Prostaglandin E2 (PGE2) EP4 receptor antagonist

Abstract

The present invention relates to compounds of formula (I) and pharmaceutical compositions comprising these compounds. The compounds provided herein can be used as prostaglandin E2 (PGE2) EP4 receptor antagonists, which makes them very useful for therapy, particularly for the treatment or prevention of cancer, neovascular eye disease, inflammatory pain or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis or endometriosis. #imgabs0#

Description

[0001] The present invention relates to novel compounds of formula (I) and pharmaceutical compositions comprising these compounds. The compounds provided herein can be used as prostaglandin E2 (PGE2) EP4 receptor antagonists, which makes them very useful for therapy, particularly for the treatment or prevention of cancer, neovascular eye disease, inflammatory pain or inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis or endometriosis.

[0002] Prostaglandin E2 (PGE2) is an eicosanoid described as a major mediator of inflammation, exhibiting both pro-inflammatory and anti-inflammatory effects, depending on the context. This bioactive lipid, the most widely produced prostanoid in animal species and humans, is synthesized from arachidonic acid by the cyclooxygenases COX-1 or COX-2 and the specific prostanoid synthases cPGES-1, m-PGES-1, and m-PGES-2. PGE2 is involved in a variety of physiological effects, including pain, fever, inflammation, regulation of vascular tone, mucosal integrity, bone 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 primarily binds to G αS Protein coupling leads to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels when PGE2 is activated (Konya V. et al., Pharmacology & Therapeutics, 2013, 485; Yokoyama U. et al., Pharmacological reviews, 2013, 1010). In addition, the EP4 receptor can be activated by G αi signaling through other pathways involving proteins or β-arrestins.

[0003] Interference with PGE2 signaling provides a tool to modulate the immune pattern of various diseases from autoimmunity to cancer (Kalinski P., The Journal of Immunology, 2012, 21). In fact, sustained levels of PGE2 in the tumor microenvironment promote immunosuppression of various immune cells, leading to subsequent cancer immune evasion. Notably, this immunosuppression is mediated by a shift from Th1 to Th2 immune responses, altered infiltration and function of antigen-presenting cells, and CD8 +The cytotoxic activity of T cells and natural killer cells is impaired and the enhancement of immunosuppressive cells (including bone marrow-derived suppressor cells (MDSC) and regulatory T cells (Treg)) plays a role. The COX-2 expression of elevation and the PGE2 level of production are found in many cancers, and are relevant to the generation and progression of tumors (O'Callaghan G. et al., British Journal of Pharmacology, 2015, 5239). Especially, it is reported that COX-2 overexpression promotes breast cancer progression and metastasis (Majumder M. et al., Cancer science, 2014, 1142). The PGE2 produced by host tissues is also shown to be most important to the growth, angiogenesis and metastasis of B16 melanoma to bone and soft tissue (Inada M. et al., The Journal of Biological Chemistry, 2015, 29781). Alternatively, the important role of PGE2 / EP4 signaling pathway in promoting oxaliplatin resistance in human colorectal cancer cells is highlighted (Huang H. et al., Scientific Reports, 2019, 4954). PGE2 is also shown to be involved in regulating PD-L1 expression in tumor-infiltrating myeloid cells, thus mediating tumor escape from the immune system (Prima et al., Proceedings of the National Academy of Science, 2017, 1117).

[0004] Prior research supports the key role of EP4 receptors in mediating the immunosuppressive effect of PGE2. Selective EP4 antagonism was previously shown to prevent lung cancer and breast cancer metastasis (Yang L., Cancer research, 2006, 9665; Ma X. et al., Cancer Research, 2006, 2923). In the B16 melanoma model, EP4 receptor antagonists eliminated metastatic tumor growth and angiogenesis in soft tissue (Inada M. et al., The Journal of Biological Chemistry, 2015, 29781). EP4 receptor antagonists are also shown to eliminate tumor growth, lymphangiogenesis and metastasis to lymph nodes and lungs (Majumder M. et al., Cancer science, 2014, 1142) in breast cancer models. Blocking EP4 has been shown to prevent tumor-mediated NK cell immunosuppression and reduce immune tolerance generated by bone marrow-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, simultaneous blocking of the EP4 receptor and the use of anti-PD-1 antibodies provide effective anti-tumor responses.

[0005] Although various antagonists of the EP4 receptor have been reported in the literature (as described above), there remains a need for new and / or improved EP4 receptor antagonists, in particular for use in cancer therapy and other EP4-related pathologies.

[0006] The present invention addresses this need and solves the problem of providing new and highly effective EP4 receptor antagonists. In particular, it was surprisingly found that the compounds provided herein have strong EP4 antagonistic activity and also show excellent anticancer therapeutic efficacy, as reflected by the significant 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]

[0009] or a pharmaceutically acceptable salt thereof.

[0010] In formula (I), group A 1and A 2 Each independently is C 1-5 Alkyl; or group A 1 and A 2 Each other and the carbon atom to which they are attached are connected to form a carbocyclic group or a heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by one or more groups R 1 The above carbocyclic or heterocyclic group (composed of A 1 、A 2 and carry A 1 and A 2 The ring is formed of carbon atoms (formed from ) and is also referred to herein as "Ring A".

[0011] In the context of the present invention, it has surprisingly been found that the presence of two alkyl groups (in particular two methyl groups) as A 1 and A 2 Or there is A 1 and A 2 The formed carbocyclic group or heterocyclic group (ring A) is very advantageous in terms of the antagonistic activity of the compound of formula (I) on the prostaglandin E2 (PGE2) EP4 receptor.

[0012] Ring B is a carbocyclic group or a heterocyclic group.

[0013] Ring D is a carbocyclic group or a heterocyclic group.

[0014] L is C 1-6 Alkylene or covalent bond, wherein the C 1-6 The one or more -CH2- units contained in the alkylene group are each optionally independently 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-, -SO2-, -CH(C 1-5 alkyl)-, -C(C 1-5 Alkyl)(C 1-5 alkyl)-, carbocyclylene and heterocyclylene groups, wherein the carbocyclylene and the heterocyclylene are each optionally replaced by one or more groups -L A -R A replace.

[0015] m is an integer from 0 to 4.

[0016] p is an integer from 0 to 4.

[0017] R 1 Each independently selected from C 1-5 Alkyl, C 2-5Alkenyl, 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 0-3 Alkylene)-CO-N(C 1-5 Alkyl)(C 1-5 Alkyl), -(C 0-3 Alkylene)-NH-CO-(C 1-5 Alkyl), -(C0-3 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 0-3 alkylene)-heterocycloalkyl and -L A -R A .

[0018] R 2 Selected from hydrogen, C 1-5 Alkyl and -CO(C 1-5 alkyl).

[0019] X is C(R 3a )(R 3b ) or N(R 3c ). Therefore, X is a carrier of a substituent R 3a and R 3b The carbon atom or X is a substituent R 3c of nitrogen atoms.

[0020] R 3a and R 3b are each independently selected from hydrogen, C1-5 Alkyl and C 2-5 Alkenyl; or R 3a and R 3b Each other and the carbon atom to which they are attached are connected to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more groups R 31 Substitute; or R 3a is a divalent group selected from a linear C 2-4 Alkylene and straight chain C 2-4 Alkenylene, wherein the divalent group is connected via one end to a group carrying R 3b and is linked via the other end to a ring atom of ring B adjacent to the ring atom carrying the group X, wherein said alkylene or said alkenylene is optionally substituted by one or more groups R 31 substituted, wherein one -CH2- unit in the alkylene or alkenylene group is optionally replaced by -O-, -S-, -NH- or -N(C 1-5 alkyl)-substituted, and R 3b Selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl.

[0021] R 3c Selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl.

[0022] R 31 Each independently selected from 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(C1-5 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).

[0023] R 4 Each independently selected from 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(C1-5 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(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 .

[0024] R 5 Selected from -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, C 1-5 Haloalkyl, -CN, hydrogen, C 1-4 Alkyl, -OH, -O(C 1-4 alkyl), carbocyclyl and heterocyclyl, wherein the carbocyclyl or the heterocyclyl is optionally substituted by one or more groups -L A -R A replace.

[0025] R 6 Each independently selected from 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), -(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 0-3 Alkylene)-O-CO-NH(C 1-5 Alkyl), -(C 0-3 Alkylene)-O-CO-N(C 1-5 Alkyl)(C1-5 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 .

[0026] L 1 C 1-6 Alkylene or covalent bond, wherein the C 1-6 The one or more -CH2- units contained in the alkylene group are each optionally independently selected from -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 alkyl)-group replacement.

[0027] R 61 is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more groups R 62 replace.

[0028] R 62 Each independently selected from 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, -(C0-3 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-(C 1-5 Alkyl), -(C 0-3 Alkylene)-NH-COO(C 1-5 Alkyl), -(C 0-3 Alkylene)-N(C 1-5alkyl)-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 alkylene)-heterocycloalkyl.

[0029] L A Each independently selected from a covalent bond, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups 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 alkyl), and further wherein the one or more -CH2- units contained in the alkylene, the alkenylene or the alkynylene are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- groups.

[0030] R A Each independently selected from -OH, -O(C 1-5 alkyl), -O(C1-5 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 Halogenated alkyl), -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 1-5 alkyl), -SO2-(C 1-5 alkyl), -SO-(C 1-5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more groups independently selected from C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, halogen, C 1-5 Haloalkyl, -CN, -OH, -O(C 1-5alkyl), -SH, -S(C 1-5 alkyl), -NH2, -NH(C 1-5 alkyl) and -N(C 1-5 Alkyl)(C 1-5 alkyl).

[0031] 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. Therefore, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the above entities and a pharmaceutically acceptable excipient for use as a medicament.

[0032] The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising any of the above entities and a pharmaceutically acceptable excipient, which is used to treat or prevent cancer, inflammatory pain, inflammatory diseases or neovascular eye diseases. Therefore, the present invention particularly provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient as an active ingredient, which is used to treat or prevent cancer, inflammatory pain, inflammatory diseases or neovascular eye diseases.

[0033] The present invention also relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing cancer, inflammatory pain, inflammatory disease or neovascular eye disease.

[0034] Similarly, the present invention relates to a method for treating or preventing cancer, inflammatory pain, inflammatory disease or neovascular eye disease, the method comprising administering to an individual (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 above entities and a pharmaceutically acceptable excipient. It should be understood that a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (or pharmaceutical composition) is administered according to the method.

[0035] As mentioned above, the diseases / disorders treated or prevented using the compounds of formula (I) or pharmaceutically acceptable salts thereof (or corresponding pharmaceutical compositions) according to the present invention particularly include cancer, inflammatory pain, inflammatory diseases or neovascular eye diseases. Particularly preferably, the disease / disorder treated or prevented according to the present invention is cancer.

[0036] The cancer to be treated or prevented according to the present invention may be a solid cancer or a blood cancer, and is preferably selected from lung cancer (e.g. small cell lung cancer or non-small cell lung cancer; in particular non-small cell lung cancer), renal cancer, gastrointestinal cancer, gastric 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, bile duct cancer, hepatobiliary cancer, neuroblastoma, brain cancer (e.g. glioblastoma), breast cancer (e.g. triple-negative breast cancer, In particular, triple-negative breast cancer expressing COX-2 is included), head and / or neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkel cell carcinoma, epidermoid carcinoma, squamous cell carcinoma (e.g., oral squamous cell carcinoma), bone cancer (or osteosarcoma), fibrosarcoma, Ewing's sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, oral 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. In addition, the cancer to be treated or prevented (including any of the specific types of cancer mentioned above) may also be a metastatic cancer.

[0037] As mentioned above, the cancer to be treated or prevented according to the present invention may be a blood cancer. In this case, the hematological cancer is preferably selected from the group consisting of: Hodgkin's lymphoma, including, for example, the nodular sclerosing subtype of Hodgkin's lymphoma, the mixed cellular 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; peripheral / cutaneous T-cell lymphoma, including, for example, mycosis fungoides, Sézary's disease, T-zone lymphoma, lymphoepithelioid 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 enteropathy (e.g., thalassemia); multiple myeloma, including, for example, Kahler's disease or myelomatosis; plasma cell leukemia; lymphoid leukemia, including, for example, acute lymphocytic leukemia, chronic lymphocytic leukemia, subacute lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia (e.g., leukemic reticuloendothelial proliferation), or adult T-cell leukemia; myeloid leukemia, including, for example, acute myeloid leukemia, chronic myeloid leukemia, subacute myeloid leukemia, myeloid sarcoma (e.g., chloroma or granulocytic sarcoma), acute myelocytic leukemia, or acute monocytic leukemia; myeloproliferative neoplastic disorders, including, for example, polycythemia vera, essential thrombocythemia, or idiopathic myelofibrosis; monocytic leukemia; acute polycythemia or erythroleukemia, including, for example, acute erythroblastic myelopathy or Di Guglielmo disease; chronic polycythemias, including, for example, Heilmeyer- disease; acute megakaryoblastic leukemia; mast cell leukemia; acute panmyelopathy; acute myelofibrosis; Levy-Siegel disease.

[0038] The inflammatory pain treated or prevented according to the present invention may be acute inflammatory pain or chronic inflammatory pain, and in particular may be osteoarthritis pain, inflammatory pain associated with rheumatoid arthritis or inflammatory post-operative pain.

[0039] The inflammatory disease to be treated or prevented according to the present invention may be an acute inflammatory disease or a chronic inflammatory disease, and is preferably selected from the group consisting of multiple sclerosis, rheumatoid arthritis, endometriosis and osteoarthritis.

[0040] The neovascular eye disease to be treated or prevented according to the present invention is preferably selected from the group consisting of neovascular degenerative maculopathy (or "wet" macular degeneration), proliferative diabetic retinopathy, neovascular glaucoma and retinopathy of prematurity.

[0041] The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound for the study of prostaglandin E2 receptor subtype 4 (EP4), in particular for antagonizing EP4 receptors. Therefore, the present invention relates to the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an EP4 receptor antagonist, and in particular to the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a research tool compound for use as an EP4 receptor antagonist. Similarly, the present invention relates to a method for antagonizing the EP4 receptor, in particular an in vitro method, which comprises applying a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for antagonizing the EP4 receptor, which comprises applying a compound of formula (I) or a pharmaceutically acceptable salt thereof to a test sample (e.g., a biological sample) or a test animal (i.e., a non-human test animal). The present invention also relates to a method for antagonizing the EP4 receptor in a sample (e.g., a biological sample), in particular an in vitro method, which comprises applying a compound of formula (I) or a pharmaceutically acceptable salt thereof to the sample. The present invention also provides a method for antagonizing the EP4 receptor, which comprises contacting a test sample (e.g., a 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 cell or subcellular extracts; biopsy material obtained from an animal (e.g., a human) or an extract thereof; or blood, serum, plasma, saliva, urine, feces, or any other body fluid or extract thereof. It should be understood that in this particular context, the term "in vitro" means "outside a living human or animal," and particularly includes tests using cells, cells, or subcellular extracts and / or biomolecules in an artificial environment, such as aqueous solutions or culture media that can be provided, for example, in flasks, test tubes, culture dishes, microtiter plates, and the like.

[0042] The compounds of formula (I) and their pharmaceutically acceptable salts are described in more detail below:

[0043]

[0044] In formula (I), group A 1 and A 2 Each independently is C 1-5 Alkyl (eg, methyl or ethyl); or group A 1 and A 2 Each other and the carbon atom to which they are attached are linked to form a carbocyclic group or a heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by one or more (e.g. one, two, three or four) groups R 1 The above carbocyclic or heterocyclic group (composed of A 1 、A 2 and carry A 1 and A2 The carbon atoms of 1 and A 2 Each independently is C 1-5 Alkyl (eg, methyl).

[0045] In the context of the present invention, it has surprisingly been found that the presence of two alkyl groups (in particular two methyl groups) as A 1 and A 2 Or there is A 1 and A 2 The formed carbocyclic group or heterocyclic group (ring A) is very advantageous in terms of the antagonistic activity of the compound of formula (I) on the prostaglandin E2 (PGE2) EP4 receptor.

[0046] Preferably, A 1 and A 2 Each independently is C 1-5 More preferably, A 1 and A 2 are each independently methyl or ethyl. Even more preferably, A 1 and A 2 Each is a methyl group.

[0047] As mentioned above, group A 1 and A 2 They can also be linked to each other together with the carbon atoms to which they are linked to form a carbocyclic group or a heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by one or more (e.g. one, two, three or four) groups R 1 In this case, the compound of formula (I) may be a compound having the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0048]

[0049] wherein Ring A in Formula (Ia) is a carbocyclic group or a heterocyclic group, wherein n is an integer from 0 to 4, and wherein the other groups / variables in Formula (Ia) (especially including Ring B, Ring D, R 1 、R 2 、R 4 、R 5 、R 6 , X, L, m and p) have the same meanings as described and defined in connection with formula (I), including the same preferred meanings.

[0050] As also shown in (Ia), the moiety -CO-N(R 2 )-XB[(-R 4 ) m ]-R 5 and part of -LD[(-R 6 )p ] is connected to the same ring carbon atom of ring A, thereby it is a divalent carbocyclic group or heterocyclic group. It should be understood that the following description of ring A as shown in formula (Ia) is also applicable to the ring A in formula (I) 1 and A 2 (and the carbon atom to which it is attached) to form a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more groups R 1 replace.

[0051] Ring A is preferably saturated. Therefore, it is preferred that Ring A is a 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 Cycloalkylene or monocyclic 4-9-membered heterocycloalkylene.

[0052] Preferred examples of ring A include in particular cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g. tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothienylene (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. thiam-2,2-diyl, thiam-3,3-diyl or thiam-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 even more preferred that ring A is cyclopropylene (i.e. cyclopropane-1,1-diyl).

[0053] Ring B is a carbocyclic group or a heterocyclic group.

[0054] As also shown in formula (I), ring B is a divalent group that is linked to X and further to group R 5 .

[0055] Preferably, ring B is selected from arylene, heteroarylene (e.g. pyridylene; particularly 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 3-9More preferably, ring B is phenylene (for example, benzene-1,4-diyl), cyclohexylene, cycloheptylene, spiro[3.3]heptylene (for example, spiro[3.3]hept-2,6-diyl), or bicyclo[1.1.1]pentylene. Even more preferably, ring B is phenylene (for example, benzene-1,4-diyl), cyclohexylene (for example, cyclohexane-1,4-diyl), or cyclohexylene (for example, cyclohexane-1,4-diyl). Even more preferably, ring B is phenylene (for example, benzene-1,4-diyl, benzene-1,3-diyl, or benzene-1,2-diyl). Still more preferably, ring B is benzene-1,4-diyl.

[0056] Ring D is a carbocyclic group or a heterocyclic group. 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, pyridyl (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. Still more preferably, ring D is phenyl.

[0057] L is C 1-6 Alkylene or covalent bond, wherein the C 1-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently 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-, -SO2-, -CH(C 1-5 alkyl)-, -C(C 1-5 Alkyl)(C 1-5 alkyl)-, carbocyclylene and heterocyclylene groups, wherein the carbocyclylene and the heterocyclylene are each optionally replaced by one or more (e.g., one, two or three) groups -L A -R A replace.

[0058] Preferably, the C 1-6 Up to one -CH2- unit contained in the alkylene group is optionally replaced by a carbocyclylene group (e.g. cycloalkylene or arylene) or a heterocyclylene group (e.g. heterocycloalkylene or heteroarylene), preferably by a heterocyclylene group, more preferably by a heterocycloalkylene group, wherein the carbocyclylene group or the heterocyclylene group (or the heterocycloalkylene group) is optionally replaced by one or more groups -LA -R A The carbocyclylene or heterocyclylene (or the heterocycloalkylene) is preferably linked in the 1,3-direction (e.g., in compounds according to Example 134 or Example 138). Preferred examples include, in particular, pyrrolidine-1,3-diyl or piperidine-1,3-diyl.

[0059] Preferably, L is C 3-6 Alkylene (e.g., propylene, butylene, or pentylene), wherein the C 3-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently 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-, -SO2-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 alkyl)-, in particular by a group independently 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[-(C 0-4 Alkylene)-cyclopropyl]-), -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 Alkyl)-, more preferably replaced by a group independently selected from -O-, -NH- and -N(C 1-5 alkyl)-(e.g., -N(-CH3)- or -N(-CH2CH3)-); optionally, L is C 2-4 Alkylene (e.g., ethylene, n-propylene, or n-butylene), wherein the C 2-4 One -CH2- unit contained in the alkylene group (preferably connected to ring A or to a ring carrying A 1 and A 2 The -CH2- unit of the carbon atom of 2-4 Another -CH2- unit contained in the alkylene group (preferably the -CH2- unit connected to the ring D) is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 Alkyl)-、-N[-CO-(C1-5 alkyl)]-、-N[-(C 0-4 Alkylene)-cycloalkyl]-, -N[-(C 0-4 -alkylene)-heterocycloalkyl]-, -S-, -SO- and -SO2- (preferably replaced by a group selected from -O-, -NH- and -N(C 1-5 alkyl)-, more preferably replaced by a group -O-), wherein the carbocyclylene or the heterocyclylene is preferably attached in 1,3-direction, and further wherein the carbocyclylene or the heterocyclylene is optionally replaced by one or more groups -L A -R A replace.

