TW202241399A - Combination of ep receptor antagonist with immune checkpoint inhibitor and/or ep receptor antagonist - Google Patents

Abstract

An object of the present invention is to provide an effective cancer treatment method. As a solution, provided is a combination of a compound represented by general formula (IA): (wherein all symbols have the same meanings as those described in the specification), a pharmaceutically acceptable salt thereof, their hydrates with an immune checkpoint inhibitor (eg, anti-PD-1 antibody, etc.) and/or an EP4 receptor antagonist. The combination of the present invention exerts a strong antitumor effect and is therefore useful for cancer treatment.

Description

Combinations of EP2 receptor antagonists with immune checkpoint inhibitors and/or EP4 receptor antagonists

(式中，所有的符號表示與後述相同的意義) This disclosure relates to compounds represented by general formula (IA), their pharmaceutically acceptable salts or their hydrates (hereinafter also referred to as compounds used in the present invention), and immune checkpoint inhibitors and/or Combination therapy with EP ₄ receptor antagonists.

(In the formula, all the symbols have the same meanings as described below)

Prostaglandin E ₂ (PGE ₂ ) is known as a metabolite in the Arachidonic Acid Cascade, and is known to have cytoprotective effects, uterine contraction effects, pain threshold lowering effects, peristalsis of the digestive tract Exercise promoting effect, awakening effect, gastric acid secretion inhibitory effect, blood pressure lowering effect, diuretic effect, etc.

There are different subtypes of PGE ₂ receptors, which are called EP ₁ receptors, EP ₂ receptors, EP ₃ receptors, and EP ₄ receptors (Non-Patent Document 1).

Among these subtypes, it is known that the EP ₂ receptor-related cAMP signal is associated with relaxation of the rotiform muscle of the trachea or ileum or dilation of various blood vessels. In addition, it is known that the EP2 _receptor is associated with the expression of PI3K, Akt, or GSK-3β, or with IL-1β, IL-6, IL-12, IL-23, and IL-27. In addition, it is believed that EP2 _receptor and MCP-1 production from macrophages are suppressed, TNF-α, IL-2, and IFN-γ production from lymphocytes are suppressed, and anti-inflammation due to enhanced IL-10 production is believed , vasodilation, angiogenesis, inhibition of elastic fiber formation, and regulation of MMP-9 expression. In addition, EP ₂ receptors are also associated with myeloid-derived immunosuppressive cells (Myeloid Derived Suppressor Cells), regulatory T cells and natural killer cells to regulate cancer immunity.

From this point of view, it is known that EP2 _receptors are associated with anti-inflammatory effects, neuroprotective effects, and antitumor effects, and it is believed that compounds that strongly bind to EP2 _receptors and have antagonistic effects can be used to treat diseases caused by EP2 _receptors . Activation of diseases such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative Pain, Interstitial Cystitis, Leiomyoma, Irritable Bowel Syndrome, Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Rheumatism, Osteoarthritis, gout, allergic diseases, hypertension, brain dysfunction, ischemia, cerebral hemorrhage, kidney disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, Prevention and/or treatment of glomerulonephritis, sarcoidosis, vasculitis, and autoimmune diseases (Non-Patent Documents 2 to 4).

It is believed that the _EP4 receptor system is involved in the inhibition of MCP-1 production from macrophages, the inhibition of TNF-α, IL-2 and IFN-γ production from lymphocytes, and the anti-inflammatory and vascular effects caused by enhanced IL-10 production. Relaxation, angiogenesis, inhibition of elastic fiber formation, inhibition of MMP-9 expression. Furthermore, it is considered that _EP4 receptors are also involved in cancer immunity controlled by myeloid-derived Suppressor Cells, regulatory T cells, and natural killer cells.

From this point of view, it is believed that compounds that strongly bind to the EP2 _receptor and have an antagonistic effect can be used for diseases caused by the activation of the EP2 _receptor , such as bone disease, cancer, systemic granuloma, immune disease, Allergies, atopy, asthma, pyorrhea, gingivitis, periodontal disease, Alzheimer's disease, Kawasaki disease, burns, multiple organ failure, chronic headache, pain, vasculitis, venous collapse, venous aneurysm, artery prevention and/or treatment of aneurysms, aortic aneurysms, hemorrhoids, urinary tract diseases, pressure, endometriosis, adenomyosis, neonatal ductus arteriosus patency, cholelithiasis, etc. (Non-Patent Documents 5 to 10 ).

On the other hand, the compound represented by the following general formula (A) described in Patent Document 1 is described for use in the treatment of diseases associated with SRS-A, such as allergic diseases, ischemic heart disease, or inflammation.

(式中，A _A表示氫原子、苯基、或苯氧基； n _A表示3至10的整數； R _1A表示氫原子或低級烷氧基； X _1A表示-CO-Y _2A-(Y _2A為-NH-等)等；

表示

等， R _2A表示氫原子、鹵素、低級鹵烷基等， X _2A表示-Y _3A-Y _4A-，Y _3A表示單鍵等，Y _4A表示由1至6個碳原子所構成之伸烷基等； D _A表示羧基、低級烷氧基羰基等(摘錄一部分之基的定義))。 General formula (A) is

(In the formula, A _A represents a hydrogen atom, phenyl, or phenoxy; n _A represents an integer from 3 to 10; R _1A represents a hydrogen atom or a lower alkoxy group; X _1A represents -CO-Y _2A -(Y _2A for -NH- etc.), etc.;

express

etc., R _2A represents a hydrogen atom, halogen, lower haloalkyl, etc., X _2A represents -Y _3A -Y _4A -, Y _3A represents a single bond, etc., Y _4A represents an alkylene group composed of 1 to 6 carbon atoms etc.; D _A represents a carboxyl group, a lower alkoxycarbonyl group, etc. (a part of the definition of the base is extracted)).

Also, known EP ₂ antagonists include, for example, compounds represented by the following general formula (B) in Patent Document 2, or compounds represented by the following general formula (C) in Patent Document 3, and the like.

(式中，A ^B表示NR ^5B等； U ^B表示CX ^5B或N； W ^B表示CX ^6B或N； n ^B表示1、2、3、或4； R ^1B表示碳環、芳基、雜環等； X ^1B、X ^2B、X ^3B、X ^4B分別可為相同或不同，且表示氫原子、烷基、鹵素等； R ^5B表示氫原子或烷基等； X ^5B、X ^6B分別可為相同或不同，且表示氫原子或烷基等(摘錄一部分之基的定義))。 General formula (B) is

(In the formula, A ^B represents NR ^5B etc.; U ^B represents CX ^5B or N; W ^B represents CX ^6B or N; n ^B represents 1, 2, 3, or 4; R ^1B represents carbocyclic, aryl, heterocyclic etc.; X ^1B , X ^2B , X ^3B , and X ^4B can be the same or different, and represent a hydrogen atom, an alkyl group, a halogen, etc.; R ^5B represents a hydrogen atom or an alkyl group, etc.; X ^5B , X ^6B can be the same respectively or different, and represent a hydrogen atom or an alkyl group, etc. (excerpt from the definition of a part of the group)).

(式中，A ^c表示可經取代之C5至12的雜芳基； R ^’c表示‐S(O) _p-C1至C6烷基等，p為0至2； R ^1c表示氫原子或C1至C6烷基等； R ^2c、R ^3c、R ^4c分別表示氫原子或鹵素等； X ^c表示-C=C-等； Y ^c表示-(CH ₂) _n-，n為2或3(摘錄一部分之基的定義))。 The general formula (C) is

(In the formula, A ^c represents a C5 to 12 heteroaryl group that can be substituted; ^R'c represents -S(O) _p -C1 to C6 alkyl, etc., p is 0 to 2; R ^1c represents a hydrogen atom or C1 to C6 alkyl, etc.; R ^2c , R ^3c , R ^4c represent hydrogen atoms or halogens, etc.; X ^c represents -C=C-, etc.; Y ^c represents -(CH ₂ ) _n -, n is 2 or 3 (excerpt part of the base definition)).

Patent Document 4 describes 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]propanoic acid Methyl ester, and 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2-chlorophenyl]propanoic acid .

However, none of the prior art documents describe or suggest the combination of the present invention described later.

On the other hand, in the microenvironment of cancer cells and cancer, there are various immune checkpoint molecules that interfere with the immune response to cancer. Immune checkpoint inhibitors are a novel treatment that relieves the immune suppression mechanism and activates the immune response to cancer. Currently, as far as immune checkpoint inhibitors are concerned, anti-CTLA-4 (cytotoxic T lymphocyte-associated antibodies (cytotoxic T lymphocyte-associated antibodies) -associated antigen-4)) antibody for ipilimumab, anti-PD-1 (programmed cell death-1) antibody for nivolumab and pembrolizumab Pembrolizumab and others have been approved in Japan and overseas, and are used for cancer treatment. [Prior Art Literature] [Patent Document]

[Patent Document 1] International Publication No. 1986/005779 Pamphlet [Patent Document 2] International Publication No. 2012/177618 Pamphlet [Patent Document 3] International Publication No. 2008/152097 [Patent Document 4] International Publication No. 2007/052843 Booklet [Non-patent literature]

[Non-Patent Document 1] Journal of Lipid Mediators and Cell Signaling, Vol. 12, pp. 379-391, 1995 [Non-Patent Document 2] Journal of the Medicinal Chemistry, Vol. 57, Pages 4454-4465, 2014 [Non-Patent Document 3] Trends in Pharmacological Science, Vol. 34, Pages 413-423, 2013 [Non-Patent Document 4] International Journal of molecular medicine, Vol. 42, pp. 1203-1214, 2018 [Non-Patent Document 5] Pharmacological Reviews, Vol. 65, pp. 1010-1052, July, 2013 [Non-Patent Document 6] The 105th American Association for Cancer Research (AACR), Abstract Number: LB-265, Lecture Title: ONO-AE3-208 inhibits myeloid developed suppressor cells and glioma growth, Lecture Date: April 8, 2014 day [Non-Patent Document 7] FEBS Letters, Vol. 364, pp. 339-341, 1995 [Non-Patent Document 8] Cancer Science, Vol. 105, pp. 1142-1151, 2014 [Non-Patent Document 9] Cancer Research, Volume 70, Pages 1606-1615, 2010 [Non-Patent Document 10] Cancer Research, Vol. 62, Pages 28-32, 2002

(Problem to be solved by the invention)

One of the objects of the present disclosure is to provide an effective cancer treatment method. (means to solve the problem)

The inventors of the present invention conducted intensive studies to solve the aforementioned problems, and as a result, found that a compound represented by general formula (I-A) described later, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an immune checkpoint inhibitor and/or EP4 were combined. A combination of receptor antagonists (hereinafter also simply referred to as the combination of the present invention) can be an effective cancer treatment method.

That is, this disclosure includes the following embodiments.

