkylene. Even more preferably, A is a monocyclic C 3~9 and a monocyclic 4- to 9-membered heterocycloalkylene. Preferred examples of ring A include, in particular, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g., tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothiophenylene (e.g., tetrahydrothiophene-2,2-diyl or tetrahydrothiophene-3,3-diyl), tetrahydropyranylene (e.g., tetrahydropyran-2,2-diyl, tetrahydropyran-3,3-diyl or tetrahydropyran-4,4-diyl), or thianylene (e.g., thian-2,2-diyl, thian-3,3-diyl or thian-4,4-diyl). It is particularly preferred that ring A is tetrahydrofuranylene (preferably tetrahydrofuran-3,3-diyl), tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl), cyclopropylene (i.e., cyclopropane-1,1-diyl), cyclobutylene (i.e., cyclobutane-1,1-diyl), cyclopentylene (i.e., cyclopentane-1,1-diyl), or cyclohexylene (i.e., cyclohexane-1,1-diyl).

[0179] In this fifth specific embodiment, Ring B is a carbocyclic group or a heterocyclic group. Preferably, Ring B is selected from arylene, heteroarylene (e.g., pyridinylene; particularly including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is further preferred that Ring B is monocyclic. More preferably, Ring B is arylene or cycloalkylene. Even more preferably, Ring B is phenylene or C 3~9 More preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phen-1,4-diyl.

[0180] In this fifth specific embodiment, Ring D is phenyl. In this fifth specific embodiment, L is C 2~4 alkylene (e.g., ethylene, n-propylene, or n-butylene), 2~4 One -CH2- unit in the alkylene (preferably the -CH2- unit bonded to ring A) is replaced by carbocyclylene or heterocyclylene (preferably heterocyclylene), wherein 2~4 One additional —CH2— unit contained in the alkylene (preferably the —CH2— unit bonded to ring D) may be selected from —O—, —CO—, —NH—, —N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO- and -SO2- (preferably -O-, -NH- and -N(C 1~5and optionally, by a group selected from the group consisting of -alkyl)-, more preferably by a group -O-), wherein said carbocyclylene or said heterocyclylene is preferably attached in a 1,3-orientation, and further wherein said carbocyclylene or said heterocyclylene is optionally replaced by one or more groups -L A -R A Preferably, L is -heterocyclylene-(CH2) 1~2 -heterocyclylene-(CH2) 1~2 -One -CH2- unit contained in - is -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (especially -O-, -NH- and -N(C 1~5 and -heterocyclylene-(CH) 1~2 The heterocyclylene in - is substituted with one or more groups -L A -R A and further, the -heterocyclylene-(CH2) 1~2 The heterocyclylene in - is preferably bonded in a 1,3-orientation. More preferably, L is -heterocycloalkylene-CH-, wherein the -CH- units in said -heterocycloalkylene-CH- are not -O-, -CO-, -NH-, -N(C 1~5 alkyl)- and -N[-CO-(C 1~5 alkyl)]- (in particular -O-, -NH- and -N(C 1~5It is further preferred that the -heterocycloalkylene-CH- is bonded to Ring D via a -CH- unit in the -heterocycloalkylene-CH- (which may be replaced as described above). Even more preferably, L is -heterocycloalkylene-O-, which is bonded to Ring D via an oxygen atom in the group -heterocycloalkylene-O-, where the heterocycloalkylene in the -heterocycloalkylene-O- is bonded in a 1,3-orientation; the heterocycloalkylene in the -heterocycloalkylene-O- is preferably a monocyclic 4- to 9-membered (more preferably a monocyclic 5-, 6-, or 7-membered) heterocycloalkylene, which is bonded to Ring A via a nitrogen ring atom and to the oxygen (-O-) in the -heterocycloalkylene-O- via a carbon ring atom, where the nitrogen ring atom and the carbon ring atom are separated by one carbon ring atom. Thus, L can be, for example, a group

[0181] [ka]

[0182] wherein the group is attached to ring D through an oxygen atom (—O—), and wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected through a single bond, wherein one or two of said ring atoms (Z) are each independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z), if any, are all carbon atoms. In particular, L is a group

[0183] [ka]

[0184] wherein the group is attached to ring D via an oxygen atom (—O—), where y is 1, 2, 3, 4, or 5, where y is preferably 2, 3, or 4 (so that the heterocycloalkylene ring preferably has a total of 5, 6, or 7 ring members). Particularly preferred examples of L are:

[0185] [ka]

[0186] each of these groups is attached to Ring D via a terminal oxygen atom contained therein. In this fifth specific embodiment, n is 0, 1, 2, 3, or 4. Preferably, n is 0, 1, or 2. More preferably, n is 0 or 1. Even more preferably, n is 0.

[0187] In this fifth specific embodiment, m is 0, 1, 2, 3, or 4. Preferably, m is 0, 1, or 2. More preferably, m is 0 or 1. Even more preferably, m is 0.

[0188] In this fifth specific embodiment, p is 0, 1, 2, 3, or 4. Preferably, p is 0, 1, or 2. More preferably, p is 1. In this fifth specific embodiment, each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A Preferably, each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl (e.g., -CH2-cyclopropyl), -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 1 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 1 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN. Two groups R 1 A preferred example of ring A substituted with is 4,4-difluoro-cyclohexane-1,1-diyl, i.e., two fluoro atoms (R 1 and cyclohexylene (as ring A) substituted with cyclohexylene (as ring B).

[0189] In this fifth specific embodiment, R 2 is hydrogen, C 1~5 Alkyl and -CO(C 1~5 alkyl). Preferably, R 2 is hydrogen or C 1~5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 is hydrogen.

[0190] In this fifth specific embodiment, X is C(R 3a )(R 3b ) Therefore, X is a substituent R 3a and R 3b is a carbon atom having the formula: In this fifth specific embodiment, R 3a and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Preferably, R 3a and R 3b is hydrogen and C1~5 alkyl (e.g., methyl or ethyl). More preferably, R 3a is C 1~5 alkyl (e.g., methyl or ethyl), and R 3b is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl). Even more preferably, R 3a is methyl and R 3b is hydrogen.

[0191] X, R 3a and R 3b According to the above definition of

[0192] [ka]

[0193] teeth,

[0194] [ka]

[0195] It is particularly preferred that: In this fifth specific embodiment, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A Preferably, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 4 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 4 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0196] In this fifth specific embodiment, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), halogen (e.g., -F or -Cl), C 1~5 Haloalkyl (e.g., -CF3), -CN, hydrogen, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl (e.g., aryl or cycloalkyl), and heterocyclyl (e.g., heteroaryl or heterocycloalkyl), wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2, or 3) groups -L A -R A Preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), -CN, -O(C 1~4 alkyl) (e.g., —OCH) and heteroaryl (e.g., tetrazolyl). More preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl) (e.g., -CO-NH-CH3), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., -CO-N(CH3)-CH3), -SO2-(C 1~5 alkyl) (e.g., -SO2-CH3), -S(=O)(=NH)-(C 1~5 alkyl) (e.g., —S(═O)(═NH)—CH) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH or tetrazolyl (especially 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is —COOH or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH.

[0197] In this fifth specific embodiment, each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~6 alkyl), -(C 0~3 alkylene)-O(C 1~5alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 Preferably, each R 6 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L 1 -R 61 More preferably, each R 6 is C 1~5 Alkyl, -OH, -O(C 1~6 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., -CF3), -O-(C 1~5 haloalkyl) (e.g., -OCF3), -CN and -L 1 -R 61 Even more preferably, each R 6 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., -N(CH3)2), halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 And even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, -CF and -OCF. Even more preferably, each R 6 is independently selected from -CH, -OCH, -F, -Cl, and -CF. 6 is particularly preferably independently —Cl or —CF 3 .

[0198] In this fifth specific embodiment, when p is 1, R 6 is attached to ring D in a 1,2-, 1,3-, or 1,4-orientation relative to the attachment point of group L to ring D, and more preferably, R 6is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D. Furthermore, when p is greater than 1 (e.g., 2, 3, or 4), group R 6 is preferably attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D.

[0199] In this fifth specific embodiment, p and R 6 According to the above definition of p is 1 and the group R 6 is attached to ring D in a 1,3-orientation relative to the attachment point of group L to ring D, and said group R 6 is -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br, or -I), -CF3, -OCF3, -CN, and -L 1 -R 61 More preferably, the group R 6 is selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3, even more preferably said group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, even more preferably said group R 6 is particularly preferably selected from -Cl and -CF3.

[0200] In this fifth specific embodiment, L 1 is C 1~6 alkylene or a covalent bond, 1~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 and each of L is independently replaced by a group selected from the group consisting of alkyl, methyl ... 1 is C 1~4 alkylene, wherein C 1~4One or more (for example, one or two) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 The alkylene is preferably replaced by a group independently selected from C 2~4 It is an alkylene (e.g., ethylene, propylene, or butylene), more preferably -(CH2)2-, -(CH2)3-, or -(CH2)4-, and even more preferably -(CH2)2-. Furthermore, the one or more -CH2- units are selected from -O-, -S-, -NH-, and -N(C 1~5 Preferably, each of L may be replaced by a group independently selected from -alkyl), in particular by -O-. 1 is bonded to ring D via -O- (i.e., L 1 contains a terminal -CH2- unit replaced by -O-, and L 1 is connected to ring D via the —O—. 1 is -(CH2) 2~4 -, wherein said -(CH) 2~4 -One -CH2- unit contained in - is -O-, -S-, -NH- and -N(C 1~5 It may be replaced by a group selected from the group -alkyl)-, in particular by the group -O-. Even more preferably, L 1 is -O-(CH2) 1~3 -, where L 1 In ring D, the -O-(CH2) 1~3 More preferably, L 1 is -O-CH2- or -O-CH2-CH2-, where L 1is bonded to ring D via the oxygen atom in said —O—CH— or said —O—CH—CH—. Even more preferably, L 1 is —O—CH 2 — and is bonded to ring D via the oxygen atom (—O—) contained in —O—CH 2 —.

[0201] In this fifth specific embodiment, R 61 is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2 or 3) groups R 62 Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and heteroaryl (e.g., pyridinyl), wherein said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl are each independently selected from one or more (e.g., 1, 2, or 3) groups R 62 More preferably, R 61 is a cycloalkyl or aryl, wherein said cycloalkyl or said aryl is selected from one or more R 62 Even more preferably, R 61 is C 3~9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein said C 3~9 The cycloalkyl or the phenyl may be one or more R 62 and even more preferably, R 61 is C 5~9 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl), wherein the cycloalkyl is selected from one or more R 62 and even more preferably, R 61is cyclohexyl or cycloheptyl, wherein said cyclohexyl or said cycloheptyl is selected from one or more R 62 Even more preferably, R 61 is cyclohexyl, and the cyclohexyl is selected from one or more R 62 The cyclic group (R 61 ) is not a group R 62 More preferably, it is unsubstituted.

[0202] In this fifth specific embodiment, each R 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 Preferably, each R is independently selected from the group consisting of alkylene-heterocycloalkyl. 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 More preferably, each R 62 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 62 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0203] In this fifth specific embodiment, each L A is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 Each of the alkylene, alkenylene, and alkynylene groups may be substituted with one or more (e.g., 1, 2, or 3) groups independently selected from -O-, -NH-, -N(C 1~5 Each of the alkyl groups may be replaced by a group independently selected from -CO-, -S-, -SO-, and -SO2-.

[0204] In this fifth specific embodiment, each R A -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0205] In a sixth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is selected from one or more (e.g., 1, 2, or 3) groups R31 As defined in the fifth specific embodiment, except that it may be substituted with

[0206] In this sixth specific embodiment, R 3a and R 3b are linked together with the carbon atoms to which they are attached, forming C 3~5 form a cycloalkyl or a 3 to 5 membered heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is substituted with one or more (e.g., one or two) groups R 31 Preferably, R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cyclopropyl.

[0207] In this sixth specific embodiment, therefore, the moiety

[0208] [ka]

[0209] but,

[0210] [ka]

[0211] It is particularly preferred that: In this sixth specific embodiment, each R 31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), and -SO2-(C 1~5 alkyl). Preferably, each R 31 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Independently selected from haloalkyl (eg, —CF 3 ) and —CN.

[0212] In a seventh specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which L is C 3~6 alkylene (e.g., propylene, butylene, or pentylene), wherein 3~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 In particular, by groups independently selected from -O-, -CO-, -NH-, -N(C alkyl)- 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 More preferably, by groups independently selected from —O—, —NH— and —N(C alkyl)- 1~5 As defined in the fifth specific embodiment, except that L may each be replaced by a group independently selected from -(CH)- or -N(-CHCH)-. Preferably, L is -(CH)-. 3~5 -, wherein said -(CH) 3~5 One or more (e.g., 1, 2, or 3) —CH2— units in — are selected from —O—, —CO—, —NH—, —N(C1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 alkyl)-, in particular -O-, -NH- and -N(C 1~5 More preferably, L is -CH-CH-CH-CH-, wherein one or more (e.g., 1, 2, or 3) -CH- units in said -CH-CH-CH-CH- are selected from -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]- (e.g., -N(-CH2-cyclopropyl)-), -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 alkyl)-, in particular -O-, -NH- and -N(C 1~5 More preferably, L is -CH-CH-CH-O-, and the -CH-CH-CH-O- is bonded to ring D via an oxygen atom (-O-) in the -CH-CH-CH-O- group, and one or more (e.g., one or two) -CH- units contained in the -CH-CH-CH-O- are selected from -O-, -CO-, -NH-, -N(C 1~4 alkyl)-, -N[-CO-(C 1~4 alkyl)]-, -N[-(C 1~3 alkylene)-cyclopropyl]-, -CH(C 1~4 alkyl)- and -C(C 1~4 Alkyl)(C 1~4 alkyl)-, in particular -O-, -NH- and -N(C 1~4and each -CH2- unit (furthest from the oxygen atom in -CH2-CH2-CH2-O-) may be replaced by a group as defined above (e.g., -N(C 1~4 It is further preferred that L is replaced by -alkyl)-, in particular by -N(CH3)-. Corresponding preferred examples of L include, in particular, -CH2-CH2-CH2-O-, -NH-CH2-CH2-O-, -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(isopropyl)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -N(-CO-CH3)-CH2-CH2-O-, -NH-CO-CH2-O- or -O-CH2-CH2-O-, each of which groups is bonded to ring D via the terminal oxygen atom (-O-) contained therein. Particularly preferred examples of L include -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O- or -O-CH2-CH2-O-, each of which is bonded to Ring D via a terminal oxygen atom contained therein. An even more preferred example of L is -N(-CH3)-CH2-CH2-O-, which is bonded to Ring D via a terminal oxygen atom contained therein.