[0060] More preferably, L is -(CH2) 3-5 -, wherein said -(CH2) 3-5 - one or more (e.g. one, two or three) -CH2- units contained in - are each optionally independently 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 selected from -O-, -NH- and -N(C 1-5 or L is -heterocyclylene-(CH2) 1-2 -, wherein said -heterocyclylene-(CH2) 1-2 - is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(especially selected from -O-, -NH- and -N(C 1-5 alkyl)-) group, wherein said -heterocyclylene-(CH2) 1-2 - in the heterocyclylene group is optionally replaced by one or more groups -L A -R A substituted, and further wherein said -heterocyclylene-(CH2) 1-2 The heterocyclylene group in - is preferably linked in the 1,3-direction.

[0061] Even more preferably, L is -CH2-CH2-CH2-CH2-, wherein the one or more (e.g., one, two or three) -CH2- units contained in said -CH2-CH2-CH2-CH2- are each optionally independently 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 selected from -O-, -NH- and -N(C 1-5 or L is -heterocycloalkylene-CH2-, wherein the -CH2- unit in the -heterocycloalkylene-CH2- is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(especially selected from -O-, -NH- and -N(C 1-5 The -heterocycloalkylene-CH2- is preferably substituted by a -CH2- group, more preferably a -O- group, and the heterocycloalkylene of the -heterocycloalkylene-CH2- is preferably linked in a 1,3-direction. It is also preferred that the -heterocycloalkylene-CH2- is linked to ring D via a -CH2- unit in the -heterocycloalkylene-CH2- (which may optionally be substituted as described above).

[0062] According to the above general and preferred definitions of L, it is particularly preferred that in any of these definitions of L, the corresponding group L is linked to the ring D via -CH2- or via -O-, even more preferably via -O- (i.e. the corresponding group L comprises a -CH2- unit which is replaced by -O-, and the group L is linked to the ring D via said -O-).

[0063] Still even more preferably, L is -CH2-CH2-CH2-O connected to ring D via an oxygen atom (-O-) in the group -CH2-CH2-CH2-O-, and wherein the one or more (e.g. one or two) -CH2- units contained in the -CH2-CH2-CH2-O- are each optionally independently 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)(C1-4 -alkyl)-, in particular selected from -O-, -NH- and -N(C 1-4 alkyl)-, wherein the terminal -CH2- unit (the furthest distance from the oxygen atom in -CH2-CH2-CH2-O-) is preferably replaced by a group as defined above (e.g. by -N(C 1-4 alkyl)-, in particular substituted by -N(CH3)-); or L is -heterocycloalkylene-O-, which is connected to ring D via the oxygen atom in the group -heterocycloalkylene-O-, and wherein the heterocycloalkylene of the -heterocycloalkylene-O- is connected in the 1,3-direction. 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 connected to ring A (or to a ring carrying A) via a nitrogen ring atom. 1 and A 2 and is connected to the oxygen (-O-) of the -heterocycloalkylene-O- through a carbon ring atom, wherein the nitrogen ring atom and the carbon ring atom are separated by a carbon ring atom. Thus, L can be, for example, a group It is connected to ring D via an oxygen atom (-O-), wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected by single bonds, wherein 1 or 2 of the ring atoms (Z) are independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z) (if any) are carbon atoms. In particular, L can be a group It is linked to ring D via an oxygen atom (—O—), wherein y is 1, 2, 3, 4 or 5, and wherein y is preferably 2, 3 or 4 (so that the heterocycloalkylene ring preferably has a total of 5, 6 or 7 ring members).

[0064] 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(isopropyl)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -N(-CO-CH3)-CH2-CH2-O-, -NH-CO-CH2-O-, -O-CH2-CH2-O-, or Each of these groups is connected to the ring D via a terminal oxygen atom (—O—) contained therein.

[0065] Additional examples of L include any of the groups listed in the previous paragraph wherein the terminal oxygen atom (through which these groups are attached to ring D) is replaced by a methylene (-CH2)- group.

[0066] 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-, or wherein each of these groups is linked to ring D via a terminal oxygen atom contained therein. Even more preferred examples of L include -N(-CH3)-CH2-CH2-O-, or Each of these groups is linked to ring D via a terminal oxygen atom contained therein.

[0067] If L is a group It is then also preferred that this group is present in the compound of formula (I) in the following stereochemical configuration:

[0068]

[0069] If L is a group It is further preferred that the group is present in the compound of formula (I) in the following stereochemical configuration:

[0070]

[0071] If the group A in formula (I) 1 and A 2 Each is C 1-5 Alkyl (such as methyl), then L is particularly preferably or Each of these groups is linked to ring D via a terminal oxygen atom contained therein.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] It is understood that m represents a substituent R attached to ring B in the compound of formula (I) or (Ia) 4 If m is 0, then ring B is not bound by any group R 4 substituted, i.e. by hydrogen instead of R 4 In addition, p represents a substituent R bonded to the ring D in the compound of formula (I) or (Ia).6 If p is 0, then ring D is not surrounded by any group R 6 substituted, i.e. by hydrogen instead of R 6 Likewise, n represents a substituent R bound to ring A in the compound of formula (Ia) 1 If n is 0, then ring A is not surrounded by any group R 1 substituted, i.e. by hydrogen instead of R 1 It should be further understood that the substituent R 1 、R 4 and R 6 The maximum number is limited by the number of available attachment positions on the corresponding ring groups, ie, Ring A, Ring B and Ring D, respectively.

[0076] R 1 Each independently selected from 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, -(C0-3 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 0-3 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 .

[0077] Preferably, R 1 Each independently selected from 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 1-5 alkyl), -SO-(C 1-5 alkyl), -SO2-(C1-5 Alkyl), -(C 0-3 Alkylene)-cycloalkyl (e.g. -CH2-cyclopropyl), -(C 0-3 alkylene)-heterocycloalkyl and -L A -R A More preferably, R 1 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 1 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0078] By two groups R 1 A preferred example of substituted ring A is 4,4-difluoro-cyclohexane-1,1-diyl, ie, cyclohexylene (as ring A) substituted by two fluorine atoms (as R 1 ) is substituted in the para position.

[0079] R 2 Selected from hydrogen, C 1-5 Alkyl and -CO(C 1-5 Preferably, R 2 is hydrogen or C 1-5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 For hydrogen.

[0080] X is C(R 3a )(R 3b ) or N(R 3c ). Therefore, X is a carrier of a substituent R 3a and R 3bThe carbon atom or X is a substituent R 3c Preferably, X is C(R 3a )(R 3b ).

[0081] R 3a and R 3b are each independently selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl; or R 3a and R 3b Each other and the carbon atom to which they are attached are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more (e.g. one, two or three) groups R 31 Substitute; or R 3a is a divalent group selected from a linear C 2-4 Alkylene and straight chain C 2-4 Alkenylene, wherein the divalent group is connected via one end to a group carrying R 3b and is linked via the other end to a ring atom of ring B adjacent to the ring atom (of ring B) carrying a group X, wherein said alkylene or said alkenylene is optionally substituted by one or more (e.g. one, two or three) groups R 31 substituted, wherein one -CH2- unit in the alkylene or alkenylene group is optionally replaced by -O-, -S-, -NH- or -N(C 1-5 alkyl)-substituted, and R 3b Selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl.

[0082] As mentioned above, R 3a It can be a divalent group selected from linear C 2-4 Alkylene (e.g. -CH2CH2- or -CH2CH2CH2-) and straight chain C 2-4 Alkenylene (e.g., -CH=CH-, -CH=CH-CH2-, or -CH2-CH=CH-), wherein the divalent group is connected at one end to a radical carrying R 3b and is connected via the other end to a ring atom of ring B adjacent to the ring atom carrying a group X (of ring B), wherein said alkylene or said alkenylene is optionally substituted by one or more groups R 31 substituted, wherein one -CH2- unit in the alkylene or alkenylene group is optionally replaced by -O-, -S-, -NH- or -N(C 1-5 alkyl)-substituted, and R 3b Selected from hydrogen, C 1-5 Alkyl and C 2-5 In particular, R 3aIt can be a divalent group selected from -CH2CH2- and -CH2CH2CH2-, wherein the divalent group is connected to a group carrying R 3b and is connected via the other end to a ring atom of ring B adjacent to the ring atom (of ring B) carrying a group X, wherein the divalent group is optionally substituted by one or more groups R 31 Replace, and R 3b It can be hydrogen, C 1-5 Alkyl or C 2-5 Alkenyl, especially hydrogen. Thus, Can be a group or (in particular or ), wherein the group is attached to two adjacent ring atoms of ring B via two bonds marked with an asterisk (*), and wherein the group is optionally substituted by one or more (e.g., one, two, or three) R 31 replace.

[0083] In addition, as mentioned above, R 3a and R 3b can be linked to each other together with the carbon atoms to which they are attached to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more groups R 31 It should be understood that R 3a and R 3b The cycloalkyl or heterocycloalkyl formed by carrying R 3a and R 3b The carbon atom of is connected to the rest of the compound of formula (I). Therefore, the cycloalkyl or heterocycloalkyl is a divalent group, which is connected to the ring B and the ring carrying R through the same ring carbon atom. 2 For example, if R 3a and R 3b Each other and the carbon atom to which they are connected are connected to form a cyclopropyl group, then the cyclopropyl group is a cyclopropane-1,1-diyl group, i.e., a group

[0084] In addition, as mentioned above, R 3a and R 3b can be independently selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl. For example, R 3a Can be C 1-5 Alkyl or C 2-5 Alkenyl, and R 3b It can be hydrogen, C 1-5 Alkyl or C 2-5 In particular, R 3a Can be C 1-5 Alkyl, and R3b It can be hydrogen or C 1-5 alkyl.

[0085] Preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 Alkyl, or R 3a and R 3b Each other and the carbon atoms to which they are connected form C 3-5 Cycloalkyl or 3- to 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more (eg one or two) groups R 31 More preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 Alkyl (such as methyl or ethyl) or R 3a and R 3b are linked to each other and the carbon atom to which they are linked to form a cyclopropyl group. Even more preferably, R 3a C 1-5 alkyl (eg, methyl or ethyl), and R 3b is hydrogen or C 1-5 Alkyl (such as methyl or ethyl), or R 3a and R 3b are linked to each other and the carbon atom to which they are linked to form a cyclopropyl group. Even more preferably, R 3a is a methyl group, and R 3b is hydrogen, R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0086] R 3c Selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl.

[0087] Preferably, R 3c is hydrogen or C 1-5 More preferably, R 3c is hydrogen or methyl. Even more preferably, R 3c It is a methyl group.

[0088] According to X, R 3a and R 3b The above definition, particularly preferably the part in formula (I) or (Ia) for (e.g. as in the compound of Example 1) or

[0089] R 31 Each independently selected from C 1-5 Alkyl, C2-5 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 1-5 alkyl), -SO-(C 1-5 Alkyl) and -SO2-(C 1-5 Preferably, R 31 Each independently selected from C 1-5 Alkyl, -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), -NH2, -NH(C 1-5 Alkyl), -N(C 1-5 Alkyl)(C 1-5 alkyl), halogen, C 1-5 Haloalkyl (eg, -CF3) and -CN.

[0090] R 4 Each independently selected from 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-(C 1-5Alkyl), -(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 0-3 alkylene)-heterocycloalkyl and -L A -R A .

[0091] Preferably, R 4 Each independently selected from C 1-5 Alkyl, C2-5 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 1-5 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, R 4Each independently selected from 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. -CF3) and -CN. Even more preferably, R 4 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0092] R 5 Selected from -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 the carbocyclyl or the heterocyclyl is optionally substituted by one or more (e.g. one, two or three) groups -L A -R A replace.

[0093] Preferably, R 5 Selected from -COOH, -CO-NH2, -CO-NH(C1-5 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, C 1-5 Haloalkyl, -CN, C 1-4 Alkyl, -OH, -O(C 1-4 alkyl), carbocyclyl and heterocyclyl, wherein the carbocyclyl or the heterocyclyl is optionally substituted by one or more groups -L A -R A More preferably, R 5 Selected from -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 More preferably, R 5 Selected from -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 5 Selected from -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)-CH3) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH2 or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH or tetrazolyl (particularly 1H-tetrazolyl-5-yl or 2H-tetrazolyl-5-yl). Even more preferably, R 5 is -COOH.

[0094] According to ring B, X, R 2 、R 3a 、R 3b 、R 4 、R 5 and m as defined above, particularly preferably part Has the following structure:

[0095] or

[0096] In addition, if ring B is cyclohexylene, then part For example, it can have the following structure:

[0097] in particular

[0098] R 6 Each independently selected from 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 1-5Alkyl), -(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 1-5 Alkyl), -(C 0-3 Alkylene)-O-CO-NH(C 1-5 Alkyl), -(C 0-3 Alkylene)-O-CO-N(C 1-5Alkyl)(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 .

[0099] Preferably, R 6 Each independently selected from 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 1-5alkyl), -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, R 6 Each independently selected from 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, R 6 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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 Even more preferably, R 6 Each is independently selected from -CH3, -OH, -OCH3, halogen (such as -F, -Cl, -Br or -I), -CF3, -OCF3, -CN and -L 1 -R 61 Even more preferably, R 6 are each independently selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3. Still more preferably, R 6 Each is independently selected from -CH3, -OCH3, -F, -Cl and -CF3. 6 Each is independently -Cl or -CF3.

[0100] If p is 1, then R is preferred 6 The group L is connected to the ring D in a 1,2-direction, a 1,3-direction or a 1,4-direction relative to the point of connection of the group L to the ring D, and more preferably R 6 is attached to ring D in a 1,3-direction relative to the point of attachment of group L to ring D. In this regard, it is understood that the point of attachment of group L to ring D (i.e., the ring atom of ring D to which L is bound) is numbered as position 1, and either of the two immediately adjacent ring atoms is numbered as position 2, etc. Thus, if p is 1 and ring D is phenyl, then preferably R 6 is attached to ring D in the meta position relative to the point of attachment of group L to ring D (corresponding to the 1,3-direction). Likewise, if p is greater than 1 (e.g., 2, 3, or 4), then group R is preferably 6 At least one of the groups R is attached to ring D in the 1,3 direction relative to the point of attachment of the group L to ring D; for example, if p is 2 and ring D is phenyl, then the two groups R 6 Each is connected to the phenyl group at the meta position relative to the point of attachment of the group L to the phenyl group (ie, a group R 6 At position 3, and another group R 6 in the 5th position).

[0101] According to the above p and R 6 The definition of p is particularly preferably 1, the group R 6 is connected to the ring D (which may be, for example, a phenyl group) in the 1,3 direction relative to the point of connection of L to the ring D, and the group R 6 is selected from -CH3, -OH, -OCH3, halogen (e.g., -F, -Cl, -Br or -I), -CF3, -OCF3, -CN and -L 1 -R 61 , more preferably the group R6 is selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3, even more preferably the group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, and still more preferably the group R 6 Selected from -Cl and -CF3.

[0102] L 1 C 1-6 Alkylene or covalent bond, wherein the C 1-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently selected from -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 alkyl)-group replacement.

[0103] Preferably, L 1 C 1-4 Alkylene, wherein the C 1-4 One or more (eg, one or two) -CH2- units contained in the alkylene group are each optionally independently selected from -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 group is preferably C 2-4 Alkylene (e.g. ethylene, propylene or butylene), more preferably -(CH2)2-, -(CH2)3- or -(CH2)4-, and even more preferably -(CH2)2-. In addition, it is preferred that the one or more -CH2- units are each optionally independently selected from -O-, -S-, -NH- and -N(C 1-5 alkyl)-, in particular replaced by -O-. Also preferred is L 1 Connected to ring D (i.e. L 1 Contains a terminal -CH2- unit which is replaced by -O-, and L 1 is linked to the ring D) via said -O-.

[0104] More preferably, L 1 -(CH2) 2-4 -, wherein said -(CH2)2-4 - is optionally selected from -O-, -S-, -NH- and -N(C 1-5 alkyl)-, in particular by a -O- group. Even more preferably, L 1 -O-(CH2) 1-3 -, where L 1 By the -O-(CH2) 1-3 - is connected to ring D. Even more preferably, L 1 is -O-CH2- or -O-CH2-CH2-, wherein L 1 It is connected to ring D through the oxygen atom in said -O-CH2- or said -O-CH2-CH2-. Still more preferably, L 1 is -O-CH2-, which is connected to the ring D through the oxygen atom (-O-) contained in the -O-CH2-.

[0105] R 61 is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (eg one, two or three) groups R 62 replace.

[0106] Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g. tetrahydrofuranyl or tetrahydropyranyl) and heteroaryl (e.g. pyridyl), wherein the cycloalkyl, the aryl, the heterocycloalkyl and the heteroaryl are each optionally substituted by one or more (e.g. one, two or three) groups R 62 More preferably, R 61 is a cycloalkyl or aryl group, wherein the cycloalkyl or the aryl group is optionally substituted by one or more R 62 Even more preferably, R 61 Selected from C 3-9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein the C 3-9 The cycloalkyl group or the phenyl group is optionally replaced by one or more R 62 Even more preferably, R 61 C 5-9 Cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl), optionally substituted by one or more R 62 Even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein the cyclohexyl or the cycloheptyl is optionally substituted by one or more R 62 Still more preferably, R 61 is a cyclohexyl group, which is optionally substituted with one or more R 62Also preferred are the cyclic groups (R 61 ) is not replaced by any group R 62 replace.

[0107] R 62 Each independently selected from 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-(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(C1-5 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 and -(C 0-3 alkylene)-heterocycloalkyl.

[0108] Preferably, R 62 Each independently selected from 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(C1-5 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, R 62 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 62 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0109] L A Each independently selected from a covalent bond, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more (e.g., one, two or three) groups 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 alkyl), and further wherein the one or more (e.g., one, two, or three) -CH2- units contained in the alkylene, the alkenylene, or the alkynylene are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- groups.

[0110] R A Each independently selected from -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)(C1-5 alkyl), halogen, C 1-5 Haloalkyl, -O(C 1-5 Halogenated alkyl), -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 1-5 alkyl), -SO2-(C 1-5 alkyl), -SO-(C 1-5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more (e.g., one, two or three) groups 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).

[0111] Particularly preferably, the compound of formula (I) is any one of the specific compounds of formula (I) described in the Examples section of this specification, including any one of Examples 1-210 further described below, which is in non-salt form or a pharmaceutically acceptable salt of the corresponding compound.

[0112] Therefore, it is particularly preferred that the compound of formula (I) is selected from:

[0113] 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0114] 4-[(1S)-1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0115] N-[(1S)-1-(4-Carbamoylphenyl)ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide;

[0116] N-[(1S)-1-[4-(methylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide;

[0117] N-[(1S)-1-[4-(dimethylcarbamoyl)phenyl]ethyl]-4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carboxamide;

[0118] 4-[(1S)-1-[[4-[Acetyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0119] 4-[(1S)-1-[[4-[(2-phenoxyacetyl)amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0120] 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0121] 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0122] 4-[(1S)-1-[[4-[2-(3-chlorophenoxy)ethyl-ethyl-amino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0123] 4-[(1S)-1-[[4-[2-(4-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0124] 4-[(1S)-1-[[4-[2-[3-(trifluoromethyl)phenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0125] 4-[(1S)-1-[[4-[2-[3-methoxyphenoxy]ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0126] 4-[(1S)-1-[[4-[2-(3-methylphenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0127] 4-[(1S)-1-[[4-[2-(4-cyanophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0128] 4-[(1S)-1-[[4-[2-(3,5-difluorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0129] 4-[(1S)-1-[[4-[2-(3,4-dichlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0130] 4-[(1S)-1-[[4-(3-phenylpropylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0131] 4-[(1S)-1-[[4-(2-phenylethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0132] 4-[(1S)-1-[[4-[(3-Fluorophenyl)methylamino]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0133] 4-[(1S)-1-[[4-(cyclohexylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0134] 4-[(1S)-1-[[4-(3-pyridinylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0135] 4-[(1S)-1-[[4-(2-pyridinylmethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0136] 4-[1-[[4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0137] 4-[1-[[4-[Methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0138] 4-[1-[[4-[propyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0139] 4-[1-[[4-[Cyclopropylmethyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0140] 4-[1-[[4-[2-(3-chlorophenoxy)ethylamino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0141] 4-[1-[[4-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0142] 4-[1-[[4-[2-(2-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0143] 4-[1-[[4-[2-(4-chlorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0144] 4-[1-[[4-[2-(3-Fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0145] 4-[1-[[4-[2-(2-Fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0146] 4-[1-[[4-[2-(4-Fluorophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0147] 4-[1-[[4-[2-(3-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0148] 4-[1-[[4-[2-(2-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0149] 4-[1-[[4-[2-(4-methylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0150] 4-[1-[[4-[2-(3-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0151] 4-[1-[[4-[2-(2-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0152] 4-[1-[[4-[2-(4-methoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0153] 4-[1-[[4-[2-(3-Trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0154] 4-[1-[[4-[2-(2-trifluoromethylphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0155] 4-[1-[[4-[2-(3-Trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0156] 4-[1-[[4-[2-(2-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0157] 4-[1-[[4-[2-(4-trifluoromethoxyphenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0158] 4-[1-[[4-[2-(3-Cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0159] 4-[1-[[4-[2-(2-Cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0160] 4-[1-[[4-[2-(4-Cyanophenoxy)ethyl-methyl-amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0161] 2-Fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0162] 3-Fluoro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0163] 2-Chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0164] 3-Chloro-4-[1-[[4-[methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0165] 5-[1-[[4-[Methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-2-carboxylic acid;

[0166] 6-[1-[[4-[Methyl(2-phenoxyethyl)amino]tetrahydropyran-4-carbonyl]amino]cyclopropyl]pyridine-3-carboxylic acid;