(式中， L ¹表示(CR ³⁸R ³⁹)-(CR ⁴⁰R ⁴¹)-， R ³⁸、R ³⁹、R ⁴⁰及R ⁴¹分別獨立地表示(1)氫原子、(2)鹵素原子、或(3)C1-4烷基， R ³⁸、R ³⁹、R ⁴⁰及R ⁴¹中的C1-4烷基可分別獨立地經至少1個鹵素原子取代， 從R ³⁸、R ³⁹、R ⁴⁰及R ⁴¹選出之2個取代基為C1-4烷基時，可與要鍵結的碳原子一起形成C3-6飽和碳環， L ²表示(1)鍵結鍵、(2)C1-8伸烷基、(3)C2-8伸烯基、或(4)C2-8伸炔基，該C1-8伸烷基、C2-8伸烯基、及C2-8伸炔基中的1至2個碳原子(-CH ₂-)可經氧原子(-O-)或可經氧化的硫原子取代(-S-、-SO-、或-SO ₂-)(或者，以-CH ₂-O-的方式添加)，該C1-8伸烷基、C2-8伸烯基、及C2-8伸炔基可經1至8個鹵素原子取代， Y表示(1)鍵結鍵、(2)氧原子、或(3)可經氧化的硫原子， R ¹表示(1)-COOR ¹⁰、(2)-SO ₃H、(3)-SO ₂NHR ¹¹、(4)-CONHSO ₂R ¹²、(5)-SO ₂NHCOR ¹³、(6)-CONR ¹⁴R ¹⁵、(7)四唑基、或(8)羥胺酸基(-CONHOH)， R ¹⁰、R ¹¹、R ¹²、R ¹³、R ¹⁴及R ¹⁵分別獨立地表示(1)氫原子或(2)C1-4烷基， R ²表示(1)氫原子或(2)C1-4烷基， R ³表示(1)鹵素原子、(2)C1-6烷基、(3)C2-6烯基、(4)C2-6炔基、(5)C1-6烷氧基、(6)3-6員環狀基、(7)(3-6員環狀基)-O-、或(8)(3-6員環狀基)-(C1-4伸烷基)-， R ³中的(2)至(8)可經1至9個R ¹⁶取代， R ³為複數個時，複數個R ³可分別相同或不同， R ¹⁶表示(1)鹵素原子、(2)C1-4烷基、(3)C1-4烷氧基、(4)C2-6醯基、(5)C3-6環烷基、(6)羥基、或(7)-NR ¹⁷R ¹⁸， R ¹⁶為複數個時，複數個R ¹⁶可分別相同或不同， R ¹⁷及R ¹⁸分別獨立地表示(1)氫原子或(2)C1-4烷基， R ⁴表示(1)鹵素原子、(2)C1-6烷基、(3)C2-6烯基、(4)C2-6炔基、(5)C1-6烷氧基、(6)3-6員環狀基、(7)(3-6員環狀基)-O-、或(8)(3-6員環狀基)-(C1-4伸烷基)-， R ⁴中的(2)至(8)可經1至9個R ¹⁹取代， R ⁴為複數個時，複數個R ⁴可分別相同或不同， R ¹⁹表示(1)鹵素原子、(2)C1-4烷基、(3)C1-4烷氧基、(4)C2-6醯基、 (5)C3-6環烷基、(6)羥基、或(7)-NR ²⁰R ²¹， R ²⁰及R ²¹分別獨立地表示(1)氫原子或(2)C1-4烷基， R ¹⁹為複數個時，複數個R ¹⁹可分別相同或不同， R ⁵表示(1)氫原子、(2)C3-10碳環、或(3)3-10員雜環，該C3-10碳環及3-10員雜環可經1至5個R ²²取代， 但是，L ²為鍵結鍵時，R ⁵不為氫原子， R ²²表示(1)C1-6烷基、(2)C2-6烯基、(3)C2-6炔基、(4)C3-6環烷基、(5)C1-6烷氧基、(6)C3-6環烷氧基、(7)C2-6醯基、(8)C2-6醯基氧基、(9)C1-6烷硫基、(10)C3-6環烷硫基、(11)C1-6烷基亞磺醯基、(12)C3-6環烷基亞磺醯基、(13)C1-6烷基磺醯基、(14)C3-6環烷基磺醯基、(15)C1-6烷氧基羰基、(16)5-6員環狀基、(17)(5-6員環狀基)-(C1-4伸烷基)-、(18)(5-6員環狀基)-(C1-4伸烷基)-O-基、(19)(5-6員環狀基)-C1-4醯基、(20)鹵素原子、(21)羥基、(22)硝基、(23)氰基、(24)-NR ²³R ²⁴、(25)-CONR ²⁵R ²⁶或(26)-SO ₂NR ²⁷R ²⁸， R ²³、R ²⁴、R ²⁵、R ²⁶、R ²⁷及R ²⁸分別獨立地表示(1)氫原子、(2)C1-6烷基、(3)C2-6醯基或(4)C1-6烷基磺醯基， R ²²中的(1)至(19)的基可經1至9個R ²⁹取代， R ²²為複數個時，複數個R ²²可分別相同或不同， R ²⁹表示(1)C1-4烷基、(2)C1-4烷氧基、(3)C2-6醯基、(4)C3-6環烷基、(5)羥基、(6)-NR ³⁰R ³¹或(7)鹵素原子， R ³⁰及R ³¹分別獨立地表示(1)氫原子或(2)C1-4烷基， R ²⁹為複數個時，複數個R ²⁹可分別相同或不同， Q表示(1)氧原子或(2)硫原子， X表示(1)CR ⁶或(2)NR ⁷， R ⁶表示(1)鹵素原子、(2)C1-6烷基、(3)C2-6烯基、(4)C2-6炔基、(5)C1-6烷氧基、(6)3-6員環狀基、(7)(3-6員環狀基)-O-、或(8)(3-6員環狀基)-(C1-4伸烷基)-， R ⁶中的(2)至(8)可經1至9個R ³²取代， R ³²表示(1)鹵素原子、(2)C1-4烷基、(3)C1-4烷氧基、(4)C2-6醯基、(5)C3-6環烷基、(6)羥基、或(7)-NR ³³R ³⁴， R ³³及R ³⁴分別獨立地表示(1)氫原子或(2)C1-4烷基， R ³²為複數個時，複數個R ³²可分別相同或不同， R ⁷表示(1)C1-6烷基、(2)C2-6烯基、(3)C2-6炔基、(4)3-6員環狀基、或(5)(3-6員環狀基)-(C1-4伸烷基)-， R ⁷可經1至9個R ³⁵取代， R ³⁵表示(1)鹵素原子、(2)C1-4烷基、(3)C1-4烷氧基、(4)C2-6醯基、(5)C3-6環烷基、(6)羥基、或(7)-NR ³⁶R ³⁷， R ³⁶及R ³⁷分別獨立地表示(1)氫原子或(2)C1-4烷基， R ³⁵為複數個時，複數個R ³⁵可分別相同或不同， 環A表示(1)苯環、或(2)5-6員含氮芳香族雜環， 環A中的

表示單鍵或雙鍵， n表示1至4的整數， m表示0至3的整數， 但是， 排除3-[3-[(2,6-二甲氧基苯甲醯基)胺基]-4-丙氧基苯基]丙酸、 3-[5-({[1-第三丁基-5-(4-氟苯基-1H-吡唑-4-基]羰基}胺基-2-氯苯基]丙酸甲酯、 3-[5-({[1-第三丁基-5-(4-氟苯基-1H-吡唑-4-基]羰基}胺基-2-氯苯基]丙酸、 α-乙基-3-[N-(1’-苯基-5’-甲基-1’,2’,3’-三唑羰基)]胺基-2,4,6-三碘氫桂皮酸、及 α-乙基-3-{N-(1’-(4’’-碘苯基)-5’-甲基-1,2,3-三唑羰基]}胺基-2,4,6-三碘氫桂皮酸)； 在此，術語「與免疫檢查點抑制劑及/或EP ₄受體拮抗藥組合投予的癌症治療劑」係指包含在免疫檢查點抑制劑及/或EP ₄受體拮抗藥的投予之前、與投予同時、投予後、或者在投予前及後被投予的癌症治療劑。 [1] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is administered in combination with an immune checkpoint inhibitor and/or an _EP4 receptor antagonist, and contains A compound represented by general formula (IA), a pharmaceutically acceptable salt thereof, or a hydrate thereof,

(In the formula, L ¹ represents (CR ³⁸ R ³⁹ )-(CR ⁴⁰ R ⁴¹ )-, R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ independently represent (1) hydrogen atom, (2) halogen atom, or (3) C1-4 alkyl, the C1-4 alkyl in R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ can be independently substituted by at least one halogen atom, from R ³⁸ , R ³⁹ , R ⁴⁰ and R When the two substituents selected from ⁴¹ are C1-4 alkyl groups, they can form a C3-6 saturated carbocyclic ring together with the carbon atom to be bonded, and L ² represents (1) bonding bond, (2) C1-8 alkylene Base, (3) C2-8 alkenyl, or (4) C2-8 alkynyl, 1 to 2 of the C1-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl A carbon atom (-CH ₂ -) may be replaced by an oxygen atom (-O-) or an oxidizable sulfur atom (-S-, -SO-, or -SO ₂ -) (or, with -CH ₂ -O - added), the C1-8 alkylene, C2-8 alkenyl, and C2-8 alkynyl can be substituted by 1 to 8 halogen atoms, Y represents (1) bond, (2) Oxygen atom, or (3) oxidizable sulfur atom, R ¹ represents (1)-COOR ¹⁰ , (2)-SO ₃ H, (3)-SO ₂ NHR ¹¹ , (4)-CONHSO ₂ R ¹² , (5)-SO ₂ NHCOR ¹³ , (6)-CONR ¹⁴ R ¹⁵ , (7) tetrazolyl, or (8) hydroxylamic acid (-CONHOH), R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ independently represent (1) hydrogen atom or (2) C1-4 alkyl, R ² represents (1) hydrogen atom or (2) C1-4 alkyl, R ³ represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy, (6) 3-6 membered cyclic group, (7 )(3-6 membered cyclic group)-O-, or (8)(3-6 membered cyclic group)-(C1-4 alkylene)-, (2) to (8) in R ³ can be Substituted by 1 to 9 R ¹⁶ , when R ³ is plural, the plurality of R ³ can be the same or different, R ¹⁶ represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 Alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7) -NR ¹⁷ R ¹⁸ , when there are plural R ¹⁶ , the plural R ¹⁶ can be are the same or different, R ¹⁷ and R ¹⁸ independently represent (1) hydrogen atom or (2) C1-4 alkyl, R ⁴ represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy, (6) 3-6 membered cyclic group, (7 )(3-6 membered cyclic group)-O-, or (8)(3-6 membered cyclic group)-(C1-4 alkylene)-, (2) to (8) in R ⁴ can be Substituted by 1 to 9 R ¹⁹ , when R ⁴ is plural, the plurality of R ⁴ can be the same or different, R ¹⁹ represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 Alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7) -NR ²⁰ R ²¹ , R ²⁰ and R ²¹ independently represent (1) Hydrogen atom or (2) C1-4 alkyl, when R ¹⁹ is plural, the plurality of R ¹⁹ can be the same or different, R ⁵ represents (1) hydrogen atom, (2) C3-10 carbon ring, or (3 ) 3-10-membered heterocycle, the C3-10 carbocycle and 3-10-membered heterocycle can be substituted by 1 to 5 R ²² , however, when L ² is a bonding bond, R ⁵ is not a hydrogen atom, R ²² Represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) C3-6 cycloalkyl, (5) C1-6 alkoxy, (6) )C3-6cycloalkoxy, (7)C2-6acyl, (8)C2-6acyloxy, (9)C1-6alkylthio, (10)C3-6cycloalkylthio, (11) C1-6 alkyl sulfinyl, (12) C3-6 cycloalkyl sulfinyl, (13) C1-6 alkyl sulfinyl, (14) C3-6 cycloalkyl sulfinyl Base, (15) C1-6 alkoxycarbonyl, (16) 5-6 member cyclic group, (17) (5-6 member cyclic group) - (C1-4 alkylene) -, (18) (5-6 member cyclic group)-(C1-4 alkylene)-O-group, (19) (5-6 member cyclic group)-C1-4 acyl group, (20) halogen atom, (21 ) hydroxyl, (22) nitro, (23) cyano, (24)-NR ²³ R ²⁴ , (25)-CONR ²⁵ R ²⁶ or (26)-SO ₂ NR ²⁷ R ²⁸ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ independently represent (1) hydrogen atom, (2) C1-6 alkyl, (3) C2-6 acyl or (4) C1-6 alkylsulfonyl , the groups (1) to (19) in R ²² can be substituted by 1 to 9 R ²⁹ , when R ²² is plural, the plural R ²² can be the same or different, R ²⁹ represents (1) C1-4 Alkyl, (2) C1-4 alkoxy, (3) C2-6 acyl, (4) C3-6 cycloalkyl, (5) hydroxyl, (6) -NR ³⁰ R ³¹ or (7) halogen atom, R ³⁰ and R ³¹ independently represent (1) hydrogen atom or (2) C1-4 alkyl group, when R ²⁹ is plural, the plurality of R ²⁹ can be the same or different, Q represents (1) oxygen atom or (2) sulfur atom, X represents (1) CR ⁶ or (2) NR ⁷ , R ⁶ represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy, (6) 3 -6-membered cyclic group, (7) (3-6-membered cyclic group)-O-, or (8) (3-6-membered cyclic group)-(C1-4 alkylene)-, R ⁶ (2) to (8) can be substituted by 1 to 9 R ³² , R ³² represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C2 -6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7) -NR ³³ R ³⁴ , R ³³ and R ³⁴ independently represent (1) hydrogen atom or (2) C1- 4 alkyl groups, when R ³² is plural, the plurality of R ³² can be the same or different, R ⁷ represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl , (4) 3-6-membered cyclic group, or (5) (3-6-membered cyclic group)-(C1-4 alkylene)-, R ⁷ can be substituted by 1 to 9 R ³⁵ , R ³⁵ Represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7)-NR ³⁶ R ³⁷ , R ³⁶ and R ³⁷ each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, and when there are plural R ^35s , the plural R ^35s may be the same or different , Ring A represents (1) benzene ring, or (2) 5-6 membered nitrogen-containing aromatic heterocycle, in Ring A

Represents a single bond or a double bond, n represents an integer from 1 to 4, m represents an integer from 0 to 3, but excludes 3-[3-[(2,6-dimethoxybenzoyl)amino]- 4-propoxyphenyl]propanoic acid, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2 -Chlorophenyl]propionic acid methyl ester, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2- Chlorophenyl] propionic acid, α-ethyl-3-[N-(1'-phenyl-5'-methyl-1',2',3'-triazolecarbonyl)]amino-2,4 ,6-triiodohydrocinnamic acid, and α-ethyl-3-{N-(1'-(4''-iodophenyl)-5'-methyl-1,2,3-triazolecarbonyl] }amino-2,4,6-triiodohydrocinnamic acid); Herein, the term "cancer therapeutic agent administered in combination with immune checkpoint inhibitors and/or _EP4 receptor antagonists" refers to the A cancer therapeutic agent administered before, simultaneously with, after, or before and after administration of a checkpoint inhibitor and/or _EP4 receptor antagonist.

[2-1] The cancer therapeutic agent as described in [1] above, which is administered in combination with an immune checkpoint inhibitor.

[2-2] The cancer therapeutic agent as described in [1] above, which is administered in combination with an EP ₄ receptor antagonist.

[2-3] The cancer therapeutic agent as described in [1] above, which is administered in combination with an immune checkpoint inhibitor and an _EP4 receptor antagonist.

Here, "administered in combination with an immune checkpoint inhibitor and an _EP4 receptor antagonist" means an aspect including administration of an immune checkpoint inhibitor, an _EP4 receptor antagonist, and a cancer therapeutic agent in any order or simultaneously .

[2-4] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer) containing an immune checkpoint inhibitor, which is the general formula (I-A) described in the aforementioned [1] The indicated compounds, their pharmaceutically acceptable salts, or a combination of these hydrates are administered.

[2-5] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer) comprising an EP ₄ receptor antagonist, which is the same as the general formula (IA ) compound, a pharmaceutically acceptable salt thereof, or a combination of these hydrates is administered.

(式中，所有的符號表示與前述[1]記載的符號相同的意義)。 [3] The cancer therapeutic agent described in any one of [1], [2-1], [2-2], [2-3], [2-4] and [2-5] above, wherein , the compound shown in general formula (IA) is the compound shown in general formula (I),

(In the formula, all the symbols have the same meanings as those described in [1] above).