[0213] In an eighth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which L is C 3~6 alkylene (e.g., propylene, butylene, or pentylene), wherein 3~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4alkylene)-heterocycloalkyl]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 In particular, by groups independently selected from -O-, -CO-, -NH-, -N(C alkyl)- 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-cycloalkyl]-, -N[-(C 0~4 alkylene)-heterocycloalkyl]-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 More preferably, by groups independently selected from —O—, —NH— and —N(C alkyl)- 1~5 As defined in the sixth specific embodiment, except that L may each be replaced by a group independently selected from -(CH)- or -N(-CHCH)-. Preferably, L is -(CH)-. 3~5 -, wherein said -(CH) 3~5 One or more (e.g., 1, 2, or 3) —CH2— units in — are selected from —O—, —CO—, —NH—, —N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]- (e.g., -N(-CH2-cyclopropyl)-), -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 alkyl)-, in particular -O-, -NH- and -N(C 1~5 More preferably, L is -CH-CH-CH-CH-, wherein one or more (e.g., 1, 2, or 3) -CH- units in said -CH-CH-CH-CH- are selected from -O-, -CO-, -NH-, -N(C 1~5alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -N[-(C 0~4 alkylene)-(C 3~7 cycloalkyl)]- (e.g., -N(-CH2-cyclopropyl)-), -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 alkyl)-, in particular -O-, -NH- and -N(C 1~5 More preferably, L is -CH-CH-CH-O-, and the -CH-CH-CH-O- is bonded to ring D via an oxygen atom (-O-) in the -CH-CH-CH-O- group, wherein one or more (e.g., one or two) -CH- units contained in the -CH-CH-CH-O- are selected from -O-, -CO-, -NH-, -N(C 1~4 alkyl)-, -N[-CO-(C 1~4 alkyl)]-, -N[-(C 1~3 alkylene)-cyclopropyl]-, -CH(C 1~4 alkyl)- and -C(C 1~4 Alkyl)(C 1~4 alkyl)-, in particular -O-, -NH- and -N(C 1~4 and each -CH2- unit (furthest from the oxygen atom in -CH2-CH2-CH2-O-) may be replaced by a group as defined above (e.g., -N(C 1~4It is further preferred that L is replaced by -alkyl)-, in particular by -N(CH3)-. Corresponding preferred examples of L include, in particular, -CH2-CH2-CH2-O-, -NH-CH2-CH2-O-, -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(isopropyl)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -N(-CO-CH3)-CH2-CH2-O-, -NH-CO-CH2-O- or -O-CH2-CH2-O-, each of which groups is bonded to ring D via the terminal oxygen atom (-O-) contained therein. Particularly preferred examples of L include -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O- or -O-CH2-CH2-O-, each of which is bonded to Ring D via a terminal oxygen atom contained therein. An even more preferred example of L is -N(-CH3)-CH2-CH2-O-, which is bonded to Ring D via a terminal oxygen atom contained therein.

[0214] In a ninth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the fifth specific embodiment, except that ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl. Ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0215] In a tenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the sixth specific embodiment, except that ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl. Ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0216] In an eleventh specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the seventh specific embodiment, except that ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl. Ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0217] In a twelfth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the eighth specific embodiment, except that ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl. Ring D is preferably selected from pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), azetidinyl (e.g., azetidin-1-yl or azetidin-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl), and piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl). More preferably, ring D is pyridinyl.

[0218] In a thirteenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which X is C(R 3a )(R 3b ), where R 3a and R 3b are as defined in the first specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0219] In a fourteenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which X is C(R 3a )(R 3b ), where R 3a and R 3b are as defined in the third specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0220] In a fifteenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which X is C(R 3a )(R 3b ), where R 3a and R3b are as defined in the fifth specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0221] In a sixteenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is one in which X is C(R 3a )(R 3b ), where R 3a and R 3b are as defined in the seventh specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0222] In a seventeenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound wherein X is C(R 3a )(R 3b ), where R 3a and R 3b are as defined in the ninth specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0223] In an eighteenth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound wherein X is C(R 3a )(R 3b ), where R 3a and R 3b are as defined in the eleventh specific embodiment, except that each is hydrogen (i.e., X is -CH-), and ring B is cyclohexylene (preferably, ring B is cyclohexane-1,4-diyl).

[0224] In a nineteenth specific embodiment, the compound of formula (I) has the formula:

[0225] [ka]

[0226] or a pharmaceutically acceptable salt thereof. In this nineteenth specific embodiment, L is a covalent bond. In this nineteenth specific embodiment, Ring D is phenyl or pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl). Preferably, Ring D is phenyl.

[0227] In this nineteenth specific embodiment, p is 0, 1, or 2. More preferably, p is 1. When p is 1, R 6 is attached to ring D in a 1,3- or 1,4-orientation relative to the point of attachment of ring A to ring D (via the covalent bond group L), more preferably R 6 is preferably attached to Ring D in a 1,3-orientation relative to the point of attachment of Ring A to Ring D. Thus, when p is 1 and Ring D is phenyl, R 6 is preferably attached to said phenyl (as Ring D) at the meta or para position relative to the attachment point of Ring A to said phenyl (as Ring D), more preferably at the meta position (corresponding to a 1,3-orientation). Furthermore, when p is 1 and Ring D is pyridinyl, R 6 is preferably attached to the pyridinyl (as ring D) in a 1,3- or 1,4-orientation relative to the attachment point of ring A to ring D. In particular, when p is 1 and ring D is pyridin-2-yl or pyridin-3-yl, R 6 may be attached to said pyridin-2-yl or said pyridin-3-yl, for example, in a 1,4-orientation relative to the attachment point of ring A to ring D. When p is 1 and ring D is pyridin-4-yl, R 6 may be attached to said pyridin-4-yl, for example, in a 1,3-orientation relative to the point of attachment of ring A to ring D.

[0228] In this nineteenth specific embodiment, each R 6 independently represent a group -L 1 -R 61 is. In this nineteenth specific embodiment, L 1 is C 1~6 alkylene or a covalent bond, 1~6 One or more (e.g., 1, 2, or 3) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 and each may be replaced by a group independently selected from:

[0229] Preferably, L 1 is C 1~4 alkylene, wherein C 1~4 One or more (for example, one or two) -CH2- units contained in the alkylene may be -O-, -CO-, -NH-, -N(C 1~5 alkyl)-, -N[-CO-(C 1~5 alkyl)]-, -S-, -SO-, -SO2-, -CH(C 1~5 alkyl)- and -C(C 1~5 Alkyl)(C 1~5 The alkylene is preferably replaced by a group independently selected from C 2~4 It is an alkylene (e.g., ethylene, propylene, or butylene), more preferably -(CH2)2-, -(CH2)3-, or -(CH2)4-, and even more preferably -(CH2)2-. Furthermore, the one or more -CH2- units are selected from -O-, -S-, -NH-, and -N(C 1~5 Preferably, each of L may be replaced by a group independently selected from -alkyl), in particular by -O-. 1 is bonded to ring D via -O- (i.e., L1 contains a terminal -CH2- unit replaced by -O-, and L 1 is more preferably connected to ring D via the —O—.

[0230] More preferably, L 1 is -(CH2) 2~4 -, wherein said -(CH) 2~4 -One -CH2- unit contained in - is -O-, -S-, -NH- and -N(C 1~5 It may be replaced by a group selected from the group consisting of alkyl, in particular by the group -O-. 1 is -O-(CH2) 1~3 -, where L 1 In ring D, the -O-(CH2) 1~3 More preferably, L 1 is -O-CH2- or -O-CH2-CH2-, where L 1 is bonded to ring D via the oxygen atom in said —O—CH— or said —O—CH—CH—. Even more preferably, L 1 is —O—CH 2 — and is bonded to ring D via the oxygen atom (—O—) contained in —O—CH 2 —.

[0231] In this nineteenth specific embodiment, R 61 is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2 or 3) groups R 62 Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g., tetrahydrofuranyl or tetrahydropyranyl), and heteroaryl (e.g., pyridinyl), wherein said cycloalkyl, said aryl, said heterocycloalkyl, and said heteroaryl are each independently selected from one or more (e.g., 1, 2, or 3) groups R 62 More preferably, R61 is a cycloalkyl or aryl, wherein said cycloalkyl or said aryl is selected from one or more R 62 Even more preferably, R 61 is C 3~9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein said C 3~9 The cycloalkyl or the phenyl may be one or more R 62 and even more preferably, R 61 is C 5~9 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl), wherein the cycloalkyl is selected from one or more R 62 and even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein said cyclohexyl or said cycloheptyl is selected from one or more R 62 Even more preferably, R 61 is cyclohexyl, and the cyclohexyl is selected from one or more R 62 The cyclic group (R 61 ) is not a group R 62 More preferably, it is unsubstituted.

[0232] In this nineteenth specific embodiment, each R 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 Preferably, each R is independently selected from the group consisting of alkylene-heterocycloalkyl. 62 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, and -(C 0~3 More preferably, each R 62 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 62 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0233] In this nineteenth specific embodiment, ring A is cycloalkylene or heterocycloalkylene. Preferably, ring A is a monocyclic cycloalkylene or a monocyclic heterocycloalkylene. Even more preferably, ring A is a monocyclic C 4~9 It is a cycloalkylene or a monocyclic 4- to 9-membered heterocycloalkylene.

[0234] Preferred examples of ring A include, in particular, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g., tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothiophenylene (e.g., tetrahydrothiophene-2,2-diyl or tetrahydrothiophene-3,3-diyl), tetrahydropyranylene (e.g., tetrahydropyran-2,2-diyl, tetrahydropyran-3,3-diyl or tetrahydropyran-4,4-diyl), or thianylene (e.g., thian-2,2-diyl, thian-3,3-diyl or thian-4,4-diyl). Ring A is particularly preferably tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl) or cyclopentylene (i.e., cyclopentane-1,1-diyl).

[0235] In this nineteenth specific embodiment, Ring B is a carbocyclic or heterocyclic group. Preferably, Ring B is selected from arylene, heteroarylene (e.g., pyridinylene; particularly including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is further preferred that Ring B is monocyclic. More preferably, Ring B is arylene or cycloalkylene. Even more preferably, Ring B is phenylene or C 3~9 More preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phenylene (e.g., phen-1,4-diyl, phenyl-1,3-diyl, or phen-1,2-diyl). Even more preferably, ring B is phen-1,4-diyl.

[0236] In this nineteenth specific embodiment, n is 0, 1, 2, 3, or 4. Preferably, n is 0, 1, or 2. More preferably, n is 0 or 1. Even more preferably, n is 0.

[0237] In this nineteenth specific embodiment, m is 0, 1, 2, 3, or 4. Preferably, m is 0, 1, or 2. More preferably, m is 0 or 1. Even more preferably, m is 0.

[0238] In this nineteenth specific embodiment, each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A Preferably, each R 1 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl (e.g., -CH2-cyclopropyl), -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 1 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 1 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4 alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0239] In this nineteenth specific embodiment, R 2 is hydrogen, C 1~5 Alkyl and -CO(C 1~5 alkyl). Preferably, R 2 is hydrogen or C 1~5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 is hydrogen.

[0240] In this nineteenth specific embodiment, X is C(R 3a )(R 3b ) or N(R 3c ) Therefore, X is a substituent R 3a and R 3b or X is a carbon atom bearing a substituent R 3c Preferably, X is a nitrogen atom having the formula C(R 3a )(R 3b )

[0241] In this nineteenth specific embodiment, R 3a and R 3b is hydrogen, C 1~5 Alkyl and C 2~5alkenyl; or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cycloalkyl or heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is linked to one or more (e.g., 1, 2, or 3) groups R 31 or R 3a is a linear C 2~4 Alkylene and Linear C 2~4 alkenylene, wherein the divalent group is connected via one end to R 3b and is bonded through its other end to a ring atom of ring B adjacent to the ring atom (of ring B) bearing group X, wherein said alkylene or said alkenylene is bonded through one or more (e.g., 1, 2, or 3) groups R 31 wherein one —CH2— unit in said alkylene or said alkenylene is substituted with —O—, —S—, —NH— or —N(C 1~5 alkyl)-, and R 3b is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Preferably, R 3a and R 3b is hydrogen and C 1~5 alkyl, or R 3a and R 3b are linked together with the carbon atoms to which they are attached, forming C 3~5 form a cycloalkyl or a 3 to 5 membered heterocycloalkyl, wherein said cycloalkyl or said heterocycloalkyl is substituted with one or more (e.g., one or two) groups R 31 More preferably, R 3a and R 3b is hydrogen and C 1~5 alkyl (e.g., methyl or ethyl), or R 3a and R 3bare linked together with the carbon atoms to which they are attached to form a cyclopropyl. Even more preferably, R 3a is C 1~5 alkyl (e.g., methyl or ethyl), and R 3b is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl), or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cyclopropyl. And even more preferably, R 3a is methyl and R 3b is hydrogen or R 3a and R 3b are linked together with the carbon atoms to which they are attached to form a cyclopropyl.

[0242] In this nineteenth specific embodiment, R 3c is hydrogen, C 1~5 Alkyl and C 2~5 alkenyl. Preferably, R 3c is hydrogen or C 1~5 alkyl (e.g., methyl or ethyl). More preferably, R 3c is hydrogen or methyl. Even more preferably, R 3c is methyl.

[0243] In this nineteenth specific embodiment, X, R 3a and R 3b According to the above definition of

[0244] [ka]

[0245] teeth,

[0246] [ka]

[0247] It is particularly preferred that: In this nineteenth specific embodiment, each R 31 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5alkyl), -SO-(C 1~5 alkyl), and -SO2-(C 1~5 alkyl). Preferably, each R 31 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Independently selected from haloalkyl (eg, —CF 3 ) and —CN.

[0248] In this nineteenth specific embodiment, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -(C 0~3 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-O(C 1~5 alkylene)-OH, -(C 0~3 alkylene)-O(C 1~5 alkylene)-O(C 1~5 alkyl), -(C 0~3 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-S(C 1~5 alkylene)-SH, -(C 0~3 alkylene)-S(C 1~5 alkylene)-S(C 1~5 alkyl), -(C 0~3 alkylene)-NH2, -(C 0~3 alkylene)-NH(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 Alkyl)(C1~5 alkyl), -(C 0~3 alkylene)-halogen, -(C 0~3 alkylene)-(C 1~5 haloalkyl), -(C 0~3 alkylene)-O-(C 1~5 haloalkyl), -(C 0~3 alkylene)-CN, -(C 0~3 alkylene)-CHO, -(C 0~3 alkylene)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-COOH, -(C 0~3 alkylene)-CO-O-(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-CO-NH2, -(C 0~3 alkylene)-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-CO-(C 1~5 alkyl), -(C 0~3 alkylene)-NH-COO(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-COO(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-NH(C 1~5 alkyl), -(C 0~3 alkylene)-O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-NH2, -(C 0~3 alkylene)-SO2-NH(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-N(C 1~5Alkyl)(C 1~5 alkyl), -(C 0~3 alkylene)-NH-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-SO-(C 1~5 alkyl), -(C 0~3 alkylene)-SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A Preferably, each R 4 is C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O-(C 1~5 haloalkyl), -CN, -CHO, -CO-(C 1~5 alkyl), -COOH, -CO-O-(C 1~5 alkyl), -O-CO-(C 1~5 alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO-(C 1~5 alkyl), -N(C 1~5 alkyl)-CO-(C 1~5alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -(C 0~3 alkylene)-cycloalkyl, -(C 0~3 alkylene)-heterocycloalkyl and -L A -R A More preferably, each R 4 is C 1~5 Alkyl, -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 haloalkyl (e.g., —CF) and —CN. Even more preferably, each R 4 is C 1~4 Alkyl (e.g., methyl or ethyl), -OH, -O(C 1~4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1~4 alkyl) (e.g., -NHCH), -N(C 1~4 Alkyl)(C 1~4alkyl) (e.g., —N(CH3)2), halogen (e.g., —F, —Cl, —Br, or —I), —CF3, and —CN.