[0167] 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0168] 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0169] 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0170] 4-[(1S)-1-[[1-[2-(3-methylphenoxy)ethylamino]cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0171] 4-[(1S)-1-[[1-[methyl-[2-(3-methylphenoxy)ethyl]amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0172] 4-[(1S)-1-[[1-[2-(3-methoxyphenoxy)ethyl-methyl-amino]cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0173] 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0174] 4-[(1S)-1-[[1-[methyl(2-phenoxyethyl)amino]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0175] 4-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0176] 3-[(1S)-1-[[1-[2-(3-chlorophenoxy)ethylamino]cyclopentanecarbonyl]amino]ethyl]bicyclo[1.1.1]pentane-1-carboxylic acid;

[0177] 4-[(1S)-1-[[4,4-difluoro-1-(2-phenoxyethylamino)cyclohexanecarbonyl]amino]ethyl]benzoic acid;

[0178] 4-[(1S)-1-[[4-(2-phenoxyethylamino)tetrahydrothiopyran-4-carbonyl]amino]ethyl]benzoic acid;

[0179] 4-[(1S)-1-[[1,1-dioxo-4-(2-phenoxyethylamino)thiazane-4-carbonyl]amino]ethyl]benzoic acid;

[0180] 4-[(1S)-1-[[2-(2-phenoxyethylamino)spiro[3.3]heptane-2-carbonyl]amino]ethyl]benzoic acid;

[0181] 4-[(1S)-1-[[1-(2-phenoxyethylamino)cyclobutanecarbonyl]amino]ethyl]benzoic acid;

[0182] 4-[(1S)-1-[[8,8-Dimethyl-7-(2-phenoxyethylamino)-2-oxabicyclo[4.2.0]octane-7-carbonyl]amino]ethyl]benzoic acid;

[0183] 4-[(1S)-1-[[2,2-dimethyl-4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0184] 4-[(1S)-1-[[2,2-dimethyl-4-(2-phenoxyethylamino)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0185] 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydropyran-3-carbonyl]amino]ethyl]benzoic acid;

[0186] 4-[(1S)-1-[[3-[methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid;

[0187] 4-[(1S)-1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]ethyl]benzoic acid;

[0188] 4-[1-[[3-[Methyl(2-phenoxyethyl)amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid;

[0189] 4-[1-[[3-[2-(3-chlorophenoxy)ethyl-methyl-amino]tetrahydrofuran-3-carbonyl]amino]cyclopropyl]benzoic acid;

[0190] 4-[(1S)-1-[[1-methyl-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid;

[0191] 4-[(1S)-1-[[1-(2-methoxyethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid;

[0192] 4-[(1S)-1-[[1-(cyclopropylmethyl)-4-(2-phenoxyethylamino)piperidine-4-carbonyl]amino]ethyl]benzoic acid;

[0193] 4-[(1S)-1-[[4-(3-phenoxypropyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0194] 4-[1-[[4-[2-(3-chlorophenoxy)ethoxy]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0195] 4-[(1S)-1-[[4-(3-Fluorophenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0196] 4-[(1S)-1-[[4-[4-(2-methylpentyloxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0197] 4-[(1S)-1-[[4-(4-Methoxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0198] 4-[(1S)-1-[[4-(3-Isopropoxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0199] 4-[(1S)-1-[[4-[3-(2,2,2-trifluoroethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0200] 4-[(1S)-1-[[4-(4-Benzyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0201] 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0202] 4-[(1S)-1-[[4-[4-(tetrahydropyran-4-ylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0203] 4-[(1S)-1-[[4-[4-(2,2,2-trifluoroethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0204] 4-[(1S)-1-[[4-[4-(3-phenylpropyloxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0205] 4-[(1S)-1-[[4-[4-(2-tetrahydropyran-4-ylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0206] 4-[(1S)-1-[[4-[4-(3-phenylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0207] 4-[(1S)-1-[[4-[4-(2-cyclohexylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0208] 4-[(1S)-1-[[4-[4-(3-pyridylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0209] 4-[(1S)-1-[[4-[3-(cyclohexylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0210] 4-[(1S)-1-[[4-[3-(tetrahydropyran-4-ylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0211] 4-[(1S)-1-[[4-(3-Benzyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0212] 4-[(1S)-1-[[4-[3-(cyclohexyloxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0213] 4-[(1S)-1-[[4-[3-(cyclopropylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0214] 4-[(1S)-1-[[4-[3-(cyclopentylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0215] 4-[(1S)-1-[[4-[3-(Cycloheptylmethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0216] 4-[(1S)-1-[[4-(3-Isopentyloxyphenyl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0217] 4-[(1S)-1-[[4-[3-(2-cyclohexylethoxy)phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0218] 4-[(1S)-1-[[4-[3-[[(3S)-Tetrahydrofuran-3-yl]methoxy]phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0219] 4-[(1S)-1-[[4-[3-[[(3R)-tetrahydrofuran-3-yl]methoxy]phenyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0220] 4-[(1S)-1-[[1-[4-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0221] 4-[(1S)-1-[[1-(4-Benzyloxyphenyl)cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0222] 4-[(1S)-1-[[1-[4-(2-cyclohexylethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0223] 4-[(1S)-1-[[1-[4-(2-cyclohexylethoxy)phenyl]cyclopentanecarbonyl]-methyl-amino]ethyl]benzoic acid;

[0224] 4-[(1S)-1-[[1-[3-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0225] 4-[(1S)-1-[[1-(3-Benzyloxyphenyl)cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0226] 4-[(1S)-1-[[1-[2-(cyclohexylmethoxy)phenyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0227] 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0228] 4-[(1S)-1-[[4-[2-(cyclohexylmethoxy)-4-pyridinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0229] 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)-2-pyridinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0230] 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0231] 4-[(1S)-1-[[4-[5-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0232] 4-[(1S)-1-[[4-[5-(2-cyclohexylethoxy)-2-pyridinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0233] 4-[(1S)-1-[[4-[6-(cyclohexylmethoxy)-3-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0234] 4-[(1S)-1-[[4-[6-(2-cyclohexylethoxy)-3-pyridinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0235] 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0236] 4-[(1S)-1-[[1-[2-(cyclohexylmethoxy)-4-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0237] 4-[(1S)-1-[[1-[4-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0238] 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0239] 4-[(1S)-1-[[1-[5-(cyclohexylmethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0240] 4-[(1S)-1-[[1-[5-(2-cyclohexylethoxy)-2-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0241] 4-[(1S)-1-[[1-[6-(cyclohexylmethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0242] 4-[(1S)-1-[[1-[6-(2-cyclohexylethoxy)-3-pyridyl]cyclopentanecarbonyl]amino]ethyl]benzoic acid;

[0243] 4-[(1S)-1-[[4-[4-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0244] 4-[(1S)-1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0245] 4-[1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0246] 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0247] 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0248] 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0249] 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0250] 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0251] 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0252] 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0253] 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0254] 4-[(1S)-1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0255] 4-[1-[[4-[(3R)-3-(3-fluorophenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0256] 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0257] 4-[1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0258] 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0259] 4-[1-[[4-[(3R)-3-[3-(trifluoromethoxy)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0260] 4-[(1S)-1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0261] 4-[1-[[4-[(3R)-3-(3-methoxyphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0262] 4-[(1S)-1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0263] 4-[1-[[4-[(3R)-3-(3-methylphenoxy)pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0264] 4-[(1S)-1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0265] 4-[1-[[4-((3R)-3-phenoxypyrrolidin-1-yl)tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid;

[0266] 4-[(1S)-1-[[4-[(3R)-3-(cyclohexyloxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid;

[0267] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid;

[0268] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid;

[0269] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid;

[0270] 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]cyclopropyl]benzoic acid;

[0271] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid;

[0272] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid;

[0273] 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid;

[0274] 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclohexane-1-carbonyl]amino]ethyl]benzoic acid;

[0275] 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-4,4-difluorocyclohexane-1-carbonyl]amino]ethyl]benzoic acid;

[0276] 4-[(1S)-1-[[1-[(3R)-3-[3-trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopentane-1-carbonyl]amino]ethyl]benzoic acid;

[0277] 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzoic acid;

[0278] 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclopropane-1-carbonyl]amino]ethyl]benzoic acid;

[0279] 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid;

[0280] 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]amino]ethyl]benzamide;

[0281] 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]methylamino]ethyl]benzamide;

[0282] 4-[(1S)-1-[[4-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]tetrahydropyran-4-carbonyl]dimethylamino]ethyl]benzamide;

[0283] 4-[(1S)-1-[[1-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide;

[0284] 4-[(1S)-1-[[1-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]cyclobutane-1-carbonyl]amino]ethyl]benzamide;

[0285] 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide;

[0286] 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzamide;

[0287] N-((S)-1-(4-(2H-tetrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0288] N-((S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0289] N-((S)-1-(4-(1H-pyrazol-5-yl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0290] N-((S)-1-(4-sulfamoylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0291] N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0292] N-((1S)-1-(4-(S-methylaminosulfonimidoylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0293] N-((S)-1-(4-hydroxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0294] N-((S)-1-(4-cyanophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0295] N-((S)-1-phenylethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0296] N-((S)-1-(pyridin-4-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0297] N-((S)-1-(pyridin-3-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0298] N-((S)-1-(pyridin-2-yl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0299] N-((S)-1-(4-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0300] N-((S)-1-(3-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0301] N-((S)-1-(2-fluorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0302] N-((S)-1-(4-bromophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0303] N-((S)-1-(3-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0304] N-((S)-1-(2-chlorophenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0305] N-((S)-1-(4-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0306] N-((S)-1-(3-methylphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0307] N-((S)-1-(4-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0308] N-((S)-1-(3-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0309] N-((S)-1-(2-methoxyphenyl)ethyl)-4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamide;

[0310] (R)-2-methyl-4-(1-(4-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)cyclopropyl)benzoic acid;

[0311] (R)-6-(4-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)spiro[3.3]heptane-2-carboxylic acid;

[0312] (1R,4R)-4-((4-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)tetrahydro-2H-pyran-4-carboxamido)methyl)cyclohexane-1-carboxylic acid;

[0313] (1R,4R)-4-((2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propionamido)methyl)cyclohexane-1-carboxylic acid;

[0314] (1R,4R)-4-((2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propionamido)methyl)cyclohexane-1-carboxamide;

[0315] 2-methyl-N-((S)-1-(4-sulfamoylphenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide;

[0316] 2-methyl-N-((S)-1-(4-(methylsulfonyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide;

[0317] 2-Methyl-N-((1S)-1-(4-(S-methylaminoimidenesulfonyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide;

[0318] N-((S)-1-(4-(1,2,4- oxadiazole-3-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide;

[0319] N-((S)-1-(4-(1,2,4- oxadiazole-5-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide;

[0320] 4-((1S)-1-(2-(3-benzylpyrrolidin-1-yl)-2-methylpropionylamino)ethyl)benzoic acid;

[0321] 4-((S)-1-(2-((R)-3-((3-chlorophenoxy)methyl)pyrrolidin-1-yl)-2-methylpropionylamino)ethyl)benzoic acid;

[0322] 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-ethylbutane-carbonyl]amino]ethyl]benzoic acid;

[0323] and a pharmaceutically acceptable salt of any one of the above compounds.

[0324] The present invention also relates to each intermediate further described in the Examples section of this specification as follows, including any of these intermediates, which are in non-salt form or in salt form (e.g., pharmaceutically acceptable salts) of the corresponding compounds. Such intermediates can be particularly useful in synthesizing compounds of formula (I).

[0325] In a first particular embodiment, the compound of formula (I) is a compound of the formula

[0326]

[0327] or a pharmaceutically acceptable salt thereof.

[0328] In this first particular embodiment, A 1 and A 2 Each independently is C 1-5 More preferably, A 1 and A 2 are each independently methyl or ethyl. Even more preferably, A 1 and A 2 Each is a methyl group.

[0329] In this first particular embodiment, ring B is a carbocyclyl or heterocyclyl. Preferably, ring B is selected from arylene, heteroarylene (e.g., pyridylene, particularly including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is also preferred that ring B is monocyclic. More preferably, ring B is arylene or cycloalkylene. Even more preferably, ring B is phenylene or C 3-9Cycloalkylene. Even more preferably, ring B is phenylene (especially benzene-1,4-diyl) or cyclohexylene (especially cyclohexane-1,4-diyl). Even more preferably, ring B is phenylene (e.g., benzene-1,4-diyl, benzene-1,3-diyl or benzene-1,2-diyl). Still more preferably, ring B is benzene-1,4-diyl.

[0330] In this first particular embodiment, ring D is phenyl.

[0331] In this first particular embodiment, L is C 2-4 Alkylene (e.g., ethylene, n-propylene, or n-butylene), wherein the C 2-4 A -CH2- unit contained in the alkylene group (preferably connected to a 1 and A 2 The -CH2- unit of the carbon atom of 2-4 The other -CH2- unit contained in the alkylene group (preferably the -CH2- unit connected to the ring D) is optionally 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 replaced by a group selected from -O-, -NH- and -N(C 1-5 alkyl)-, more preferably replaced by a group -O-), wherein the carbocyclylene or the heterocyclylene is preferably linked in 1,3-direction, and further wherein the carbocyclylene or the heterocyclylene is optionally replaced by one or more groups -L A -R A Preferably, L is -heterocyclylene-(CH2) 1-2 -, wherein said -heterocyclylene-(CH2) 1-2 - is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(especially selected from -O-, -NH- and -N(C 1-5 alkyl)-) group, wherein said -heterocyclylene-(CH2) 1-2 - in the heterocyclylene group is optionally replaced by one or more groups -L A -R A substituted, and further wherein said -heterocyclylene-(CH2) 1-2-heterocyclylene is preferably connected in 1,3-direction. More preferably, L is -heterocyclylene-CH2-, wherein the -CH2- unit in said -heterocyclylene-CH2- is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(especially selected from -O-, -NH- and -N(C 1-5 -heterocycloalkylene-CH2- is preferably linked in the 1,3-direction; and it is also preferred that the -heterocycloalkylene-CH2- is linked to ring D via a -CH2- unit (which may be optionally substituted as described above) in the -heterocycloalkylene-CH2-. Even more preferably, L is -heterocycloalkylene-O-, which is linked to ring D via an oxygen atom in the -heterocycloalkylene-O-, and wherein the -heterocycloalkylene-O- is linked in the 1,3-direction; 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 linked to the ring carrying A via a nitrogen ring atom. 1 and A 2 and is connected to the oxygen (-O-) in the -heterocycloalkylene-O- through a carbon ring atom, wherein the nitrogen ring atom and the carbon ring atom are separated by a carbon ring atom. Thus, L can be, for example, a group It is connected to ring D via an oxygen atom (-O-), wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected by single bonds, wherein 1 or 2 of the ring atoms (Z) are independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z) (if any) are carbon atoms. In particular, L can be a group It is linked to ring D via an oxygen atom (-O-), wherein y is 1, 2, 3, 4 or 5, and wherein 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 include or wherein each of these groups is linked to ring D via a terminal oxygen atom contained therein. If L is a group or It is then also preferred that the corresponding group L is present in the following stereochemical configuration:

[0332] or

[0333] In this first particular 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.

[0334] In this first particular embodiment, p is 0, 1, 2, 3 or 4. Preferably, p is 0, 1 or 2. More preferably, p is 1.

[0335] In this first particular embodiment, R 2 Selected from hydrogen, C 1-5 Alkyl and -CO(C 1-5 Preferably, R 2 is hydrogen or C 1-5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 For hydrogen.

[0336] In this first particular embodiment, X is C(R 3a )(R 3b ). Therefore, X is a carrier of a substituent R 3a and R 3b of carbon atoms.

[0337] In this first particular embodiment, R 3a and R 3b are each independently selected from hydrogen, C 1-5 Alkyl and C 2-5 Preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 More preferably, R 3a C 1-5 alkyl (eg, methyl or ethyl), and R 3b is hydrogen or C 1-5 More preferably, R 3a is a methyl group, and R 3b For hydrogen.

[0338] According to the above X, R 3a and R 3b Definition, particularly preferred part for

[0339] In this first particular embodiment, R 4 Each independently selected from 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-(C 1-5 Alkyl), -(C 0-3 Alkylene)-NH-COO(C 1-5 Alkyl), -(C 0-3 Alkylene)-N(C1-5 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, R 4 Each independently selected from 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 1-5alkyl), -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, R 4 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 4 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -N(C 1-4Alkyl)(C 1-4 alkyl) (e.g., -N(CH3)2), halogen (e.g., -F, -Cl, -Br or -I), -CF3 and -CN.

[0340] In this first particular embodiment, R 5 Selected from -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 the carbocyclyl or the heterocyclyl is optionally substituted by one or more (e.g. one, two or three) groups -L A -R A Preferably, R 5 Selected from -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 More preferably, R 5 Selected from -COOH, -CO-NH2, -CO-NH(C 1-5 alkyl) (e.g., -CO-NH-CH3), -CO-N(C 1-5 Alkyl)(C 1-5alkyl) (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)-CH3) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH2 or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH or tetrazolyl (particularly 1H-tetrazolyl-5-yl or 2H-tetrazolyl-5-yl). Even more preferably, R 5 is -COOH.

[0341] In this first particular embodiment, R 6 Each independently selected from 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 0-3 Alkylene)-CN,-(C0-3 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 0-3 Alkylene)-SO-(C 1-5 Alkyl), -(C 0-3 Alkylene)-SO2-(C 1-5 Alkyl), -(C 0-3Alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocycloalkyl and -L 1 -R 61 Preferably, R 6 Each independently selected from 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(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 1-5Alkyl), -(C 0-3 Alkylene)-cycloalkyl, -(C 0-3 alkylene)-heterocycloalkyl and -L 1 -R 61 More preferably, R 6 Each independently selected from 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, R 6 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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 Even more preferably, R 6 Each is independently selected from -CH3, -OH, -OCH3, halogen (such as -F, -Cl, -Br or -I), -CF3, -OCF3, -CN and -L 1 -R 61 Even more preferably, R 6 are each independently selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3. Still more preferably, R 6 Each is independently selected from -CH3, -OCH3, -F, -Cl and -CF3. 6 Each is independently -Cl or -CF3.

[0342] In this first particular embodiment, if p is 1, then preferably R 6The group L is connected to the ring D in the 1,2-direction, 1,3-direction or 1,4-direction relative to the point of connection of the group L to the ring D, and more preferably R 6 is attached to ring D in the 1,3 direction relative to the point of attachment of group L to ring D. Furthermore, if p is greater than 1 (eg 2, 3 or 4), then group R is preferably 6 At least one of the groups L is attached to the ring D in the 1,3-direction relative to the point of attachment of the group L to the ring D.

[0343] In this first particular embodiment, according to the above p and R 6 The definition of p is particularly preferably 1, the group R 6 The group R is connected to the ring D in the 1,3 direction relative to the point of connection of the group L to the ring D, and the group R 6 is selected from -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 the group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, and still more preferably the group R 6 Selected from -Cl and -CF3.

[0344] In this first particular embodiment, L 1 C 1-6 Alkylene or covalent bond, wherein the C 1-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently selected from -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 Preferably, L 1 C 1-4 Alkylene, wherein the C 1-4 One or more (eg, one or two) -CH2- units contained in the alkylene group are each optionally independently selected from -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 1-5Alkyl)(C 1-5 The alkylene group is preferably C 2-4 Alkylene (e.g. ethylene, propylene or butylene), more preferably -(CH2)2-, -(CH2)3- or -(CH2)4-, and even more preferably -(CH2)2-. In addition, it is preferred that the one or more -CH2- units are each optionally independently selected from -O-, -S-, -NH- and -N(C 1-5 alkyl)-, in particular replaced by -O-. Also preferred is L 1 Connected to ring D (i.e. L 1 Contains a terminal -CH2- unit which is replaced by -O-, and L 1 is connected to ring D via said -O-). More preferably, L 1 -(CH2) 2-4 -, wherein said -(CH2) 2-4 - is optionally selected from -O-, -S-, -NH- and -N(C 1-5 Even more preferably, L 1 -O-(CH2) 1-3 -, where L 1 By the -O-(CH2) 1-3 - is connected to ring D. Even more preferably, L 1 is -O-CH2- or -O-CH2-CH2-, wherein L 1 It is connected to ring D through the oxygen atom in said -O-CH2- or said -O-CH2-CH2-. Still more preferably, L 1 is -O-CH2-, which is connected to the ring D through the oxygen atom (-O-) contained in the -O-CH2-.

[0345] In this first particular embodiment, R 61 is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (eg one, two or three) groups R 62 Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g. tetrahydrofuranyl or tetrahydropyranyl) and heteroaryl (e.g. pyridyl), wherein the cycloalkyl, the aryl, the heterocycloalkyl and the heteroaryl are each optionally substituted by one or more (e.g. one, two or three) groups R 62 More preferably, R 61 is a cycloalkyl or aryl group, wherein the cycloalkyl or the aryl group is optionally substituted by one or more R 62 Even more preferably, R 61Selected from C 3-9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein the C 3-9 The cycloalkyl group or the phenyl group is optionally replaced by one or more R 62 Even more preferably, R 61 C 5-9 Cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl), optionally substituted by one or more R 62 Even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein the cyclohexyl or the cycloheptyl is optionally substituted by one or more R 62 Still more preferably, R 61 is a cyclohexyl group, which is optionally substituted with one or more R 62 Also preferred are the cyclic groups (R 61 ) is not affected by any group R 62 replace.