(式中，X ^a表示CR ^6a或NR ^7a， R ^6a表示(1)鹵素原子、(2)C1-6烷基、(3)C2-6烯基、(4)C2-6炔基、(5)C1-6烷氧基、(6)(3-6員環狀基)-O-、或(7)(3-6員環狀基)-(C1-4伸烷基)-， R ^6a中的(2)至(7)可經1至9個R ³²取代， R ^7a表示(1)C1-6烷基、(2)C2-6烯基、(3)C2-6炔基、(4)3-6員環狀基、或(5)(3-6員環狀基)-(C1-4伸烷基)-， R ^7a可經1至9個R ³⁵取代， R ^3a、R ^3b及R ^3c分別獨立地表示(1)氫原子(2)鹵素原子、(3)C1-6烷基、(4)C2-6烯基、(5)C2-6炔基、(6)C1-6烷氧基、(7)3-6員環狀基、(8)(3-6員環狀基)-O-、或(9)(3-6員環狀基)-(C1-4伸烷基)-， R ^3a、R ^3b及R ^3c中的(3)至(9)可經1至9個R ¹⁶取代， 但是，R ^3a、R ^3b及R ^3c中的至少一個表示氫原子以外的取代基， 其他符號表示與前述[1]記載的符號相同的意義， 但是，不包含3-[3-[(2,6-二甲氧基苯甲醯基)胺基]-4-丙氧基苯基]丙酸)。 [4] The cancer therapeutic agent as described in any one of [1], [2-1], [2-2], [2-3], [2-4], and [2-5] above, wherein , the compound shown in general formula (IA) is the compound shown in general formula (IB),

(wherein, X ^a represents CR ^6a or NR ^7a , R ^6a represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, ( 5) C1-6 alkoxy group, (6) (3-6 membered cyclic group) -O-, or (7) (3-6 membered cyclic group) - (C1-4 alkylene) -, R (2) to (7) in ^6a may be substituted by 1 to 9 R ³² , R ^7a represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) 3-6-membered cyclic group, or (5) (3-6-membered cyclic group)-(C1-4 alkylene)-, R ^7a can be substituted by 1 to 9 R ³⁵ , R ^3a , R ^3b and R ^3c independently represent (1) hydrogen atom (2) halogen atom, (3) C1-6 alkyl, (4) C2-6 alkenyl, (5) C2-6 alkynyl, (6) C1-6 alkoxy group, (7) 3-6 membered cyclic group, (8) (3-6 membered cyclic group) -O-, or (9) (3-6 membered cyclic group) - (C1 -4 alkylene)-, (3) to (9) in R ^3a , R ^3b and R ^3c may be substituted by 1 to 9 R ¹⁶ , however, at least one of R ^3a , R ^3b and R ^3c represents For substituents other than hydrogen atoms, other symbols have the same meanings as those described in [1] above, but 3-[3-[(2,6-dimethoxybenzoyl)amino]- 4-propoxyphenyl]propionic acid).

(式中，p表示1至4的整數，其他符號表示與前述[1]記載的符號相同的意義)。 [5] The cancer therapeutic agent described in any one of [1], [2-1], [2-2], [2-3], [2-4], and [2-5] above, wherein , the compound shown in general formula (IA) is the compound shown in general formula (I-1),

(In the formula, p represents an integer of 1 to 4, and other symbols have the same meanings as those described in [1] above).

(式中，X ^a表示CR ^6a或NR ^7a， R ^6a表示(1)鹵素原子、(2)C1-6烷基、(3)C2-6烯基、(4)C2-6炔基、(5)C1-6烷氧基、(6)(3-6員環狀基)-O-、或(7)(3-6員環狀基)-(C1-4伸烷基)-， R ^6a中的(2)至(7)可經1至9個R ³²取代， R ^7a表示(1)C1-6烷基、(2)C2-6烯基、(3)C2-6炔基、(4)3-6員環狀基、或(5)(3-6員環狀基)-(C1-4伸烷基)-， R ^7a可經1至9個R ³⁵取代， R ^3a、R ^3b及R ^3c分別獨立地表示(1)氫原子(2)鹵素原子、(3)C1-6烷基、(4)C2-6烯基、(5)C2-6炔基、(6)C1-6烷氧基、(7)3-6員環狀基、(8)(3-6員環狀基)-O-、或(9)(3-6員環狀基)-(C1-4伸烷基)-， R ^3a、R ^3b及R ^3c中的(3)至(9)可經1至9個R ¹⁶取代， 但是，R ^3a、R ^3b及R ^3c中的至少一個表示氫原子以外的取代基， p表示1至4的整數， 其他符號表示與前述[1]記載的符號相同的意義)。 [6] The cancer therapeutic agent described in any one of [1], [2-1], [2-2], [2-3], [2-4], and [2-5] above, wherein , the compound shown in general formula (IA) is the compound shown in general formula (IC),

(wherein, X ^a represents CR ^6a or NR ^7a , R ^6a represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, ( 5) C1-6 alkoxy group, (6) (3-6 membered cyclic group) -O-, or (7) (3-6 membered cyclic group) - (C1-4 alkylene) -, R (2) to (7) in ^6a may be substituted by 1 to 9 R ³² , R ^7a represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) 3-6-membered cyclic group, or (5) (3-6-membered cyclic group)-(C1-4 alkylene)-, R ^7a can be substituted by 1 to 9 R ³⁵ , R ^3a , R ^3b and R ^3c independently represent (1) hydrogen atom (2) halogen atom, (3) C1-6 alkyl, (4) C2-6 alkenyl, (5) C2-6 alkynyl, (6) C1-6 alkoxy group, (7) 3-6 membered cyclic group, (8) (3-6 membered cyclic group) -O-, or (9) (3-6 membered cyclic group) - (C1 -4 alkylene)-, (3) to (9) in R ^3a , R ^3b and R ^3c may be substituted by 1 to 9 R ¹⁶ , however, at least one of R ^3a , R ^3b and R ^3c represents For substituents other than hydrogen atoms, p represents an integer of 1 to 4, and other symbols have the same meanings as those described in [1] above).

[7] Any one of [1], [2-1], [2-2], [2-3], [2-4], [2-5], and [3] to [6] above The cancer therapeutic agent according to item 1, wherein ring A is a pyrrole ring, and Y is a bond.

[8] Any one of [1], [2-1], [2-2], [2-3], [2-4], [2-5], and [3] to [6] above The cancer therapeutic agent according to item 1, wherein ring A is a benzene ring, and Y is an oxygen atom.

[9] Any one of [1], [2-1], [2-2], [2-3], [2-4], [2-5], and [3] to [8] above The cancer therapeutic agent described in item 1, wherein the compound represented by the general formula (IA), a pharmaceutically acceptable salt thereof, or a hydrate thereof is an EP ₄ receptor antagonist.

[10] The cancer therapeutic agent as described in any one of [1], [2-1], [2-2], [2-3], [2-4], and [2-5] above, wherein , the compound shown in general formula (I-A) is: (1) rel-(1R,2S)-2-[3-({[1-second butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (3) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (4) rel-(1R,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (5) rel-(1R,2S)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (6) rel-(1R,2R)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (7) (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-methoxyphenyl}cyclopropanecarboxylic acid, (10) (1S,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (11) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (12) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-chlorophenyl}cyclopropanecarboxylic acid, (13) (1R,2S)-2-{3-[({5-[2-(Benzyloxy)ethyl]-1-[(2S)-2-butyl]-1H-pyrrole- 2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (14) rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-fluoro-4-pyridyl)oxy ]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-chloro-6-fluoro-4-pyridyl) Oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (16) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2-chloro-3,5-difluorophenoxy) Ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (17) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2,4-difluorophenoxy)ethyl]- 1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(1-methyl-1H-pyrazol-4-yl )oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(tri Fluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl ) phenyl] cyclopropane carboxylic acid, (21) (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}-4-fluorophenyl)cyclopropanecarboxylic acid, (23) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}-4-fluorophenyl)cyclopropanecarboxylic acid, (24) (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl) Cyclopropane carboxylic acid, (26) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}phenyl)cyclopropanecarboxylic acid, (27) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}phenyl)cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform Base) phenyl] cyclopropane carboxylic acid, (29) (1S,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform Base) phenyl] cyclopropane carboxylic acid, (30) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzyl Acyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (31) (1R,2S)-2-[3-{[4-(2-Cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (32)(1R,2S)-2-{3-[(2,6-Dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)phenyl} ring propane carboxylic acid, (33) (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (34) (1R,2S)-2-[3-{[4-(Benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (35) (1R,2S)-2-[3-{[4-(2-Methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (36) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (37) (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (38) (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (39) (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (40) (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino) -4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (41) (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (42) (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (43) (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino)- 4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (44) (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridyl)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (45) (1R,2S)-2-[3-({4-[2-(4-hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (46) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]propane acid, (47) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]butyl acid, (48) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]- 2-Methylpropionic acid, (49) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform base) phenyl] cyclobutane carboxylic acid, or (50) (1R,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform base) phenyl]-1-methylcyclopropanecarboxylic acid.

[11] The cancer therapeutic agent described in any one of [1], [2-1], [2-2], [2-3], [2-4], and [2-5] above, wherein , the compound shown in general formula (I-A) is: (1) (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)benzene Base] cyclopropane carboxylic acid, (2) (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (3) (1R,2S)-2-[3-{[4-(2-Phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (4) (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (5) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(1,2,3,4-tetrahydro-1-naphthylmethoxy)benzoyl ]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (6) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(3-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (7) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(4-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(2-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (10) (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (11) (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (12) (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (13) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (14) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl]amine Base}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-{3-[(2,6-Dimethyl-4-{[6-(trifluoromethyl)-2-pyridyl]oxy}benzoyl) Amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (16) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoyl] Amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (17) rel-(1R,2S)-2-(3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methyl Phenyl)cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[4-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (19) (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (20) (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (21) (1R,2S)-2-[3-{[3-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (22) (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (23) (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (24) (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl ]amino}phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (26) (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (27) (1R,2S)-2-[3-({[2,6-Dimethyl-4-(2-phenylethoxy)phenyl]thiocarbonyl}amino)-4-(three Fluoromethyl)phenyl]cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]thiocarbonyl}amino)-4-( Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1R,2S)-2-[3-({[2-second butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or (31) (1R,2S)-2-[3-({[2-(2-methyl-2-propyl)-1-(3-phenylpropyl)-1H-pyrrol-3-yl] Carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid.

[12] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), administered in combination with an immune checkpoint inhibitor and/or an _EP4 receptor antagonist, and comprising (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)benzene base] cyclopropanecarboxylic acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[13] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), administered in combination with an immune checkpoint inhibitor, and comprising (1R,2S)-2-[ 3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutical salts or their hydrates.

[14] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), administered in combination with an _EP4 receptor antagonist, comprising (1R,2S)-2- [3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its Pharmaceutically acceptable salts or hydrates thereof.

[15] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), administered in combination with an immune checkpoint inhibitor and an _EP4 receptor antagonist, and comprising (1R ,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl] Cyclopropanecarboxylic acid, its pharmaceutically acceptable salts, or their hydrates.

[16] A cancer therapeutic agent (or pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is combined with (1R,2S)-2-[3-{[2,6-dimethyl -4-(2-Phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salt or its hydrate is administered in combination and includes an immune checkpoint inhibitor.

[17] A cancer therapeutic agent (or pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is combined with (1R,2S)-2-[3-{[2,6-dimethyl -4-(2-Phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salt or its hydrate The combination is administered and includes an _EP4 receptor antagonist.

[18] The cancer described in any one of [1], [2-1], [2-3], [2-4], [3] to [13], [15] and [16] above The therapeutic agent, wherein the immune checkpoint inhibitor is selected from CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR Inhibitors of immune checkpoint molecules in the group consisting of , VISTA, IDO1, Arginase I (Arginase I), TIGIT and CD115.

[19] Any one of the aforementioned [1], [2-1], [2-3], [2-4], [3] to [13], [15], [16] and [18] The described cancer therapeutic agent, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[20] Any one of the aforementioned [1], [2-2], [2-3], [2-5], [3] to [12], [14], [15] and [17] The cancer therapeutic agent described above, wherein the EP ₄ receptor antagonist is a compound described in the general formula (I) described in WO2016/111347, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[21] As mentioned above [1], [2-2], [2-3], [2-5], [3] to [12], [14], [15], [17] and [20] The cancer therapeutic agent according to any one of the above, wherein the EP4 receptor antagonist is 4-[ ₄ -cyano-2-({(2'R,4S)-6-[(propan-2-yl) Carbamoyl]-2,3-dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, its pharmaceutically acceptable salts or hydrates thereof.

[22] A cancer therapeutic agent (or pharmaceutical composition, or a pharmaceutical composition used to prevent and/or treat cancer), which is combined with anti-PD-1 body and/or 4-[4-cyano-2-({ (2'R,4S)-6-[(Propan-2-yl)aminoformyl]-2,3-dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]]-2 '-Carbonyl}amino)phenyl]butanoic acid, its pharmaceutically acceptable salts, or a combination of these hydrates, and includes (1R,2S)-2-[3-{[2,6-di Methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salts or the like Hydrate.

[23] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is administered in combination with an anti-PD-1 antibody and contains (1R,2S)-2- [3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its Pharmaceutically acceptable salts or hydrates thereof.

[24] A cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is combined with 4-[4-cyano-2-({(2'R,4S) -6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]]-2'-carbonyl}amino) Phenyl]butanoic acid, its pharmaceutically acceptable salts, or a combination of these hydrates, and comprising (1R,2S)-2-[3-{[2,6-dimethyl-4-(2 -phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, pharmaceutically acceptable salts thereof, or hydrates thereof.

[25] A cancer therapeutic agent (or pharmaceutical composition, or a pharmaceutical composition used to prevent and/or treat cancer), which is combined with anti-PD-1 body and 4-[4-cyano-2-({(2 'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]]-2'- Carbonyl}amino)phenyl]butyric acid, its pharmaceutically acceptable salts, or a combination of these hydrates, and contains (1R,2S)-2-[3-{[2,6-dimethyl -4-(2-Phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salt or its hydrate .

[26] A cancer therapeutic agent (or pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is combined with (1R,2S)-2-[3-{[2,6-dimethyl yl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salts or hydrates thereof The composition is administered and includes an anti-PD-1 antibody.