[0249] In this nineteenth specific embodiment, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), halogen (e.g., -F or -Cl), C 1~5 Haloalkyl (e.g., -CF3), -CN, hydrogen, C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), carbocyclyl (e.g., aryl or cycloalkyl), and heterocyclyl (e.g., heteroaryl or heterocycloalkyl), wherein said carbocyclyl or said heterocyclyl is selected from one or more (e.g., 1, 2, or 3) groups -L A -R A Preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-OH, -SO2-O-(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -S(=O)(=NH)-(C 1~5 alkyl), -CN, -O(C 1~4alkyl) (e.g., —OCH) and heteroaryl (e.g., tetrazolyl). More preferably, R 5 are -COOH, -CO-NH2, -CO-NH(C 1~5 alkyl) (e.g., -CO-NH-CH3), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl) (e.g., -CO-N(CH3)-CH3), -SO2-(C 1~5 alkyl) (e.g., -SO2-CH3), -S(=O)(=NH)-(C 1~5 alkyl) (e.g., —S(═O)(═NH)—CH) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH or tetrazolyl (especially 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is —COOH or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH.

[0250] In this nineteenth specific embodiment, rings B, X, R 2 , R 3a , R 3b , R 4 , R 5 and according to the above definition of m, the part

[0251] [ka]

[0252] has the following structure:

[0253] [ka]

[0254] It is particularly preferred that In this nineteenth specific embodiment, each L A is a covalent bond, C 1~5 Alkylene, C 2~5 Alkenylene and C 2~5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 Each of the alkylene, alkenylene, and alkynylene groups may be substituted with one or more (e.g., 1, 2, or 3) groups independently selected from -O-, -NH-, -N(C 1~5 Each of the alkyl groups may be replaced by a group independently selected from -CO-, -S-, -SO-, and -SO2-.

[0255] In this nineteenth specific embodiment, each R A -OH, -O(C 1~5 alkyl), -O(C 1~5 alkylene)-OH, -O(C 1~5 alkylene)-O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -S(C 1~5 alkylene)-SH, -S(C 1~5 alkylene)-S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl), -N(C 1~5 Alkyl)(C 1~5 Alkyl), halogen, C 1~5 Haloalkyl, -O(C 1~5 haloalkyl), -CN, -CHO, -CO(C 1~5 alkyl), -COOH, -COO(C 1~5 alkyl), -O-CO(C 1~5alkyl), -CO-NH2, -CO-NH(C 1~5 alkyl), -CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-CO(C 1~5 alkyl), -N(C 1~5 alkyl)-CO(C 1~5 alkyl), -NH-COO(C 1~5 alkyl), -N(C 1~5 alkyl)-COO(C 1~5 alkyl), -O-CO-NH(C 1~5 alkyl), -O-CO-N(C 1~5 Alkyl)(C 1~5 alkyl), -SO2-NH2, -SO2-NH(C 1~5 alkyl), -SO2-N(C 1~5 Alkyl)(C 1~5 alkyl), -NH-SO2-(C 1~5 alkyl), -N(C 1~5 alkyl)-SO2-(C 1~5 alkyl), -SO2-(C 1~5 alkyl), -SO-(C 1~5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are independently selected from C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, halogen, C 1~5 Haloalkyl, -CN, -OH, -O(C 1~5 alkyl), -SH, -S(C 1~5 alkyl), -NH2, -NH(C 1~5 alkyl) and -N(C 1~5 Alkyl)(C 1~5 alkyl).

[0256] In a twentieth specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the nineteenth specific embodiment, except that ring A is tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl) and ring D is phenyl.

[0257] In a twenty-first specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the nineteenth specific embodiment, except that ring A is cyclopentylene (i.e., cyclopentane-1,1-diyl) and ring D is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl; preferably pyridin-4-yl).

[0258] Various methods for preparing the compounds of general formula (I) and their pharmaceutically acceptable salts will be readily apparent to those skilled in the art of synthetic chemistry. For example, the compounds of the present invention can be prepared according to or in analogy with the synthetic routes detailed in the Examples section. In particular, the compounds of formula (I) can generally be synthesized according to the methods described in the following schemes.

[0259] Examples F, O, X, and AI can be obtained by saponification or acid hydrolysis of esters E, N, W, and AH, respectively (Schemes 1, 2, 3, 4). Saponification can generally be carried out in basic aqueous conditions, typically using aqueous sodium hydroxide or lithium hydroxide. If necessary, a mixture with an organic solvent such as THF or dioxane can be used. Acid hydrolysis can generally be carried out in acidic aqueous conditions, typically using aqueous HCl. If necessary, a mixture with an organic solvent such as dioxane can be used. Examples G and AJ can be obtained starting from Examples F and AI, respectively, by amide coupling with an appropriate amine via an activated acid intermediate (Schemes 1 and 4). Typically, this activated acid intermediate can be the corresponding acyl chloride or can be obtained by using a coupling agent such as BOP or HATU.

[0260] Intermediate E can be obtained from intermediate D (Scheme 1). The Y moiety can be introduced by using a suitable electrophile. For example, the moiety can be introduced by reductive amination in the presence of a suitable aldehyde or ketone and a reducing agent such as sodium triacetoxyborohydride. The moiety can also be introduced by amide coupling by reaction with an activated acid intermediate such as an acyl chloride or a carboxylic acid in the presence of a coupling agent such as BOP or HATU. In a similar manner, intermediate D can be obtained from intermediate C. The Y moiety can be introduced using a suitable electrophile, typically a suitable aldehyde or ketone, or by reaction with an activated acid intermediate as described above. Intermediate C can be obtained in two steps from a protected amino acid A and an amine B. The first step can consist of amide coupling via an activated acid intermediate, typically using an acyl chloride or a coupling agent such as BOP or HATU, followed by a deprotection step. This latter applies to the protecting group used in intermediate A: typically, in the case of a Boc-protected amino acid A, the Boc group can be removed in acidic conditions such as a TFA / organic solvent mixture.

[0261] [ka]

[0262] Intermediates N and W can be obtained in two steps from amine B and intermediates J and V, respectively (Schemes 2 and 3). First, saponification of ester J or V occurs in basic aqueous conditions, typically using aqueous sodium hydroxide or lithium hydroxide. If necessary, a mixture with an organic solvent such as THF or dioxane can be used. The resulting carboxylic acid can then undergo amide coupling with the appropriate amine B via preparation of an activated acid intermediate as previously described.

[0263] Intermediates J and L can be obtained from intermediates H and K, respectively, via α-arylation of ester I catalyzed by a transition metal such as palladium (Scheme 2). Intermediate J can alternatively be obtained by functionalization of phenol M, typically via a Mitsunobu reaction with an aliphatic alcohol in the presence of a dialkyl azodicarboxylate such as DIAD and triphenylphosphine, either in solution or polymer-bound. Intermediate J can also be obtained from phenol M via nucleophilic substitution using an appropriate electrophile and a base such as potassium carbonate. Intermediate M can be obtained by deprotection of protected phenol L. In the case of trimethylsilyl-protected phenol L, a simple acidic workup can generate phenol M. Similarly, silyl-protected phenol L can be cleaved under acidic conditions, typically in HCl solution in an organic solvent, or in the presence of a fluoride anion such as TBAF.

[0264] [ka]

[0265] Intermediate V can be obtained from intermediate T in a two-step sequence (Scheme 3). First, hydration of cyanide T can generate the corresponding primary amide, typically in the presence of HO under basic aqueous conditions, which can ultimately afford ester V upon treatment with DMF-DMA in methanol or a mixture of methanol and another organic solvent. Where appropriate, intermediate T can be obtained from halogeno-heteroaryl R by aromatic nucleophilic substitution in the presence of a nucleophile, such as an alcoholate generated in situ from an aliphatic alcohol and a strong base, such as sodium hydride. Otherwise, intermediate T can be obtained by transition metal, such as palladium, catalyzed coupling between halogeno-heteroaryl R and the appropriate aliphatic alcohol. This two-step sequence can be reversed to generate intermediate V via intermediate U. Intermediate R can be obtained directly from di-halogeno-heteroaryl P by nucleophilic aromatic substitution with a suitable nucleophile, such as a carbanion generated at the α-position of the cyanide using a strong base such as n-BuLi or KHMDS. Alternatively, intermediate R can be generated in a two-step sequence from di-halogeno-heteroaryl P. First, nucleophilic aromatic substitution with a carbanion of acetonitrile, generated by treatment of acetonitrile with a strong base such as n-BuLi or KHMDS, can yield intermediate Q. Intermediate R can then be obtained by nucleophilic substitution with a suitable electrophile in the presence of a strong base such as sodium hydride.

[0266] [ka]

[0267] Intermediate AH can be obtained by amide coupling between intermediate AG and amine B via the preparation of an activated acid intermediate as previously described (Scheme 4). Intermediate AG can be obtained in two ways different from intermediate AD. Dinucleophilic substitution of an amino-ester AE in intermediate AD under basic conditions, typically by using potassium carbonate as a base in an organic solvent, followed by saponification of the ester under basic aqueous conditions can produce intermediate AG. Alternatively, dinucleophilic substitution of an amino-alcohol AF in intermediate AD under basic conditions, typically by using potassium carbonate as a base in an organic solvent, followed by oxidation of the primary alcohol can also produce intermediate AG. In some cases, the addition of sodium iodide can facilitate these dinucleophilic substitutions. Dibrominated intermediate AD can be obtained from the corresponding di-alcohol intermediate AC using a brominating agent such as N-bromosuccinimide in the presence of triphenylphosphine. Intermediate AC can be obtained by deprotection of the primary alcohol of intermediate AB. This deprotection is adapted to the protecting group used. For example, in the case of an ester group, a reduction step using a reducing agent such as lithium aluminum hydride can be carried out to generate intermediate AC. In the case of a silyl protecting group, di-alcohol intermediate AC can be obtained in the presence of a fluoride anion, for example TBAF. Intermediate AB can be obtained from secondary alcohol AA either via a Mitsunobu reaction, if appropriate, or via nucleophilic substitution with a suitable electrophile under basic conditions.

[0268] [ka]

[0269] The following definitions apply throughout the specification and claims, unless specifically stated otherwise. The term "hydrocarbon group" refers to a group consisting of carbon and hydrogen atoms.

[0270] The term "alicyclic" is used in connection with a cyclic group to indicate that the corresponding cyclic group is non-aromatic. As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group that may be straight-chained or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1~5 "Alkyl" refers to an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl) or butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to a C 1~4 It refers to alkyl, more preferably methyl or ethyl, even more preferably methyl.

[0271] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be straight-chained or branched and that contains one or more (e.g., one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bonds. 2~5 "Alkenyl" refers to an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1,3-dien-1-yl or buta-1,3-dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless otherwise defined, the term "alkenyl" preferably refers to an alkenyl group having from 2 to 5 carbon atoms. 2~4 refers to alkenyl.

[0272] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be straight-chained or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. 2~5"Alkynyl" refers to an alkynyl group having from 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to an alkynyl group having from 2 to 5 carbon atoms. 2~4 refers to alkynyl.

[0273] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be straight-chained or branched. 1~5 "Alkylene" refers to an alkylene group having 1 to 5 carbon atoms, and the term "C 0~3 "Alkylene" can be either a covalent bond (corresponding to the option "C0 alkylene") or a C 1~3 indicates the presence of alkylene. Preferred exemplary alkylene groups are methylene (-CH-), ethylene (e.g., -CH-CH- or -CH(-CH)-), propylene (e.g., -CH-CH-CH-, -CH(-CH-CH)-, -CH-CH(-CH)- or -CH(-CH)-CH-), or butylene (e.g., -CH-CH-CH-CH-). Unless otherwise defined, the term "alkylene" preferably refers to a C 1~4 Alkylene (especially linear C 1~4 alkylene), more preferably methylene or ethylene, even more preferably methylene.

[0274] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group that may be straight-chained or branched, and that contains one or more (e.g., one or two) carbon-carbon double bonds, but does not contain any carbon-carbon triple bonds. 2~5 "Alkenylene" refers to an alkenylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to an alkenylene group having 2 to 5 carbon atoms. 2~4 Alkenylene (especially linear C 2~4 (including alkenylene).

[0275] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group that may be straight-chained or branched, and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. 2~5 "Alkynylene" refers to an alkynylene group having from 2 to 5 carbon atoms. Unless otherwise defined, the term "alkynylene" preferably refers to an alkynylene group having from 2 to 5 carbon atoms. 2~4 Alkynylene (especially linear C 2~4 (including alkynylene).

[0276] As used herein, the term "carbocyclyl" refers to hydrocarbon ring groups, including monocyclic rings as well as bridged, spiro, and / or fused ring systems (e.g., which may be composed of two or three rings), where the ring groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to aryl, cycloalkyl, or cycloalkenyl.

[0277] As used herein, the term "heterocyclyl" refers to ring groups, including monocyclic rings as well as bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings), wherein said ring groups contain one or more (e.g., 1, 2, 3, or 4, etc.) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, wherein one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further wherein said ring groups can be saturated, partially unsaturated (i.e., unsaturated but not aromatic), or aromatic. For example, each heteroatom-containing ring within the ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (optionally oxidized) and / or 1, 2, 3, or 4 N atoms (optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (optionally oxidized) in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0278] As used herein, the term "carbocyclic group" has the same meaning as "carbocyclyl," and the term "heterocyclic group" has the same meaning as "heterocyclyl." Rings A and B, which may each be a carbocyclic group or a heterocyclic group, are divalent ring groups (i.e., ring A is -CO-N(R 2 )-XB[(-R 4 ) m ]-R 5 and -LD[(-R 6 ) p ]; ring B is bonded to atom X and group R 5 and further, ring A is connected to the moiety —CO—N(R ) through the same ring carbon atom (of ring A), as depicted in formula (Ia). 2)-XB[(-R 4 ) m ]-R 5 and the part -LD[(-R 6 ) p It will be understood that these features of rings A and B also apply to each ring group definition provided herein, including the exemplary ring groups (as far as rings A or B are concerned) indicated in each definition. For example, if ring A is arylene, it will be understood that phenylene (as ring A), disclosed herein as an exemplary arylene group, must exist as phen-1,1-diyl.

[0279] As used herein, the term "carbocyclylene" refers to a carbocyclyl group as defined hereinabove but having two points of attachment (i.e., a divalent carbocyclyl group). Unless otherwise defined, "carbocyclylene" preferably refers to a cycloalkylene or arylene.

[0280] As used herein, the term "heterocyclylene" refers to a heterocyclyl group as defined hereinabove but having two points of attachment (i.e., a divalent heterocyclyl group). Unless otherwise defined, "heterocyclylene" preferably refers to a heterocycloalkylene or heteroarylene.