[0346] In this first particular embodiment, R 62 Each independently selected from 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 1-5 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 and -(C 0-3 Preferably, R 62 Each independently selected from 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-(C1-5 alkyl), -SO-(C 1-5 alkyl), -SO2-(C 1-5 Alkyl), -(C 0-3 alkylene)-cycloalkyl and -(C 0-3 More preferably, R 62 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 62 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0347] In this first particular embodiment, L A Each independently selected from a covalent bond, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more (e.g., one, two or three) groups 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 alkyl), and further wherein the one or more (e.g., one, two, or three) -CH2- units contained in the alkylene, the alkenylene, or the alkynylene are each optionally independently selected from -O-, -NH-, -N(C 1-5alkyl)-, -CO-, -S-, -SO- and -SO2- groups.

[0348] In this first particular embodiment, R A Each independently selected from -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 Halogenated alkyl), -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 1-5 alkyl), -SO2-(C 1-5 alkyl), -SO-(C 1-5alkyl), hydrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more (e.g., one, two or three) groups 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).

[0349] In a second special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the first special embodiment except that R 3a and R 3b Each other and the carbon atom to which they are attached are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more (e.g. one, two or three) groups R 31 replace.

[0350] In this second particular embodiment, preferably R 3a and R 3b Each other and the carbon atoms to which they are connected form C 3-5 Cycloalkyl or 3- to 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more (eg one or two) groups R 31 More preferably, R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0351] In this second particular embodiment, it is therefore particularly preferred that part for

[0352] In this second particular embodiment, R 31 Each independently selected from 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 1-5Alkylene)-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) and -SO2-(C 1-5 Preferably, R 31 Each independently selected from 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 (eg, -CF3) and -CN.

[0353] In a third particular embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the first particular embodiment, except that ring D is a monocyclic heteroaryl or a monocyclic heterocycloalkyl.

[0354] In this third particular embodiment, preferably ring D is 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.

[0355] In a fourth particular embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the second embodiment, except that ring D is a monocyclic heteroaryl or monocyclic heterocycloalkyl.

[0356] In this fourth particular embodiment, preferably ring D is 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.

[0357] In a fifth particular embodiment, the compound of formula (I) is a compound of the formula

[0358]

[0359] or a pharmaceutically acceptable salt thereof.

[0360] In this fifth particular embodiment, Ring A is carbocyclyl or heterocyclyl. Additionally, as shown in the above formula, the moiety -CO-N(R 2 )-XB[(-R 4 ) m ]-R 5 and part of -LD[(-R 6 ) p ] is connected to the same ring carbon atom of ring A, thereby being a divalent carbocyclic group or heterocyclic group. Ring A is preferably saturated. Therefore, preferably, ring A is a cycloalkylene group or a heterocycloalkylene group; the cycloalkylene group or the heterocycloalkylene group is preferably monocyclic or bicyclic. More preferably, A is a monocyclic cycloalkylene group or a monocyclic heterocycloalkylene group. Even more preferably, A is a monocyclic C 3-9Cycloalkylene or monocyclic 4 to 9-membered heterocycloalkylene. Preferred examples of ring A include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g., tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothienylene (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., thiam-2,2-diyl, thiam-3,3-diyl or thiam-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).

[0361] In this fifth particular embodiment, ring B is a carbocyclyl or heterocyclyl. Preferably, ring B is selected from arylene, heteroarylene (e.g., pyridylene, particularly including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is also 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 Cycloalkylene. Even more preferably, ring B is phenylene (especially benzene-1,4-diyl) or cyclohexylene (especially cyclohexane-1,4-diyl). Even more preferably, ring B is phenylene (e.g., benzene-1,4-diyl, benzene-1,3-diyl or benzene-1,2-diyl). Still more preferably, ring B is benzene-1,4-diyl.

[0362] In this fifth particular embodiment, ring D is phenyl.

[0363] In this fifth particular embodiment, L is C 2-4 Alkylene (e.g., ethylene, n-propylene, or n-butylene), wherein the C 2-4 One -CH2- unit contained in the alkylene group (preferably the -CH2- unit connected to ring A) is replaced by a carbocyclylene group or a heterocyclylene group (preferably a heterocyclylene group), wherein the C 2-4 Another -CH2- unit contained in the alkylene group (preferably the -CH2- unit connected to the ring D) is optionally 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- groups (preferably selected from -O-, -NH- and -N(C 1-5 alkyl)-, more preferably substituted by a group -O-), wherein the carbocyclylene or the heterocyclylene is preferably linked in 1,3-direction, and further wherein the carbocyclylene or the heterocyclylene is optionally substituted by one or more groups -L A -R A Preferably, L is -heterocyclylene-(CH2) 1-2 -, wherein said -heterocyclylene-(CH2) 1-2 - is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(particularly selected from -O-, -NH- and -N(C 1-5 alkyl)-) group, wherein said -heterocyclylene-(CH2) 1-2 - in the heterocyclylene group is optionally replaced by one or more groups -L A -R A substituted, and further wherein said -heterocyclylene-(CH2) 1-2 -heterocyclylene is preferably connected in 1,3-direction. More preferably, L is -heterocyclylene-CH2-, wherein the -CH2- unit in said -heterocyclylene-CH2- is optionally selected from -O-, -CO-, -NH-, -N(C 1-5 alkyl)- and -N[-CO-(C 1-5 -alkyl)]-(especially selected from -O-, -NH- and -N(C 1-5 -alkyl)-, more preferably -O-), and wherein the heterocycloalkylene in said -heterocycloalkylene-CH2- is preferably linked in the 1,3-direction; it is also preferred that said -heterocycloalkylene-CH2- is linked to ring D via a -CH2- unit in said -heterocycloalkylene-CH2- (which may optionally be substituted as described above). Even more preferably, L is -heterocycloalkylene-O-, which is linked to ring D via an oxygen atom in said group -heterocycloalkylene-O-, and wherein the heterocycloalkylene in said -heterocycloalkylene-O- is linked in the 1,3-direction; 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 linked to ring A via a nitrogen ring atom and to the oxygen (-O-) in said -heterocycloalkylene-O- via a carbon ring atom, wherein the nitrogen ring atom and the carbon ring atom are separated by one carbon ring atom. Thus, L can be, for example, a group It is connected to ring D via an oxygen atom (-O-), wherein Z refers to 1, 2, 3, 4 or 5 ring atoms connected by single bonds, wherein 1 or 2 of the ring atoms (Z) are independently selected from nitrogen, oxygen, sulfur and carbon, and the remaining ring atoms (Z) (if any) are carbon atoms. In particular, L can be a group It is linked to ring D via an oxygen atom (-O-), wherein y is 1, 2, 3, 4 or 5, and wherein 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 include or Each of these groups is linked to ring D via a terminal oxygen atom contained therein.

[0364] In this fifth particular 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.

[0365] In this fifth particular 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.

[0366] In this fifth particular embodiment, p is 0, 1, 2, 3 or 4. Preferably, p is 0, 1 or 2. More preferably, p is 1.

[0367] In this fifth particular embodiment, R 1 Each independently selected from 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 0-3Alkylene)-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 0-3 Alkylene)-SO2-NH2, -(C 0-3 Alkylene)-SO2-NH(C 1-5 Alkyl), -(C 0-3 Alkylene)-SO2-N(C 1-5 Alkyl)(C 1-5Alkyl), -(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, R 1 Each independently selected from 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(C1-5 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, R 1 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 1 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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. 1 A preferred example of substituted ring A is 4,4-difluoro-cyclohexane-1,1-diyl, ie, cyclohexylene (as ring A) substituted at the para position by two fluorine atoms (as R 1 )replace.

[0368] In this fifth particular embodiment, R 2 Selected from hydrogen, C 1-5 Alkyl and -CO(C 1-5 Preferably, R 2is hydrogen or C 1-5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 For hydrogen.

[0369] In this fifth particular embodiment, X is C(R 3a )(R 3b ). Therefore, X is a carrier of a substituent R 3a and R 3b of carbon atoms.

[0370] In this fifth particular embodiment, R 3a and R 3b are each independently selected from hydrogen, C 1-5 Alkyl and C 2-5 Preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 More preferably, R 3a C 1-5 alkyl (eg, methyl or ethyl), and R 3b is hydrogen or C 1-5 More preferably, R 3a is a methyl group, and R 3b For hydrogen.

[0371] According to the above X, R 3a and R 3b Definition, particularly preferred part for

[0372] In this fifth particular embodiment, R 4 Each independently selected from 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 1-5 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 Preferably, R 4 Each independently selected from 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, R 4 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 4 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0373] In this fifth particular embodiment, R 5 Selected from -COOH, -CO-NH2, -CO-NH(C 1-5 Alkyl), -CO-N(C1-5 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 the carbocyclyl or the heterocyclyl is optionally substituted by one or more (e.g. one, two or three) groups -L A -R A Preferably, R 5 Selected from -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 More preferably, R 5 Selected from -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)-CH3) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5is -COOH, -CO-NH2 or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH or tetrazolyl (particularly 1H-tetrazolyl-5-yl or 2H-tetrazolyl-5-yl). Even more preferably, R 5 is -COOH.

[0374] In this fifth particular embodiment, R 6 Each independently selected from 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 0-3 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 0-3Alkylene)-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 0-3 alkylene)-heterocycloalkyl and -L 1 -R 61 Preferably, R 6 Each independently selected from C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, -OH, -O(C1-6 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(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, R 6 Each independently selected from C 1-5 Alkyl, -OH, -O(C 1-6alkyl), -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, R 6 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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 Even more preferably, R 6 Each is independently selected from -CH3, -OH, -OCH3, halogen (such as -F, -Cl, -Br or -I), -CF3, -OCF3, -CN and -L 1 -R 61 Even more preferably, R 6 are each independently selected from -CH3, -OCH3, -F, -Cl, -CF3 and -OCF3. Still more preferably, R 6 Each is independently selected from -CH3, -OCH3, -F, -Cl and -CF3. 6 Each is independently -Cl or -CF3.

[0375] In this fifth particular embodiment, if p is 1, then preferably R 6 The group L is connected to the ring D in the 1,2-direction, 1,3-direction or 1,4-direction relative to the point of connection of the group L to the ring D, and more preferably R 6 is attached to ring D in the 1,3 direction relative to the point of attachment of group L to ring D. Furthermore, if p is greater than 1 (eg 2, 3 or 4), then group R is preferably 6 At least one of the groups L is attached in the 1,3-direction relative to the point of attachment of the group L to the ring D.

[0376] In this fifth particular embodiment, according to the above p and R 6 The definition of p is particularly preferably 1, the group R 6 The group R is connected to the ring D in the 1,3 direction relative to the point of connection of the group L to the ring D, and the group R 6 is selected from -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 the group R 6 is selected from -CH3, -OCH3, -F, -Cl and -CF3, and still more preferably the group R 6 Selected from -Cl and -CF3.

[0377] In this fifth particular embodiment, L 1 C 1-6 Alkylene or covalent bond, wherein the C 1-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently selected from -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 Preferably, L 1 C 1-4 Alkylene, wherein the C 1-4 One or more (eg, one or two) -CH2- units contained in the alkylene group are each optionally independently selected from -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 group is preferably C 2-4 Alkylene (e.g. ethylene, propylene or butylene), more preferably -(CH2)2-, -(CH2)3- or -(CH2)4-, and even more preferably -(CH2)2-. In addition, it is preferred that the one or more -CH2- units are each optionally independently selected from -O-, -S-, -NH- and -N(C 1-5alkyl)-, preferably -O-. Also preferably L 1 Connected to ring D (i.e. L 1 Contains a terminal -CH2- unit which is replaced by -O-, and L 1 is connected to ring D via said -O-). More preferably, L 1 -(CH2) 2-4 -, wherein said -(CH2) 2-4 - is optionally selected from -O-, -S-, -NH- and -N(C 1-5 alkyl)-, in particular by a -O- group. Even more preferably, L 1 -O-(CH2) 1-3 -, where L 1 By the -O-(CH2) 1-3 - is connected to ring D. Even more preferably, L 1 is -O-CH2- or -O-CH2-CH2-, wherein L 1 It is connected to ring D through the oxygen atom in said -O-CH2- or said -O-CH2-CH2-. Still more preferably, L 1 is -O-CH2-, which is connected to the ring D through the oxygen atom (-O-) contained in the -O-CH2-.

[0378] In this fifth particular embodiment, R 61 is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (eg one, two or three) groups R 62 Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g. tetrahydrofuranyl or tetrahydropyranyl) and heteroaryl (e.g. pyridyl), wherein the cycloalkyl, the aryl, the heterocycloalkyl and the heteroaryl are each optionally substituted by one or more (e.g. one, two or three) groups R 62 More preferably, R 61 is a cycloalkyl or aryl group, wherein the cycloalkyl or the aryl group is optionally substituted by one or more R 62 Even more preferably, R 61 Selected from C 3-9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein the C 3-9 The cycloalkyl group or the phenyl group is optionally replaced by one or more R 62 Even more preferably, R 61 C 5-9Cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl), optionally substituted by one or more R 62 Even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein the cyclohexyl or the cycloheptyl is optionally substituted by one or more R 62 Still more preferably, R 61 is a cyclohexyl group, which is optionally substituted with one or more R 62 Also preferred are the cyclic groups (R 61 ) is not affected by any group R 62 replace.

[0379] In this fifth particular embodiment, R 62 Each independently selected from 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 1-5 Alkyl), -(C 0-3 alkylene)-cycloalkyl and -(C 0-3 Preferably, R 62 Each independently selected from C1-5 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 1-5 alkyl), -SO-(C 1-5 alkyl), -SO2-(C 1-5 Alkyl), -(C 0-3 alkylene)-cycloalkyl and -(C 0-3 More preferably, R 62 Each independently selected from C1-5 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. -CF3) and -CN. Even more preferably, R 62 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0380] In this fifth particular embodiment, L A Each independently selected from a covalent bond, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more (e.g., one, two or three) groups 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 alkyl), and further wherein the one or more (e.g., one, two, or three) -CH2- units contained in the alkylene, the alkenylene, or the alkynylene are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- groups.

[0381] In this fifth particular embodiment, R A Each independently selected from -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 Halogenated alkyl), -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 1-5 alkyl), -SO2-(C 1-5 alkyl), -SO-(C 1-5 alkyl), hydrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more (e.g., one, two or three) groups 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(C1-5 alkyl), -NH2, -NH(C 1-5 alkyl) and -N(C 1-5 Alkyl)(C 1-5 alkyl).

[0382] In a sixth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the fifth special embodiment, except that R 3a and R 3b Each other and the carbon atom to which they are attached are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more (e.g. one, two or three) groups R 31 replace.

[0383] In this sixth particular embodiment, preferably R 3a and R 3b Each other and the carbon atoms to which they are connected form C 3-5 Cycloalkyl or 3- to 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more (eg one or two) groups R 31 More preferably, R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0384] In this sixth particular embodiment, it is therefore particularly preferred that part for

[0385] In this sixth particular embodiment, R 31 Each independently selected from 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) and -SO2-(C 1-5 Preferably, R 31 Each independently selected from 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 (eg, -CF3) and -CN.

[0386] In a seventh special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the fifth special embodiment, except that L is C 3-6 Alkylene (e.g., propylene, butylene, or pentylene), wherein the C 3-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently selected from -O-, -CO-, -NH-, -N(C 1-5Alkyl)-、-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 alkyl)-, in particular by a group independently 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]-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 Alkyl)-, more preferably replaced by a group independently selected from -O-, -NH- and -N(C 1-5 Preferably, L is -(CH2) 3-5 -, wherein said -(CH2) 3-5 - one or more (e.g. one, two or three) -CH2- units contained in - are each optionally independently 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)]-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 Alkyl)-, in particular selected from -O-, -NH- and -N(C 1-5 More preferably, L is -CH2-CH2-CH2-CH2-, wherein the one or more (e.g., one, two or three) -CH2- units contained in said -CH2-CH2-CH2-CH2- are each independently 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(C1-5 Alkyl)(C 1-5 Alkyl)-, in particular selected from -O-, -NH- and -N(C 1-5 Even more preferably, L is -CH2-CH2-CH2-O-, which is connected to ring D via the oxygen atom (-O-) in the group -CH2-CH2-CH2-O-, and wherein the one or more (e.g., one or two) -CH2- units contained in the -CH2-CH2-CH2-O- are each optionally independently 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 selected from -O-, -NH- and -N(C 1-4 alkyl)-, wherein it is also preferred that the terminal -CH2- unit (furthest away from the oxygen atom in -CH2-CH2-CH2-O-) is replaced by a group as defined above (for example by -N(C 1-4 -alkyl)-, in particular replaced 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(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-, wherein each of these groups is linked to ring D via a 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-, wherein each of these groups 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.

[0387] In an eighth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the sixth special embodiment, except that L is C 3-6Alkylene (e.g., propylene, butylene, or pentylene), wherein the C 3-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently 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-, -SO2-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 alkyl)-, in particular by a group independently 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]-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 Alkyl)-, more preferably replaced by a group independently selected from -O-, -NH- and -N(C 1-5 Preferably, L is -(CH2) 3-5 -, wherein said -(CH2) 3-5 - one or more (e.g. one, two or three) -CH2- units contained in - are each optionally independently 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 selected from -O-, -NH- and -N(C 1-5 More preferably, L is -CH2-CH2-CH2-CH2-, wherein the one or more (e.g., one, two or three) -CH2- units contained in said -CH2-CH2-CH2-CH2- are each independently 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 selected from -O-, -NH- and -N(C 1-5 Even more preferably, L is -CH2-CH2-CH2-O-, which is connected to ring D via the oxygen atom (-O-) in the group -CH2-CH2-CH2-O-, and wherein the one or more (e.g., one or two) -CH2- units contained in the -CH2-CH2-CH2-O- are each optionally independently 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 selected from -O-, -NH- and -N(C 1-4 wherein the terminal -CH2- unit (which is furthest from the oxygen atom in -CH2-CH2-CH2-O-) is preferably replaced by a group as defined above (e.g. by -N(C 1-4-alkyl)-, in particular replaced 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(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-, wherein each of these groups is linked to ring D via a 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-, wherein each of these groups 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.

[0388] In a ninth particular embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the fifth particular embodiment above, except that ring D is a monocyclic heteroaryl or monocyclic heterocycloalkyl. Preferably, ring D is 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.

[0389] In a tenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the sixth special embodiment, except that ring D is a monocyclic heteroaryl or monocyclic heterocycloalkyl. Preferably, ring D is 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.

[0390] In an eleventh special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the seventh special embodiment, except that ring D is a monocyclic heteroaryl or monocyclic heterocycloalkyl. Preferably, ring D is 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.

[0391] In a twelfth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the eighth special embodiment, except that ring D is a monocyclic heteroaryl or monocyclic heterocycloalkyl. Preferably, ring D is 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.

[0392] In a thirteenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the first special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3b Each is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0393] In a fourteenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the third special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3b Each is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0394] In a fifteenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the fifth special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3bEach is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0395] In a sixteenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the seventh special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3b Each is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0396] In a seventeenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the ninth special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3b Each is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0397] In an eighteenth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the eleventh special embodiment, except that X is C(R 3a )(R 3b ), where R 3a and R 3b Each is hydrogen (ie, X is -CH2-), and except that Ring B is cyclohexylene (preferably, Ring B is cyclohexane-1,4-diyl).

[0398] In a nineteenth particular embodiment, the compound of formula (I) is a compound of the formula:

[0399]

[0400] or a pharmaceutically acceptable salt thereof.

[0401] In this nineteenth particular embodiment, L is a covalent bond.

[0402] In this nineteenth particular embodiment, ring D is phenyl or pyridyl (eg, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl). Preferably, ring D is phenyl.

[0403] In this nineteenth particular embodiment, p is 0, 1 or 2. More preferably, p is 1. If p is 1, then preferably R 6Relative to the point of attachment of ring A to ring D, it is connected to ring D in the 1,3-direction or the 1,4-direction (via group L, which is a covalent bond), more preferably R 6 is connected to ring D in the 1,3 direction relative to the point of attachment of ring A to ring D. Thus, if p is 1 and ring D is phenyl, then R is preferably 6 The connection point with respect to ring A and the phenyl group (ring D) is at the meta or para position, more preferably at the meta position (corresponding to the 1,3-direction). In addition, if p is 1 and ring D is a pyridyl group, then R is preferably 6 is connected to the pyridyl group (being ring D) in the 1,3-direction or the 1,4-direction relative to the point of connection of ring A to ring D. In particular, if p is 1 and ring D is pyridin-2-yl or pyridin-3-yl, then R 6 It can be connected to the pyridin-2-yl or pyridin-3-yl group in, for example, 1,4-direction relative to the point of connection of ring A to ring D. If p is 1 and ring D is pyridin-4-yl, then R 6 The pyridin-4-yl group may be linked to the pyridin-4-yl group, for example, in the 1,3-direction relative to the point of attachment of ring A to ring D.

[0404] In this nineteenth particular embodiment, R 6 Each is independently a group -L 1 -R 61 .

[0405] In this nineteenth particular embodiment, L 1 C 1-6 Alkylene or covalent bond, wherein the C 1-6 One or more (eg, one, two, or three) -CH2- units contained in the alkylene group are each optionally independently selected from -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 alkyl)-group replacement.