[27] A -2,3-cancer therapeutic agent (or a pharmaceutical composition, or a pharmaceutical composition for preventing and/or treating cancer), which is combined with (1R,2S)-2-[3-{[2, 6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salt or The hydrates of these are administered in combination and contain 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3 - dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]]-2'-carbonyl}amino)phenyl]butanoic acid, its pharmaceutically acceptable salts or their hydrates.

[28] Any one of the aforementioned [1], [2-1], [2-2], [2-3], [2-4], [2-5] and [3] to [27] The agent described, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, uveal melanoma (uveal melanoma), thymoma, mesothelioma, esophageal cancer, gastric cancer, Duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, kidney cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer, malignant bone tumor, soft tissue sarcoma, chondrosarcoma , leukemia, myelodysplastic syndrome, brain tumor, or multiple myeloma.

[29] Any one of the aforementioned [1], [2-1], [2-2], [2-3], [2-4], [2-5] and [3] to [28] The agent described above, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer or gastric cancer.

[30] A medicine (or treatment kit), which is a compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an immune checkpoint inhibitor and / or combination of EP ₄ receptor antagonists.

Here, the term "combined medicine" refers to a compound comprising the general formula (IA), a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an immune checkpoint inhibitor and/or EP ₄ receptor Body antagonists are contained in the form of a single dosage form respectively.

[30-1] A medicine (or treatment kit), which is the compound represented by the general formula (I-A) described in [1] above, its pharmaceutically acceptable salt, or a hydrate thereof, and an immune checkpoint inhibitor combination of agents.

[30-2] A medicine (or treatment kit), which is the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt or hydrate thereof, and _EP4 receptor A combination of antagonists.

[30-3] A medicine (or treatment kit), which is the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt or hydrate thereof, and an immune checkpoint inhibitor Agents and EP ₄ receptor antagonists combined.

[30-4] The medicine described in any one of [30], [30-1], [30-2] and [30-3] above, which is used to prevent and/or treat cancer.

[31] A method of treatment comprising administering an effective amount of the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt, or a combination thereof, separately or simultaneously, to a patient in need of cancer treatment Hydrate, and an effective amount of immune checkpoint inhibitors and/or _EP4 receptor antagonists.

[31-1] A method of treatment comprising administering an effective amount of the compound represented by the general formula (I-A) described in [1] above, its pharmaceutically acceptable salt, or the same, separately or simultaneously, to a patient in need of cancer treatment Etc. hydrate, and an effective amount of an immune checkpoint inhibitor.

[31-2] A method of treatment comprising administering an effective amount of the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt, or the same, separately or simultaneously, to a patient in need of cancer treatment Etc. hydrate, and an effective amount of EP ₄ receptor antagonist.

[31-3] A method of treatment comprising administering an effective amount of the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt, or the same, separately or simultaneously, to a patient in need of cancer treatment and other hydrates, and effective doses of immune checkpoint inhibitors and EP ₄ receptor antagonists.

[32] A method of treatment comprising administering an effective amount of the compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof to a patient in need of cancer treatment, The method further comprises administering an effective amount of an immune checkpoint inhibitor and/or an _EP4 receptor antagonist.

[32-1] A method of treatment comprising administering to a patient in need of cancer treatment an effective amount of the compound represented by the general formula (I-A) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof The method further comprises administering an effective amount of an immune checkpoint inhibitor.

[32-2] A method of treatment comprising administering to a patient in need of cancer treatment an effective amount of the compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof The method further comprises administering an effective amount of an _EP4 receptor antagonist.

[32-3] A method of treatment comprising administering an effective amount of the compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof to a patient in need of cancer treatment The method further comprises administering effective doses of immune checkpoint inhibitors and _EP4 receptor antagonists.

[32-4] A method of treatment comprising administering an effective amount of an immune checkpoint inhibitor to a patient in need of cancer treatment, the method further comprising administering an effective amount of the general formula (I-A) described in [1] above compounds, their pharmaceutically acceptable salts or their hydrates.

[32-5] A method of treatment comprising administering an effective amount of an _EP4 receptor antagonist to a patient in need of cancer treatment, the method further comprising administering an effective amount of the formula (IA) described in [1] above The indicated compounds, their pharmaceutically acceptable salts or their hydrates.

[33] A compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, in combination with an immune checkpoint inhibitor and/or an _EP4 receptor antagonist used in combination for cancer treatment.

[33-1] A compound represented by the general formula (I-A) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, used in combination with an immune checkpoint inhibitor for cancer treatment.

[33-2] A compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, used in combination with an _EP4 receptor antagonist for cancer treatment .

[33-3] A compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, in combination with an immune checkpoint inhibitor and an _EP4 receptor antagonist used in combination for cancer treatment.

[33-4] An immune checkpoint inhibitor used for cancer treatment in combination with the compound represented by the general formula (I-A) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[ _33-5 ] An EP4 receptor antagonist used in cancer treatment in combination with the compound represented by the general formula (IA) described in [1] above, its pharmaceutically acceptable salt, or a hydrate thereof .

[34] Use of a compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a cancer therapeutic agent, which is combined with Combination administration of immune checkpoint inhibitors and/or _EP4 receptor antagonists.

[34-1] Use of a compound represented by the general formula (I-A) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a cancer therapeutic agent, the cancer therapeutic agent Administered in combination with immune checkpoint inhibitors.

[34-2] Use of a compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a cancer therapeutic agent, the cancer therapeutic agent It is administered in combination with _EP4 receptor antagonists.

[34-3] Use of a compound represented by the general formula (IA) described in [1] above, a pharmaceutically acceptable salt thereof, or a hydrate thereof for producing a cancer therapeutic agent, the cancer therapeutic agent It is administered in combination with immune checkpoint inhibitors and _EP4 receptor antagonists.

[34-4] The use of an immune checkpoint inhibitor for the manufacture of a cancer therapeutic agent, which is the same as the compound represented by the general formula (I-A) described in [1] above, and its pharmaceutically acceptable Salts or combinations of these hydrates are administered.

[34-5] The use of an _EP4 receptor antagonist for the manufacture of a cancer therapeutic agent that is pharmaceutically acceptable to the compound represented by the general formula (IA) described in [1] above. Salts or hydrates of these combinations are administered. (Effect of Invention)

Combinations of the invention are useful in cancer therapy.

The present disclosure is described in detail below. [Compounds used in the present invention]

(式中，所有的符號與後述(或前述[1])相同意義)。 The compound used in the present invention is the compound represented by the general formula (IA), its pharmaceutically acceptable salt or the hydrate thereof.

(In the formula, all symbols have the same meanings as those described below (or [1] above).)

As shown in Drug Experiment Example 1 described later, the compound used in the present invention is an EP ₂ receptor antagonist having EP ₂ receptor antagonistic activity.

In this specification, the term "halogen atom" refers to fluorine, chlorine, bromine, and iodine atoms.

In this specification, the term "C1-4 alkyl" refers to methyl, ethyl, propyl, butyl, and their isomers.

In the present specification, C1-6 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, and their isomers.

In this specification, the so-called C2-6 alkenyl group means, for example, a C2-6 alkenyl group having 1 to 2 double bonds, specifically vinyl, propenyl, butenyl, butadienyl, pentenyl group, pentadienyl group, hexenyl group, hexadienyl group, and their isomers.

In this specification, the so-called C2-6 alkynyl means, for example, a C2-6 alkynyl group having 1 to 2 triple bonds, specifically, ethynyl, propynyl, butynyl, butadiynyl, pentynyl group, pentadynyl, hexynyl, hexadiynyl, and their isomers.

In this specification, the so-called C1-4 alkylene group refers to methylene group, ethylene group, propylidene group, butylene group, and these isomers.

In this specification, the so-called C1-8 alkylene refers to methylene, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomers of these things.

In this specification, the so-called C2-8 alkenyl group means, for example, a C2-8 alkenyl group having 1 to 2 double bonds, which is vinylene, propenyl, butenyl, butadienyl , Pentenyl, Pentadienyl, Hexenyl, Hexadienyl, Heptenyl, Heptadienyl, Octenyl, Octadienyl, and the iso structure.

In this specification, the so-called C2-8 alkynyl group means, for example, a C2-8 alkynyl group having 1 to 2 triple bonds, specifically, ethynyl, propynyl, butynyl, alkynyl, etc. butadiynyl, pentynyl, pentynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl, octadiynyl, and These isomers and the like.

In this specification, C1-4 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, and their isomers.

In this specification, C1-6 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and their isomers.

In the present specification, the C1-6 alkylthio group refers to methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and isomers thereof.

In this specification, the so-called C1-6 alkylsulfinyl refers to methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl , hexylsulfinyl, and isomers thereof.

In this specification, the so-called C1-6 alkylsulfonyl refers to methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and their isomers.

In this specification, the so-called C3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In this specification, the term "C3-6 cycloalkoxy" refers to cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

In this specification, the term "C3-6 cycloalkylthio" refers to cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio.

In this specification, the so-called C3-6 cycloalkylsulfinyl refers to cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, and cyclohexylsulfinyl.

In this specification, the so-called C3-6 cycloalkylsulfonyl refers to cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl.

In this specification, the so-called C1-6 alkoxycarbonyl refers to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and their isomers .

In the present specification, the term "C1-4 acyl" refers to methacyl, acetyl, propionyl, butyryl, and their isomers.

In this specification, the so-called C2-6 acyl group refers to acetyl group, propionyl group, butyryl group, pentyl group, hexyl group, and these isomers.

In this specification, the term "C2-6 acyloxy" refers to acetyloxy, propionyloxy, butyryloxy, pentyloxy, hexyloxy, and their isomers.

In the present specification, the C3-6 saturated carbocyclic ring refers to, for example, cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings.

In this specification, the so-called 5-membered nitrogen-containing aromatic heterocyclic ring system means a 5-membered aromatic heterocyclic ring containing one or more nitrogen atoms, specifically, pyrrole, imidazole, triazole, pyrazole, oxazole, Isoxazole, thiazole, and isothiazole ring, etc.

In this specification, the so-called 5-6 membered nitrogen-containing aromatic heterocyclic ring system means a 5-membered or 6-membered aromatic heterocyclic ring containing more than one nitrogen atom, specifically, pyrrole, imidazole, triazole, pyrrole, Azole, pyridine, pyrazine, pyrimidine, pyridazine, oxazole, isoxazole, thiazole, and isothiazole ring, etc.

In the present specification, the term "5-6 membered ring system" means a C5-6 carbocyclic ring and a 5-6 membered heterocyclic ring.

Examples of C5-6 carbocyclic ring systems include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene and the like.

5-6 membered heterocyclic ring systems such as pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, Isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazole morphine, tetrazoline, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, Dihydropyridazine, Tetrahydropyridazine, Perhydropyridazine, Dihydrofuran, Tetrahydrofuran, Dihydropyran, Tetrahydropyran, Dihydrothiophene, Tetrahydrothiophene, Dihydrothiopyran, Tetrahydrothiopyran , dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole , Tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofuran, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazoline), dihydrooxazine, tetrahydrooxazine, two Hydroxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine , morpholine, thiomorpholine, oxathiolane, dioxolane, dioxane, dithiolane, and dithiolane ring, etc.

In the present specification, a 5-6-membered cyclic group is a group composed of a 5-6-membered ring and has a valence (for example, 1 or 2 valence) of a partner to be bonded. Furthermore, in the case of being described as a C5-6 carbocyclic ring and a 5-6 membered heterocyclic ring in this specification, these may also represent a C5-6 carbocyclic group and a 5-6 membered heterocyclic group, respectively.

In the present specification, the term "3-6 membered ring system" refers to a C3-6 carbocyclic ring and a 3-6 membered heterocyclic ring.

The so-called C3-6 carbon ring refers to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cyclobutadiene, cyclopentadiene, cyclohexadiene, and benzene ring etc.

The so-called 3-6 membered heterocycle refers to aziridine, azetidine, oxirane, oxetane, thiirane, thietane, and the aforementioned 5-6 membered heterocycle, etc.

In the present specification, a 3-6-membered cyclic group is a group composed of a 3-6-membered ring, and has a valence (for example, monovalent or divalent) corresponding to a partner to be bonded. Furthermore, in the case of being described as a C3-6 carbocyclic ring and a 3-6 membered heterocyclic ring in this specification, these may also represent a C3-6 carbocyclic group and a 3-6 membered heterocyclic group, respectively.

In this specification, C3-10 carbon ring system such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclobutene, cyclopentene, Cyclohexene, Cycloheptene, Cyclooctene, Cyclononene, Cyclodecene, Cyclobutadiene, Cyclopentadiene, Cyclohexadiene, Cycloheptadiene, Cyclooctadiene, Benzene, Pentadiene , perhydropentarene, azulene, perhydroazulene, indene, perhydroindene, indenane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene rings.

In this specification, the so-called 3-10 membered heterocyclic rings are, for example, the aforementioned 5-6 membered heterocyclic rings, and aziridine, azetidine, oxirane, oxetane, thiirane, thiidine ring, Acridine, diacril, oxa, thiazine, oxazir, oxadiazan, thiazamide, thiadiazan, indole, isoindole, indolezine, benzofuran, isobenzofuran , Benzothiophene, Isobenzothiophene, Dithionaphthalene, Indazole, Quinoline, Isoquinoline, Quinazine, Purine, Phthalazine, Pteridine, Nadine, Quinoxaline, Quinazoline, Cinnoline, Benzoxazole, benzothiazole, benzimidazole, benzopyran (chromene), benzofurazan, benzothiadiazole, benzotriazole, dihydroacridine, tetrahydroacridine, perhydroacridine呯, Dihydrodiacril, Tetrahydrodiazan, Perhydrodiazan, Dihydrooxan, Tetrahydrooxan, Perhydrooxan, Dihydrothioxan, Tetrahydrothioxan, Perhydrothioxan, Dihydrooxazines, Tetrahydrooxacridines, Perhydrooxazines, Dihydrooxadiazines, Tetrahydrooxadiazines, Perhydrooxadiazines, Dihydrothiazides, Tetrahydrooxazines , perhydrothiadiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, two Hydrogen isobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, two Hydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Dihydroisoquinoline, Tetrahydroisoquinoline, Perhydroisoquinoline, Dihydrooxazine, Tetrahydrooxazine, Perhydrooxazine, Dihydronaphthalene Pyridine, tetrahydroquinazine, perhydroquinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydroquinazoline Cinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, Perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxindanes, benzodioxanes, dihydrobenzopyrans, Benzodithiolane, Benzodithiolane, Azaspiro[4.4]nonane, Oxazaspiro[4.4]nonane, Dioxaspiro[4.4]nonane, Azaspiro[4.5]decane, Thiaspiro[4.5]decane, Dithiaspiro[4.5]decane, Dioxaspiro[4.5]decane, Oxazaspiro[4.5]decane Decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane ring, etc.