[0281] As used herein, the term "aryl" refers to aromatic hydrocarbon ring groups, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, where at least one of the fused rings is aromatic; or a bridged ring system consisting of two or three rings, where at least one of the bridged rings is aromatic). "Aryl" may refer to, for example, phenyl, naphthyl, diarylnyl (i.e., 1,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, and even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0282] As used herein, the term "arylene" refers to a divalent aromatic hydrocarbon ring group, including aryl groups as defined hereinabove but having two points of attachment, i.e., monocyclic aromatic rings, as well as bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system composed of two or three fused rings, where at least one of the fused rings is aromatic; or a bridged ring system composed of two or three rings, where at least one of the bridged rings is aromatic). "Arylene" includes, for example, phenylene (e.g., phen-1,2-diyl, phen-1,3-diyl, or phen-1,4-diyl), naphthylene (e.g., naphthalene-1,2-diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl, naphthalene-2,3-diyl, naphthalene-2,5-diyl, "Arylene" may refer to arylene, 1,2-diyl, 1,2-dihydronaphthylene, 1,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless otherwise defined, "arylene" preferably has from 6 to 14 ring atoms, more preferably from 6 to 10 ring atoms, and even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (especially phen-1,4-diyl).

[0283] As used herein, the term "heteroaryl" refers to aromatic ring groups, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system composed of two or three fused rings, where at least one of the fused rings is aromatic; or a bridged ring system composed of two or three rings, where at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more (e.g., 1, 2, 3, or 4, etc.) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring within the aromatic ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (optionally oxidized) and / or 1, 2, 3, or 4 N atoms (optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl" includes, for example, thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl nyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, aryl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl) or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benz isoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,[3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl) or coumarinyl. Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably, 5- to 10-membered) monocyclic ring or fused ring system containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0284]

[0023] As used herein, the term "heteroarylene" refers to a divalent aromatic ring group, including heteroaryl groups as defined hereinabove but having two points of attachment, i.e., monocyclic aromatic rings, and bridged and / or fused ring systems containing at least one aromatic ring (e.g., a ring system composed of two or three fused rings, where at least one of the fused rings is aromatic; or a bridged ring system composed of two or three rings, where at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more (e.g., 1, 2, 3, or 4, etc.) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (optionally oxidized) and / or 1, 2, 3, or 4 N atoms (optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroarylene" includes, for example, thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indo Indolylene, isoindolylene, indazolylene, indolizinylene, prinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene e), β-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazole-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazole-2,4-diyl, oxazole-2,5-diyl or oxazole-4,5-diyl), isoxazolylene (e.g., isoxazole-3,4-diyl, isoxazole-3,5-diyl or isoxazole-4,5-diyl), oxadiazolylene (e.g., 1,2,4-oxadiazole-3,5-diyl, 1,2,5-oxadiazole-3,4-diyl or 1,3,4-oxadiazole-2,5-diyl), thiadiazolylene (e.g., 1,2,4-thiadiazole-3,5-diyl, 1,2,5-thiadiazole-3,4-diyl, or 1,3,4-thiadiazole-2,5-diyl), phenoxazinylene, pyrazolo[1,5-a]pyrimidinylene, 1,2-benzisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene , benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1H-1,2,3-triazolylene, 2H-1,2,3-triazolylene, 1H-1,2,4-triazolylene, or 4H-1,2,4-triazolylene), benzotriazolylene, 1H-tetrazolyle ne), 2H-tetrazolylene, triazinylene (e.g., 1,2,3-triazinylene, 1,2,4-triazinylene, or 1,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., , imidazo[1,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene, 1,3-benzodioxylene, benzodioxanylene (e.g., 1,3-benzodioxanylene or 1,Unless otherwise defined, the term "heteroarylene" preferably refers to a divalent 5- to 14-membered (more preferably 5- to 10-membered) monocyclic ring or fused ring system containing one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroarylene" refers to a divalent 5- or 6-membered monocyclic ring containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized. A "heteroarylene," including any of the specific heteroarylene groups described herein, may be linked via two carbon ring atoms, particularly via those two carbon ring atoms that have the greatest distance from each other (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene.

[0285] As used herein, the term "cycloalkyl" refers to saturated hydrocarbon ring groups, including monocyclic rings as well as bridged rings, spiro rings, and / or fused ring systems (e.g., may be composed of two or three rings; e.g., fused ring systems composed of two or three fused rings, etc.). "Cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to a C 3~11 It refers to cycloalkyl, more preferably C 3~7Particularly preferred "cycloalkyls" are monocyclic saturated hydrocarbon rings having from 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0286] As used herein, the term "cycloalkylene" refers to a cycloalkyl group, as defined hereinabove, but having two points of attachment, i.e., a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged rings, spiro rings and / or fused ring systems (e.g., which may be composed of 2 or 3 rings; e.g., fused ring systems composed of 2 or 3 fused rings, etc.). "Cycloalkylene" may refer to, for example, cyclopropylene (e.g., cyclopropane-1,1-diyl or cyclopropane-1,2-diyl), cyclobutylene (e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, or cyclobutane-1,3-diyl), cyclopentylene (e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, or cyclopentane-1,3-diyl), cyclohexylene (e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, or cyclohexane-1,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless otherwise defined, "cycloalkylene" preferably refers to a cycloalkylene having a C 3~11 It refers to cycloalkylene, more preferably C 3~7 Particularly preferred "cycloalkylene" is a divalent monocyclic saturated hydrocarbon ring having from 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene).

[0287] As used herein, the term "heterocycloalkyl" refers to saturated ring groups, including monocyclic rings as well as bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings; e.g., fused ring systems composed of two or three fused rings, etc.), wherein the ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring within the saturated ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (optionally oxidized) and / or 1, 2, 3, or 4 N atoms (optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl" includes, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxy, oxy, oxy- ... It may refer to thiaryl, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, 1,1-dioxothiaryl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl.Unless otherwise defined, "heterocycloalkyl" preferably refers to a 3- to 11-membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein the ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5- to 7-membered saturated monocyclic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0288] As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group, as defined hereinabove, but having two points of attachment, i.e., a divalent saturated ring group, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings; e.g., a fused ring system composed of two or three fused rings, etc.), wherein said ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, and further, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in said saturated ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (which may be optionally oxidized) and / or 1, 2, 3 or 4 N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring.Examples of "heterocycloalkylene" include aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, and the like. It may refer to tetrahydrofuranylene, 1,3-dioxolanylene, tetrahydropyranylene, 1,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1,3-dithiolanylene, thianylene, 1,1-dioxothianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene.Unless otherwise defined, "heterocycloalkylene" preferably refers to a divalent 3- to 11-membered saturated ring radical, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein the ring radical contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a divalent 5- to 7-membered saturated monocyclic ring radical containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and one or more carbon ring atoms are optionally oxidized.

[0289] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged rings, spiro rings, and / or fused ring systems (e.g., may be composed of two or three rings; e.g., fused ring systems composed of two or three fused rings, etc.), wherein the hydrocarbon ring group contains one or more (e.g., one or two) carbon-carbon double bonds and does not contain any carbon-carbon triple bonds. "Cycloalkenyl" may refer, for example, to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to a C 3~11 It refers to cycloalkenyl, more preferably C 3~7 Particularly preferred "cycloalkenyls" are monocyclic unsaturated alicyclic hydrocarbon rings having 3 to 7 ring members and containing one or more (e.g., 1 or 2; preferably 1) carbon-carbon double bonds.

[0290] As used herein, the term "heterocycloalkenyl" refers to unsaturated alicyclic (non-aromatic) ring groups, including monocyclic rings and bridged rings, spiro rings, and / or fused ring systems (e.g., which may be composed of two or three rings; e.g., fused ring systems composed of two or three fused rings, etc.), wherein the ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) can be optionally oxidized, one or more carbon ring atoms can be optionally oxidized (i.e., to form an oxo group), and further wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated alicyclic ring group may contain 1 or 2 O atoms and / or 1 or 2 S atoms (optionally oxidized) and / or 1, 2, 3, or 4 N atoms (optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and there is at least one carbon ring atom (optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" includes, for example, imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H- pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl) or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3- to 11-membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein the ring group contains one or more (e.g., 1, 2, 3, or 4) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group has at least one bicyclic bond between adjacent ring atoms. more preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., 1, 2, or 3) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms.

[0291] As used herein, the term "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br) or iodo (-I). As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluoro, chloro, bromo, and iodo, preferably all of which are fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available bonding sites and, therefore, determined by the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" may refer to, for example, -CF, -CHF, -CHF, -CF-CH, -CH-CF, -CH-CHF, -CH-CF-CH, -CH-CF-CF, or -CH(CF). A particularly preferred "haloalkyl" group is -CF.

[0292] The terms "bond" and "covalent bond" are used interchangeably herein unless clearly indicated otherwise or contradicted by context. As used herein, the terms "optionally," "optionally," and "may" indicate that the indicated feature may be present or may not be present. Whenever the terms "optionally," "optionally," or "may" are used, the invention specifically relates to both possibilities, i.e., the presence of the corresponding feature, or alternatively, the absence of the corresponding feature. For example, the phrase "X may be optionally substituted with Y" (or "X may be substituted with Y") means that X is substituted with Y or is unsubstituted. Similarly, when a component of a composition is designated as "optionally," the invention specifically relates to both possibilities, i.e., the presence of the corresponding component (contained in the composition) or the absence of the corresponding component in the composition.

[0293] Various groups are referred to herein as "optionally substituted". Generally, these groups may have one or more substituents, for example, 1, 2, 3 or 4 substituents. It will be understood that the maximum number of substituents is limited by the number of available bonding sites in the substituted moiety. Unless otherwise defined, the "optionally substituted" groups referred to herein preferably have no more than two substituents, and in particular may have only one substituent. Moreover, unless otherwise defined, it is preferred that there are no optional substituents, i.e., the corresponding group is unsubstituted.

[0294] Those skilled in the art will recognize that the substituents contained in the compounds of the present invention may be attached to the remainder of the respective compound through several different positions of the corresponding specific substituent. Unless otherwise specified, the preferred attachment positions for the various specific substituents are as illustrated in the examples.

[0295] As used herein, unless clearly indicated otherwise or contradicted by context, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one." Thus, for example, a composition comprising "a" compound of Formula (I) can be interpreted as referring to a composition comprising "one or more" compounds of Formula (I).

[0296] Wherever numerical ranges are provided / disclosed herein, it is to be understood that all values ​​and subranges encompassed by each numerical range are intended to be encompassed within the scope of the present invention. Accordingly, the present invention specifically and individually relates to each value falling within the numerical ranges disclosed herein and each subrange encompassed by the numerical ranges disclosed herein.

[0297] As used herein, the term "about" preferably refers to ±10% of the indicated numerical value, more preferably ±5% of the indicated numerical value, and particularly to the indicated exact numerical value. When the term "about" is used in connection with the endpoints of a range, the term preferably refers to a range from the lower endpoint of the indicated numerical value -10% to the upper endpoint of the indicated numerical value +10%, more preferably a range from the lower endpoint -5% to the upper endpoint +5%, and even more preferably a range defined by the exact numerical values ​​of the lower and upper endpoints.

[0298] As used herein, the term "comprising" (or "comprise," "comprises," "contain," "contains," or "containing") has the meaning of "containing, inter alia," i.e., "containing, among other optional elements," unless clearly indicated otherwise or contradicted by context. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of." For example, the term "A comprising B and C" has the meaning of "A containing, inter alia, B and C," where A may contain additional optional elements (e.g., "A containing B, C, and D" would also be encompassed), but the term also has the meanings of "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not include any components other than B and C).

[0299] The scope of the present invention encompasses all pharmaceutically acceptable salt forms of the compounds of formula (I), which may be formed, for example, by protonation of an atom having a lone pair of electrons susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts include, for example: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts, such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts, such as pyridine salts, picoline salts, quinoline salts, or isoquinoline salts; quaternary ammonium salts, such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts, such as arginine salts, lysine salts, or histidine salts.Exemplary acid addition salts include, for example: mineral acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfates (such as sulfate or hydrogen sulfate), nitrate, phosphates (such as phosphate, hydrogen phosphate or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate or thiocyanate; organic acid salts, such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate. , gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphor, glucoheptanoate, or pivalate; sulfonates, such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; glycerophosphate; and acidic amino acid salts, such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate, and phosphate. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt. Thus, the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is preferably in the form of a hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate or phosphate, and the compound of formula (I) is particularly preferably in the form of a hydrochloride salt.

[0300] The present invention also specifically relates to compounds of formula (I), including any one of the specific compounds of formula (I) described herein in non-salt form. Furthermore, the scope of the present invention encompasses the compound of formula (I) in any solvated form, including, for example, solvates with water (i.e., hydrates) or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs) of the compound of formula (I), are also encompassed within the scope of the present invention. It should be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compound of formula (I) are also encompassed within the scope of the present invention.

[0301] Furthermore, compounds of formula (I) may exist in different isomeric, particularly stereoisomers (including, for example, geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers such as keto / enol tautomers or thione / thiol tautomers). All such isomers of compounds of formula (I), either in admixture or in pure or substantially pure form, are contemplated as being part of the present invention. With respect to stereoisomers, the present invention encompasses isolated optical isomers of compounds according to the present invention and any mixtures thereof (including, in particular, racemic mixtures / racemates). Racemates can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of compounds of formula (I). It will be understood that some compounds may exhibit tautomerism.In such cases, the formulas provided herein expressly depict only one possible tautomer.The formulas and chemical names provided herein are intended to encompass all tautomers of the corresponding compounds and are not limited to the specific tautomers depicted by the drawings or identified by the compound names.

[0302] The scope of the present invention also includes compounds of formula (I) in which one or more atoms have been replaced by a specific isotope of the corresponding atom. For example, the present invention includes compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) have been replaced by a deuterium atom (i.e., 2 H; also referred to as "D"). Thus, the present invention also encompasses compounds of formula (I) that are enriched with deuterium. Naturally occurring hydrogen is approximately 99.98 mol-% hydrogen-1 ( 1 H) and approximately 0.0156 mol-% deuterium ( 2 The deuterium content at one or more hydrogen positions of a compound of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I), or a reactant or precursor used in the synthesis of a compound of formula (I), can be subjected to a H / D exchange reaction using, for example, heavy water (DO). Further suitable deuteration techniques are described in Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labeled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, the compounds of formula (I) are preferably not deuterium enriched. Thus, the naturally occurring hydrogen atoms or 1 The presence of H hydrogen atoms is preferred.

[0303] The present invention relates to a compound in which one or more atoms are, for example, 18 F, 11 C. 13 N, 15 O. 76 Br, 77 Br, 120 I and / or 124The present invention also encompasses compounds of formula (I) in which one or more fluorine atoms (or, for example, all fluorine atoms) are replaced by a positron-emitting isotope of the corresponding atom, such as I. Such compounds may be used as tracers, trackers, or imaging probes in positron emission tomography (PET). Thus, the present invention provides compounds in which (i) one or more fluorine atoms (or, for example, all fluorine atoms) are 18 (ii) a compound of formula (I) in which one or more carbon atoms (or, for example, all carbon atoms) are replaced by a F atom; 11 (iii) compounds of formula (I) in which one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced by a C atom; 13 (iv) compounds of formula (I) in which one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by N atoms; 15 (v) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by an O atom; 76 (vi) compounds of formula (I) in which one or more bromine atoms (or, for example, all bromine atoms) are replaced by Br atoms; 77 (vii) a compound of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by Br atoms; 120 and (viii) compounds of formula (I) in which one or more iodine atoms (or, for example, all iodine atoms) are replaced by 124 This includes compounds of formula (I) in which any atom in a compound of formula (I) is replaced by a specific isotope. Generally, it is preferred that none of the atoms in a compound of formula (I) is replaced by a specific isotope.