[0406] Preferably, L 1 C 1-4 Alkylene, wherein the C 1-4 One or more (eg, one or two) -CH2- units contained in the alkylene group are each optionally independently selected from -O-, -CO-, -NH-, -N(C 1-5 Alkyl)-、-N[-CO-(C 1-5 alkyl)]-、-S-、-SO-、-SO2-、-CH(C 1-5alkyl)- and -C(C 1-5 Alkyl)(C 1-5 The alkylene group is preferably C 2-4 Alkylene (e.g. ethylene, propylene or butylene), more preferably -(CH2)2-, -(CH2)3- or -(CH2)4-, and even more preferably -(CH2)2-. In addition, it is preferred that the one or more -CH2- units are each optionally independently selected from -O-, -S-, -NH- and -N(C 1-5 alkyl)-, in particular replaced by -O-. Also preferred is L 1 Connected to ring D (i.e. L 1 Contains a terminal -CH2- unit which is replaced by -O-, and L 1 is linked to the ring D) via said -O-.

[0407] More preferably, L 1 -(CH2) 2-4 -, wherein said -(CH2) 2-4 - is optionally selected from -O-, -S-, -NH- and -N(C 1-5 Even more preferably, L 1 -O-(CH2) 1-3 -, where L 1 By the -O-(CH2) 1-3 - is connected to ring D. Even more preferably, L 1 is -O-CH2- or -O-CH2-CH2-, wherein L 1 It is connected to ring D through the oxygen atom in said -O-CH2- or said -O-CH2-CH2-. Still more preferably, L 1 is -O-CH2-, which is connected to the ring D through the oxygen atom (-O-) contained in the -O-CH2-.

[0408] In this nineteenth particular embodiment, R 61 is a carbocyclic or heterocyclic group, wherein the carbocyclic or heterocyclic group is optionally substituted by one or more (eg one, two or three) groups R 62 Preferably, R 61 is selected from cycloalkyl, aryl, heterocycloalkyl (e.g. tetrahydrofuranyl or tetrahydropyranyl) and heteroaryl (e.g. pyridyl), wherein the cycloalkyl, the aryl, the heterocycloalkyl and the heteroaryl are each optionally substituted by one or more (e.g. one, two or three) groups R 62 More preferably, R 61is a cycloalkyl or aryl group, wherein the cycloalkyl or the aryl group is optionally substituted by one or more R 62 Even more preferably, R 61 Selected from C 3-9 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl) or phenyl, wherein the C 3-9 The cycloalkyl group or the phenyl group is optionally replaced by one or more R 62 Even more preferably, R 61 C 5-9 Cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl), optionally substituted by one or more R 62 Even more preferably, R 61 is cyclohexyl or cycloheptyl, wherein the cyclohexyl or the cycloheptyl is optionally substituted by one or more R 62 Still more preferably, R 61 is a cyclohexyl group, which is optionally substituted with one or more R 62 Also preferred are the cyclic groups (R 61 ) is not affected by any group R 62 replace.

[0409] In this nineteenth particular embodiment, R 62 Each independently selected from 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 1-5 Alkyl)(C 1-5 Alkyl), -(C 0-3 Alkylene)-NH-SO2-(C 1-5 Alkyl), -(C 0-3Alkylene)-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, R 62 Each independently selected from 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, R 62 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 62 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0410] In this nineteenth particular embodiment, Ring A is a 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 Cycloalkylene or monocyclic 4- to 9-membered heterocycloalkylene.

[0411] Preferred examples of ring A include cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene (e.g., tetrahydrofuran-2,2-diyl or tetrahydrofuran-3,3-diyl), tetrahydrothiopheneylene (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., thiam-2,2-diyl, thiam-3,3-diyl or thiam-4,4-diyl). Ring A is particularly preferably tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl) or cyclopentylene (i.e., cyclopentane-1,1-diyl).

[0412] In this nineteenth particular embodiment, ring B is a carbocyclyl or heterocyclyl. Preferably, ring B is selected from arylene, heteroarylene (e.g., pyridylene, particularly including pyridine-2,5-diyl or pyridine-3,6-diyl), cycloalkylene, and heterocycloalkylene. It is also 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 Cycloalkylene. Even more preferably, ring B is phenylene (especially benzene-1,4-diyl) or cyclohexylene (especially cyclohexane-1,4-diyl). Even more preferably, ring B is phenylene (e.g., benzene-1,4-diyl, benzene-1,3-diyl or benzene-1,2-diyl). Still more preferably, ring B is benzene-1,4-diyl.

[0413] In this nineteenth particular 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.

[0414] In this nineteenth particular 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.

[0415] In this nineteenth particular embodiment, R 1 Each independently selected from 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, -(C0-3 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 0-3 Alkylene)-N(C 1-5 alkyl)-COO(C 1-5 Alkyl), -(C 0-3 Alkylene)-O-CO-NH(C 1-5 Alkyl), -(C 0-3Alkylene)-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, R 1 Each independently selected from 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 1-5alkyl), -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, R 1 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 1 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0416] In this nineteenth particular embodiment, R 2 Selected from hydrogen, C 1-5 Alkyl and -CO(C 1-5 Preferably, R 2 is hydrogen or C 1-5 More preferably, R 2 is hydrogen, methyl or ethyl. Even more preferably, R 2 For hydrogen.

[0417] In this nineteenth particular embodiment, X is C(R 3a )(R 3b ) or N(R 3c ). Therefore, X is a carrier of a substituent R 3a and R 3b The carbon atom or X is a substituent R 3c Preferably, X is C(R 3a )(R 3b ).

[0418] In this nineteenth particular embodiment, R 3a and R 3b are each independently selected from hydrogen, C 1-5 Alkyl and C 2-5 Alkenyl; or R 3a and R 3b Each other and the carbon atom to which they are attached are linked to form a cycloalkyl group or a heterocycloalkyl group, wherein the cycloalkyl group or the heterocycloalkyl group is optionally substituted by one or more (e.g. one, two or three) groups R 31 Substitute; or R 3a is a divalent group selected from a linear C 2-4 Alkylene and straight chain C 2-4 Alkenylene, wherein the divalent group is connected via one end to a group carrying R 3b and is connected via the other end to a ring atom of ring B, which is adjacent to the ring atom (of ring B) carrying the group X, wherein said alkylene or said alkenylene is optionally substituted by one or more (e.g. one, two or three) groups R 31 substituted, wherein one -CH2- unit in the alkylene or alkenylene group is optionally replaced by -O-, -S-, -NH- or -N(C 1-5 alkyl)-substituted, and R 3b Selected from hydrogen, C 1-5 Alkyl and C 2-5 Preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 Alkyl, or R 3a and R 3bEach other and the carbon atoms to which they are connected form C 3-5 Cycloalkyl or 3- to 5-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by one or more (eg one or two) groups R 31 More preferably, R 3a and R 3b are each independently selected from hydrogen and C 1-5 Alkyl (such as methyl or ethyl), or R 3a and R 3b are linked to each other and the carbon atom to which they are linked to form a cyclopropyl group. Even more preferably, R 3a C 1-5 alkyl (eg, methyl or ethyl), and R 3b is hydrogen or C 1-5 Alkyl (such as methyl or ethyl), or R 3a and R 3b are linked to each other and the carbon atom to which they are linked to form a cyclopropyl group. Even more preferably, R 3a is methyl and R 3b is hydrogen, or R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0419] In this nineteenth particular embodiment, R 3c Selected from hydrogen, C 1-5 Alkyl and C 2-5 Preferably, R 3c is hydrogen or C 1-5 More preferably, R 3c is hydrogen or methyl. Even more preferably, R 3c It is a methyl group.

[0420] In this nineteenth special embodiment, according to the above X, R 3a and R 3b Definition, particularly preferred part for or

[0421] In this nineteenth particular embodiment, R 31 Each independently selected from 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(C1-5 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) and -SO2-(C 1-5 Preferably, R 31 Each independently selected from 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 (eg, -CF3) and -CN.

[0422] In this nineteenth particular embodiment, R 4 Each independently selected from 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-(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(C1-5 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 0-3 alkylene)-heterocycloalkyl and -L A -R A Preferably, R 4 Each independently selected from 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 1-5Alkylene)-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, -(C 0-3 alkylene)-heterocycloalkyl and -L A -R A More preferably, R 4 Each independently selected from 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. -CF3) and -CN. Even more preferably, R 4 Each independently selected from C 1-4 Alkyl (such as methyl or ethyl), -OH, -O(C 1-4 alkyl) (e.g., -OCH3 or -OCH2CH3), -NH2, -NH(C 1-4 alkyl) (e.g., -NHCH3), -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.

[0423] In this nineteenth particular embodiment, R 5 Selected from -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 the carbocyclyl or the heterocyclyl is optionally substituted by one or more (e.g. one, two or three) groups -L A -R A Preferably, R 5 Selected from -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 1-5alkyl), -SO2-(C 1-5 alkyl), -S(=O)(=NH)-(C 1-5 alkyl), -CN, -O(C 1-4 More preferably, R 5 Selected from -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)-CH3) and tetrazolyl (e.g., 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). More preferably, R 5 is -COOH, -CO-NH2 or tetrazolyl (particularly 1H-tetrazol-5-yl or 2H-tetrazol-5-yl). Even more preferably, R 5 is -COOH or tetrazolyl (particularly 1H-tetrazolyl-5-yl or 2H-tetrazolyl-5-yl). Even more preferably, R 5 is -COOH.

[0424] In this nineteenth special embodiment, according to the above ring B, X, R 2 、R 3a 、R 3b 、R 4 、R 5 and m, particularly preferably Has the following structure:

[0425] or

[0426] In this nineteenth particular embodiment, L A Each independently selected from a covalent bond, C 1-5 Alkylene, C 2-5 Alkenylene and C 2-5 wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more (e.g., one, two or three) groups 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 1-5Alkyl)(C 1-5 alkyl), and further wherein the one or more (e.g., one, two, or three) -CH2- units contained in the alkylene, the alkenylene, or the alkynylene are each optionally independently selected from -O-, -NH-, -N(C 1-5 alkyl)-, -CO-, -S-, -SO- and -SO2- groups.

[0427] In this nineteenth particular embodiment, R A Each independently selected from -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 Halogenated alkyl), -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 the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more (e.g., one, two or three) groups 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).

[0428] In a twentieth special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the nineteenth special embodiment, except that Ring A is tetrahydropyranylene (preferably tetrahydropyran-4,4-diyl) and Ring D is phenyl.

[0429] In a twenty-first special embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as defined in the nineteenth special embodiment, except that ring A is cyclopentylidene (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).

[0430] For those skilled in the art of synthetic chemistry, a variety of methods for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof will be apparent. For example, the compounds of the present invention can be prepared according to or similar to the synthetic routes described in detail in the Examples section. In particular, compounds of formula (I) can generally be synthesized according to the methods described in the following schemes.

[0431] 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 under alkaline aqueous conditions, typically using aqueous sodium hydroxide or lithium hydroxide. If desired, organic solvents such as THF or dihydrogen phosphate can be used. Acid hydrolysis can usually be carried out in an acidic aqueous solution, usually using aqueous HCl. If necessary, an organic solvent such as dihydrogen phosphate can be used. Examples G and AJ can be obtained by amide coupling starting from Examples F and AI, respectively, with appropriate amines via activated acid intermediates (Schemes 1 and 4). Typically, the activated acid intermediates can be the corresponding acid chlorides, or can be obtained by using coupling agents such as BOP or HATU.

[0432] Intermediate E can be obtained from intermediate D (Scheme 1). The Y3 part can be introduced by using a suitable electrophilic reagent. For example, it can be introduced by reductive amination in the presence of a suitable aldehyde or ketone and a reducing agent such as sodium triacetoxyborohydride. It can also be introduced by reacting 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 for amide coupling. In a similar manner, intermediate D can be obtained from intermediate C. The Y2 part can be introduced by using a suitable electrophilic reagent (usually a suitable aldehyde or ketone) or by reacting with an activated acid intermediate, as described above. Intermediate C can be obtained in two steps from protected amino acid A and amine B. The first step can include amide coupling through an activated acid intermediate, typically using an acyl chloride or a coupling agent such as BOP or HATU, followed by a deprotection step. The latter is suitable for the protecting group used for intermediate A: typically, in the case of a Boc-protected amino acid A, the Boc group can be removed under acidic conditions such as a TFA / organic solvent mixture.

[0433] Option 1: General preparation of Examples F and G

[0434]

[0435] Intermediates N and W can be obtained in two steps from amine B and intermediates J and V, respectively (Schemes 2 and 3). First, ester J or V is saponified under alkaline aqueous conditions, typically using aqueous sodium hydroxide or lithium hydroxide. If desired, the reaction can be carried out using an organic solvent such as THF or dihydrogen hydride. The resulting carboxylic acid can then undergo amide coupling with an appropriate amine B by preparing an activated acid intermediate as described above.

[0436] Intermediates J and L can be obtained from intermediates H and K, respectively, by α-arylation of ester I catalyzed by transition metals such as palladium (Scheme 2). Alternatively, intermediate J can be obtained by functionalizing phenol M, typically via a Mitsunobu reaction with an aliphatic alcohol, in the presence of a dialkyl azodicarboxylate (such as DIAD) and triphenylphosphine, in solution or in the case of polymer binding. 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 deprotecting the protected phenol L. In the case of trimethylsilyl-protected phenol L, a simple acidic workup can yield phenol M. Similarly, silyl-protected phenol L can be cleaved under acidic conditions, typically in HCl solution in an organic solvent, or, for example, in the presence of a fluoride anion such as TBAF.

[0437] Option 2: General Preparation of Example O

[0438]

[0439] Intermediate V can be obtained from intermediate T in a two-step sequence (Scheme 3). First, hydration of cyanide T can produce the corresponding primary amide, usually under alkaline aqueous conditions in the presence of H2O2, which can be treated with DMF-DMA in methanol or in a mixture of methanol and another organic solvent to ultimately produce ester V. If appropriate, intermediate T can be obtained from halo-heteroaryl R by aromatic nucleophilic substitution in the presence of a nucleophile (e.g., an alcoholate generated in situ from an aliphatic alcohol and a strong base such as sodium hydride). Alternatively, intermediate T can be obtained by coupling between halo-heteroaryl R and a suitable aliphatic alcohol catalyzed by a transition metal such as palladium. This two-step sequence can also be reversed, generating intermediate V via intermediate U. Intermediate R can be obtained directly from dihalogenated heteroaryl P by aromatic nucleophilic 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, it can be generated in a two-step sequence from a dihalogenated heteroaryl group P. First, aromatic nucleophilic substitution with the carbanion of acetonitrile generated by treating acetonitrile with a strong base such as n-BuLi or KHMDS can provide intermediate Q. Intermediate R can then be obtained by nucleophilic substitution with an appropriate electrophile in the presence of a strong base such as sodium hydride.

[0440] Option 3: General Preparation of Example X

[0441]

[0442] Intermediate AH can be obtained by amide coupling between intermediate AG and amine B, by preparing an activated acid intermediate as previously described (Scheme 4). Intermediate AG can be obtained from intermediate AD in two different ways. Dinucleophilic substitution of amino ester AE on intermediate AD under alkaline conditions, typically by using potassium carbonate as a base in an organic solvent, followed by saponification of the ester under alkaline aqueous conditions, can produce intermediate AG. Alternatively, dinucleophilic substitution of amino alcohol AF on intermediate AD under alkaline 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 promote these dinucleophilic substitutions. Dibrominated intermediate AD can be obtained from the corresponding diol 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. The deprotection is appropriate for the protecting group used. For example, in the case of an ester group, a reducing agent such as lithium aluminum hydride can be used to perform a reduction step to produce intermediate AC. In the case of a silyl protecting group, the diol intermediate AC can be obtained, for example, in the presence of a fluoride anion such as TBAF. The intermediate AB can be obtained from the secondary alcohol AA, where appropriate by a Mitsunobu reaction, or by nucleophilic substitution on a suitable electrophile under basic conditions.

[0443] Option 4: General Preparation of Examples AH, AI and AJ

[0444]

[0445] The following definitions apply throughout this specification and claims, unless otherwise stated.

[0446] The term "hydrocarbyl" refers to a group consisting of carbon and hydrogen atoms.

[0447] The term "alicyclic" is used in conjunction with a cyclic group and indicates that the corresponding cyclic group is non-aromatic.

[0448] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group that may be straight-chain or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1-5 "Alkyl" means 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 The alkyl group more preferably refers to a methyl group or an ethyl group, and even more preferably refers to a methyl group.

[0449] As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon double bonds, while it does not contain any carbon-carbon triple bonds. 2-5 "Alkenyl" means 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 a C 2-4 Alkenyl.

[0450] As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be linear or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally contains one or more (e.g., one or two) carbon-carbon double bonds. 2-5 "Alkynyl" means an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (eg, propargyl), or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to a C 2-4 Alkynyl.

[0451] As used herein, the term "alkylene" refers to an alkanediyl group, i.e., a divalent saturated acyclic hydrocarbon group which may be straight-chain or branched. 1-5 "Alkylene" means an alkylene group having 1 to 5 carbon atoms, and the term "C 0-3 "Alkylene" indicates the presence of a covalent bond (equivalent to selecting "C0 alkylene") or C 1-3 Alkylene. Preferred exemplary alkylene groups are methylene (-CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2-CH(-CH3)- or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless otherwise defined, the term "alkylene" preferably refers to a C 1-4 Alkylene (especially including straight chain C 1-4 alkylene), more preferably refers to methylene or ethylene, and even more preferably refers to methylene.

[0452] As used herein, the term "alkenylene" refers to an alkenediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon double bonds, while it does not contain any carbon-carbon triple bonds. 2-5"Alkenylene" means an alkenylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to a C 2-4 Alkenylene (especially including straight chain C 2-4 alkenylene).

[0453] As used herein, the term "alkynylene" refers to an alkynediyl group, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally contains one or more (e.g., one or two) carbon-carbon double bonds. 2-5 "Alkyne" means an alkynyl group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkynyl" preferably refers to a C 2-4 Alkynylidene (especially including straight chain C 2-4 alkynylene).

[0454] As used herein, the term "carbocyclyl" refers to a hydrocarbon ring group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may, for example, be composed of two or three rings), wherein the ring group may be saturated, partially unsaturated (i.e., unsaturated, but not aromatic) or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to an aryl, cycloalkyl or cycloalkenyl group.

[0455] As used herein, the term "heterocyclyl" refers to a cyclic group, including monocyclic and bridged, spiro and / or fused ring systems (which may be composed of, for example, two or three rings), wherein the cyclic group contains one or more (e.g., one, two, three or four) 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) may be optionally oxidized, wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring contained in the cyclic group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0456] As used herein, the term "carbocyclic group" has the same meaning as "carbocyclyl", and the term "heterocyclic group" has the same meaning as "heterocyclyl". It should be understood that rings A and B, which may each be a carbocyclic group or a heterocyclic group, are divalent ring groups (i.e., ring A is connected to -CO-N(R2 )-XB[(-R 4 ) m ]-R 5 and connected to -LD[(-R 6 ) p ]; Ring B is connected to atom X and to group R 5 ), and furthermore, ring A is linked to the moiety -CO-N(R) via the same ring carbon atom (of ring A) 2 )-XB[(-R 4 ) m ]-R 5 and part of -LD[(-R 6 ) p ], also shown in Formula (Ia); these characteristics of Rings A and B also apply to the definitions of the corresponding ring groups provided herein, including the exemplary ring groups indicated in each definition (as long as Ring A or B is involved). For example, if Ring A is an arylene group, it should be understood that the phenylene group (for Ring A) disclosed herein as an exemplary arylene group must be present as a benzene-1,1-diyl group.

[0457] As used herein, the term "carbocyclylene" refers to a carbocyclyl as defined above, but with two points of attachment (ie, a divalent carbocyclyl). Unless otherwise defined, "carbocyclylene" preferably refers to a cycloalkylene or arylene group.

[0458] As used herein, the term "heterocyclylene" refers to a heterocyclyl as defined above, but with two points of attachment (ie, a divalent heterocyclyl). Unless otherwise defined, "heterocyclylene" preferably refers to a heterocycloalkylene or heteroarylene.

[0459] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, 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, wherein at least one of the fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of the bridged rings is aromatic). "Aryl" may, for example, refer to phenyl, naphthyl, dihydronaphthyl (dialinyl) (i.e., 1,2-dihydronaphthyl), tetrahydronaphthyl (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 6-14 ring atoms, more preferably 6-10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0460] As used herein, the term "arylene" refers to an aryl group as defined above, but having two points of attachment, i.e., a divalent aromatic hydrocarbon ring radical, 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, wherein at least one of the fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of the bridged rings is aromatic). “Arylene” may, for example, refer to a phenylene group (e.g., benzene-1,2-diyl, benzene-1,3-diyl, or benzene-1,4-diyl), a naphthylene group (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, naphthalene-2,6-diyl, naphthalene-2,7-diyl, or naphthalene-2,8-diyl), a 1,2-dihydronaphthylene group, a 1,2,3,4-tetrahydronaphthylene group, an indanylene group, an indenylene group, an anthrylene group, a phenanthrenylene group, a 9H-fluorenylene group, or an azulenylene group. Unless otherwise defined, "arylene" preferably has 6-14 ring atoms, more preferably 6-10 ring atoms, even more preferably refers to phenylene or naphthylene, most preferably refers to phenylene (especially benzene-1,4-diyl).