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is preferably the compound represented by the general formula (I), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，環A-1表示苯環或5員含氮芳香族雜環，其他符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is preferably the compound represented by the general formula (Ia), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, Ring A-1 represents a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, and other symbols have the same meanings as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred embodiment of the compound represented by the general formula (IA) is the compound represented by the general formula (Ib), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred embodiment of the compound represented by the general formula (IA) is the compound represented by the general formula (Ic), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (I-1), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by general formula (IA) is the compound represented by general formula (Id), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ie), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another better embodiment of the compound represented by the general formula (IA) is the compound represented by the general formula (If), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ig), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ih), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred embodiment of the compound represented by the general formula (IA) is the compound represented by the general formula (IB), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ii), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ij), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred aspect of the compound represented by the general formula (IA) is the compound represented by the general formula (Ik), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, another preferred embodiment of the compound represented by the general formula (IA) is the compound represented by the general formula (IL), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (Im), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (In), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (Io), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (Ip), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (Iq), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is more preferably the compound represented by the general formula (IC), its pharmaceutically acceptable salt or the hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

(式中，所有的符號表示與前述相同的意義)。 In this disclosure, the compound represented by the general formula (IA) is preferably the compound represented by the general formula (II), its pharmaceutically acceptable salt or a hydrate thereof:

(In the formula, all the symbols have the same meaning as above).

In the present disclosure, R ¹ is preferably -COOR ¹⁰ or -CONR ¹⁴ R ¹⁵ , more preferably COOR ¹⁰ , and even more preferably -COOH.

In the present disclosure, R ¹⁰ is preferably a hydrogen atom.

In the present disclosure, R ² is preferably a hydrogen atom.

In the present disclosure, R ³ is preferably a halogen atom, a C1-6 alkyl group which may be substituted by at least one halogen atom, or a C1-6 alkoxy group which may be substituted by at least one halogen atom. In the aforementioned C1-6 alkoxy group which may be substituted by at least one halogen atom, the halogen atom is, for example, a fluorine atom, a chlorine atom, or a bromine atom, preferably a fluorine atom, and the number of the halogen atoms is, for example, 1 to 6. R ³ is more preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a methoxy group, or a trifluoromethyl group, most preferably a trifluoromethyl group.

In the present disclosure, at least one of R ^3a , R ^3b , and R ^3c represents a substituent other than a hydrogen atom. Regarding the combination of R ^3a , R ^3b , and R ^3c , R ^3b is a substituent other than a hydrogen atom and R ^3a and/or R ^3c can be a hydrogen atom, R ^3c is a substituent other than a hydrogen atom and R ^3a and /or R ^3b can be a hydrogen atom, R ^3a and R ^3b can be a substituent other than a hydrogen atom and R ^3c can be a hydrogen atom, R ^3a and R ^3c can be a substituent other than a hydrogen atom and R ^3b can be a hydrogen atom, R ^3b and R ^3c are substituents other than hydrogen atoms and R ^3a can be hydrogen atoms, R ^3a to R ^3c can be substituents other than hydrogen atoms, preferably R ^3a is substituents other than hydrogen atoms and R ^3b and/or or R ^3c is a hydrogen atom. More preferably, R ^3a is a substituent other than a hydrogen atom and R ^3b and R ^3c are hydrogen atoms. The substituent other than the hydrogen atom is preferably a halogen atom, a C1-6 alkyl group which may be substituted by at least one halogen atom, or a C1-6 alkoxy group which may be substituted by at least one halogen atom, more preferably a fluorine atom , a chlorine atom, a bromine atom, a methyl group, a methoxy group, or a trifluoromethyl group, preferably a trifluoromethyl group.

In the present disclosure, R ⁴ is preferably a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, more preferably a C1-6 alkyl group, and even more preferably a methyl group.

In the present disclosure, R ⁵ is preferably a hydrogen atom, a C3-6 carbocycle, or a 3-6 membered heterocycle, more preferably a C3-6 carbocycle, or a 3-6 membered heterocycle, or more preferably a hydrogen atom , cyclopropane, benzene, or a 5-6 membered heterocyclic ring, more preferably cyclopropane, benzene, imidazole, pyrazole, pyridine, furan, or tetrahydropyran ring, most preferably a benzene ring. R ⁵ may be substituted by 1 to 5 R ²² .

In the present disclosure, R ²² is preferably a halogen atom, a hydroxyl group, or a C1-6 alkyl group, more preferably a fluorine atom, a chlorine atom, a hydroxyl group, or a methyl group.

In the present disclosure, R ⁶ is preferably a halogen atom, or a C1-6 alkyl group which may be substituted by at least one halogen atom. Among the aforementioned C1-6 alkyl groups which may be substituted by at least one halogen atom, the halogen atom is, for example, a fluorine atom, a chlorine atom, or a bromine atom, preferably a fluorine atom, and the number of the halogen atoms is, for example, 1 to 6. R ⁶ is preferably C1-6 alkyl, more preferably methyl or isopropyl, particularly preferably methyl.

In this disclosure, R ^6a is preferably a halogen atom, or a C1-6 alkyl group that may be substituted by at least one halogen atom, more preferably a C1-6 alkyl group, even more preferably a methyl group or an isopropyl group, especially Preferably methyl.

為雙鍵時，R ⁷不存在。 In this disclosure, R ⁷ is preferably C1-6 alkyl or 3-6 membered cyclic group, more preferably isopropyl, 2-butyl, 3-pentyl, or cyclopropyl, and more preferably Isopropyl, 3-pentyl, or 2-butyl, more preferably 2-butyl. In addition, ring A's

When it is a double bond, R ⁷ does not exist.

為雙鍵，R ^7a不存在。 In this disclosure, R ^7a is preferably C1-6 alkyl or 3-6 membered cyclic group, more preferably isopropyl, 2-butyl, 3-pentyl, or cyclopropyl, and more preferably Isopropyl, 3-pentyl, or 2-butyl, more preferably 2-butyl. In addition, ring A's

For a double bond, R ^7a does not exist.

In the present disclosure, R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ are preferably each independently a hydrogen atom or a C1-4 alkyl group.

In the present disclosure, Q is preferably an oxygen atom.

(式中，*表示與苯環或與R ¹的鍵結位置，鍵結的方向任一皆可)，更佳為

(式中，*表示與苯環或與R ¹的鍵結位置，鍵結的方向任一皆可)。又，於本揭示中，L ¹較佳為C3-6飽和碳環。 In this disclosure, L ¹ is preferably

(In the formula, ^* represents the bonding position with the benzene ring or with R, and the direction of the bonding is arbitrary), more preferably

(In the formula, * represents the bonding position with the benzene ring or with R ¹ , and any direction of the bonding is acceptable). Also, in the present disclosure, L ¹ is preferably a C3-6 saturated carbocyclic ring.

In the present disclosure, ring A is preferably a benzene ring or a 5-membered nitrogen-containing aromatic heterocycle, more preferably a benzene, pyrrole, or pyrazole ring, particularly preferably a benzene or pyrrole ring.

In the present disclosure, Y is preferably a bond or an oxygen atom.

In this disclosure, the combination of ring A and Y is preferably a combination of ring A being a benzene ring and Y being an oxygen atom, and ring A being a 5-membered nitrogen-containing aromatic heterocycle (more preferably pyrrole or pyrazole ring, especially preferably is a pyrrole ring) and Y is a combination of bonding bonds.

In this disclosure, L ² is preferably a bond, or a C1-8 alkylene group in which one carbon atom (-CH ₂ -) can be substituted by an oxygen atom (-O-) (or two adjacent A C1-8 alkylene group containing ₁ oxygen atom between carbon atoms), more preferably a C1-8 alkylene group (or A C1-8 alkylene group that may contain one oxygen atom between two adjacent carbon atoms), and more preferably an ethylene group, a propylidene group, -OCH ₂ CH ₂ -, or -CH ₂ OCH ₂ CH ₂ -.

In the present disclosure, ring A-1 is preferably a benzene, pyrrole, or pyrazole ring, more preferably a benzene or pyrrole ring.

In the present disclosure, p is preferably 1 or 2, more preferably 1.

In the present disclosure, m is preferably 0, 1, or 2, more preferably 0 or 1.

In the present disclosure, n is preferably 1, 2, or 3, more preferably 1.

In this disclosure, the above general formula (IA), general formula (I), general formula (I-1), general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id) , general formula (Ie), general formula (If), general formula (Ig), general formula (Ih), general formula (Ii), general formula (Ij), general formula (Ik), general formula (IL), general formula In formula (Im), general formula (In), general formula (Io), general formula (Ip), general formula (Iq), general formula (IB), general formula (IC), or general formula (II), respectively Independently, L ² is preferably a bond, or a C1-8 alkylene group in which one carbon atom (-CH ₂ -) may be substituted by an oxygen atom (-O-) (or may be in two adjacent carbon atoms A C1-8 alkylene group containing 1 oxygen atom between them), more preferably a C1-8 alkylene group with 1 carbon atom (-CH ₂ -) which may be substituted by an oxygen atom (-O-) (or may be in C1-8 alkylene group containing 1 oxygen atom between two adjacent carbon atoms), more preferably ethylidene, propylidene, -OCH ₂ CH ₂ -, or -CH ₂ OCH ₂ CH ₂ -, R ⁵ is preferably a C3-6 carbocycle or a 3-6 membered heterocycle, the C3-6 carbocycle and 3-6 membered heterocycle can be substituted by 1 to 5 R ²² , R ¹ is preferably COOH, R ² is preferably a hydrogen atom.

In this disclosure, the general formula (IA) is preferably each of the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q, ring A, L ¹ , L ² , X, Y, n, and m Combinations of better definitions.

In this disclosure, the general formula (I) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, L ¹ , L ² , X, Y, n, and m are respectively compared to A combination of good definitions.

In this disclosure, the general formula (I-1) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ³⁸ , R ⁴⁰ , ring A, L ² , X, Y, p, A combination of respective preferred definitions of n and m.

In this disclosure, the general formula (Ia) is preferably each of the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A-1, L ¹ , L ² , X, Y, n, and m Combinations of better definitions.

In this disclosure, the general formula (Ib) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ² , Y, n, and m are each preferably defined combination.

In this disclosure, the general formula (Ic) is preferably defined by the respective preferred definitions of the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , L ¹ , L ² , n, and m combination.

In this disclosure, the general formula (Id) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ³⁸ , R ⁴⁰ , ring A-1, L ² , X, Y, p, A combination of respective preferred definitions of n and m.

In this disclosure, the general formula (Ie) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ³⁸ , R ⁴⁰ , L ² , Y, p, n, and m Combinations of respectively preferred definitions.

In this disclosure, the general formula (If) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ³⁸ , R ⁴⁰ , L ² , p, n, and m respectively. combination of better definitions.

In this disclosure, the general formula (Ig) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Q, ring A, L ¹ , L ² , X ^a , Y, n, and m Combinations of respectively preferred definitions.

In this disclosure, the general formula (Ih) is preferably the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , Q, ring A, L ¹ , L ² , X, Y , and m are respectively preferred combinations of definitions.

In this disclosure, the general formula (Ii) is preferably the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , Q, ring A-1, L ¹ , L ² , X ^a , Y, and m are respectively preferred combinations of definitions.

In this disclosure, the general formula (Ij) is preferably the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ^6a , Q, L ¹ , L ² , Y, and A combination of respectively preferred definitions of m.

In this disclosure, the general formula (Ik) is preferably each of the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ^7a , Q, L ¹ , L ² , and m Combinations of better definitions.

In this disclosure, the general formula (IL) is preferably each of the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ^6a , Q, L ¹ , L ² , and m Combinations of better definitions.

In this disclosure, the general formula (Im) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ³⁸ , R ⁴⁰ , Q, ring A, L ² , X, Y, p, A combination of respective preferred definitions of n and m.

In this disclosure, the general formula (In) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ³⁸ , R ⁴⁰ , Q, ring A-1, L ² , X, Y, A combination of respective preferred definitions of p, n, and m.

In this disclosure, the general formula (Io) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ³⁸ , R ⁴⁰ , Q, L ² , Y, p, n, and a combination of respective preferred definitions of m.

In this disclosure, the general formula (Ip) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ³⁸ , R ⁴⁰ , Q, L ² , p, n, and m Combinations of respectively preferred definitions.

In this disclosure, the general formula (Iq) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ³⁸ , R ⁴⁰ , Q, L ² , p, n, and m Combinations of respectively preferred definitions.

In this disclosure, the general formula (IB) is preferably the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , Q, ring A, L ¹ , L ² , X ^a , A combination of Y and m's respective preferred definitions.

In this disclosure, the general formula (IC) is preferably the aforementioned R ¹ , R ² , R ^3a , R ^3b , R ^3c , R ⁴ , R ⁵ , R ³⁸ , R ⁴⁰ , Ring A, L ² , X ^a , Y, p, and m are respectively preferred combinations of definitions.

In this disclosure, the general formula (II) is preferably the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ , ring A, L ¹ , L ² , X, Y, n, and m are respectively compared to A combination of good definitions.

In this disclosure, other aspects of the general formula (I-A) are preferably the example compounds described in the examples described later, their pharmaceutically acceptable salts, or their hydrates.