[0304] The compounds provided herein may be administered as the compound itself or may be formulated as a medicament. The medicament / pharmaceutical composition may optionally include one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or solubility enhancers.

[0305] The pharmaceutical composition may be, for example, a poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG200, PEG300, PEG400, or PEG600), ethylene glycol, propylene glycol, glycerol, a nonionic surfactant, tyloxapol, polysorbate 80, macrogol 15 hydroxystearate (e.g., Kolliphor® HS15, CAS 70142-34-6), phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, di The composition may include one or more solubility enhancers such as hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and any combination thereof.

[0306] The pharmaceutical compositions may also include one or more preservatives, particularly one or more antimicrobial preservatives such as, for example, benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0307] Pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those published in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd Edition. Pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, intranasal, topical, aerosol, or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, candies, lozenges, liquids, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets, and effervescent tablets. Dosage forms for parenteral administration include liquids, emulsions, suspensions, dispersions, and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovulae. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example, by a metered-dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0308] The compounds of formula (I), or the pharmaceutical compositions described above comprising compounds of formula (I), may be administered to a subject by any convenient route of administration, whether systemically / peripherally or to the desired site of action, including oral (e.g., as tablets, capsules, or as ingestible liquids), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection or infusion techniques, and e.g., by injection, e.g., subcutaneous, intradermal, intramuscular). , intravenous, intra-arterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid or intrasternal, including, e.g., by depot implant, e.g., subcutaneously or intramuscularly), pulmonary (e.g., using an aerosol, e.g., via the mouth or nose, e.g., by inhalation or insufflation therapy), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0309] When the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of administering the compound or pharmaceutical composition intravenously, intraarterially, intraperitoneally, intrathecally, intracerebroventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly, or subcutaneously, and / or by using infusion techniques. For parenteral administration, the compound is best used in the form of a sterile aqueous solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0310] The compound or pharmaceutical composition may also be administered orally in the form of a tablet, capsule, ovoid, elixir, solution or suspension, which may contain flavoring or coloring agents for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0311] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, and glycine; disintegrants such as starch (preferably corn, potato, or tapioca starch), sodium starch glycolate, croscarmellose sodium, and certain complex silicates; and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Similar types of solid compositions may be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. In aqueous suspensions and / or elixirs, the agents may be combined with various sweetening or flavoring agents, coloring substances or dyes, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof.

[0312] In oral administration, the compound or pharmaceutical composition is preferably administered by ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition can be administered through the mouth into the gastrointestinal tract, which can also be referred to as "oral-gastrointestinal" administration.

[0313] Alternatively, the compounds or pharmaceutical compositions may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the invention may also be administered dermally or transdermally, for example, by the use of a skin patch.

[0314] The compound or pharmaceutical composition may be administered by a sustained-release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, such as films or microcapsules. Sustained-release matrices include, for example, polylactide, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(-)-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include compounds encapsulated in liposomes. Therefore, the present invention also relates to liposomes containing the compounds of the present invention.

[0315] The compound or pharmaceutical composition may be administered via pulmonary route, rectal route or ocular route.For ophthalmic route, the compound or pharmaceutical composition may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, optionally combined with a preservative such as benzalkonium chloride.Alternatively, the compound or pharmaceutical composition may be formulated in an ointment such as petrolatum.

[0316] It is also contemplated to prepare dry powder formulations of the compound of formula (I) for pulmonary administration, particularly inhalation.Such dry powders can be prepared by spray drying under conditions that result in substantially amorphous glassy or substantially crystalline bioactive powders.Therefore, the dry powder of the compound of the present invention can be prepared according to the emulsification / spray drying process.

[0317] For topical application to the skin, the compound or pharmaceutical composition may be formulated as a suitable ointment, for example, containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, the compound or pharmaceutical composition may be formulated as a suitable lotion or cream, for example, suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol, and water.

[0318] Therefore, the present invention relates to compounds or pharmaceutical compositions provided herein, wherein the corresponding compounds or pharmaceutical compositions are to be administered by any one of the following routes: oral; topical route, including transdermal, intranasal, ocular, buccal or sublingual; parenteral route, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial, using injection or infusion techniques; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including intravitreal or intracameral route; rectal route; or intravaginal route. Preferred administration routes are oral or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that each compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0319] Typically, a physician will determine the actual dosage that will be most suitable for an individual subject. The specific dose level and frequency of administration for any particular individual subject may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of that compound, age, body weight, general health, sex, dietary habits, mode and time of administration, excretion rate, drug combination, severity of the particular condition, and the individual subject undergoing therapy.

[0320] A suggested non-limiting dose of a compound according to the present invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of active ingredient per unit dose. The unit dose may be administered, for example, 1 to 3 times per day. The unit dose may be administered 1 to 7 times per week, for example, not more than once per day. It will be appreciated that routine variations in dosage may be necessary depending on the age and weight of the patient / subject and the severity of the condition being treated. The exact dose and route of administration will also ultimately be at the discretion of the attending physician or veterinarian.

[0321] The compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can be administered in monotherapy (e.g., without the concomitant administration of any additional therapeutic agent, or without the concomitant administration of any additional therapeutic agent for the same disease to be treated or prevented with the compound of formula (I)). Thus, the present invention relates to the compound of formula (I) or the corresponding pharmaceutical composition for use in the monotherapy treatment of cancer, angiogenic eye disease, inflammatory pain, or inflammatory disease. In particular, the present invention relates to the monotherapy administration of the compound of formula (I) or the corresponding pharmaceutical composition without the concomitant administration of any additional anticancer agent, and / or without the concomitant administration of any additional active agent for angiogenic eye disease, and / or without the concomitant administration of any additional analgesic agent, and / or without the concomitant administration of any additional anti-inflammatory agent.

[0322] However, the compound of formula (I) or a pharmaceutical composition comprising the compound of formula (I) can also be administered in combination with one or more additional therapeutic agents. When the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease or condition, the dosage of each compound may differ from that when the corresponding compound is used alone; in particular, a lower dose of each compound may be used. The combination of the compound of formula (I) with one or more additional therapeutic agents may involve simultaneous / concomitant administration of the compound of formula (I) and the additional therapeutic agent (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or sequential / separate administration of the compound of formula (I) and the additional therapeutic agent(s). When administration is sequential, either the compound of formula (I) according to the present invention or one or more additional therapeutic agents may be administered first. When administration is simultaneous, the one or more additional therapeutic agents may be included in the same pharmaceutical formulation as the compound of formula (I), or the additional therapeutic agents may be administered in two or more different (separate) pharmaceutical formulations.

[0323] Preferably, in the context of treating or preventing cancer, the one or more additional therapeutic agents to be administered in combination with the compounds of the invention are anti-cancer agents. Anti-cancer drugs to be administered in combination with the compounds of formula (I) according to the present invention include, for example, tumor angiogenesis inhibitors (e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors or vascular endothelial growth factor receptor kinase inhibitors); cytotoxic drugs (e.g., antimetabolites such as purine and pyrimidine analog antimetabolites); antimitotic agents (e.g., microtubule stabilizing agents or antimitotic alkaloids); platinum coordination complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine agents (e.g., corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists or somatostatin analogs); or compounds that target overexpressed enzymes or receptors and / or are otherwise involved in specific metabolic pathways that are deregulated (or misregulated) in tumor cells (e.g., ATP and and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitors), and various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors); methionine, aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g., cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), poly ADP-ribose polymerase inhibitors (PARP inhibitors), and epidermal growth factor receptor (EGFR) inhibitors / antagonists.

[0324] Alkylating agents that may be used as anticancer drugs in combination with the compounds of the invention may be, for example, nitrogen mustards (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), alkyl sulfonates (such as busulfan, mannosulfan, or treosulfan), aziridines (such as hexamethylmelamine (altretamine), triethylenemelamine, thiotepa (N,N'N'-triethylenethiophosphoramide), carboquone, or triaziquone), hydrazines (such as procarbazine), triazenes (such as dacarbazine), or imidazotetrazines (such as temozolomide).

[0325] Platinum coordination complexes that can be used as anticancer agents in combination with the compounds of the invention can be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.

[0326] Cytotoxic agents that may be used as anti-cancer agents in combination with the compounds of the invention may be antimetabolites, including, for example, folate analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

[0327] Antimitotic agents that may be used as anti-cancer agents in combination with the compounds of the invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel / taxol, tesetaxel or nab-paclitaxel (e.g., Abraxane®)), a vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E or epothilone F) or an epothilone B analogue (such as ixabepilone / azaepothilone B).

[0328] Antitumor antibiotics that may be used as anticancer drugs in combination with the compounds of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone or pixantrone), or an antitumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).

[0329] Tyrosine kinase inhibitors that may be used as anti-cancer drugs in combination with the compounds of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib or vemurafenib.

[0330] The topoisomerase inhibitor that may be used as an anticancer drug in combination with the compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).

[0331] PARP inhibitors that may be used as anti-cancer drugs in combination with the compounds of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP9722, MK4827, E7016, or 3-aminobenzamide.

[0332] EGFR inhibitors / antagonists that may be used as anti-cancer drugs in combination with the compounds of the invention may be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, poziotinib, ABT-414, AV-412, PD153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.

[0333] Additional anti-cancer drugs may be used in combination with the compounds of the present invention. Anti-cancer drugs include TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, tretinoin, anaguanidine, riboflavin, riboflavin, riboflavin-1, riboflavin-2, riboflavin-3, riboflavin-4, riboflavin-5, riboflavin-6, riboflavin-7, riboflavin-8, riboflavin-9, riboflavin-10, riboflavin-11, riboflavin-12, riboflavin-13, riboflavin-14, riboflavin-15, riboflavin-15, riboflavin-15, riboflavin-16, riboflavin-17, riboflavin-18, riboflavin-19, riboflavin-20, riboflavin-21, riboflavin-22, riboflavin-23, riboflavin-24, riboflavin-25, riboflavin-25, riboflavin-25, riboflavin-26, riboflavin-27, riboflavin-28, riboflavin-29, riboflavin-29, riboflavin-29, ri The compounds may include biological or chemical molecules such as leride, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucide, lonidamine, lucantone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, citimagine, seladenovec, tegafur, testolactone, tiazofurine, tipifarnib, vorinostat, iniparib, or copanlisib.

[0334] Biological agents such as antibodies, antibody fragments, antibody constructs (e.g., single-chain constructs) and / or modified antibodies (such as CDR-grafted antibodies, humanized antibodies, "fully human" antibodies, etc.) directed against cancer or tumor markers / factors / cytokines involved in proliferative diseases can also be used in co-therapeutic approaches with the compounds of the present invention. Examples of such biomolecules are anti-HER2 antibodies (e.g., trastuzumab, Herceptin®), anti-CD20 antibodies (e.g., rituximab, Rituxan®, MabThera®, Reditux®), anti-CD19 / CD3 constructs (see, e.g., EP1071752), and anti-TNF antibodies (see, e.g., Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328). Further antibodies, antibody fragments, antibody constructs and / or modified antibodies to be used in co-therapeutic approaches with the compounds of the present invention can be found, for example, in Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328; or Roxana A, Maedica, 2006, 1(1):63-65.

[0335] Anti-cancer drugs that may be used in combination with the compounds of the present invention are, in particular, tumor immunotherapy drugs. The immuno-oncology therapeutic may be, for example, an antibody (e.g., a monoclonal or polyclonal antibody), an antibody fragment, an antibody construct (e.g., a single-chain construct), or a modified antibody (e.g., a CDR-grafted antibody, a humanized antibody, or a "fully human" antibody), which targets any one of CTLA-4, PD-1, PD-L1, TIM3, LAG3, OX40, CSF1R, IDO, or CD40. Such immuno-oncology therapeutics include, for example, anti-CTLA-4 antibodies (particularly antagonistic or pathway-blocking anti-CTLA-4 antibodies; e.g., ipilimumab or tremelimumab), anti-PD-1 antibodies (particularly antagonistic or pathway-blocking anti-PD-1 antibodies; e.g., nivolumab (BMS-936558), pembrolizumab (MK-3475), pidilizumab (CT-01), or the like. 1), AMP-224 or APE02058), anti-PD-L1 antibodies (particularly pathway-blocking anti-PD-L1 antibodies; e.g., BMS-936559, MEDI4736, MPDL3280A (RG7446), MDX-1105 or MEDI6469), anti-TIM3 antibodies (particularly pathway-blocking anti-TIM3 antibodies), anti-LAG3 antibodies (particularly antagonistic or pathway-blocking anti-LAG3 antibodies; e.g., BMS-9 86016, IMP701 or IMP731), anti-OX40 antibodies (particularly agonistic anti-OX40 antibodies; e.g., MEDI0562), anti-CSF1R antibodies (particularly pathway-blocking anti-CSF1R antibodies; e.g., IMC-CS4 or RG7155), anti-IDO antibodies (particularly pathway-blocking anti-IDO antibodies) or anti-CD40 antibodies (particularly agonistic anti-CD40 antibodies; e.g., CP-870,893 or Chi Lob 7 / 4).Additional immuno-oncology therapeutic agents are known in the art and are described, for example, in Kyi C et al., FEBS Lett, 2014, 588(2):368-76; Intlekofer AM et al., J Leukoc Biol, 2013, 94(1):25-39; Callahan MK et al., J Leukoc Biol, 2013, 94(1):41-53; Ngiow SF et al., Cancer Res, 2011, 71(21):6567-71; and Blattman JN et al., Science, 2004, 305(5681):200-5.

[0336] It is particularly advantageous to administer a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) in combination with an immune checkpoint inhibitor, preferably an antibody (or antigen-binding fragment thereof, or antibody construct) against CTLA-4, PD-1 or PD-L1. Corresponding examples include, in particular, any one of the anti-CTLA-4 antibodies ipilimumab or tremelimumab, any one of the anti-PD-1 antibodies nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, AMP-224 or AMP-514, and / or any one of the anti-PD-L1 antibodies atezolizumab, avelumab, zurvalumab, KN035 or CK-301. Thus, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or pharmaceutical composition is to be administered in combination with one or more immune checkpoint inhibitors, wherein said one or more immune checkpoint inhibitors are preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies and / or anti-PD-L1 antibodies; more preferably, said one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, AMP-224, AMP-514, atezolizumab, avelumab, zurvalumab, KN035 and CK-301.

[0337] The combinations mentioned above may be conveniently presented for use in the form of pharmaceutical preparations.The individual components of such combinations may be administered by any convenient route, either sequentially or simultaneously / concomitantly in separate or combined pharmaceutical preparations.When administration is sequential, either the compound of the present invention (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof) or the additional therapeutic agent may be administered first.When administration is simultaneous, the combination may be administered in the same pharmaceutical composition or in different pharmaceutical compositions.It will be understood that when combined in the same preparation, the two or more compounds must be stable and compatible with each other and with the other components of the preparation.When formulated separately, the compounds may be provided in any convenient preparation.