[0461] As used herein, the term "heteroaryl" refers to an aromatic ring group, 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, wherein at least one of the fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more (e.g., one, two, three or four) 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) may be optionally oxidized, and further wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic cyclic group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroaryl" can be, 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 ( pyridyl; for example, 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (for example, 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, permidinyl, phenanthrolinyl (for example, [1,10]phenanthrolinyl, [1,7]phenanthrolinyl or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, Azolyl, iso Azolyl, Oxazolyl (e.g. 1,2,4- Oxazolyl, 1,2,5- oxadiazole (i.e. furazanyl) or 1,3,4- oxadiazole), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl), phenanthracene oxazine, pyrazolo[1,5-a]pyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidin-3-yl), 1,2-benzisothiazine, Azoles-3-yl, benzothiazolyl, benzothiadiazolyl, benzo Azolyl, benzyl oxazolyl, benzimidazolyl, benzo[b]thienyl (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, dihydrofuro[2,3-c]pyridinyl, pyridinyl (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, benzodioxolyl, Alkyl (e.g. 1,3-benzodione Alkyl or 1,4-benzodione Unless otherwise defined, the term "heteroaryl" preferably refers to a 5-14 membered (more preferably 5-10 membered) monocyclic or fused ring system comprising one or more (e.g., one, two, three, or four) 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; even more preferably, "heteroaryl" refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two, or three) 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.

[0462] As used herein, the term "heteroarylene" refers to a heteroaryl group as defined above, but with two points of attachment, i.e., a divalent aromatic ring group, 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, wherein at least one of the fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more (e.g., one, two, three or four) 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) may be optionally oxidized, and further wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic cyclic group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and that there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heteroarylene" may refer to, for example, thienylene (i.e., thiophenylene; for example, thiophene-2,3-diyl, thiophene-2,4-diyl, or thiophene-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furylene; for example, furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofurylene, isobenzofurylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, oxythioxanthenylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene ( pyridylene) (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, β-carbolylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazolylene-2,4-diyl, thiazolylene-2,5-diyl, or thiazolylene-4,5-diyl), isothiazinylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, pyridinylene Azolyl (e.g. oxadiazole-2,4-diyl, oxazole-2,5-diyl or oxadiazole-4,5-diyl), isopropylidene Azolyl (e.g., iso oxadiazole-3,4-diyl, iso oxadiazole-3,5-diyl or iso oxadiazole-4,5-diyl), oxadiazole Oxazolyl (e.g. 1,2,4- oxadiazole-3,5-diyl, 1,2,5- oxadiazole-3,4-diyl or 1,3,4- oxadiazole-2,5-diyl), thiadiazolylidene (e.g., 1,2,4-thiadiazolyl-3,5-diyl, 1,2,5-thiadiazolyl-3,4-diyl or 1,3,4-thiadiazolyl-2,5-diyl), phenadiazole-2,5-diyl), Oxazine, pyrazolo[1,5-a]pyrimidinyl, 1,2-benzisidine Azolyl, benzothiazolyl, benzothiadiazolyl, benzo Azolyl, benzoiso oxazolyl, benzimidazolylene, benzo[b]thienyl (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), furano[2,3-c]pyridyl, diazolyl, pyridylene, imidazo[1,2-a]pyridylene, imidazo[3,2-a]pyridylene, quinazolinylene, thienopyridylene, tetrahydrothienopyridylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridylene), dibenzofuranylene, 1,3-benzodioxolylene, benzodioxolylene, Alkyl (e.g. 1,3-benzodione Alkyl or 1,4-benzodione Unless otherwise defined, the term "heteroarylene" preferably refers to a divalent 5-14 membered (more preferably 5-10 membered) monocyclic or fused ring system comprising one or more (e.g., one, two, three, or four) 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; even more preferably, "heteroarylene" refers to a divalent 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two, or three) 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. "Heteroarylene", including any of the special trans heteroarylene groups described herein, may be linked via two carbon ring atoms, in particular via two carbon ring atoms that are at the maximum distance from each other (the number of ring atoms that are separated by the shortest possible link) within a single ring or within the complete ring system of the corresponding heteroarylene.

[0463] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group, including a monocyclic ring as well as a bridged ring, a spirocyclic ring and / or a fused ring system (which may be composed of, for example, two or three rings, such as a fused ring system composed of two or three fused rings). "Cycloalkyl" may, for example, refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthyl (i.e., decahydronaphthyl) or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to a C 3-11 Cycloalkyl, more preferably refers to C 3-7 Cycloalkyl. Particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (eg, cyclopropyl or cyclohexyl).

[0464] As used herein, the term "cycloalkylene" refers to a cycloalkyl group as defined above, but having two points of attachment, i.e., a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged, spirocyclic and / or fused ring systems (which may consist of, for example, two or three rings; for example, a fused ring system consisting of two or three fused rings). "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, decahydronaphthylene (i.e., decahydronaphthylene) or adamantylene. Unless otherwise defined, "cycloalkylene" preferably refers to C 3-11Cycloalkylene, and more preferably refers to C 3-7 Cycloalkylene. Particularly preferred "cycloalkylene" is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members (eg, cyclopropylene or cyclohexylene).

[0465] As used herein, the term "heterocycloalkyl" refers to a saturated cyclic group, including monocyclic and bridged, spirocyclic and / or fused ring systems (which may be composed of two or three rings, for example, a fused ring system composed of two or three fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) 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) may be optionally oxidized, and further wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated cyclic group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three, or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4, and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkyl" may refer to, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), Oxazolidinyl, isocyanate oxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxirane, oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxolane alkyl, oxepanyl, thiirane, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1,3-dithiolanyl, thianyl, 1,1-dioxathianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless otherwise defined, "heterocycloalkyl" preferably refers to a 3-11 membered saturated ring group which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) 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; more preferably, "heterocycloalkyl" refers to a 5-7 membered saturated monocyclic group which contains one or more (e.g., one, two, or three) 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.

[0466] As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group as defined above, but with two points of attachment, i.e., a divalent saturated ring group, including monocyclic as well as bridged, spirocyclic and / or fused ring systems (which may consist of two or three rings; for example, a fused ring system consisting of two or three fused rings), wherein the ring group contains one or more (e.g., one, two, three or four) 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) may be optionally oxidized, and further wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated cyclic group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkylene" may, for example, refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1,4-diazepanyl), cycloheptanyl, ... Oxazolidinyl, isocyanide Oxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, oxazepanyl, oxirane, oxetane, tetrahydrofuranyl, 1,3-dioxolane, tetrahydropyranyl, 1,4-dioxolane alkyl, oxepanylene, thiiraneylene, thietanylene, tetrahydrothienylene (i.e., thiolanylene), 1,3-dithiolanylene, thianylene, 1,1-dioxathianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless otherwise defined, "heterocycloalkylene" preferably refers to a divalent 3-11 membered saturated cyclic group which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the cyclic group contains one or more (e.g., one, two, three, or four) 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) may be optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a divalent 5-7 membered saturated monocyclic group which contains one or more (e.g., one, two, or three) 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.

[0467] As used herein, the term "cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including a monocyclic ring as well as a bridged ring, a spirocyclic and / or fused ring system (which may be composed of, for example, two or three rings; for example, a fused ring system composed of two or three fused rings), 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, for example, refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 Cycloalkenyl, and more preferably refers to C 3-7 Cycloalkenyl. A particularly preferred "cycloalkenyl" group is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (eg, one or two; preferably one) carbon-carbon double bonds.

[0468] As used herein, the term "heterocyclenyl" refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic as well as bridged, spiro and / or fused ring systems (which may consist of, for example, two or three rings; for example, a fused ring system consisting of two or three fused rings), wherein the ring group contains one or more (e.g., one, two, three or four) 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) may be optionally oxidized, wherein one or more carbon ring atoms may 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 can contain one or two O atoms and / or one or two S atoms (which can be optionally oxidized) and / or one, two, three or four N atoms (which can be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and there is at least one carbon ring atom in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" may refer, for example, to imidazolidinyl (e.g., 2-imidazolidinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolidinyl, or 4-imidazolidinyl), 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 3-11 membered unsaturated alicyclic ring group which is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) 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 contains at least one double bond between adjacent ring atoms. , and does not contain any triple bonds between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5-7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two or three) 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 contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms.

[0469] As used herein, the term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0470] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (preferably 1-6, more preferably 1-3) halogen atoms independently selected from fluorine, chlorine, bromine and iodine, preferably all fluorine atoms. It should be understood that the maximum number of halogen atoms is limited by the available attachment sites and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "Haloalkyl" can, for example, refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3 or -CH(CF3)2. Particularly preferred "haloalkyl" is -CF3.

[0471] The terms "valent bond" and "covalent bond" are used synonymously herein unless the context clearly indicates otherwise or is contradicted.

[0472] As used herein, the terms "optional", "optionally" and "may" indicate that a given feature may or may not be present. Whenever the terms "optional", "optionally" and "may" are used, the present invention specifically contemplates both possibilities, namely that the corresponding feature is present or, alternatively, that the corresponding feature is not present. For example, the expression "X is optionally substituted by Y" (or "X may be substituted by Y") means that X is substituted by Y or that X is unsubstituted. Similarly, if a component of a composition is stated as "optional", the present invention specifically contemplates both possibilities, namely that the corresponding component is present (included in the composition) or that the corresponding component is not present in the composition.

[0473] Various groups are referred to as "optionally substituted" in this specification. Typically, these groups may carry one or more substituents, such as one, two, three or four substituents. It will be appreciated that the maximum number of substituents is limited by the number of available attachment sites on the substituted moiety. Unless otherwise defined, the "optionally substituted" groups referred to in this specification preferably carry no more than two substituents, and in particular may only carry one substituent. Furthermore, unless otherwise defined, it is preferred that there are no optional substituents, i.e., the corresponding group is unsubstituted.

[0474] It will be appreciated by those skilled in the art that the substituents included in the compounds of the present invention can be connected to the remainder of the corresponding compound through many different positions of the corresponding specific substituents. Unless otherwise defined, the preferred connection positions of the various specific substituents are as shown in the examples.

[0475] As used herein, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one," unless expressly stated otherwise or contradicted by context. Thus, for example, a composition comprising "a" compound of Formula (I) can be interpreted to mean a composition comprising "one or more" compounds of Formula (I).

[0476] It should be understood that no matter where a numerical range is provided / disclosed herein, all values and subranges encompassed by the corresponding numerical range are intended to be encompassed within the scope of the present invention. Therefore, the present invention is specifically and individually directed to each value falling within the numerical range disclosed herein, and each subrange encompassed by the numerical range disclosed herein.

[0477] As used herein, the term "about" preferably refers to ±10% of the stated numerical value, more preferably ±5% of the stated numerical value, and especially the exact numerical value stated. If the term "about" is used in conjunction with an endpoint of a range, it preferably refers to a range from -10% of the lower endpoint to +10% of the upper endpoint of the stated numerical value, more preferably -5% of the lower endpoint to +5% of the upper endpoint, and even more preferably refers to a range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0478] As used herein, unless expressly stated otherwise or contradicted by the context, the term "comprising" (or "including," "containing," "containing") has the meaning of "especially containing," i.e., "containing in addition to other optional elements...". In addition, the term also includes the narrower meanings of "essentially consisting of" and "consisting of." For example, the term "A comprises B and C" has the meaning "A especially contains B and C," where A may contain additional optional elements (e.g., "A contains B, C, and D"), but the term also includes the meaning "A essentially consists of B and C" and the meaning "A consists of B and C" (i.e., A does not contain elements other than B and C).

[0479] The scope of the present invention includes all pharmaceutically acceptable salt forms of the compounds of formula (I), which can be formed, for example, by protonating an atom carrying a lone electron pair susceptible to protonation, such as an amino group, with an inorganic or organic acid or as a salt of an acid group (e.g. 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 salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; arylalkylamine salts, such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts, such as pyridinium salts, picoline salts, quinolinium salts, or isoquinolinium 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, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (e.g., sulfate or hydrogen sulfate), nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate, or thiocyanate; organic acid salts such as acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, The pharmaceutically acceptable salts of the compound of formula (I) include, for example, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (phenylsulfonate), p-toluenesulfonate (toluenesulfonate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-phenylsulfonate or camphorsulfonate; glycerophosphate; and acidic amino acid salts such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of the compound of formula (I) include hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride.Thus, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride, hydrobromide, methanesulfonate, sulfate, tartrate, fumarate, acetate, citrate or phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0480] The present invention also particularly relates to compounds of formula (I), including any of the specific compounds of formula (I) described herein, in non-salt form.

[0481] In addition, the scope of the present invention includes any solvated form of the compound of formula (I), including, for example, solvates (i.e., hydrates) with water or solvates with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO or acetonitrile. All physical forms of the compound of formula (I), including any amorphous or crystalline form (i.e., polymorphs) are also included within the scope of the present invention. It should be understood that the present invention also includes such solvates and physical forms of the pharmaceutically acceptable salts of the compound of formula (I).

[0482] In addition, the compounds of formula (I) may exist in different isomeric forms, in particular 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 thiol / thiol tautomers). All such isomers of the compounds of formula (I) are considered to be part of the present invention, either as mixtures or in pure or substantially pure form. With respect to stereoisomers, the present invention includes the isolated optical isomers of the compounds of the invention as well as any mixtures thereof (including in particular racemic mixtures / racemates). The racemates can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can also be obtained from the racemates by forming salts with optically active acids followed by crystallization. The present invention also includes any tautomer of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulas provided herein specifically depict one of the possible tautomeric forms. It is intended that the formulas and chemical names provided herein include any tautomeric form of the corresponding compounds, but are not limited to the specific tautomeric form depicted or identified by the compound name.

[0483] The scope of the present invention also includes compounds of formula (I) in which one or more atoms are replaced by specific isotopes of the corresponding atoms. For example, the present invention includes compounds in which one or more hydrogen atoms (or, for example, all hydrogen atoms) are replaced by deuterium atoms (i.e. 2H; also referred to as "D") substituted compounds of formula (I). Therefore, the present invention also includes deuterium-enriched compounds of formula (I). Naturally occurring hydrogen is a compound containing about 99.98 mol-% hydrogen-1 ( 1 H) and about 0.0156 mol-% deuterium ( 2 H or D) isotope mixtures. Deuteration techniques known in the art can be used to increase the deuterium content in one or more hydrogen positions in the compound of formula (I). For example, the compound of formula (I) or the reactants or precursors for synthesizing the compound of formula (I) can use, for example, heavy water (DO) to perform an H / D exchange reaction. Other suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20 (18), 5658-5667, 2012; William JS et al., Journal of Labelled 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 otherwise specified, it is preferred that the compound of formula (I) is not enriched in deuterium. Therefore, it is preferred that naturally occurring hydrogen atoms or 1 H hydrogen atom.

[0484] The present invention also includes the case where one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, e.g. 18 F. 11 C. 13 N. 15 O. 76 Br, 77 Br, 120 I and / or 124 I substituted compounds of formula (I). Such compounds are useful as tracers, tracking agents or imaging probes in positron emission tomography (PET). Thus, the present invention includes (i) wherein one or more fluorine atoms (or, for example, all fluorine atoms) are replaced by 18 F atom substituted compounds of formula (I), (ii) wherein one or more carbon atoms (or, for example, all carbon atoms) are replaced by 11 C atom substituted compounds of formula (I), (iii) wherein one or more nitrogen atoms (or, for example, all nitrogen atoms) are replaced by 13 A compound of formula (I) wherein one or more oxygen atoms (or, for example, all oxygen atoms) are replaced by 15 O atom-substituted compounds of formula (I), (v) wherein one or more bromine atoms (or, for example, all bromine atoms) are replaced by 76Br atoms, (vi) wherein one or more bromine atoms (or, for example, all bromine atoms) are replaced by 77 A compound of formula (I) wherein one or more iodine atoms (or, for example, all iodine atoms) are replaced by 120 I atom substituted compounds of formula (I), and (viii) wherein one or more iodine atoms (or, for example, all iodine atoms) are replaced 124 Compounds of formula (I) wherein no atoms in the compounds of formula (I) are replaced by a specific isotope. In general, it is preferred that no atoms in the compounds of formula (I) are replaced by a specific isotope.

[0485] The compounds provided herein can be administered as the compounds themselves, or can be formulated into medicaments. The medicaments / pharmaceutical compositions can optionally contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and / or solubility enhancers.

[0486] The pharmaceutical composition may include one or more solubility enhancers, such as poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g., HS 15,CAS 70142-34-6), phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin Dextrin, 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 sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0487] The pharmaceutical composition may further comprise one or more preservatives, in particular one or more antimicrobial preservatives, such as 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.

[0488] Pharmaceutical composition can be prepared by technology known to those skilled in the art, for example, in " Remington:TheScience and Practice of Pharmacy ", Pharmaceutical Press, disclosed in the 22nd edition. Pharmaceutical composition can be formulated into dosage forms for oral, parenteral administration, for example intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, local, aerosol or vaginal administration. The dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, dragees, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstruction, dispersible powders and granules, medicated glue, chewable tablets and effervescent tablets. The dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstruction. Emulsions are preferred dosage forms for parenteral administration. The dosage forms for rectal and vaginal administration include suppositories and vaginal suppositories. The dosage forms for nasal administration can be administered by suction and insufflation, for example, by metered dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0489] The compounds of formula (I) or the pharmaceutical compositions described above comprising the compounds of formula (I) may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the desired site of action, including, but not limited to, one or more of the following: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection or infusion techniques, including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal, via, for example, a reservoir implant, e.g., subcutaneous or intramuscular), pulmonary (e.g., by inhalation or insufflation therapy, using, for example, an aerosol, e.g., through the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal, or vaginal administration.

[0490] If the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracardial, intracranial, intramuscular or subcutaneous administration of the compound or pharmaceutical composition, and / or the use of infusion techniques. For parenteral administration, the compound is preferably administered in the form of a sterile aqueous solution that may contain other substances, such as sufficient salts or glucose, to make the solution isotonic with the blood. If necessary, the aqueous solution should be appropriately buffered (preferably at a pH of 3 to 9). Suitable parenteral formulations can be easily prepared under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art.

[0491] The compounds or pharmaceutical compositions may also be administered orally in the form of tablets, capsules, pessaries, elixirs, solutions or suspensions, which may contain flavorings or coloring agents for immediate-, delayed-, modified-, sustained-, pulsed-, or controlled-release applications.

[0492] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, and glycine, disintegrants such as starch (preferably corn starch, potato starch, or tapioca starch), sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, and certain complex silicates, and granulation binders such as polyvinyl pyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin, and gum arabic. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may also be included. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the active agent may be combined with a variety of sweeteners or flavorings, colorants, or dyes, with emulsifiers and / or suspending agents, and with diluents such as water, ethanol, propylene glycol, and glycerol, and combinations thereof.

[0493] For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition can be administered so as to enter the gastrointestinal tract through the mouth, which may also be referred to as "oral-gastrointestinal" administration.

[0494] Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or pessary, or may be administered 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 using a skin patch.

[0495] The compound or pharmaceutical composition can also be used by a sustained release system. The applicable example of sustained release composition includes a semi-permeable polymer matrix of a shaped article such as a membrane or microcapsule form. The sustained release matrix includes a copolymer of, for example, polylactide, L-glutamic acid and γ-ethyl-L-glutamic acid, poly-(2-hydroxyethyl methacrylate), ethylene vinyl acetate or poly-D-(-)-3-hydroxybutyric acid. The sustained release pharmaceutical composition also includes a liposome-encapsulated compound. Therefore, the present invention further relates to a liposome containing the compounds of this invention.

[0496] The compounds or pharmaceutical compositions may also be administered by the pulmonary, rectal or ocular routes. For ophthalmic use, they may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated as an ointment such as petrolatum.

[0497] It is also contemplated to prepare dry powder formulations of compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders can be prepared by spray drying under conditions that result in a substantially amorphous glassy or substantially crystalline biologically active powder. Thus, dry powders of the compounds of the invention can be prepared according to an emulsification / spray drying process.

[0498] For topical application to the skin, the compound or pharmaceutical composition can be formulated into a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax, and water. Alternatively, they can be formulated into a suitable lotion or cream suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, 2-octyldodecanol, benzyl alcohol, and water.

[0499] Therefore, the present invention relates to compounds or pharmaceutical compositions provided herein, wherein the corresponding compounds or pharmaceutical compositions are administered by any of the following: oral route; topical route, including transdermal, intranasal, ocular, buccal or sublingual route; parenteral route using injection technology or infusion technology, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ocular route, including by intravitreal or intracameral route; rectal route; or vaginal route. The preferred route of administration is oral administration or parenteral administration. For each compound or pharmaceutical composition provided herein, it is particularly preferred to administer the corresponding compound or pharmaceutical composition orally (particularly by oral ingestion).

[0500] Typically, the clinician will determine the actual dosage that is most suitable for an individual subject. The particular dosage level and frequency of administration for any particular individual may vary depending on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual being treated.

[0501] A suggested, but non-limiting, dosage of the compounds of the present invention for oral administration to humans (approximately 70 kg body weight) may be 0.05-2000 mg, preferably 0.1 mg-1000 mg, of active ingredient per unit dose. The unit dose may be administered 1-3 times per day. The unit dose may also be administered 1-7 times per week, for example, not more than once per day. It will be understood that it may be necessary to routinely vary the dosage depending on the age and weight of the patient / individual and the severity of the condition being treated. The exact dosage and route of administration will ultimately be determined by the attending physician or veterinarian.

[0502] The compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) can be administered as a monotherapy (e.g., without the concomitant administration of any other therapeutic agent, or without the concomitant administration of any other therapeutic agent for the same disease treated or prevented with the compound of formula (I)). Therefore, the present invention relates to a compound of formula (I) or a corresponding pharmaceutical composition for the monotherapy treatment of cancer, neovascular eye disease, inflammatory pain or inflammatory disease. In particular, the present invention relates to the monotherapy administration of the compound of formula (I) or a corresponding pharmaceutical composition, without the concomitant administration of any other anticancer agent and / or without the concomitant administration of any other anti-neovascular eye disease active agent and / or without the concomitant administration of any additional analgesic and / or without the concomitant administration of any additional anti-inflammatory agent.