In this disclosure, as an embodiment of the general formula (I-A), it is preferably (1R,2S)-2-[3-{[2,6-dimethyl- 4-(2-Phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, its pharmaceutically acceptable salts or their hydrates.

In the present disclosure, all isomers are included unless otherwise specified. For example, an alkyl group, an alkoxy group, an alkylene group, etc. include straight-chain ones and branched-chain ones. In addition, isomers (E, Z, cis, trans) in double bonds, rings, condensed rings, isomers obtained by the presence of asymmetric carbons (R, S, α, β) , enantiomers, diastereoisomers), optically active substances with optical activity (D, L, d, l bodies), polar substances obtained by chromatographic separation (high polar substances, low polar substances), Equilibrium compounds, rotamers, mixtures of such in any ratio, and racemic mixtures are included in the disclosure. In addition, in this disclosure, all isomers obtained by tautomerism are also included.

表示與紙面的另一側(亦即α-配置)鍵結，

表示與紙面的前面側(亦即β-配置)鍵結，

表示α-配置與β-配置之任意的混合物。 [鹽] In this disclosure, unless otherwise specified, the symbol

Indicates a bond to the other side of the paper (ie, the α-configuration),

Indicates that it is bonded to the front side of the paper (ie, the β-configuration),

Indicates any mixture of α-configuration and β-configuration. [Salt]

The compound represented by the general formula (I-A) is converted into a salt by a known method.

Salts are pharmaceutically acceptable salts.

The salt is preferably water-soluble.

Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or such as acetate, lactate, tartrate, and benzoate. , citrate, methanesulfonate, ethylsulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, 2-isethionate, glucuronate, or gluconate Organic acid salts.

As an alkali metal salt, a potassium salt, a sodium salt, etc. are mentioned, for example.

As an alkaline earth metal salt, a calcium salt, a magnesium salt, etc. are mentioned, for example.

As an ammonium salt, tetramethylammonium salt etc. are mentioned, for example.

Examples of amine salts include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, and diethanolamine salts. Salt, ginseng (hydroxymethyl) aminomethane salt, lysine salt, arginine salt, and N-methyl-D-reductive glucosamine salt, etc.

In addition, the compound used in the present invention can form an N-oxide by any method. The so-called N-oxylate means that the nitrogen atom of the compound represented by the general formula (I-A) has been oxidized.

The compound represented by the general formula (I-A) and the pharmaceutically acceptable salt thereof may exist in an unsolvated form, or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvate is preferably a hydrate. The compound represented by general formula (I-A) and its pharmaceutically acceptable salts can be converted into solvates by known methods.

The compound represented by the general formula (I-A) can form a co-crystal with an appropriate co-crystal former. Co-crystals are preferably pharmaceutically acceptable formed with pharmaceutically acceptable co-crystal formers. Co-crystals are typically defined as crystals formed by two or more different molecules through intermolecular interactions other than ionic bonds. Also, co-crystals may be complexes of neutral molecules and salts. Co-crystals can be prepared by known methods such as melt crystallization, recrystallization from a solvent, or physically pulverizing components together. Suitable co-crystal formers include those described in WO2006/007448.

In this disclosure, the content of the compounds used in the present invention includes all compounds represented by the general formula (I-A), their pharmaceutically acceptable salts, their N-oxides, their solvates (such as hydrates), or a cocrystal thereof, or an N-oxide of a salt of a compound represented by general formula (I-A), a solvate (eg, hydrate) thereof, or a cocrystal thereof. [Prodrug]

The prodrug of the compound represented by the general formula (I-A) refers to a compound that is converted into the compound represented by the general formula (I-A) through reactions caused by enzymes or gastric acid in vivo. The prodrug of the compound shown in general formula (I-A) can enumerate for example: when the compound shown in general formula (I-A) has amine group, be that this amine group is subjected to acylation, alkylation, the compound of phosphorylation (such as general The amine group of the compound shown in formula (I-A) is subjected to eicosylation, propylamino carbonylation, pentylamino carbonylation, (5-methyl-2-side oxy-1,3-dioxol Alkyl-4-yl) methoxycarbonylation, tetrahydrofurylation, pyridine methylation, trimethylacetyloxymethylation, acetyloxymethylation, tertiary butylated compounds, etc.) ; when the compound shown in general formula (I-A) has a hydroxyl group, it is the compound (for example, the hydroxyl group of the compound shown in general formula (I-A) that is subject to acylation, alkylation, phosphorylation, boronation) for this hydroxyl group. Compounds such as palmitoylation, acrylation, trimethylacetylation, succinylation, fumarylation, propylation, dimethylaminomethylcarbonylation, etc.) ; when the compound shown in general formula (I-A) has a carboxyl group, the carboxyl group is subject to esterification and amidation of the carboxyl group (for example, the carboxyl group of the compound shown in general formula (I-A) is subjected to ethyl esterification, phenyl esterification, Carboxymethyl esterification, dimethylaminomethyl esterification, trimethylacetyloxymethyl esterification, 1-{(ethoxycarbonyl)oxy}ethyl esterification, phthaloyl esterification , (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterification , methyl amidated compounds, etc.), etc. These compounds can be produced by methods known per se. Also, the prodrug of the compound represented by the general formula (I-A) may be either a hydrate or a non-hydrate. Also, the prodrug of the compound represented by the general formula (I-A) can be converted into A compound represented by the general formula (I-A).

In addition, each atom constituting the compound represented by the general formula (IA) can be selected by its isotope (such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁷⁷ Br, ¹²⁵ I, etc.) and other substitutions. [Methods for producing compounds used in the present invention]

The compound used in the present invention can be prepared by a known method such as the method shown below, according to the method, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or the methods shown in the examples, etc. are appropriately improved and combined to produce. Salts can be used as starting materials. The order of carrying out the respective reactions can be appropriately changed depending on the protecting group to be introduced or the reaction conditions.

(反應步驟式1中，R ^1-1表示可受保護之R ¹，其他符號表示與前述相同的意義) The compound used in the present invention represented by general formula (IA) can be produced by reaction step 1. <Reaction Step Formula 1>

(In the reaction step formula 1, R ^1-1 represents R ¹ that can be protected, and other symbols represent the same meaning as above)

In reaction step formula 1, reaction 1-1 is amidation reaction. Amidation reaction is well known, for example can enumerate as follows: (1) Method of using acid halogen (2) Method using mixed anhydrides, (3) The method of using a condensing agent, etc. specifying such methods, (1) The method of using an acid halogen, such as making a carboxylic acid in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and an acid halogenating agent (oxalyl chloride, thionyl chloride, etc.) ) at -20°C to reflux temperature, and the resulting acid halide is reacted in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) , react with an amine in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) at a temperature of 0 to 40°C. In addition, the obtained acid halogen can also be reacted with an amine in an organic solvent (dioxane, tetrahydrofuran, etc.) using an alkaline aqueous solution (sodium bicarbonate water or sodium hydroxide solution, etc.) at 0 to 40°C. . (2) The method of using mixed acid anhydride, such as making carboxylic acid in organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) , dimethylaminopyridine, diisopropylethylamine, etc.), with acid halides (trimethylacetyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, etc.), or acid derivatives Compounds (ethyl chloroformate, isobutyl chloroformate, etc.) The reaction is carried out at 0 to 40°C. (3) The method of using a condensing agent, such as making carboxylic acid and amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without a solvent, in a base (pyridine, In the presence or absence of triethylamine, dimethylaniline, dimethylaminopyridine, etc.), a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl- 3-[3-(Dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, 1-propane 1-propanephosphonic acid cyclic anhydride (1-propanephosphonic acid cyclic anhydride, PPA) etc.), and the reaction is carried out at 0 to 40° C. with or without 1-hydroxybenzotriazole (HOBt). The reactions of (1), (2) and (3) are all desirably carried out under anhydrous conditions under an inert gas (argon, nitrogen, etc.) atmosphere.

In the reaction step formula 1, the reaction 1-2 is a vulcanization reaction. The vulcanization reaction is known, and the compound represented by the general formula 1c is made in an organic solvent (such as tetrahydrofuran, toluene, benzene, acetonitrile, methylene chloride, pyridine, etc.), in the presence or absence of a base (sodium bicarbonate, etc.) , with sulfurization reagents (such as Lawson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithio Ether, tetraphosphorus decasulfide, phosphorus pentasulfide, hydrogen sulfide, sulfur, etc.) are produced by reacting at room temperature to reflux temperature in the presence or absence of a phosphine reagent (such as trichlorophosphate, etc.).

In the reaction step formula 1, the compound represented by the general formula (I-A) can be produced by deprotecting the compound represented by the general formula 1c or 1d as necessary.

The protecting group of the carboxyl group includes, for example, methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), benzoylmethyl, p-methoxybenzyl, trityl, 2 - Chlorotrityl, etc.

Amino or tetrazolyl protecting groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl Base) ethoxycarbonyl (Bpoc) base, trifluoroacetyl, 9-fenylmethoxycarbonyl, benzyl (Bn) base, p-methoxybenzyl, benzyloxymethyl ( BOM) group, 2-(trimethylsilyl)ethoxymethyl (SEM) group, etc.

Examples of protecting groups for hydroxyl or hydroxylamine groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM) , 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tertiary butyldimethylsilyl (TBDMS), tertiary butyldiphenyl Silyl (TBDPS), Acetyl (Ac), Trimethylacetyl, Benzoyl, Benzyl (Bn), p-Methoxybenzyl, Allyloxycarbonyl (Alloc) , 2,2,2-trichloroethoxycarbonyl (Troc) and the like.

The deprotection reaction is known and can be carried out by the following method. For example, the following can be listed: (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrolysis, (4) Deprotection reaction of silicon group, (5) Deprotection reactions using metals, (6) Deprotection reactions using metal complexes, etc.

specifying the method, (1) Deprotection reaction by alkali hydrolysis, for example, in organic solvents (such as methanol, tetrahydrofuran, dioxane, etc.), using alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, hydroxide Lithium, etc.), alkaline earth metal hydroxides (such as barium hydroxide, calcium hydroxide, etc.) or carbonates (such as sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof, at 0 to 40°C. (2) Deprotection reaction under acidic conditions, for example, in an organic solvent (such as dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.), in an organic acid (such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.), or inorganic acids (such as hydrochloric acid, sulfuric acid, etc.) or their mixture (such as hydrogen bromide/acetic acid, etc.), in 2,2 , in the presence or absence of 2-trifluoroethanol at 0 to 100°C. (3) Deprotection reaction by hydrolysis, for example, in solvents (such as ethers (such as tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (such as methanol, ethanol, etc.) etc.), benzene series (such as benzene, toluene, etc.), ketone series (such as acetone, methyl ethyl ketone, etc.), nitrile series (such as acetonitrile, etc.), amide series (such as N,N-dimethylformamide amine, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these, etc.), in a catalyst (such as palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel ), etc.) at 0 to 200° C. in the presence of hydrogen at normal pressure or under pressure or in the presence of ammonium formate. (4) The deprotection reaction of the silyl group, for example, is carried out at 0 to 40° C. using tetrabutylammonium fluoride in a water-miscible organic solvent (such as tetrahydrofuran, acetonitrile, etc.). Also, for example, in organic acids (such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.), or inorganic acids (such as hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (such as hydrogen bromide/acetic acid, etc.) , at -10 to 100°C. (5) Deprotection reactions using metals, for example, in the presence of powdered zinc in an acidic solvent (such as acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions and an organic solvent such as tetrahydrofuran), if necessary Ultrasonic waves are applied while performing at 0 to 40°C. (6) Deprotection reactions using metal complexes, such as organic solvents (such as dichloromethane, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water Or in a mixed solvent of these, in a capture reagent (such as tributyltin hydride, triethylsilane, 5,5-dimethyl-cyclohexane-1,3-dione (Dimedone), morpholine, di ethylamine, pyrrolidine, etc.), organic acids (such as acetic acid, formic acid, 2-ethylhexane acid, etc.) and/or organic acid salts (such as sodium 2-ethylhexane Potassium, etc.), in the presence or absence of phosphine-based reagents (such as triphenylphosphine, etc.), using metal complexes (such as tetraphenylphosphine palladium (0), bis(triphenylphosphine) dichloride Phenylphosphine) palladium (II), palladium (II) acetate, chlorinated ginseng (triphenylphosphine) rhodium (I), etc.), at 0 to 40°C.

Also, in addition to the above, the deprotection reaction can also be performed by the method described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, for example.

(反應步驟式2中，R ^x表示羧酸的保護基Z ¹表示羥基或硫醇基，Z ²表示鹵素原子或羥基，Z ³表示H ₂C=CH-基、羥基、胺基、硼酸基、硼酸酯基、三烷基錫基、三烷基矽烷基或鹵化鋅基，其他符號表示與前述相同的意義) 反應步驟式2中，反應2為公知者，Z ²為鹵素原子時，可藉由鹵素取代反應而製造通式2c所示之化合物。 A representative example of the carboxylic acid represented by the general formula 1a can be produced by the reaction step 2. ＜Reaction step formula 2＞

(In reaction step formula 2, R ^x represents the protective group of carboxylic acid, Z ¹ represents hydroxyl or thiol group, Z ² represents halogen atom or hydroxyl, Z ³ represents H ₂ C=CH-group, hydroxyl, amino group, boronic acid group , borate group, trialkyltin group, trialkylsilyl group or zinc halide group, other symbols represent the same meaning as above) In the reaction step formula 2, reaction 2 is a known person, when Z ² is a halogen atom, The compound represented by general formula 2c can be produced by halogen substitution reaction.

The halogen substitution reaction is well known, for example, by reacting in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, etc.) , in alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) The reaction is carried out at 0 to 100° C. in the presence of an aqueous solution thereof or a mixture thereof.

In the reaction step formula 2, when Z ¹ is a hydroxyl group or a thiol group and Z ² is a hydroxyl group, the compound represented by the general formula 2c can be produced by the Mitsunobu reaction.