[0338] The compound of formula (I) can also be administered in combination with physical therapy, such as radiation therapy. Radiation therapy can be initiated before, after, or simultaneously with the administration of the compound of the present invention. For example, radiation therapy can be initiated about 1 to 10 minutes, about 1 to 10 hours, or about 24 to 72 hours after the administration of the compound of formula (I). The subject / patient is exposed to radiation, preferably gamma radiation, whereby radiation can be provided in a single dose or in multiple doses administered over several hours, days, and / or weeks. Gamma radiation can be delivered according to standard radiation therapy protocols using standard dosages and regimens.

[0339] Thus, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of the aforementioned entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer, wherein the compound or pharmaceutical composition is to be administered in combination with one or more anti-cancer drugs (including any one or more of the specific anti-cancer drugs described herein above) and / or in combination with radiation therapy.

[0340] However, the compound of formula (I) may also be used in monotherapy, particularly in the monotherapy treatment or prevention of cancer (i.e., without administering any other anti-cancer agent until treatment with the compound of formula (I) has concluded). Accordingly, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any of the aforementioned entities, in combination with a pharmaceutically acceptable excipient, for use in the monotherapy treatment or prevention of cancer.

[0341] Additionally, the compounds of Formula (I) can be administered in combination with an antiemetic agent, either in combination with one or more additional anticancer agents (including any of the exemplary anticancer agents described above) or without any additional anticancer agents. Antiemetic agents include, for example, alosetron, azasetron, bemesetron, cilansetron, clozapine, dazopride, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (e.g., palonosetron alone or palonosetron in combination with netupitant), quetiapine, ramosetron, licasetron, tropisetron, zatosterone, clozapine, cyproheptadine, hydroxyzine, olanzapine, risperidone, ziprasidone, dronabinol, nabilone, tetrahydrocannabinol, alizapride, bromopride, chlorpromazine, thiazolidine diphosphate ... The active ingredient may be selected from cefotaxime, clebopride, domperidone, haloperidol, hydroxyzine, itopride, metoclopramide, metopimazine, prochlorperazine, thiethylperazine, trimethobenzamide, cyclizine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, promethazine, atropine, diphenhydramine, hyoscyamine, scopolamine, aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, vestipitant, cerium oxalate, dexamethasone, lorazepam, midazolam, propofol, or a combination thereof. Preferably, the antiemetic agent is a 5-HT3 antagonist (or "setron"), such as, for example, alosetron, azasetron, bemesetron, cilansetron, clozapine, dazopride, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (optionally in combination with netupitant), quetiapine, ramosetron, licasetron, tropisetron or zatosterone. A particularly preferred antiemetic agent is palonosetron.

[0342] The subject or patient to be treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male or female human) or a non-human mammal (e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, a cow, a pig, etc.). Most preferably, the subject or patient to be treated according to the present invention is a human.

[0343] The term "treatment" of a disorder or disease as used herein is well known in the art. "Treatment" of a disorder or disease implies that the disorder or disease is suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically exhibits specific clinical and / or pathological symptoms that a person skilled in the art can easily attribute to a specific pathological condition (i.e., diagnose the disorder or disease).

[0344] "Treatment" of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no worsening of symptoms) or a delay in the progression of the disorder or disease (if the halt in progression is only temporary). "Treatment" of a disorder or disease may also lead to a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) in the subject / patient suffering from the disorder or disease. Thus, "treatment" of a disorder or disease may also refer to an improvement of the disorder or disease, which treatment may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may subsequently recur. It is understood that a subject / patient may experience a wide range of responses to treatment (such as the exemplary responses as described herein above). Treatment of a disorder or disease may include, inter alia, curative treatment (preferably leading to a complete response and eventually to a cure of the disorder or disease) and palliative treatment (including relief of symptoms).

[0345] The term "prevention" of a disorder or disease, as used herein, is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may particularly benefit from the prevention of the disorder or disease. The subject / patient may have a predisposition, including, but not limited to, a susceptibility or genetic predisposition, to the disorder or disease. Such a predisposition can be determined by standard methods or assays using, for example, genetic markers or phenotypic indicators. It should be understood that the disorder or disease to be prevented in accordance with the present invention has not been or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of a compound of the present invention before any clinical and / or pathological symptoms have been or can be diagnosed or determined by the attending physician.

[0346] It is to be understood that the present invention specifically relates to any and all combinations of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the present invention specifically relates to each combination of meanings (including general and / or preferred meanings) for the various groups and variables contained in formula (I) or (Ia).

[0347] In this specification, several documents are cited, including patent applications and scientific literature. The disclosures of these documents are not considered relevant to the patentability of this invention, but are incorporated herein by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document were specifically and individually indicated to be incorporated by reference.

[0348] Reference in this specification to any prior publication (or information derived therefrom) is not, and should not be taken as, any form of acknowledgement, admission or suggestion that the corresponding prior publication (or information derived therefrom) forms part of the common general knowledge in the art to which this specification pertains.

[0349] The invention is also explained by the accompanying exemplary figures. [Brief explanation of the drawings]

[0350] [Figure 1] Comparison of the percentage of complete tumor regression in the anti-PD-1 and anti-PD1 + Example 25 groups in the CT26 tumor model (see Example 212). [Figure 2] Mean tumor volume in the Pan02 tumor model (see Example 213). [Figure 3] Mean tumor volume in the Pan02 tumor model (see Example 214). [Figure 4] Mean tumor volume in the MCA205 tumor model (see Example 215). DETAILED DESCRIPTION OF THE INVENTION

[0351] The invention will now be described by reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the invention. [Example]

[0352] The compounds of formula (I) described in this section, including in particular Examples 1 to 210, are defined by their chemical formula and their corresponding chemical name. In the event of a discrepancy between any chemical formula and corresponding chemical name referred to herein, the present invention relates to both compounds defined by the chemical formula and compounds defined by the chemical name, and in particular to compounds defined by the chemical formula. Abbreviation: The following abbreviations are used in the experimental procedures: Ac Acetyl Boc Tert-butoxycarbonyl BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BRET Bioluminescence Resonance Energy Transfer cAMP cyclic adenosine monophosphate DCM dichloromethane DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMF-DMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide DNA deoxyribonucleic acid EPAC cAMP-activated exchange protein EtOAc ethyl acetate GFP Green Fluorescent Protein HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HEK Human Embryonic Kidney HPLC High-Performance Liquid Chromatography KHMDS Potassium bis(trimethylsilyl)amide LC-MS Liquid Chromatography-Mass Spectrometry LDA Lithium diisopropylamide MeOH Methanol n-BuLi n-butyllithium NMR nuclear magnetic resonance ppm parts per million PS Polystyrene rt room temperature TBAF Tetrabutylammonium Fluoride THF tetrahydrofuran TFA trifluoroacetic acid TLC thin layer chromatography UPLC Ultra High Performance Liquid Chromatography General conditions: All reagents were commercial grade and used without further purification. Reactions were typically carried out under an argon atmosphere using anhydrous solvents. The indicated reaction temperatures are set-point temperatures. Microwave reactions were carried out under a thermostatically regulated power supply, and the indicated reaction times correspond to the time at the set-point temperature before the reaction mixture cooled. Organic layers were typically dried over sodium sulfate or magnesium sulfate or filtered through an Isolute® SPE single-frit column. Thin-layer chromatography was performed using precoated silica gel F-254 plates. Flash column chromatography was performed using a Biotage® Isolella 4 system with Biotage® SNAP cartridges KP-Sil unless otherwise specified. In certain cases, Biotage® SNAP KP-NH or Interchim PF-15SIHP-F0025 (15 μm) cartridges may be used. After purification by flash chromatography, the examples were typically triturated in diethyl ether or diisopropyl ether or pentane and then dried overnight under vacuum at 70° C. Examples were typically synthesized on a 10-100 mg scale.

[0353] The reaction was monitored and the compounds were characterized using a Waters Acquity UPLC H-Class system equipped with a photodiode array detector (190-400 nm). An Acquity CSH C18 1.7 μM 2.1 x 30 mm column was used. The mobile phase consisted of a gradient of A and B, where A was water with 0.025% trifluoroacetic acid and B was acetonitrile with 0.025% trifluoroacetic acid. The flow rate was 0.8 ml per minute. All analyses were performed at 55 °C. The UPLC system was coupled to a Waters SQD2 platform. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were acquired using positive electrospray ionization.

[0354] Preparative LC-MS was performed using a Waters HPLC system equipped with a 2767 sample manager, a 2525 pump, and a photodiode array detector (190-400 nm) capable of analytical and preparative modes. An Ekselect CSH C18 3.5 μM 4.6 x 50 mm column was used in analytical mode, and an Ekselect CSH C18 5 μM 19 x 100 mm column was used in preparative mode. The mobile phase consisted of a gradient of A and B in both cases, where A was water with 0.1% formic acid and B was acetonitrile with 0.1% formic acid. The flow rate was 1 ml per minute in analytical mode and 25 ml per minute in preparative mode. All LC-MS analyses / purifications were performed at room temperature. The HPLC system was coupled to a Waters Acquity QDa detector. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were acquired using positive electrospray ionization.