[0503] However, formula (I) compound or the pharmaceutical composition comprising formula (I) compound can also be used in combination with one or more other therapeutic agents. If formula (I) compound is used in combination with a second therapeutic agent that is active to the same disease or illness, the dosage of each compound may be different from the dosage when the corresponding compound is used alone, and in particular, each compound of lower dosage can be used. The combination of formula (I) compound and one or more other therapeutic agents can include formula (I) compound and other therapeutic agents (in a single pharmaceutical preparation or in a separate pharmaceutical preparation) or formula (I) compound or other therapeutic agents used sequentially / separately simultaneously. If used sequentially, formula (I) compound of the present invention or one or more other therapeutic agents can be first used. If used simultaneously, one or more other therapeutic agents can be included in identical pharmaceutical preparation with formula (I) compound, or they can be used in two or more different (separated) pharmaceutical preparations.

[0504] Preferably, in the case of treating or preventing cancer, the one or more additional therapeutic agents administered in combination with the compounds of the present invention are anticancer drugs. The one or more anticancer drugs administered in combination with the compounds of formula (I) according to the present invention may, for example, be selected from: 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 drugs or antimitotic alkaloids); platinum complexes; antitumor antibiotics; alkylating agents (e.g., nitrogen mustards or nitrosoureas); endocrine agents (e.g., adrenocortical steroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists or somatostatin analogs); or compounds that target enzymes or receptors of specific metabolic pathways that are overexpressed in tumor cells and / or otherwise involved in deregulation (or misregulation) (e.g., ATP and GTP phosphatases); Diesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (e.g., serine, threonine and tyrosine kinase inhibitors, such as Abelson protein tyrosine kinase inhibitor) and various growth factors, their receptors and corresponding kinase inhibitors (e.g., 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.

[0505] Alkylating agents that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, nitrogen mustards (e.g., cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or trofosfamide), nitrosoureas (e.g., carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), alkyl sulfonates (e.g., busulfan, mannosulfan, or treosulfan), aziridines (e.g., hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (N,N'N'-triethylenethiophosphoramide), carboquinone, or triaziquone); hydrazines (e.g., procarbazine), triazines (e.g., dacarbazine), or imidazotetrazines (e.g., temozolomide).

[0506] The platinum complex that can be used as an anticancer drug in combination with the compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin or triplatin tetranitrate.

[0507] Cytotoxic drugs that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, antimetabolites, including folic acid analog antimetabolites (e.g., aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (e.g., cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (e.g., cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

[0508] The antimitotic agent that can be used as an anticancer drug in combination with the compound of the present invention can be, for example, a taxane (e.g., docetaxel, larotaxel, ortataxel, paclitaxel / taxol), tesetaxel or nab-paclitaxel (e.g., )), vinca alkaloids (e.g., vinblastine, vincristine, vinflunine, vindesine, or vinorelbine), epothilones (e.g., epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F), or epothilone B analogs (e.g., ixabepilone / azaepothilone B).

[0509] The antitumor antibiotics that can be used as anticancer drugs in combination with the compounds of the present invention may be, for example, anthracyclines (e.g., aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin or daurubicin), anthracenediones (e.g., mitoxantrone or picoanthrone), or antitumor antibiotics isolated from Streptomyces (e.g., actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C) or plicamycin).

[0510] Tyrosine kinase inhibitors that can be used as anticancer drugs in combination with the compounds of the present invention can be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, axitinib, nintedanib, ponatinib, vandetanib or vemurafenib.

[0511] Topoisomerase inhibitors useful as anticancer drugs in combination with the compounds of the present invention may be, for example, topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin, belotecan, rubitecan or lamellar protein D) or topoisomerase II inhibitors (e.g., amsacrine, etoposide, etoposide phosphate, teniposide or doxorubicin).

[0512] The PARP inhibitor useful as an anticancer drug in combination with the compound of the present invention may be, for example, niraparib, olaparib, rucaparib, talazoparib, veliparib, pamiparib (BGB-290), BMN-673, CEP 9722, MK 4827, E7016 or 3-aminobenzamide.

[0513] The EGFR inhibitor / antagonist that can be used as an anticancer drug in combination with the compounds of the present invention can be, for example, gefitinib, erlotinib, lapatinib, afatinib, neratinib, osimertinib, brigatinib, dacomitinib, vandetanib, pelitinib, canertinib, icotinib, poziotinib, ABT-414, AV-412, PD 153035, PKI-166, BMS-690514, CUDC-101, AP26113, XL647, cetuximab, panitumumab, zalutumumab, nimotuzumab or matuzumab.

[0514] Other anticancer drugs can also be used in combination with the compounds of the present invention. Anticancer drugs can include biological or chemical molecules such as TNF-related apoptosis-inducing ligand (TRAIL), tamoxifen, amsacrine, bexarotene, estramustine, irofufen, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, avosidic acid, celecoxib, aminolevulinic acid methyl ester, efexirol, porfimer sodium, talaporfin, temoporfin, verteporfin, alitretinoin, retinoic acid, acid, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demeclocycline, lesiclomol, esatricin, etogluconol, lonidamine, lucanthone, masopropol, dibromomannitol, mitoguanidine, mitotane, oblimersen, omacetin, cetimagen, ceradenovec, tegafur, testolactone, thiazofurine, tipifarnib, vorinostat, iniparib, or copanlisib.

[0515] Biopharmaceuticals directed against tumor markers / factors / cytokines involved in cancer or proliferative diseases, such as antibodies, antibody fragments, antibody constructs (e.g., single chain constructs) and / or modified antibodies (e.g., CDR-grafted antibodies, humanized antibodies, "fully human" antibodies, etc.) can also be used in co-therapeutic methods with the compounds of the present invention. Examples of such biomolecules are anti-HER2 antibodies (e.g., trastuzumab, ), anti-CD20 antibodies (such as rituximab, ), anti-CD19 / CD3 constructs (see, for example, EP1071752) and anti-TNF antibodies (see, for example, Taylor PC, Curr Opin Pharmacol, 2003, 3(3):323-328). Additional antibodies, antibody fragments, antibody constructs and / or modified antibodies for use in co-therapy methods with the compounds of the 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.

[0516] The anti-cancer drug that can be used in combination with the compounds of the present invention may be, in particular, an immuno-oncology therapeutic agent targeting any one of CTLA-4, PD-1, PD-L1, TIM3, LAG3, OX40, CSF1R, IDO or CD40 (e.g., an antibody (e.g., a monoclonal antibody or a 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). Such immuno-oncology therapeutic agents 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), pirimumab (CT-011), 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-986016, 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). In addition, immuno-oncology therapeutic agents are well known in the art and described in, for example, 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.

[0517] Particularly advantageous is the administration of 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 or antibody construct thereof) directed against CTLA-4, PD-1 or PD-L1. Examples include, in particular, any of the anti-CTLA-4 antibodies ipilimumab or tremelimumab, any of the anti-PD-L1 antibodies nivolumab, pembrolizumab, cemiplizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, AMP-224 or AMP-514, and / or any of the anti-PD-L1 antibodies atezolizumab, avelumab, durvalumab, KN035 or CK-301. Therefore, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any one of the above entities and a pharmaceutically acceptable excipient, for use in treating or preventing cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more immune checkpoint inhibitors, wherein the 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, the one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplizumab, spartalizumab, carrelizumab, sintilimab, tislelizumab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035 and CK-301.

[0518] The above-mentioned combination related to can be used in the form of pharmaceutical preparations conveniently. The individual components of this type of combination can be administered sequentially or simultaneously / concomitantly in a separate or combined pharmaceutical preparation by any convenient approach. When administered sequentially, the compounds of this invention (i.e., formula (I) compound or a pharmaceutically acceptable salt thereof) or another therapeutic agent can be administered first. When administered simultaneously, the combination can be administered in the same pharmaceutical composition or in different pharmaceutical compositions. When combined in the same preparation, it should be understood that two or more compounds must be stable and compatible with each other and with the other components of the preparation. When formulated separately, they can be provided with any convenient preparation.

[0519] Formula (I) compound can also be administered in combination with physical therapy such as radiotherapy. Radiotherapy can start before, after or simultaneously with the administration of the compounds of this invention. For example, radiotherapy can start about 1 to 10 minutes, about 1 to 10 hours or about 24 to 72 hours after the administration of the compounds of formula (I). Individuals / patients are exposed to radiation, preferably gamma radiation, wherein the 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 using standard doses and protocols according to standard radiotherapy protocols.

[0520] Therefore, 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 treating or preventing cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more anticancer drugs (including any one or more specific anticancer drugs described above) and / or in combination with radiotherapy.

[0521] However, the compounds of formula (I) can also be used in monotherapy, in particular for the treatment or prevention of cancer as a monotherapy (i.e., without administering any other anticancer agent before the termination of treatment with the compound of formula (I)). Therefore, the present invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the above entities in combination with a pharmaceutically acceptable excipient, for use in the treatment or prevention of cancer as a monotherapy.

[0522] In addition, the compound of formula (I) - in combination with one or more additional anticancer agents (including any of the exemplary anticancer agents described above) or without any additional anticancer agent - can also be administered in combination with an antiemetic. The antiemetic can, for example, be selected from alosetron, azasetron, bemisetron, cilansetron, clozapine, dazopril, dolasetron, granisetron, lerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (e.g., alone or in combination with netupitant), quetiapine, ramosetron, licarsetron, tropisetron, zatosetron, clozapine, cyproheptadine, hydroxyzine, olanzapine, risperidone, ziprasidone, dronabinol, nabilone, tetrahydrocannabinol, alizapride, bromopride, chlorpromazine, clebopride, domperidone, haloperidol, hydroxyzine, itopride, metoclopramide, metoprazine, prochlorperazone, thiethylpyralid, trimethobenzamide, cyclidine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, promethazine, atropine, diphenhydramine, scutellarin, scopolamine, aprepitant, casopitant, elopitant, fosaprepitant, maropitant, netupitant, rolapitant, vertipitant, cerium oxalate, dexamethasone, lorazepam, midazolam, propofol, or a combination thereof. Preferably, the antiemetic is a 5-HT3 antagonist (or "setron"), such as alosetron, azasetron, bemisetron, cilansetron, clozapine, dazopril, dolasetron, granisetron, nerisetron, metoclopramide, mianserin, mirtazapine, olanzapine, ondansetron, palonosetron (optionally in combination with netupitant), quetiapine, ramosetron, licarsetron, tropisetron or zaltosetron. A particularly preferred antiemetic is palonosetron.

[0523] The individual or patient treated according to the present invention can be an animal (e.g., a non-human animal). Preferably, the individual / patient is a mammal. More preferably, the individual / patient is a human (e.g., a male or female human) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cattle, or pig). Most preferably, the individual / patient treated according to the present invention is a human.

[0524] As used herein, the term "treatment" of a disorder or disease is well known in the art. "Treatment" of a disorder or disease means that the disorder or disease is suspected or has been diagnosed in a patient / individual. Patients / individuals suspected of having a disorder or disease typically display specific clinical and / or pathological symptoms that can be readily attributed to a specific pathological condition (i.e., diagnosed as a disorder or disease) by those skilled in the art.

[0525] For example, "treatment" of a disorder or disease may result in cessation of 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 cessation of progression is only of a transient nature). "Treatment" of a disorder or disease may also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) in the individual / patient suffering from the disorder or disease. Therefore, "treatment" of a disorder or disease may also refer to an improvement in the disorder or disease, which may, for example, result in cessation of the progression of the disorder or disease or a delay in the progression of the disorder or disease. Relapse may occur after such a partial or complete response. It should be understood that individuals / patients may have a wide range of responses to treatment (e.g., the exemplary responses described above). The treatment of a disorder or disease may particularly include curative treatment (preferably resulting in a complete response and ultimately curing the disorder or disease) and palliative treatment (including symptom relief).

[0526] As used herein, the term "prevention" disorder or disease is also well known in the art. For example, it is suspected that the patient / individual who is prone to disorder or disease can particularly benefit from the prevention of disorder or disease. Individual / patient may have susceptibility or tendency to disorder or disease, including but not limited to genetic tendency. Such tendency 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 prevented according to the present invention has not yet been diagnosed in the patient / individual or cannot be diagnosed in the patient / individual (for example, the patient / individual does not show any clinical or pathological symptoms). Therefore, the term "prevention" includes the use of the compounds of this invention before the attending physician diagnoses or determines or can diagnose or determine any clinical and / or pathological symptoms.

[0527] It will be understood that the present invention relates in particular to each and every combination of the features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the present invention relates in particular to each and every combination of the meanings (including general and / or preferred meanings) given for the various groups and variables contained in formula (I) or (Ia).

[0528] Throughout this specification, numerous references are cited, including patent applications and scientific literature. The disclosures of these documents are incorporated herein by reference in their entirety, but they are not considered relevant to the patentability of the present invention. More specifically, all referenced documents are incorporated herein by reference to the same extent as if each individual document were specifically and individually listed.

[0529] Reference to any prior publication (or information derived therefrom) in this specification is not, and should not be taken as, an admission or acknowledgement or any form of implication that the corresponding prior publication (or information derived therefrom) constitutes part of the common general knowledge in the technical field to which this specification relates.

[0530] The invention is further described by means of the following exemplary drawings:

[0531] Figure 1 : Comparison of total tumor regression between the anti-PD-1 group and the anti-PD1 + Example 25 group in the CT26 tumor model (see Example 212).

[0532] Figure 2 : Average tumor volume in the Pan02 tumor model (see Example 213).

[0533] Figure 3 : Average tumor volume in the Pan02 tumor model (see Example 214).

[0534] Figure 4 : Average tumor volume in the MCA205 tumor model (see Example 215).

[0535] The present 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

[0536] The compounds of formula (I) described in this section, including in particular Examples 1-210, are defined by their chemical formulas and their corresponding chemical names. In the event that any chemical formula conflicts with the corresponding chemical name shown herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and in particular to the compound defined by the chemical formula.

[0537] abbreviation:

[0538] The following abbreviations are used in the test methods.

[0539] Ac acetyl

[0540] Boc tert-Butoxycarbonyl

[0541] BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphine Hexafluorophosphate

[0542] BRET Bioluminescence Resonance Energy Transfer

[0543] cAMP cyclic adenosine monophosphate

[0544] DCM dichloromethane

[0545] DIAD Diisopropyl azodicarboxylate

[0546] DIPEA N,N-Diisopropylethylamine

[0547] DMA N,N-dimethylacetamide

[0548] DMAP 4-dimethylaminopyridine

[0549] DMF N,N-dimethylformamide

[0550] DMF-DMA N,N-dimethylformamide dimethyl acetal

[0551] DMSO dimethyl sulfoxide

[0552] DNA deoxyribonucleic acid

[0553] EPAC cAMP-activated exchange protein

[0554] EtOAc

[0555] GFP Green Fluorescent Protein

[0556] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0557] HEK human embryonic kidney

[0558] HPLC high-performance liquid chromatography

[0559] KHMDS Potassium bis(trimethylsilyl)amide

[0560] LC-MS liquid chromatography-mass spectrometry

[0561] LDA lithium diisopropylamide

[0562] MeOH methanol

[0563] n-BuLi n-butyllithium

[0564] NMR Nuclear Magnetic Resonance

[0565] ppm parts per million

[0566] PS polystyrene

[0567] rt room temperature

[0568] TBAF Tetrabutylammonium fluoride

[0569] THF Tetrahydrofuran

[0570] TFA trifluoroacetic acid

[0571] TLC thin layer chromatography

[0572] UPLC Ultra-Performance Liquid Chromatography

[0573] General conditions:

[0574] All reagents were of commercial grade and used without further purification. Reactions were generally carried out using anhydrous solvents under an inert atmosphere. The indicated reaction temperatures are setpoint temperatures. Reactions under microwave irradiation were carried out at automatically adjusted power; the indicated reaction times correspond to the time the reaction mixture was at the setpoint temperature before cooling. The organic layer was generally dried over sodium sulfate or magnesium sulfate or by SPE Single Fritterd cartridge filtration. Thin layer chromatography was performed using pre-coated silica gel F-254 plates. Flash column chromatography was performed using the isolera 4 system, or if not specified, using SNAP column KP-Sil. In certain cases, you can use SNAP KP-NH or Interchim PF-15SIHP-F0025 (15 μm) column. After purification by flash chromatography, the examples were typically triturated in diethyl ether or diisopropyl ether or pentane and then dried overnight in vacuo at 70° C. The examples were typically synthesized on a 10-100 mg scale.

[0575] The reaction was monitored and the compounds were characterized using a Waters Acquity UPLC H-class system with a photodiode array detector (190-400 nm). An Acquity CSH C18 1.7 μM 2.1 × 30 mm column was used. The mobile phase consisted of a gradient of A and B: A was water containing 0.025% trifluoroacetic acid, and B was acetonitrile containing 0.025% trifluoroacetic acid. The flow rate was 0.8 mL / min. 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). Positive electrospray ionization was used to obtain mass spectra.

[0576] 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 forming analytical and preparative modes. An Xselect CSH C18 3.5 μM 4.6×50 mm column was used for analytical mode, and a CSH C18 5 μM 19×100 mm column was used for preparative mode. In both cases, the mobile phase consisted of a gradient of A and B: A was water containing 0.1% formic acid, and B was acetonitrile containing 0.1% formic acid. The flow rate was 1 mL / min in analytical mode and 25 mL / min 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). Positive electrospray ionization was used to obtain mass spectra.

[0577] All NMR experiments were recorded using a Brucker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual DMSO (2.50 ppm). Resolution patterns were assigned as s (singlet); d (doublet); dd (double of doublets); t (triplet); dt (double of triplets); td (triplet of doublets); tt (triplet of triplets); q (quartet); quint (quintet); m (multiplet); bs (broad singlet); and bd (broad doublet).

[0578] Common operations and methods:

[0579] General Method Ia: Amide Coupling Using BOP

[0580] In the solution (0.1M) of carboxylic acid (1 equivalent) in DMF, amine (1.2 equivalent), diisopropylethylamine (2 equivalents) and BOP (1.2 equivalents) are added. The reaction mixture is stirred at rt for 1 hour. Dilute the reaction mixture with EtOAc, wash with salt water, dry, then concentrate. When specified, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0581] General Method Ib: Amide Coupling using HATU

[0582] In the solution (0.1M) of carboxylic acid (1 equivalent) in DMF, add amine (1.2 equivalent), diisopropylethylamine (2 equivalents) and HATU (1.2 equivalents).Reactant mixture was stirred at rt for 1 hour.Dilute the reaction mixture with EtOAc, wash with salt water, dry, then concentrate.When specifying, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0583] General Method II-a: Boc cleavage

[0584] The solution of the amine (1 equivalent) of Boc-protection in DCM / TFA mixture (1 / 1,0.1M) was stirred at rt for 1 hour. The reaction mixture was concentrated to dryness. The residue obtained was dissolved in DCM, washed with a saturated solution of potassium carbonate and salt water, dried, and then concentrated. When specified, the crude product obtained by flash chromatography purification obtained obtained the desired compound.

[0585] General Method II-b: Boc cleavage

[0586] The amine of Boc-protection (1 equivalent) in DCM / TFA mixture (1 / 1,0.1M) was stirred at rt for 1 hour. The reaction mixture was concentrated to dryness. The residue obtained was dissolved in DCM and HCl 2M in ether was added. The precipitation obtained was filtered and then vacuum-dried to obtain the desired compound as its hydrochloride salt.

[0587] General Method II-c: Boc cleavage

[0588] A solution of the Boc-protected amine (1 equivalent) in a DCM / TFA mixture (1 / 1, 0.1 M) was stirred at rt for 1 hour. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in methanol and then filtered through an SCX resin to recover the free base. After concentrating the solution, the residue was dissolved in methanol and 1.25 M HCl in methanol was added. The concentrated solution gave the desired compound as its hydrochloride salt.

[0589] General Method III-a: Reductive Amination

[0590] In the solution (0.1M) of amine (1 equivalent) in THF, add aldehyde (1.2 equivalent), NaBH (OAc) (2 equivalents) and acetic acid (1 equivalent).Reactant mixture is stirred at rt overnight.Use EtOAc diluted reaction mixture, with saturated sodium bicarbonate solution and salt water washing, dry, then concentrate.When specifying, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0591] General Method III-b: Reductive Amination

[0592] In the solution (0.1M) of amine (1 equivalent) in THF, aldehyde (1.2 equivalent), NaBH (OAc) 3 (2 equivalents) are added. The reaction mixture is stirred at rt overnight. The reaction mixture is diluted with EtOAc, washed with saturated sodium bicarbonate solution and salt water, dried, and then concentrated. When specified, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0593] General Method IV-a: Ester Hydrolysis

[0594] A suspension of the ester (1 equivalent) in HCl 1N aqueous solution (0.1 M) was stirred at 150° C. under microwave irradiation for 5 minutes. The resulting solution was concentrated to dryness. If necessary, the residue was purified by preparative LC-MS, otherwise it was simply triturated in ether or pentane to give the desired compound.

[0595] General Method IV-b: Ester Hydrolysis

[0596] The methyl ester (1 equivalent) was dissolved in 1N aqueous HCl / dichloromethane The solution was stirred at 150°C under microwave irradiation for 5 minutes in a mixture of 7 / 3 oxanes (0.1 M). The resulting solution was concentrated to dryness. If necessary, the residue was purified by preparative LC-MS, otherwise it was simply triturated in ether or pentane to give the desired compound.

[0597] General Method Va: Saponification

[0598] To a solution of the ester (1 eq) in THF (0.2 M) was added LiOH 1 M aqueous solution (2 eq). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was concentrated to dryness to give the desired compound.