The Mitsunobu reaction is well known, for example, in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.), in an azo compound (diethyl azodicarboxylate (DEAD), Diisopropyl azodicarboxylate, 1,1'-(azobiscarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds In the presence of (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.), react with an equivalent alcohol compound at 0 to 60°C to conduct.

In terms of other methods for producing compounds represented by the general formula 2c, after triflate the compound represented by the general formula 2d, carry out a coupling reaction using a palladium catalyst with a compound represented by the general formula 2f And manufacture.

Triflate is well known and typically can be obtained by reacting with a base (e.g. pyridine, triethylamine) in an organic solvent (e.g. dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene). , dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.), with 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonyl Amine, or trifluoromethanesulfonic anhydride reaction and implementation.

The coupling reaction using a palladium catalyst includes, for example, Suzuki coupling, Stille coupling, Buchwald coupling, Negishi coupling, Heck reaction, Hiyama coupling, and the like.

These reactions are well known, for example, in an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.), in a base ( Sodium ethoxide, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride etc.)) or their aqueous solutions, or their mixtures and catalysts (tetra(triphenylphosphine) palladium (Pd(PPh ₃ ) ₄ ), bis(triphenylphosphine)palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), palladium acetate (Pd(OAc) ₂ ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (PdCl ₂ (dppf) ₂ ), diallyl di The reaction is carried out at room temperature to 120° C. in the presence of palladium chloride (PdCl ₂ (allyl) ₂ ), phenylbis(triphenylphosphine) palladium iodide (PhPdI(PPh ₃ ) ₂ ) or the like).

The carboxylic acid represented by the general formula 1a can be produced by performing the aforementioned carboxyl group deprotection reaction using the compound represented by the general formula 2c.

(式中，Z ⁴表示鹵素原子，其他符號表示與前述相同的意義) 反應步驟式3中，硝基的還原反應為公知者，例如在混合於水的溶劑(乙醇、甲醇、四氫呋喃等)中，酸(鹽酸、溴化氫酸、氯化銨、乙酸、甲酸銨等)的存在下或非存在下，使用金屬試劑(鋅、鐵、錫、氯化錫、氯化鐵、釤、銦、硼氫化鈉/氯化鎳等)，在0至150℃的溫度進行。 A representative example of the amine compound represented by the general formula 1b can be produced by the reaction step 3. ＜Reaction step formula 3＞

(In the formula, Z ⁴ represents a halogen atom, and other symbols represent the same meanings as described above) In the reaction step formula 3, the reduction reaction of the nitro group is known, for example, in a solvent (ethanol, methanol, tetrahydrofuran, etc.) mixed with water , in the presence or absence of acids (hydrochloric acid, hydrobromic acid, ammonium chloride, acetic acid, ammonium formate, etc.), using metal reagents (zinc, iron, tin, tin chloride, ferric chloride, samarium, indium, sodium borohydride/nickel chloride, etc.) at a temperature of 0 to 150°C.

In the reaction step formula 3, the coupling reaction using a palladium catalyst can produce the compound represented by the general formula 3d or the general formula 1b by performing the same reaction conditions as above.

In the reaction step formula 3, the reductive amination reaction is known, for example, in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid and the mixture thereof, etc.), in In the presence of a reducing agent (sodium triacetyloxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.), the compound represented by general formula 3f or general formula 1b is produced at a temperature of 0 to 40°C.

(式中，所有的符號表示與前述相同的意義)。 ＜反應步驟式4＞

(式中，-B(OR ^Y) ²表示硼酸或硼酸酯(例如硼酸二甲基酯、二氧雜硼雜環戊烷、4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷、二氧雜硼雜環己烷、5,5-二甲基1,3,2-二氧雜硼雜環己烷等)，其他符號表示與前述相同的意義) 反應步驟式4中，反應4-1為公知者，藉由對通式3f所示之化合物與通式4a所示之化合物施予前述的鈴木偶合反應的條件，可製造通式4b所示之化合物。就製造通式4b所示之化合物的其他方法，藉由將通式3f所示之化合物以反應4-2轉換成通式4c所示之硼酸酯後，使用通式4d所示之化合物進行反應4-3，可製造通式4b所示之胺化合物。 Among the compounds represented by the general formula (IA), Q is an oxygen atom and L is ^a compound of a C3-6 saturated carbocyclic ring, that is, the compound represented by the general formula (I-1) can be prepared by reaction step formula 4 manufacture:

(In the formula, all the symbols have the same meaning as above). ＜Reaction step formula 4＞

(wherein, -B(OR ^Y ) ² represents boric acid or boric acid ester (such as dimethyl borate, dioxaborolane, 4,4,5,5-tetramethyl-1,3, 2-dioxaborolane, dioxaborinane, 5,5-dimethyl 1,3,2-dioxaborinane, etc.), other symbols are the same as above meaning) in the reaction step formula 4, reaction 4-1 is known, by applying the conditions of the aforementioned Suzuki coupling reaction to the compound shown in the general formula 3f and the compound shown in the general formula 4a, the general formula 4b can be produced Compounds shown. For other methods of producing the compound shown in the general formula 4b, after the compound shown in the general formula 3f is converted into a borate ester shown in the general formula 4c with reaction 4-2, the compound shown in the general formula 4d is used to carry out Reaction 4-3 can produce the amine compound shown in general formula 4b.

Reaction 4-2 is known, and can be produced, for example, by Suzuki coupling reaction using bis(pinacolate)diboron.

Reaction 4-3 is known, and the compound represented by the general formula 4b can be produced by subjecting the compound represented by the general formula 4c and the compound represented by the general formula 4d to a Suzuki coupling reaction.

The compound represented by the general formula 4e can be produced by amidating the amine compound represented by the general formula 4b and the carboxylic acid compound represented by the general formula 1a by the aforementioned method.

The compound represented by the general formula (I-1) can be prepared by optionally deprotecting the compound represented by the general formula 4e.

The compound shown in the general formula (I-1) can also be reacted with the compound shown in the general formula 4a after making the compound shown in the general formula 1a and the compound shown in the general formula 3f after amidation 4-1 After that, it can be produced by deprotection if necessary.

The compound represented by the general formula (I-1) can also be made by amidating the compound represented by the general formula 1a and the compound represented by the general formula 3f, and then reacting 4-2, and then reacting with the compound represented by the general formula 4d The compound is produced by reaction 4-3, and deprotection if necessary.

(式中，X ¹、X ²分別獨立地表示CH、CR ⁴、或氮原子，其他符號表示與前述相同的意義)。 ＜反應步驟式5＞

(式中，所有的符號表示與前述相同的意義) 反應5-1為公知者，可藉由使用降莰烯的C-H活化反應來實施。例如Angewandte Chemie-International Edition,2013,vol.52,#23,p.6080–6083所記載，通式5c所示之化合物可藉由使用通式5a所示之化合物及通式5b所示之化合物，在有機溶劑(例如N,N二甲基乙醯胺、乙腈等)中，於鹼(例如碳酸鉀、碳酸氫鉀等)的存在下添加降莰烯及鈀催化劑(例如雙(乙腈)二氯鈀(II)等)，在70℃至90℃的溫度進行反應而製造。 Among the compounds represented by general formula (IA), Q is an oxygen atom, ring A is a 5-membered nitrogen-containing aromatic heterocycle, X is NR ⁷ , Y is a bond, and L ¹ is a C3-6 saturated carbocyclic compound , that is, the compound shown in the general formula (I-2) can be produced by the reaction step formula 5 shown below:

(In the formula, X ¹ and X ² independently represent CH, CR ⁴ , or a nitrogen atom, and other symbols have the same meanings as above). ＜Reaction step formula 5＞

(In the formula, all the symbols have the same meanings as above.) Reaction 5-1 is known, and can be implemented by CH activation reaction using norbornene. For example, as described in Angewandte Chemie-International Edition, 2013, vol.52, #23, p.6080-6083, the compound represented by the general formula 5c can be obtained by using the compound represented by the general formula 5a and the compound represented by the general formula 5b , in an organic solvent (such as N,N dimethylacetamide, acetonitrile, etc.), in the presence of a base (such as potassium carbonate, potassium bicarbonate, etc.), add norbornene and a palladium catalyst (such as bis(acetonitrile) di Chloropalladium (II), etc.) are produced by reacting at a temperature of 70°C to 90°C.

In the reaction step formula 5, the reaction 5-2 is known, and the compound represented by the general formula 5e can be produced by applying the aforementioned halogen substitution reaction or the aforementioned Mitsunobu reaction.

The deprotection, amidation and deprotection reactions of the carboxylic acid of the compound represented by the general formula 5e can be carried out by the same method as above.

(式中，所有的符號表示與前述相同的意義)， Among the compounds represented by the general formula (IA), Q is an oxygen atom, ring A is a 5-membered nitrogen-containing aromatic heterocycle, X is CR ⁶ , Y is a bond, and L ¹ is a C3-6 saturated carbocyclic compound , which is the general formula (I-3):

(In the formula, all symbols represent the same meaning as above),

(式中，所有的符號表示與前述相同的意義)。通式6d所示之化合物可藉由反應步驟式6來製造。 ＜反應步驟式6＞

(式中，所有的符號表示與前述相同的意義) 反應步驟式6中，鹵素取代反應與羧酸的脫保護反應可以與前述同樣的條件進行。 It can be produced by substituting the compound shown in the general formula 5f in the reaction step formula 5 with the compound shown in the general formula 6d:

(In the formula, all the symbols have the same meaning as above). The compound represented by general formula 6d can be produced by reaction step 6. <Reaction Step Formula 6>

(In the formula, all the symbols have the same meanings as above.) Reaction Step In formula 6, the halogen substitution reaction and the deprotection reaction of carboxylic acid can be carried out under the same conditions as above.

(式中，X ¹、X ²、X ³分別獨立地表示CH、或CR ⁴，其他符號表示與前述相同的意義)。 ＜反應步驟式7＞

(式中，所有的符號表示與前述相同的意義) 反應步驟式7中，反應7為公知者，Z ³為羥基時，可藉由進行前述的光延反應而製造通式7c所示之化合物。 Among the compounds represented by the general formula (IA), Q is an oxygen atom, the ring A is a benzene ring, Y is an oxygen atom, and L is ^a C3-6 saturated carbocyclic compound, that is, the compound represented by the general formula (I-4). The compound shown can be produced by the following reaction steps shown in Formula 7:

(In the formula, X ¹ , X ² , and X ³ each independently represent CH or CR ⁴ , and other symbols have the same meanings as above). ＜Reaction step formula 7＞

(In the formula, all the symbols have the same meanings as above) In the reaction step formula 7, the reaction ⁷ is known, and when Z3 is a hydroxyl group, the compound shown in the general formula 7c can be produced by carrying out the aforementioned Mitsunobu reaction.

When Z ² is a hydroxyl group and Z ³ is a halogen atom, the compound represented by general formula 7c can be produced by Ullmann etherification.

This Ullmann etherification reaction is known, for example, it can be carried out in an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.) Among them, phosphine ligands (triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), etc.), bases (sodium ethoxide, sodium hydroxide, hydrogen Potassium oxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or its aqueous solution, or the etc. and a catalyst (copper iodide, etc.) in the presence of a reaction at room temperature to 130°C.

In the reaction step formula 7, the deprotection, amidation and deprotection reactions of the carboxylic acid of the compound represented by the general formula 7c can be carried out in the same manner as above.

In each reaction in this specification, the general formula 2a, general formula 2b, general formula 2d, general formula 2f, general formula 3a, general formula 3c, general formula 3e, general formula 4a, general formula 4d used as starting materials , general formula 5a, general formula 5b, general formula 5d, general formula 6a, general formula 6b and the compound shown in general formula 7a can be known, or can be by known method, for example Comprehensive Organic Transformations: A Guide to Functional It is easy to manufacture by using methods described in Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or a method in which a part of a known method is changed in combination.

In addition, the compound used in the present invention having an amino group, a carboxyl group or a hydroxyl group may optionally be protected by a protective group commonly used with respect to these groups (for example, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014 The compounds protected by the described protecting groups) are produced by performing a known deprotection reaction after an appropriate reaction step.

Among the compounds used in the present invention, optically active compounds can be produced by using optically active starting materials or reagents, or by optically separating intermediate products of racemates, and then introducing them to the compounds used in the present invention. Compounds or racemates of the compounds used in the present invention are produced by optical resolution.

This optical separation is well known, and examples include methods such as forming salts/complexes with other optically active compounds, recrystallizing, and then isolating the target compound, or directly using a chiral separation column, etc., for separation. .

Among the reactions in the present specification, the reaction with heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as known to those skilled in the art to which the present invention pertains.

In each reaction in this specification, a solid-phase supporting reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) is used suitably.

In each reaction in this specification, the reaction product can be purified by usual purification means, such as distillation under normal pressure or reduced pressure, high-speed liquid chromatography using silica gel or magnesium silicate, thin layer chromatography , ion exchange resin, scavenger resin or column chromatography or washing, recrystallization and other methods. Purification may be performed in each reaction, or may be performed after completion of some reactions.

The compounds used in the present invention are usually formulated together with pharmaceutically acceptable carriers such as various additives and solvents, and administered orally or parenterally systemically or locally. Here, the term "pharmaceutically acceptable carrier" refers to substances other than the active ingredients used in general pharmaceutical formulations. The pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the preparation, is harmless and does not hinder the therapeutic effect of the active ingredient. In addition, pharmaceutically acceptable carriers can also be used for the purpose of improving the usefulness of active ingredients and preparations, facilitating formulation, stabilizing quality, or improving usability. Specifically, it is only necessary to select the substances described in the "Pharmaceutical Additives" (compiled by Japan Pharmaceutical Additives Association) published by Yakuji Daily in 2016 according to the purpose.