[0355] All NMR experiments were recorded on a Brucker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual DMSO (2.50 ppm). Splitting patterns are designated as s (singlet); d (doublet); dd (doublet of doublets); t (triplet); dt (doublet of triplets); td (triplet of doublets); tt (triplet of triplets); q (quartet); quint (quintuplet); m (multiplet); bs (broad singlet); bd (broad doublet). General Procedures and Methods: General Procedure Ia: Amide Coupling Using BOP To a solution of carboxylic acid (1 equivalent) in DMF (0.1 M) was added amine (1.2 equivalents), diisopropylethylamine (2 equivalents), and BOP (1.2 equivalents). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure Ib: Amide Coupling Using HATU To a solution of carboxylic acid (1 equivalent) in DMF (0.1 M) was added amine (1.2 equivalents), diisopropylethylamine (2 equivalents) and HATU (1.2 equivalents). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with brine, dried and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure II-a: Boc Cleavage A solution of Boc-protected amine (1 equivalent) in a DCM / TFA mixture (1 / 1, 0.1 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in DCM, washed with a saturated solution of potassium carbonate and brine, dried, and then concentrated. Where indicated, the resulting crude was purified by flash chromatography to give the desired compound. General Procedure II-b: Boc Cleavage A solution of Boc-protected amine (1 equivalent) in a DCM / TFA mixture (1 / 1, 0.1 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in DCM, and HCl 2M in diethyl ether was added. The resulting precipitate was filtered and then dried under vacuum to give the desired compound in its hydrochloride form. General procedure II-c: Boc cleavage A solution of Boc-protected amine (1 equivalent) in a DCM / TFA mixture (1 / 1, 0.1 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methanol and then filtered through SCX resin to recover the free base. After concentration of the solution, the residue was dissolved in methanol and HCl 1.25 M in methanol was added. The solution was concentrated to give the desired compound in its hydrochloride form. General Procedure III-a: Reductive Amination To a solution of amine (1 equivalent) in THF (0.1 M) was added aldehyde (1.2 equivalents), NaBH(OAc) (2 equivalents), and acetic acid (1 equivalent). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate solution and brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure III-b: Reductive Amination To a solution of amine (1 equivalent) in THF (0.1 M) was added aldehyde (1.2 equivalents), NaBH(OAc) (2 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated sodium bicarbonate solution and brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure IV-a: Ester Hydrolysis A suspension of the ester (1 equiv.) in 1N aqueous HCl (0.1 M) was stirred under microwave irradiation at 150° C. for 5 min. The resulting solution was concentrated to dryness. If necessary, the residue was purified by preparative LC-MS; otherwise, simple trituration in diethyl ether or pentane gave the desired compound. General Procedure IV-b: Ester Hydrolysis A solution of the methyl ester (1 equivalent) in a 1N aqueous HCl / dioxane mixture (7 / 3, 0.1 M) was stirred under microwave irradiation at 150° C. for 5 minutes. The resulting solution was concentrated to dryness. If necessary, the residue was purified by preparative LC-MS; otherwise, simple trituration in diethyl ether or pentane gave the desired compound. General Procedure Va: Saponification To a solution of the ester (1 equivalent) in THF (0.2 M) was added 1 M aqueous LiOH (2 equivalents). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was concentrated to dryness to give the desired compound. General Procedure Vb: Saponification To a solution of the ester (1 equivalent) in THF (0.2 M) was added 1 M aqueous LiOH (2 equivalents). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, acidified with 1 N aqueous HCl, and extracted with DCM. The organic layer was washed with brine, dried, and then concentrated. If necessary, the residue was purified by preparative LC-MS; otherwise, simple trituration in diethyl ether or pentane gave the desired compound. General Procedure Vc: Saponification To a solution of the ester (1 equivalent) in THF (0.2 M) was added 1 M aqueous LiOH (2 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove THF, diluted with water, and extracted with ethyl ether. The aqueous layer was acidified with 1 N aqueous HCl. The resulting precipitate was filtered. If necessary, the residue was purified by preparative LC-MS; otherwise, simple trituration in diethyl ether or pentane gave the desired compound. General Procedure Vd: Saponification To a solution of the ester (1 equivalent) in dioxane (0.2 M) was added 1 M aqueous LiOH (4 equivalents). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, acidified with 1 N aqueous HCl, and extracted with DCM. The organic layer was washed with brine, dried, and then concentrated. If necessary, the residue was purified by preparative LC-MS; otherwise, simple trituration in diethyl ether or pentane gave the desired compound. General Procedure Ve: Saponification To a solution of the ester (1 equivalent) in THF (0.2 M) was added 1 M aqueous LiOH (2 equivalents). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was directly purified by preparative LC-MS to give the desired compound. General Procedure Vf: Saponification To a solution of the ester (1 equivalent) in dioxane (0.2 M) was added 1 M aqueous LiOH (2 equivalents). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated to dryness to give the desired compound. General Procedure VI-a: α-Arylation of Esters Under an argon atmosphere, to a solution of the ester (1.7 equivalents) in toluene (0.2 M) at −15° C., LDA 1 M (1.6 equivalents) in THF was added dropwise. The reaction mixture was stirred at −15° C. for 15 minutes and then allowed to warm to room temperature. Bromoarene (1 equivalent) and {(Pt-Bu3)PdI}2 (5 mol%) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was hydrolyzed with aqueous HCl 1N and extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VI-b: α-Arylation of Esters Under an argon atmosphere, to a solution of the ester (1.7 equivalents) in toluene (0.2 M) at −15° C., LDA 1 M (1.6 equivalents) in THF was added dropwise. The reaction mixture was stirred at −15° C. for 15 minutes and then allowed to warm to room temperature. Halogeno-(hetero)arene (1 equivalent) and Pd(Pt-Bu3)2 were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was hydrolyzed with aqueous HCl 1N and extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VII-a: Nucleophilic Aromatic Substitution with Carbanions Under an argon atmosphere, to a solution of carbonitrile (1 equivalent) in toluene (0.2 M) at 0° C., KHMDS 1 M (1.05 equivalents) in THF was added dropwise. The reaction mixture was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature. Halogeno-heteroarene (2.5 equivalents) was added. The reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was hydrolyzed with a saturated solution of ammonium chloride and extracted with DCM. The organic layer was washed with a saturated solution of sodium bicarbonate and brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VII-b: Nucleophilic Aromatic Substitution with Acetonitrile To a solution of acetonitrile (3.4 equivalents) in THF (0.2 M) at −78° C. was added 1.6 M n-BuLi (3.3 equivalents) in THF. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of halogeno-heteroarene (1 equivalent) in THF (0.4 M) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was hydrolyzed with water and then extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VII-c: Nucleophilic Aromatic Substitution with Aliphatic Alcohols To a solution of an aliphatic alcohol (1.3 equivalents) in DMA (0.12 M) at 0° C., sodium hydride (1.4 equivalents) was added. The reaction mixture was stirred at 0° C. for 10 minutes. A solution of a halogeno-heteroarene (1 equivalent) in DMA (0.4 M) was added. The reaction mixture was stirred under microwave irradiation at 150° C. for 10 minutes. The reaction mixture was hydrolyzed with a saturated solution of ammonium chloride and then extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VIII-a: Saturated Carbo / Heterocycle Synthesis To a solution of ester or cyanide (1 equivalent) in DMA (0.1 M) was added sodium hydride (2 equivalents). The reaction mixture was stirred at 0° C. for 10 minutes. A di-halogenoalkane (1 equivalent) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was hydrolyzed with a saturated solution of ammonium chloride and then extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure VIII-b: Saturated Nitrogen-Containing Heterocycle Synthesis To a solution of a primary amine (1.3 equivalents) in acetonitrile (0.1 M) was added potassium carbonate (2 equivalents) and a di-halogenoalkane compound (1 equivalent). The reaction mixture was stirred at 85° C. for 6 days. The reaction mixture was cooled to 0° C., hydrolyzed with water, and extracted with DCM. The organic layer was dried and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure IX-a: Mitsunobu with Polymer-Bound Triphenylphosphine To a solution of phenol (1 equivalent) in THF (0.1 M) was added DIAD (1.6 equivalents), PS-triphenylphosphine (2.2 equivalents), and aliphatic alcohol (1.5 equivalents). The reaction mixture was stirred overnight at room temperature using an orbital shaker. The reaction mixture was filtered, diluted with EtOAc, washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure IX-b: Mitsunobu To a solution of phenol (1 equivalent) in THF (0.1 M) was added DIAD (1.5 equivalents), triphenylphosphine (1.5 equivalents), and aliphatic alcohol (1.5 equivalents). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure X: Nucleophilic Substitution with Phenols To a solution of phenol (1 equivalent) in DMF (0.1 M) was added potassium carbonate (2 equivalents) and an electrophile (1.5 equivalents). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and hydrolyzed with water. The resulting precipitate was filtered. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XI-a: Carbonitrile Hydration To a solution of carbonitrile (1 equivalent) in DMSO (0.2 M) was added potassium carbonate (1 equivalent) and 30% H2O2 in water (2 equivalents). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture. The resulting precipitate was filtered, washed with water, and then dried under vacuum at 70 °C over P2O5. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XI-b: Carbonitrile Hydration A solution of carbonitrile (1 equivalent) in concentrated H2SO4 (0.2 M) was stirred at room temperature overnight. The reaction mixture was poured into crushed ice, and then potassium carbonate was added until pH 8 was reached. The resulting precipitate was filtered, washed with water, and then dried under vacuum at 70 °C over P2O5. The obtained solid was suspended in DCM and filtered. The obtained filtrate was concentrated to give the desired compound. General Procedure XI-c: Carbonitrile Hydration / Hydrolysis A solution of the carbonitrile (1 equivalent) in 12N aqueous HCl (0.1 M) was stirred for 2 hours at 100° C. The reaction mixture was concentrated to dryness, co-evaporated with toluene, and then dried under vacuum at 70° C. to give the desired compound. General Procedure XII: Methyl Ester Synthesis from Primary Amides To the primary amide (1 equivalent) in methanol (0.1 M) was added DMF-DMA (6 equivalents). The reaction mixture was stirred at room temperature overnight. Sodium methoxide (5 equivalents) was added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was hydrolyzed with water and then extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XIII: Pd-Catalyzed Arylation of Aliphatic Alcohols To a solution of bromo-arene (1 equivalent) in dioxane (0.1 M) was added cesium carbonate (2 equivalents) and aliphatic alcohol (6 equivalents). The reaction mixture was degassed with argon for 10 minutes, and then RockPhosPd G3 (5 mol%) was added. The reaction mixture was heated at 90° C. overnight. The reaction mixture was diluted with a saturated solution of ammonium chloride and then extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XIV: Silyl Protection of Primary Alcohols To a solution of primary alcohol (1 equivalent) in DCM (0.3 M) was added t-butyl-chloro-dimethyl-silane (1.8 equivalents), triethylamine (2.2 equivalents) and DMAP (0.1 equivalents). The reaction mixture was stirred overnight at room temperature. The reaction mixture was hydrolyzed with water and then extracted with DCM. The organic layer was washed with brine, dried and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XV-a: Silyl Deprotection To a solution of silyl-protected phenol (1 equivalent) in THF (0.1 M) was added TBAF 1 M (2 equivalents) in THF. The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C, hydrolyzed with water, and extracted with EtOAc. The organic layer was washed with brine, dried, and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XV-b: Silyl Deprotection To a solution of silyl-protected phenol (1 equivalent) in methanol (0.2 M) was added HCl 4N in dioxane (5 equivalents). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XVI: Dibromination of Diols To a solution of N-bromosuccinimide (3 equivalents) in DCM (0.4 M) at −78° C. was added triphenylphosphine (3 equivalents). The reaction mixture was stirred at −78° C. for 5 minutes, and then diol (1 equivalent) in DCM (0.4 M) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated to dryness. Where indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound. General Procedure XVII: Oxidation of Primary Alcohols To a solution of primary alcohol (1 equivalent) in acetone (0.2 M) was added Jones reagent (5 equivalents). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was hydrolyzed with aqueous NaOH 6N solution until pH 12 was reached, and then washed with ethyl ether. The aqueous layer was acidified with aqueous HCl 1N solution to return to pH 4. The resulting precipitate was filtered off. The aqueous layer was extracted with EtOAc. The organic layer was dried and then concentrated to give the carboxylic acid, which was used directly in the next step. HCl salt preparation: Method 1: After purification by preparative LC-MS, aqueous HCl 1N solution was added to the combined fractions. The resulting solution was lyophilized. The solid obtained was dried under vacuum at 70°C. - Method 2: After purification by preparative LC-MS, the combined fractions were concentrated. The residue obtained was dissolved in DCM. HCl 2M in diethyl ether was added. The solution obtained was concentrated, and the solid obtained was triturated with diethyl ether and then dried under vacuum at 70 ° C. Method 3: After purification by preparative LC-MS, HCl 4M in dioxane was added to the combined fractions. The resulting solution was concentrated. The solid obtained was dried under vacuum at 70°C.

[0356] Compound and Example Synthesis: This section describes the preparation of compounds of formula (I), designated "Examples," and synthetic intermediates, designated "Compounds."

[0357] Compound 1: Methyl 4-[(1S)-1-[[4-(tert-butoxycarbonylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoate Starting from 4-(tert-butoxycarbonylamino)tetrahydropyran-4-carboxylic acid and methyl 4-[(1S)-1-aminoethyl]benzoate, compound 1 was obtained according to general procedure Ia. Purification by flash chromatography (cyclohexane / EtOAc: 100 / 0 to 20 / 80) gave compound 1 as a white powder in 98% yield. M / Z (M+Na) + :429 Compound 2: Methyl 4-[(1S)-1-[(4-aminotetrahydropyran-4-carbonyl)amino]ethyl]benzoate Starting from compound 1 and following general procedure II-a, compound 2 was obtained as a beige powder in 99% yield. M / Z (M+H) + :307 Compound 3: Methyl 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoate Starting from compound 2 and 2-phenoxyacetaldehyde, compound 3 was obtained according to general procedure III-a. Purification by flash chromatography (DCM / MeOH: 100 / 0 to 94 / 6; then DCM / MeOH: 100 / 0 to 97.5 / 2.5 on a 15 μm cartridge) gave compound 3 as a white powder in 37% yield. M / Z (M+H) + :427 Example 1: 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid, hydrochloride

[0358] [ka] 【03...

Claims

1. A compound of formula (I) 【Chemistry 1】 [In the formula, A １ and A ２ are each independently １～５ alkyl or A １ and A ２ are joined to each other and together with the carbon atom to which they are attached form a carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is bound to one or more groups R １ may be substituted with Ring B is a carbocyclic group or a monocyclic heterocyclic group; Ring D is carbocyclyl or heterocyclyl; L is -(CH ２ ) ３～５ -, wherein the -(CH ２ ) ３～５ One or more -CH ２ The units are -O-, -CO-, -NH-, -N(C １～５ alkyl)-, -N[-CO-(C １～５ alkyl)]-, -N[-(C ０～４ alkylene)-(C ３～７ cycloalkyl)]-, -CH(C １～５ alkyl)- and -C(C １～５ Alkyl) (C １～５ each L is independently replaced by a group selected from -CH ２ or -O- contained in L; or L is -heterocyclylene-(CH ２ ) １～２ -, wherein said -heterocyclylene-(CH ２ ) １～２ One -CH included in - ２ The units are -O-, -CO-, -NH-, -N(C １～５ Alkyl)- and -N[-CO-(C １～５ alkyl)]-, wherein said -heterocyclylene-(CH ２ ) １～２ The heterocyclylene in - is selected from one or more groups -L Ａ -R Ａ and L is optionally substituted with -CH ２ is bonded to ring D via - or via -O- contained in said L; m is an integer from 0 to 4; p is an integer from 0 to 4; Each R １ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-cycloalkyl, -(C ０～３ alkylene)-heterocycloalkyl and -L Ａ -R Ａ are independently selected from R ２ is hydrogen, C １～５ Alkyl and -CO(C １～５ alkyl), X is C(R 3a )(R 3b ), where R 3a is C 1-5 alkyl and R 3b is hydrogen or C 1-5 alkyl, or R 3a and R 3b are joined together with the carbon atom to which they are attached to form a cyclopropyl; Each R ４ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-cycloalkyl, -(C ０～３ alkylene)-heterocycloalkyl and -L Ａ -R Ａ are independently selected from R ５ is -COOH, -CO-NH ２ , —CO—NH(C １～５ alkyl), -CO-N(C １～５ Alkyl) (C １～５ Alkyl), -SO ２ -OH, -SO ２ -O-(C １～５ Alkyl), -SO ２ -NH ２ , -SO ２ -NH(C １～５ Alkyl), -SO ２ -N(C １～５ Alkyl) (C １～５ Alkyl), -SO ２ - (C １～５ alkyl), -S(=O)(=NH)-(C １～５ Alkyl), halogen, C １～５ Haloalkyl, -CN, C １～４ Alkyl, -OH, -O(C １～４ alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more groups -L Ａ -R Ａ may be substituted with Each R ６ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～６ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-cycloalkyl, -(C ０～３ alkylene)-heterocycloalkyl and -L １ -R ６１ are independently selected from L １ is C １～６ alkylene or a covalent bond, １～６ One or more —CH ２ The units are -O-, -CO-, -NH-, -N(C １～５ alkyl)-, -N[-CO-(C １～５ alkyl)]-, -S-, -SO-, -SO ２ -, -CH(C １～５ alkyl)- and -C(C １～５ Alkyl) (C １～５ each of which may be replaced by a group independently selected from R ６１ is carbocyclyl or heterocyclyl, wherein said carbocyclyl or said heterocyclyl is selected from one or more groups R ６２ may be substituted with Each R ６２ is C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, -(C ０～３ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-O(C １～５ alkylene)-OH, -(C ０～３ alkylene)-O(C １～５ alkylene)-O(C １～５ alkyl), -(C ０～３ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkyl), -(C ０～３ alkylene)-S(C １～５ alkylene)-SH, -(C ０～３ alkylene)-S(C １～５ alkylene)-S(C １～５ alkyl), -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-NH(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-halogen, -(C ０～３ alkylene)-(C １～５ haloalkyl), -(C ０～３ alkylene)-O-(C １～５ haloalkyl), -(C ０～３ alkylene)-CN, -(C ０～３ alkylene)-CHO, -(C ０～３ alkylene)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-COOH, -(C ０～３ alkylene)-CO-O-(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-(C １～５ alkyl), -(C ０～３ (alkylene)-CO-NH ２ , -(C ０～３ alkylene)-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ alkylene)-NH-CO-(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-CO-(C １～５ alkyl), -(C ０～３ alkylene)-NH-COO(C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ alkyl)-COO(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-NH(C １～５ alkyl), -(C ０～３ alkylene)-O-CO-N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -NH ２ , -(C ０～３ (alkylene)-SO ２ -NH(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ -N(C １～５ Alkyl) (C １～５ alkyl), -(C ０～３ (alkylene)-NH-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-N(C １～５ (alkyl)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-SO-(C １～５ alkyl), -(C ０～３ (alkylene)-SO ２ - (C １～５ alkyl), -(C ０～３ alkylene)-cycloalkyl, and -(C ０～３ alkylene)-heterocycloalkyl; Each L Ａ is a covalent bond, C １～５ Alkylene, C ２～５ Alkenylene and C ２～５ alkynylene, wherein said alkylene, said alkenylene and said alkynylene are independently selected from halogen, C １～５ Haloalkyl, -CN, -OH, -O(C １～５ alkyl), -SH, -S(C １～５ Alkyl), -NH ２ , -NH(C １～５ alkyl) and -N(C １～５ Alkyl) (C １～５ each of which may be substituted with one or more groups independently selected from the group consisting of alkylene, alkenylene, and alkynylene; ２ The units are -O-, -NH-, -N(C １～５ Alkyl)-, -CO-, -S-, -SO- and -SO ２ -, each of which may be replaced by a group independently selected from Each R Ａ is -OH, -O(C １～５ alkyl), -O(C １～５ alkylene)-OH, -O(C １～５ alkylene)-O(C １～５ alkyl), -SH, -S(C １～５ alkyl), -S(C １～５ alkylene)-SH, -S(C １～５ alkylene)-S(C １～５ Alkyl), -NH ２ , -NH(C １～５ Alkyl), -N(C １～５ Alkyl) (C １～５ Alkyl), halogen, C １～５ Haloalkyl, —O(C １～５ haloalkyl), -CN, -CHO, -CO(C １～５ alkyl), -COOH, -COO(C １～５ alkyl), -O-CO(C １～５ alkyl), —CO—NH ２ , —CO—NH(C １～５ alkyl), -CO-N(C １～５ Alkyl) (C １～５ alkyl), -NH-CO(C １～５ Alkyl), -N(C １～５ alkyl)-CO(C １～５ alkyl), -NH-COO(C １～５ Alkyl), -N(C １～５ alkyl)-COO(C １～５ alkyl), -O-CO-NH(C １～５ alkyl), -O-CO-N(C １～５ Alkyl) (C １～５ Alkyl), -SO ２ -NH ２ , -SO ２ -NH(C １～５ Alkyl), -SO ２ -N(C １～５ Alkyl) (C １～５ alkyl), -NH-SO ２ - (C １～５ Alkyl), -N(C １～５ (alkyl)-SO ２ - (C １～５ Alkyl), -SO ２ - (C １～５ alkyl), -SO-(C １～５ alkyl), hydrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl and said heterocycloalkyl are selected from C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Alkynyl, halogen, C １～５ Haloalkyl, -CN, -OH, -O(C １～５ alkyl), -SH, -S(C １～５ Alkyl), -NH ２ , -NH(C １～５ alkyl) and -N(C １～５ Alkyl) (C １～５ each of which may be substituted with one or more groups independently selected from or a pharma- ceutically acceptable salt thereof, However, the following compounds are excluded: [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester; [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester; [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester; 3-chloro-4'-((R)-1-{[3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carbonyl]-amino}-ethyl)-3'-fluoro-biphenyl-2-carboxylic acid methyl ester; (3-{(R)-1-[5'-chloro-3,3'-difluoro-2'-(2-methyl-2-H-tetrazol-5-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester; (3-{(R)-1-[5'-chloro-3,3'-difluoro-2'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester; (3-{(R)-1-[3',5'-dichloro-2'-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester; N-[(1R)-1-(5-fluoro-3-pyridinyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; 2-[1-[[3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,2-dimethyl-1-oxopropyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[[1-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]cyclobutyl]carbonyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[[1-[[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl]cyclopropyl]carbonyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-methyl-1-oxopropyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[[1-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]cyclopropyl]carbonyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-methyl-1-oxobutyl]amino]ethyl]-4-thiazolecarboxylic acid; 2-[1-[[2,2-dimethyl-1-oxo-3-(phenylmethoxy)propyl]amino]ethyl]-4-methyl-5-thiazolecarboxylic acid; N-[1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2,2-dimethyl-3-(phenylmethoxy)-propanamide; N-[1-(2-methoxyphenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; 1-[[[(phenylmethyl)amino]carbonyl]amino]-N-[1-[4-(3-pyridinyl)-2-thiazolyl]ethyl]-cyclopentanecarboxamide; α,α-Dimethyl-N-[1-[4-(3-pyridinyl)-2-thiazolyl]ethyl]-benzenepentanamide; 2-[1-[(2,2-dimethyl-1-oxo-5-phenylpentyl)amino]ethyl]-4-methyl-5-thiazolecarboxylic acid; 1-[[[(phenylmethyl)amino]carbonyl]amino]-N-[1-[3-(trifluoromethyl)phenyl]ethyl]-cyclopentanecarboxamide; N-[1-(3-ethoxyphenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(2-methoxy-5-methylphenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-[3-methoxy-4-(2-methoxyethoxy)phenyl]ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(2-chlorophenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(4-chlorophenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(2,5-dimethyl-3-furanyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-[4-(methylsulfonyl)phenyl]ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(2,4-dimethoxyphenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-[[[1-(2-chlorophenyl)ethyl]amino]carbonyl]cyclopentyl]carbamic acid phenylmethyl ester; 1-[[[(phenylmethyl)amino]carbonyl]amino]-N-[1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl]-cyclopentanecarboxamide; N-[1-(2,4-difluorophenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; N-[1-(2-methylphenyl)ethyl]-1-[[[(phenylmethyl)amino]carbonyl]amino]-cyclopentanecarboxamide; 2,3-Dihydro-2-[methyl(2-phenylethyl)amino]-N-[1-(3-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1H-indene-2-carboxamide.