[0599] General Method Vb: Saponification

[0600] The 1M aqueous solution of LiOH (2 equivalents) is added to a solution (0.2M) of ester (1 equivalent) in THF. The reaction mixture is stirred at 70 ° C overnight. The reaction mixture is cooled to rt, acidified with HCl 1N aqueous solution, extracted with DCM. The organic layer is washed with salt water, dried, and then concentrated. If necessary, the residue is purified by preparative LC-MS, otherwise it is simply ground in ether or pentane to obtain the desired compound.

[0601] General Method Vc: Saponification

[0602] The 1M aqueous solution of LiOH (2 equivalents) is added to a solution (0.2M) of ester (1 equivalent) in THF. The reaction mixture is stirred overnight at rt. The concentrated reaction mixture is diluted with water to remove THF and extracted with ether. The aqueous layer is acidified with HCl 1N aqueous solution. The precipitation obtained is filtered. If necessary, the residue is purified by preparative LC-MS, otherwise it is simply ground in ether or pentane to obtain the desired compound.

[0603] General Method Vd: Saponification

[0604] In the ester (1 equivalent) in the di The product of 4-nitro-1-oxo-2-oxo-4-oxo-1-oxo-4-oxo-2 ...

[0605] General Method Ve: Saponification

[0606] To a solution of the ester (1 eq) in THF (0.2 M) was added LiOH 1 M aqueous solution (2 eq). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was directly purified by preparative LC-MS to give the desired compound.

[0607] General Method Vf: Saponification

[0608] In the ester (1 equivalent) in the di To a solution of 1-[4-[4-[4-(4-oxo-1-yl)-2-nitropropene]propene (0.2 M) in oxane was added a 1 M aqueous solution of LiOH (2 equivalents). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated to dryness to give the desired compound.

[0609] General Method VI-a: α-Arylation of Ester

[0610] At -15 ℃ in an argon atmosphere, LDA 1M (1.6 equivalents) in THF was added dropwise in a solution (0.2M) of an ester (1.7 equivalents) in toluene. The reaction mixture was stirred at -15 ℃ for 15 minutes and then allowed to warm to rt. Bromoarene (1 equivalent) and {(Pt-Bu 3 ) PdI} 2 (5mol%) were added. The reaction mixture was stirred at rt overnight. The reaction mixture was hydrolyzed with HCl 1N aqueous solution and extracted with EtOAc. The organic layer was washed with salt water, dried, and then concentrated. When specified, the crude mixture obtained was purified by flash chromatography to obtain the desired compound.

[0611] General Method VI-b: α-Arylation of Ester

[0612] At -15 ℃ in argon atmosphere in the solution (0.2M) of ester (1.7 equivalents) in toluene, LDA 1M (1.6 equivalents) in THF was added dropwise. The reaction mixture was stirred at -15 ℃ for 15 minutes and then allowed to warm to rt. Halogenated-(hetero)arene (1 equivalent) and Pd(Pt-Bu ) 2 were added. The reaction mixture was stirred at rt overnight. The reaction mixture was hydrolyzed with HCl 1N aqueous solution and extracted with EtOAc. The organic layer was washed with salt water, dried, and then concentrated. When specified, the crude mixture obtained by flash chromatography purification gave the desired compound.

[0613] General Method VII-a: Nucleophilic Aromatic Substitution Using Carbanions

[0614] At 0 ℃ in an argon atmosphere in a solution (0.2M) of formonitrile (1 equivalent) in toluene, KHMDS 1M (1.05 equivalent) in THF was added dropwise. The reaction mixture was stirred at 0 ℃ for 15 minutes and then allowed to warm to rt. Halogenated-heteroaromatics (2.5 equivalents) was added. The reaction mixture was stirred at rt 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 salt water, dried, and then concentrated. When specified, the crude mixture obtained by flash chromatography purification gave the desired compound.

[0615] General Method VII-b: Nucleophilic Aromatic Substitution with Acetonitrile

[0616] At -78 ℃ in acetonitrile (3.4 equivalents) in THF solution (0.2M) add n-BuLi 1.6M (3.3 equivalents) in THF.Reactant mixture was stirred at -78 ℃ for 45 minutes.Add dropwise a solution (0.4M) of halo-heteroaromatics (1 equivalent) in THF.Make the reaction mixture warm to rt, and stir 2 hours at rt.The reaction mixture was hydrolyzed with water, then extracted with EtOAc.With salt water washing organic layer, dry, then concentrate.When specified, the crude mixture obtained by flash chromatography purification obtains desired compound.

[0617] General Method VII-c: Nucleophilic Aromatic Substitution Using Aliphatic Alcohols

[0618] At 0 ℃, sodium hydride (1.4 equivalents) was added to a solution (0.12M) of aliphatic alcohol (1.3 equivalents) in DMA. The reaction mixture was stirred at 0 ℃ for 10 minutes. A solution (0.4M) of halo-heteroaromatic (1 equivalent) in DMA was added. The reaction mixture was stirred at 150 ℃ for 10 minutes under microwave radiation. The reaction mixture was hydrolyzed with a saturated solution of ammonium chloride and then extracted with EtOAc. The organic layer was washed with salt water, dried, and then concentrated. When specified, the crude mixture obtained by flash chromatography was purified to obtain the desired compound.

[0619] General Method VIII-a: Saturated Carbon / Heterocycle Synthesis

[0620] To a solution (0.1M) of an ester or cyanide (1 equivalent) in DMA, sodium hydride (2 equivalents) was added. The reaction mixture was stirred at 0°C for 10 minutes. Two-haloalkane (1 equivalent) was added. The reaction mixture was stirred at rt 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 salt water, dried, and then concentrated. When specified, the crude mixture obtained by flash chromatography was purified to obtain the desired compound.

[0621] General Method VIII-b: Synthesis of Saturated Nitrogen-Containing Heterocycles

[0622] To a solution (0.1M) of primary amine (1.3 equivalents) in acetonitrile was added potassium carbonate (2 equivalents) and a di-haloalkane 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. When specified, the crude mixture obtained was purified by flash chromatography to obtain the desired compound.

[0623] General Method IX-a: Mitsunobu Method Using Polymer-Bound Triphenylphosphine

[0624] In the solution (0.1M) of phenol (1 equivalent) in THF, add DIAD (1.6 equivalent), PS-triphenylphosphine (2.2 equivalent) and aliphatic alcohol (1.5 equivalent).Use orbital oscillator that reaction mixture is stirred at rt overnight.Filter reaction mixture, dilute with EtOAc, use salt water washing, dry, then concentrate.When specifying, the thick mixture obtained by purification by flash chromatography obtains the compound of expectation.

[0625] General Method IX-b: Mitsunobu

[0626] In the solution (0.1M) of phenol (1 equivalent) in THF, add DIAD (1.5 equivalents), triphenylphosphine (1.5 equivalents) and aliphatic alcohol (1.5 equivalents).Reactant mixture was stirred 3 hours at rt.Dilute the reaction mixture with DCM, wash with salt water, dry, then concentrate.When specifying, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0627] General Method X: Nucleophilic Substitution with Phenol

[0628] To a solution of phenol (1 equivalent) in DMF (0.1 M) was added potassium carbonate (2 equivalents) and an electrophilic reagent (1.5 equivalents). The reaction mixture was stirred at rt overnight. The reaction mixture was cooled to 0°C and hydrolyzed with water. The resulting precipitate was filtered. When indicated, the resulting crude mixture was purified by flash chromatography to give the desired compound.

[0629] General Method XI-a: Hydration of MeCN

[0630] To a solution of formonitrile (1 eq) in DMSO (0.2 M) was added potassium carbonate (1 eq) and H O 30% (2 eq) in water. The reaction mixture was stirred overnight at rt. Water was added to the reaction mixture. The resulting precipitate was filtered, washed with water, and then dried under vacuum at 70° C. using P O. When specified, the resulting crude mixture was purified by flash chromatography to give the desired compound.

[0631] General Method XI-b: Hydration of MeCN

[0632] A solution of methyl nitrile (1 equivalent) in concentrated H2SO4 (0.2 M) was stirred at rt overnight. The reaction mixture was poured into crushed ice and potassium carbonate was then 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 resulting solid was suspended in DCM and filtered. The filtrate was concentrated to give the desired compound.

[0633] General Method XI-c: MeCN Hydration / Hydrolysis

[0634] A solution of carbonitrile (1 eq.) in aqueous HCl 12N (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 in vacuo at 70° C. to give the desired compound.

[0635] General Method XII: Synthesis of Methyl Esters from Primary Amides

[0636] In the solution (0.1M) of primary amide (1 equivalent) in methanol, DMF-DMA (6 equivalents) is added. The reaction mixture is stirred at rt overnight. Sodium methoxide (5 equivalents) is added. The reaction mixture is stirred at rt for 5 hours. The reaction mixture is hydrolyzed with water, then extracted with EtOAc. The organic layer is washed with salt water, dried, and then concentrated. When specified, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0637] General Method XIII: Pd-catalyzed Arylation of Aliphatic Alcohols

[0638] In the presence of bromo-arene (1 equivalent) Cesium carbonate (2 equivalents) and aliphatic alcohol (6 equivalents) were added to a solution (0.1M) in dextrose. The reaction mixture was degassed with argon for 10 minutes, followed by the addition of RockPhosPd G3 (5 mol%). 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. When specified, the crude mixture obtained was purified by flash chromatography to obtain the desired compound.

[0639] General Method XIV: Silyl Protection of Primary Alcohols

[0640] In the solution (0.3M) of primary alcohol (1 equivalent) in DCM, add tert-butyl-chloro-dimethyl-silane (1.8 equivalents), triethylamine (2.2 equivalents) and DMAP (0.1 equivalent).Reaction mixture is stirred at rt overnight.The reaction mixture is hydrolyzed with water, then extracted with DCM.With salt water washing organic layer, dry, then concentrate.When specifying, the crude mixture obtained by purification by flash chromatography obtains the desired compound.

[0641] General Procedure XV-a: Silyl Deprotection

[0642] In the solution (0.1M) of phenol (1 equivalent) in THF of silyl-protection, add TBAF 1M (2 equivalents) in THF.Reaction mixture is stirred 1 hour at rt, then cooled to 0 ℃, hydrolyzed with water, and extracted with EtOAc.With salt water washing organic layer, dry, then concentrate.When specifying, the crude mixture that obtains by flash chromatography purification obtains desired compound.

[0643] General Procedure XV-b: Silyl Deprote...

Claims

1. Compound of the following formula (I) in: A 1 and A 2 Each independently is C 1-4 Alkyl, or A 1 and A 2 Each other and the carbon atoms to which they are attached are connected to form a monocyclic or bicyclic C 3-11 Cycloalkylene or 3-11 membered monocyclic or bicyclic heterocycloalkylene, wherein the heterocycloalkylene contains one or two heteroatoms independently selected from O, S and N, and wherein the cycloalkylene or the heterocycloalkylene is optionally substituted by one or more groups R 1 replace; Ring B is phenylene, C 3-9 Cycloalkylene or pyridylene; Ring D is phenyl, cyclohexyl or pyridyl; L is -(CH2) 3-5 -, wherein said -(CH2) 3-5 - one or two -CH2- units contained in - are each optionally independently 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)]-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 alkyl)-, and further wherein L is connected to ring D through -CH2- contained in said L or through -O- contained in said L; or L is -heterocycloalkylene-(CH2) 1-2 -, wherein said -heterocycloalkylene-(CH2) 1-2 -heterocycloalkylene is a 5-7 membered monocyclic heterocycloalkylene containing one or two ring heteroatoms selected from N, wherein said -heterocycloalkylene-(CH2) 1-2 - one -CH2- unit contained in - is optionally replaced by -O-, and further wherein L is connected to ring D through -CH2- contained in said L or through -O- contained in said L; If A 1 and A 2 Each independently is C 1-4 alkyl, then L is -heterocycloalkylene-(CH2) 1-2 -, wherein said -heterocycloalkylene-(CH2) 1-2 -heterocycloalkylene is a 5-7 membered monocyclic heterocycloalkylene containing one or two ring heteroatoms selected from N, wherein said -heterocycloalkylene-(CH2) 1-2 - one -CH2- unit contained in - is optionally replaced by -O-, and further wherein L is connected to ring D through -CH2- contained in said L or through -O- contained in said L; m is an integer from 0 to 4; p is an integer from 0 to 4; R 1 Each independently selected from 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 and -CN; R 2 is hydrogen or C 1-5 alkyl; X is C(R 3a )(R 3b ); R 3a C 1-5 Alkyl, and R 3b is hydrogen or C 1-5 Alkyl; or R 3a and R 3b Each other and the carbon atoms to which they are connected form C 3-5 Cycloalkyl; R 4 Each independently selected from 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 and -CN; R 5 Selected from -COOH, -CO-NH2, -CO-NH(C 1-5 Alkyl), -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), -SO2-(C 1-5 alkyl), -S(=O)(=NH)-(C 1-5 alkyl), halogen, C 1-5 Haloalkyl, -CN, C 2-4 Alkyl, -OH, -O(C 1-4 alkyl) and heteroaryl, wherein the heteroaryl is selected from tetrazolyl, pyrazolyl and oxadiazole; R 6 Each independently selected from 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, -O-(C 1-5 haloalkyl) and -CN; L A Each independently selected from a covalent bond and C 1-5 an alkylene group; and R A Each independently selected from -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) and -CN; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A 1 and A 2 Each is methyl, or A 1 and A 2 Each other and the carbon atom to which they are attached are connected to form a cyclic group selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothienylene, tetrahydropyranylene and thianylene, wherein the cyclic group is optionally substituted by one or more groups R 1 replace.

3. The compound according to claim 1, wherein ring B is phenylene.

4. The compound of claim 1, wherein X is C(R 3a )(R 3b ); and wherein R 3a C 1-5 Alkyl, and R 3b is hydrogen or C 1-5 Alkyl, or R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

5. The compound of claim 1, wherein R 5 Selected from -COOH, -CO-NH2, -CO-NH(C 1-5 Alkyl), -CO-N(C 1-5 Alkyl)(C 1-5 alkyl), -SO2-(C 1-5 alkyl), -S(=O)(=NH)-(C 1-5 alkyl) and tetrazolyl.

6. The compound of claim 1, wherein part for 7. The compound of claim 1, wherein ring D is phenyl.

8. The compound of any one of claims 1 to 7, wherein: L is -CH2-CH2-CH2-CH2-, wherein one or two -CH2- units contained in said -CH2-CH2-CH2-CH2- are each optionally independently 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)]-, -CH(C 1-5 alkyl)- and -C(C 1-5 Alkyl)(C 1-5 alkyl)-, and further wherein L is connected to ring D through -CH2- contained in said L or through -O- contained in said L; or alternatively, L is -heterocycloalkylene-CH2-, wherein the heterocycloalkylene in said -heterocycloalkylene-CH2- is a 5-7 membered monocyclic heterocycloalkylene containing one ring heteroatom which is N, wherein the -CH2- unit in said -heterocycloalkylene-CH2- is optionally replaced by -O-, and further wherein L is connected to ring D through -CH2- contained in said L or through -O- contained in said L.

9. The compound of any one of claims 1 to 7, wherein L is -CH2-CH2-CH2-O-, which is linked to ring D via the oxygen atom of the group -CH2-CH2-CH2-O-, and wherein the terminal -CH2- unit furthest from the oxygen atom of the -CH2-CH2-CH2-O- is optionally 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 or alternatively, L is -heterocycloalkylene-O-, which is connected to ring D via the oxygen atom in the group -heterocycloalkylene-O-, wherein the heterocycloalkylene in the -heterocycloalkylene-O- is a 5-7 membered monocyclic heterocycloalkylene containing one ring heteroatom which is N, and wherein the heterocycloalkylene in the -heterocycloalkylene-O- is connected in a 1,3-direction.

10. The compound of any one of claims 1 to 7, wherein L is selected from -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -O-CH2-CH2-O-, wherein each of the above groups is linked to the ring D via a terminal oxygen atom contained therein.

11. The compound of claim 1, wherein: -A 1 and A 2 Each independently is methyl or ethyl, or A 1 and A 2 Each other and the carbon atom to which they are attached are connected to form a cyclic group selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, tetrahydrofuranylene, tetrahydrothienylene, tetrahydropyranylene and thianylene, wherein the cyclic group is optionally substituted by one or more groups R 1 replace; -X is C(R 3a )(R 3b ); where R 3a C 1-5 Alkyl, and R 3b is hydrogen or C 1-5 Alkyl, or wherein R 3a and R 3b are joined to each other and the carbon atom to which they are attached to form a cyclopropyl group; and -L is selected from -CH2-CH2-CH2-O-, -NH-CH2-CH2-O-, -N(-CH3)-CH2-CH2-O-, -N(-CH2CH3)-CH2-CH2-O-, -N(-CH2CH2CH3)-CH2-CH2-O-, -N(-CH2-cyclopropyl)-CH2-CH2-O-, -N(-CO-CH3)-CH2-CH2-O-, -NH-CO-CH2-O-, -O-CH2-CH2-O-, wherein each of the above groups is linked to the ring D via a terminal oxygen atom contained therein.

12. The compound of any one of claims 1 to 7 or 11, wherein p is 1, wherein R 6 is attached to ring D in a 1,3 direction relative to the point of attachment of group L to ring D, and wherein R 6 Selected from -CH3, -OH, -OCH3, halogen, -CF3, -OCF3 and -CN.

13. The compound of claim 1, wherein the compound is 4-[(1S)-1-[[2-[(3R)-3-[3-(trifluoromethyl)phenoxy]pyrrolidin-1-yl]-2-methylpropane-carbonyl]amino]ethyl]benzoic acid or a pharmaceutically acceptable salt thereof.

14. A compound selected from the group consisting of: 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)thiazane-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-[6-(cyclohexylmethoxy)-2-pyridyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[2-(cyclohexylmethoxy)-4-pyridinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-(cyclohexylmethoxy)-2-pyridinyl]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-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[(1S)-1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[4-[(3-chlorophenyl)methoxy]-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3S)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]cyclopropyl]benzoic acid; 4-[(1S)-1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidinyl]tetrahydropyran-4-carbonyl]amino]ethyl]benzoic acid; 4-[1-[[4-[(3R)-3-(3-chlorophenoxy)-1-piperidinyl]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-methylaminoimidenesulfonyl)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-methylaminoimidenesulfonyl)phenyl)ethyl)-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4- oxadiazole-3-yl)phenyl)ethyl)-2-methyl-2-((R)-3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)propanamide; N-((S)-1-(4-(1,2,4- oxadiazole-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-methylpropionylamino)ethyl)benzoic acid; 4-((S)-1-(2-((R)-3-((3-chlorophenoxy)methyl)pyrrolidin-1-yl)-2-methylpropionylamino)ethyl)benzoic acid; and 4-[(1S)-1-[[2-[(3R)-3-(3-chlorophenoxy)pyrrolidin-1-yl]-2-ethylbutane-carbonyl]amino]ethyl]benzoic acid; or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, 11, 13 or 14 and a pharmaceutically acceptable excipient.

16. Use of a compound according to any one of claims 1 to 7, 11, 13 or 14 in the preparation of a medicament for treating or preventing a disease selected from the group consisting of EP4-related cancers, EP4-related inflammatory diseases and EP4-related neovascular eye diseases.

17. The use according to claim 16, wherein the disease is EP4-related cancer.

18. The method of claim 17, wherein the EP4-associated cancer is selected from the group consisting of lung cancer, gastrointestinal cancer, malignant familial adenomatous polyposis, anal cancer, genitourinary cancer, liver cancer, pancreatic cancer, bile duct cancer, neuroblastoma, brain cancer, breast cancer, head and / or neck cancer, skin cancer, bone cancer, malignant mesothelioma, thymoma, neuroendocrine cancer, and blood cancer.

19. The method of claim 17, wherein the EP4-related cancer is selected from the group consisting of non-small cell lung cancer, gastric cancer, colorectal cancer, renal cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, prostate cancer, testicular cancer, hepatobiliary cancer, fibrosarcoma, Ewing sarcoma, esophageal cancer, laryngeal cancer, oral cancer, leukemia, lymphoma, multiple myeloma, melanoma, Merkel cell carcinoma, epidermoid carcinoma, and squamous cell carcinoma.

20. The use of claim 17, wherein the EP4-related cancer is selected from colon cancer and acute myeloid leukemia.

21. The use according to claim 16, wherein the disease is EP4-related inflammatory pain.

22. The use of claim 21, wherein the EP4-related inflammatory pain is selected from osteoarthritis pain, inflammatory pain associated with rheumatoid arthritis, and inflammatory post-operative pain.

23. The use according to claim 16, wherein the disease is an EP4-related inflammatory disease.

24. The use of claim 23, wherein the EP4-related inflammatory disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, endometriosis and osteoarthritis.

25. The use according to claim 16, wherein the disease is EP4-related neovascular eye disease.

26. The use of claim 25, wherein the EP4-related neovascular eye disease is selected from the group consisting of neovascular degenerative maculopathy, proliferative diabetic retinopathy, neovascular glaucoma and retinopathy of prematurity.

27. The use of any one of claims 17-20, wherein the medicament is administered in combination with one or more immune checkpoint inhibitors.

28. The use of claim 27, wherein the one or more immune checkpoint inhibitors are selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies and / or anti-PD-L1 antibodies.

29. The method of claim 27, wherein the one or more immune checkpoint inhibitors are selected from ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, and CK-301.

30. Use of a compound as defined in any one of claims 1 to 7, 11, 13 or 14 as an EP4 receptor antagonist in vitro.

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