2. A １ and A ２ However, each independently, C １～４ alkyl or A １ and A ２ are joined to each other and together with the carbon atom to which they are attached form a monocyclic or bicyclic cycloalkylene or a monocyclic or bicyclic heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is selected from one or more groups R １ may be substituted with; L is -CH ２ -CH ２ -CH ２ -CH ２ -, wherein said -CH ２ -CH ２ -CH ２ -CH ２ One or more -CH ２ The units are -O-, -CO-, -NH-, -N(C １～５ alkyl)-, -N[-CO-(C １～５ alkyl)]-, -N[-(C ０～４ alkylene)-(C ３～７ cycloalkyl)]-, -CH(C １～５ alkyl)- and -C(C １～５ Alkyl) (C １～５ Each of the —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, —CH—, ２ - or -O-, or L is -heterocycloalkylene-CH ２ -, wherein said -heterocycloalkylene-CH ２ -CH in - ２ The - units may be replaced by -O-, and further, L may be -CH ２ The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is bonded to ring D via - or via -O-.

3. A １ and A ２ are each methyl, or A １ and A ２ are joined together with the carbon atoms to which they are attached to form a cyclic group selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothiophenylene, tetrahydropyranylene and thianylene, wherein said cyclic group is selected from one or more groups R １ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

4. 4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein ring B is phenylene or cyclohexylene, preferably ring B is phenylene.

5. X is C(R ３ａ ) (R ３ｂ ), where R ３ａ is methyl, R ３ｂ is hydrogen or R ３ａ and R ３ｂ are linked together with the carbon atom to which they are attached to form a cyclopropyl; or a pharma- ceutically acceptable salt thereof.

6. R ５ -COOH, -CO-NH ２ , —CO—NH(C １～５ alkyl), -CO-N(C １～５ Alkyl) (C １～５ Alkyl), -SO ２ - (C １～５ alkyl), -S(=O)(=NH)-(C １～５ 6. The compound of claim 1, wherein the aryl group is aryl, arylalkyl, or tetrazolyl; or a pharma- ceutically acceptable salt thereof.

7. portion 【Chemistry 2】 but, 【Chemistry 3】 7. The compound of claim 1, wherein:

8. 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein Ring D is selected from phenyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, and cyclohexyl.

9. L is -CH ２ -CH ２ -CH ２ -CH ２ -, wherein said -CH ２ -CH ２ -CH ２ -CH ２ One or more -CH ２ - The unit is -O-, -CO-, -NH-, -N(C １～５ alkyl)-, -N[-CO-(C １～５ alkyl)]-, -N[-(C ０～４ alkylene)-(C ３～７ cycloalkyl)]-, -CH(C １～５ alkyl)- and -C(C １～５ Alkyl) (C １～５ each of L is independently replaced by a group selected from -CH ２ or is bonded to ring D via - or via -O- contained in said L, or alternatively, L is -heterocycloalkylene-CH ２ -, wherein said -heterocycloalkylene-CH ２ -CH in - ２ The - units may be replaced by -O-, and L is -CH ２ The compound according to any one of claims 1 or 3 to 8, wherein L is bonded to ring D via - or via -O- contained in L, or a pharma- ceutically acceptable salt thereof.

10. L is -CH ２ -CH ２ -CH ２ -O-, -CH ２ -CH ２ -CH ２ -O- is the group -CH ２ -CH ２ -CH ２ is bonded to ring D via the oxygen atom in —O—, ２ -CH ２ -CH ２ The —CH at the end farthest from the oxygen atom in —O— ２ - The unit is -O-, -CO-, -NH-, -N(C １～４ alkyl)-, -N[-CO-(C １～４ alkyl)]-, -N[-(C １～３ alkylene)-cyclopropyl]-, -CH(C １～４ alkyl)- and -C(C １～４ Alkyl) (C １～４ or alternatively, L is -heterocycloalkylene-O-, wherein said -heterocycloalkylene-O- is attached to Ring D via an oxygen atom in said group -heterocycloalkylene-O-, and the heterocycloalkylene in said -heterocycloalkylene-O- is attached in a 1,3-orientation; or a pharma- ceutically acceptable salt thereof.

11. L is -N(-CH ３ )-CH ２ -CH ２ -O-, -N(-CH ２ CH ３ )-CH ２ -CH ２ -O-, -N(-CH ２ -cyclopropyl)-CH ２ -CH ２ -O-, -O-CH ２ -CH ２ -O-, 【Chemistry 4】 and each of the foregoing groups is bonded to Ring D through a terminal oxygen atom contained therein; or a pharma- ceutically acceptable salt thereof.

12. A １ and A ２ are each independently methyl or ethyl, or A １ and A ２ are joined together with the carbon atoms to which they are attached to form a cyclic group selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothiophenylene, tetrahydropyranylene and thianylene, wherein said cyclic group is selected from one or more groups R １ may be substituted with; Lは、-CH ２ -CH ２ -CH ２ -O-、-NH-CH ２ -CH ２ -O-、-N(-CH ３ )-CH ２ -CH ２ -O-、-N(-CH ２ CH ３ )-CH ２ -CH ２ -O-、-N(-CH ２ CH ２ CH ３ )-CH ２ -CH ２ -O-、-N(-CH ２ -シクロプロピル)-CH ２ -CH ２ -O-、-N(-CO-CH ３ )-CH ２ -CH ２ -O-、-NH-CO-CH ２ -O-、-O-CH ２ -CH ２ -O-、 【Chemistry 5】 and each of these groups is bonded to Ring D through a terminal oxygen atom contained therein; or a pharma- ceutically acceptable salt thereof.

13. p is 1, R ６ is attached to ring D in a 1,3-orientation relative to the point of attachment of group L to ring D; R ６ But -CH ３ , -OH, -OCH ３ , halogen, -CF ３ , -OCF ３ , -CN and -L １ -R ６１ Preferably, R ６ But -CH ３ , -OCH ３ , -F, -Cl and -CF ３ 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, selected from:

14. 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; N-[(1S)-1-(4-carbamoylphenyl)ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; N-[(1S)-1-[4-(methylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; N-[(1S)-1-[4-(dimethylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide; 4-[(1S)-1-[[4-[acetyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[(2-phenoxyacetyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-ethyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(4-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-[3-(trifluoromethyl)phenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-[3-methoxyphenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3-methylphenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(4-cyanophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3,5-difluorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(3,4-dichlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-phenylpropylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(2-phenylethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[propyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[cyclopropylmethyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(3-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(2-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[4-[2-(4-cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 2-fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 3-fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 2-chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 3-chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 5-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-2-carboxylic acid; 6-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-3-carboxylic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-methylphenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[methyl-[2-(3-methylphenoxy)ethyl]amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-methoxyphenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[methyl(2-phenoxyethyl)amino]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 3-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]bicyclo[1.1.1]pentane-1-carboxylic acid; 4-[(1S)-1-[[4,4-difluoro-1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydrothiopyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1,1-dioxo-4-(2-phenoxyethylamino)thiane-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-(2-phenoxyethylamino)spiro[3.3]heptane-2-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclobutanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[8,8-dimethyl-7-(2-phenoxyethylamino)-2-oxabicyclo[4.2.0]octane-7-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2,2-dimethyl-4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydropyran-3-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid; 4-[1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[1-methyl-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(2-methoxyethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-(cyclopropylmethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-(3-phenoxypropyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[2-(3-chlorophenoxy)ethoxy]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(cyclohexylmethoxy)-4-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[2-(cyclohexylmethoxy)-4-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[4-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(cyclohexyloxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]methylamino]ethyl]benzamide; 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]dimethylamino]ethyl]benzamide; 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide; 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide; N-((S)-1-(4-(2H-tetrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(1H-pyrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-sulfamoylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((1S)-1-(4-(S-methylsulfonimidoyl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-hydroxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-cyanophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-bromophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(4-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(3-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; N-((S)-1-(2-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide; (R)-2-methyl-4-(1-(4-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)cyclopropyl)benzoic acid; 2-methyl-N-((S)-1-(4-sulfamoylphenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 2-methyl-N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 2-methyl-N-((1S)-1-(4-(S-methylsulfonimidoyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4-oxadiazol-3-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4-oxadiazol-5-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; 4-((1S)-1-(2-(3-benzylpyrrolidin-1-yl)-2-methylpropanamido)ethyl)benzoic acid; 4-((S)-1-(2-((R)-3-((3-chlorophenoxy)methyl)pyrrolidin-1-yl)-2-methylpropanamido)ethyl)benzoic acid; and 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-ethylbutane-carbonyl]amino]ethyl]benzoic acid; 2. The compound of claim 1 selected from:

15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15 for the treatment or prevention of cancer, inflammatory pain, inflammatory diseases or angiogenic eye diseases.

17. 15. Use of a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of cancer, inflammatory pain, inflammatory diseases or angiogenic eye diseases.

18. 16. The pharmaceutical composition according to claim 15 for the treatment or prevention of cancer, wherein said cancer is preferably selected from lung cancer, non-small cell lung cancer, renal cancer, gastrointestinal cancer, stomach cancer, colorectal cancer, colon cancer, malignant familial adenomatous polyposis, anal cancer, genitourinary cancer, bladder cancer, liver cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, prostate cancer, testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, brain cancer, breast cancer, head and / or neck cancer, skin cancer, melanoma, Merkel cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, bone cancer, fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral cancer, thymoma, neuroendocrine cancer, blood cancer, leukemia, acute myeloid leukemia, lymphoma and multiple myeloma.

19. 15. Use of a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of cancer, wherein the cancer is preferably selected from lung cancer, non-small cell lung cancer, renal cancer, gastrointestinal cancer, stomach cancer, colorectal cancer, colon cancer, malignant familial adenomatous polyposis, anal cancer, genitourinary cancer, bladder cancer, liver cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, prostate cancer, testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, brain cancer, breast cancer, head and / or neck cancer, skin cancer, melanoma, Merkel cell carcinoma, squamous cell carcinoma, squamous cell carcinoma, bone cancer, fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral cancer, thymoma, neuroendocrine cancer, blood cancer, leukemia, acute myeloid leukemia, lymphoma and multiple myeloma.

20. 16. A pharmaceutical composition according to claim 15 for the treatment or prevention of inflammatory pain, said inflammatory pain being preferably selected from osteoarthritis pain, inflammatory pain associated with rheumatoid arthritis and inflammatory post-operative pain.

21. 15. Use of a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of inflammatory pain, said inflammatory pain being preferably selected from osteoarthritis pain, inflammatory pain associated with rheumatoid arthritis and inflammatory post-operative pain.

22. 16. A pharmaceutical composition according to claim 15 for the treatment or prevention of an inflammatory disease, said inflammatory disease being preferably selected from multiple sclerosis, rheumatoid arthritis, endometriosis and osteoarthritis.

23. 15. Use of a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an inflammatory disease, said inflammatory disease being preferably selected from multiple sclerosis, rheumatoid arthritis, endometriosis and osteoarthritis.

24. 16. The pharmaceutical composition according to claim 15 for the treatment or prevention of an angiogenic eye disease, wherein the angiogenic eye disease is preferably selected from neovascular macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma and retinopathy of prematurity.

25. 15. Use of a compound according to any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of an angiogenic eye disease, said angiogenic eye disease being preferably selected from neovascular macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma and retinopathy of prematurity.

26. 19. The pharmaceutical composition according to claim 18 for the treatment or prevention of cancer, wherein said pharmaceutical composition is to be administered in combination with one or more immune checkpoint inhibitors, said one or more immune checkpoint inhibitors being preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies and / or anti-PD-L1 antibodies, more preferably said one or more immune checkpoint inhibitors being selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, AMP-224, AMP-514, atezolizumab, avelumab, zurvalumab, KN035 and CK-301.

27. 20. The use according to claim 19, wherein the medicament is to be administered in combination with one or more immune checkpoint inhibitors, preferably selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies and / or anti-PD-L1 antibodies, more preferably the one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, AMP-224, AMP-514, atezolizumab, avelumab, zurvalumab, KN035 and CK-301.

28. EP ４ 15. The in vitro use of a compound as defined in any one of claims 1 to 14 or a pharma- ceutically acceptable salt thereof as a receptor antagonist.

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