As dosage forms for administration, for example, preparations for oral administration (such as tablets, capsules, granules, powders, oral liquids, syrups, oral gels, etc.), preparations for oral cavity (such as: oral lozenges, oral sprays, oral semi-solid preparations, cough preparations, etc.), injection preparations (e.g. injections, etc.), dialysis preparations (e.g. dialysis preparations, etc.), inhalation preparations (e.g. inhalation preparations, etc.), ophthalmic preparations (such as eye drops, eye ointments, etc.), otic preparations (such as ear drops, etc.), nasal preparations (such as nasal drops, etc.), rectal preparations ( For example: suppositories, rectal semisolids, enemas, etc.), vaginal preparations (such as: vaginal lozenges, vaginal suppositories, etc.), and skin preparations (such as: external solids, external liquids, sprays, ointments , cream, gel, patch, etc.) etc.

Since the dosage of the compound used in the present invention varies according to age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., usually, each adult is administered once a day in the range of 0.1ng to 1000mg. Up to several times of oral administration, or for each adult, once a day to several times of parenteral administration in the range of 0.1ng to 100mg, or continuous intravenous administration in the range of 1 hour to 24 hours a day give. Of course, as mentioned above, the dose varies depending on various conditions, so there may be cases where a smaller dose than the above-mentioned dose is sufficient, and there may be cases where it is necessary to exceed the range. [Immune Checkpoint Inhibitors]

In this disclosure, an immune checkpoint molecule refers to a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal. Immune checkpoint molecules are known: CTLA-4, PD-1, PD-L1 (programmed cell death ligand 1 (programmed cell death-ligand 1)), PD-L2 (programmed cell death ligand 2 (programmed cell death ligand 2) cell date-ligand 2)), LAG-3 (lymphocyte activation gene 3 (Lymphocyte activation gene 3)), TIM3 (T cell immunoglobulin and mucin-3 (T cell immunoglobulin and mucin-3)), BTLA (B and T lymphocyte attenuator (B and T lymphocyte attenuator)), B7H3, B7H4, 2B4, CD160, A2aR (adenosine A2a receptor (adenosine A2a receptor)), KIR (killer inhibitory receptor (killer inhibitory receptor) ), VISTA (V-domine Ig-contacting support of T cell activation), TIGIT (T cell immunoglobulin and ITIM domine (T cell immunoglobulin and ITIM domine)), etc. (see Nature Reviews Cancer, 12, pp. 252-264, 2012; Cancer Cell, 27, pp. 450-461, 2015), there are no particular restrictions as long as the molecule has a function consistent with the definition.

The immune checkpoint inhibitor used in the combination of the present invention is a substance that inhibits the function of immune checkpoint molecules. The immune checkpoint inhibitor may be a small molecule or an antibody as long as it is a substance capable of inhibiting the function (signal) of an immune checkpoint molecule, and is not particularly limited.

The immune checkpoint inhibitor is preferably an inhibitor of a human immune checkpoint molecule, more preferably a neutralizing antibody against a human immune checkpoint molecule.

Examples of immune checkpoint inhibitor series: selected from CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, 2B4, CD160, A2aR, KIR, VISTA and TIGIT Inhibitors of immune checkpoint molecules in the group consisting. Examples of immune checkpoint inhibitors are listed below, but immune checkpoint inhibitors are not limited thereto.

Immune checkpoint inhibitors such as anti-CTLA-4 antibodies (e.g. Ipilimumab (YERVOY®), Tremerimumab, Zalifrelizumab (AGEN-1884) ), anti-PD-1 antibodies (eg, nivolumab (registered trademark)), cemiplimab (REGN-2810), pembrolizumab (KEYTRUDA®) , Spartanzumab (PDR-001), Tisslelizumab (BGB-A317), AMP-514 (MEDI0680), Prolgolimab (BCD-100) , Sintilimab (IBI-308), Toriparimab (JS-001), Sasanlimab (PF-60801591), Duvalumab ( Durvalumab) (ANB011/TSR-042), Camrelizumab (SHR-1210), Genolimzumab (CBT-381), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab (MGA012), Balstilimab (AGEN2034), CS1003, Serplimab (HLX10), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym-21, Geptanolimab (GB226), SSI-361, JY034, HX008, ISU106, Budigalimab (ABBV181), CX-188, Sirelinumab (Cetrelimab) (JNJ-63722383), anti-PD-L1 antibodies (eg, Atezolizumab (RG7446, MPDL3280A), Avelumab (PF-06834635) MSB0010718C), Duvalumab Monoclonal antibody (Durvalumab) (MEDI4736), BMS-936559, STI-1014, Envafolimab (KN035), CA-170, Lodapolimab (Lodapolimab) (LY-330 0054), HLX20, SHR-1316, CS1001(WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK104, ZKAB001, FAZ053, CBT-502 (TQB2450), JS003 and CX-072), anti-PD -L2 antibody (e.g., rHIgM12B7), PD-L1 fusion protein, PD-L2 fusion protein (e.g., AMP-224), anti-Tim-3 antibody (e.g., MBG453), anti-LAG-3 antibody (e.g., BMS-986016 , LAG525), anti-KIR antibodies (eg, Lirilumab (Lirilumab)), IDO1 (eg, Epacadostat, Linrodostat) and the like. Furthermore, antibodies comprising the complementarity determining regions (CDRs) or variable regions (VRs) of the heavy and light chains of known antibodies are also a form of immune checkpoint inhibitors. For example, another aspect of the anti-PD-1 antibody can include, for example, an antibody comprising the complementarity determining region (CDR) or variable region (VR) of the heavy chain and light chain of nivolumab.

The immune checkpoint inhibitors used in combination in the present invention are preferably anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-L1 fusion proteins, and PD-L2 fusion proteins. More preferably anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein. Particularly preferred is an anti-PD-1 antibody.

In the present invention, the preferred anti-PD-1 antibodies are: Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tissellizumab, Toripalimab, Sintilimab and Camrelizumab; preferred anti-PD-L1 antibody: Atezolizumab Anti-(Atezolizumab), Avelumab (Avelumab), Durvalumab (Durvalumab) and BMS-936559; CTLA-4 antibody is better: Ipilimumab (Ipilimumab) and tremelimumab ( Tremelimumab). Furthermore, the anti-PD-1 antibody is more preferably Nivolumab, Simiprimumab and Pembrolizumab, and more preferably Nivolumab.

According to the present disclosure, any one or plural antibodies or fusion proteins of these immune checkpoint inhibitors can be used in combination with the disclosed compound (EP ₂ receptor antagonist) used in the present invention.

In the present invention, immune checkpoint inhibitors can be prepared by conventional methods. Nivolumab can be produced according to the method described in WO2006/121168, pembrolizumab can be produced according to the method described in WO2008/156712, and BMS-936559 can be produced according to the method described in WO2007/005874. Ipilimumab can be produced according to the method described in WO2001/014424.

The dosage of immune checkpoint inhibitors used in the combination of the present invention varies with age, body weight, symptoms, therapeutic effects, administration methods, treatment time, etc., but can be adjusted to achieve the best desired effect.

For example, the active ingredient as an immune checkpoint inhibitor can be administered at about 1 to 10 mg/kg (body weight) once or about 200 to 1200 mg once at intervals of 2 to 4 weeks for about 30 minutes to about 60 minutes or Intravenous administration (eg, intravenous drip) is performed over about 60 minutes. Furthermore, the administration interval is, for example, 2 weeks, 3 weeks, or 4 weeks, and the time for one administration is, for example, about 30 minutes, about 60 minutes, or more than about 60 minutes.

For example, when the immune checkpoint inhibitor is nivolumab, which is an anti-PD-1 antibody, it is administered in the following usage and dosage. That is, for patients with malignant melanoma, nivolumab is given as an intravenous infusion of 3 mg/kg (body weight) once at 2-week intervals or 2 mg/kg (body weight) at 3-week intervals once . For patients with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin's lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma, nivolumab is administered once at 3 mg/kg (body weight) at intervals of 2 weeks Administered intravenously. Furthermore, in terms of other usage and dosage, for example, for malignant melanoma, non-small cell lung cancer, renal cell carcinoma, classical Hodgkin's lymphoma, urothelial carcinoma, MSI-H or dMMR-positive colorectal cancer (also Including children over 12 years old), head and neck cancer, gastric cancer, hepatocellular carcinoma, small cell lung cancer, esophageal cancer, and malignant pleural mesenteric cancer patients, Nivolumab is 240 mg once at 2-week intervals or 480 mg once at 4 Intravenous infusion was performed at weekly intervals. Furthermore, in terms of other usage and dosage, for example, for children with classical Hodgkin's lymphoma, nivolumab is given as an intravenous infusion of 3 mg/kg (body weight) at intervals of 2 weeks give. Furthermore, for children weighing more than 40 kg, nivolumab may also be given as an intravenous infusion of 240 mg at 2-week intervals or 480 mg at 4-week intervals. Furthermore, in terms of other usage and dosage, for example, for patients with malignant melanoma, in the combined use with ipilimumab, there is also nivolumab at 1 mg/kg (body weight) once for 3 weeks Intravenous infusion is performed 4 times at intervals, and then, nivolumab is given as an intravenous infusion of 3 mg/kg (body weight) at intervals of 2 weeks; or, nivolumab is given as 80 mg or more once Intravenous infusions were performed 4 times at intervals of 3 weeks, and then nivolumab was intravenously infused once at 2-week intervals at 2-week intervals or 480 mg at 4-week intervals. Furthermore, for example, for patients with renal cell carcinoma or colorectal cancer, in combination with ipilimumab, nivolumab is also given as a 240 mg intravenous infusion 4 times at intervals of 3 weeks, and then Nivolumab is given as an intravenous infusion of 240 mg at 2-week intervals or 480 mg at 4-week intervals. Furthermore, for example, for patients with non-small cell lung cancer or malignant pleural mesothelioma, in combination with ipilimumab, there is also nivolumab 240 mg once at 2-week intervals or once Intravenous infusion of 360mg at intervals of 3 weeks.

Furthermore, for example, for patients with non-small cell lung cancer, renal cell carcinoma, or colorectal cancer, in combination with ipilimumab, nivolumab is also administered intravenously at 240 mg once every 3 weeks Inject 4 times, and then nivolumab is intravenously infused once at 2-week intervals or 480 mg at 4-week intervals.

In addition, in the case of pembrolizumab, which is also an anti-PD-1 antibody, it is administered in the following usage and dosage. That is, malignant melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H or dMMR positive solid cancer or colorectal cancer, urothelial carcinoma, esophageal squamous cell carcinoma, renal cell carcinoma, For patients with breast cancer, cervical cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma, pembrolizumab is 200 mg once at 3-week intervals or 400 mg once Intravenous infusion was administered at intervals of 6 weeks. Furthermore, in terms of other usage and dosage, for example, for patients with classical Hodgkin's lymphoma, MSI-H or dMMR-positive solid cancer or colorectal cancer and primary mediastinal B-cell lymphoma in children over 2 years old, send Bombumab was administered by intravenous infusion of 2 mg/kg (body weight) once (up to 200 mg once) at intervals of 3 weeks.

Furthermore, when the active ingredient is avelumab which is an anti-PD-L1 antibody, avelumab is given once for each patient with Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma. 10 mg/kg (body weight) was administered intravenously at intervals of 2 weeks. Atezolizumab, which is also an anti-PD-L1 antibody, for each patient with non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, and urothelial cancer, atezolizumab is 1200 mg once at an interval of 3 weeks Intravenous infusion was performed; for patients with triple-negative breast cancer, in combination with paclitaxel, atezolizumab was administered as an intravenous infusion of 840 mg once at 2-week intervals. What's more, Duvalumab, which is also an anti-PD-L1 antibody, is for each patient with non-small cell lung cancer and urothelial cancer. Duvalumab is 10 mg/kg (body weight) once for 2 weeks. Intravenous infusion was performed at intervals. For patients with small cell lung cancer, durvalumab was administered by intravenous infusion of 1500 mg once at intervals of 3 weeks. Then, durvalumab was administered by intravenous infusion of 1500 mg once at intervals of 4 weeks. In addition, in the case of a body weight of 30 kg or less, the dosage for one administration was set at 20 mg/kg (body weight).

Furthermore, in the case of ipilimumab, which is an anti-CTLA-4 antibody, for patients with malignant melanoma, ipilimumab is 3 mg/time alone or in combination with nivolumab. kg (body weight) for 4 intravenous infusions at intervals of 3 weeks, for each patient with renal cell carcinoma and MSI-H or dMMR-positive colorectal cancer, in combination with nivolumab, ipilimumab is 1 mg/kg (body weight) for 4 times at intervals of 3 weeks. For patients with non-small cell lung cancer and malignant pleural mesothelioma, ipilimumab is 1 mg/kg (body weight) once for 6 Intravenous infusion at weekly intervals.

In the present invention, the above usage and dosage can also be used in the combination of the present invention. [EP4 antagonists]

The EP4 antagonist (EP4 receptor antagonist) used in the combination of the present invention is not particularly limited as long as it is a compound having an EP4 antagonistic effect. _In one embodiment, a series of examples: _AN0025 , _E7046 , IK-007 , RMX-1002, grabiprant, AAT-007, CR6086, INV-1120, BYD-001, TT-038, DT095895, P-001, ER-819762, MK-2894, MF498, evatanepag, CJ-042794, EP4A, BGC201531 , CJ-023423, GW627368, AH23848, DT-9081, or WO2016/111347, WO2001/062708, WO2002/020462, WO2002/032900, WO2002/050032, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/016311, WO2002/01631, WO2002/0161611 WO2003/087061、WO2003/099857、WO2003/016254、WO2005/021508、WO2004/067524、WO2005/037812、WO2005/061475、WO2005/105732、WO2005/105733、WO2006/122403、WO2007/121578、WO2008/017164、WO2008/ 104055、WO2008/116304、WO2008/123207、WO2007/143825、WO2009/005076、WO2009/139373、WO2010/019796、WO2010/034110、WO2012/039972、WO2012/043634、WO2012/076063、WO2012/103071、WO2013/004290、 WO2013/096496、WO2013/096501、WO2013/101733、WO2013/101598、WO2014/004229、WO2014/004230、WO2014/086739、WO2014/126746、WO2014/186218、WO2014/200075、WO2015/094902、WO2015/094912、WO2015/ 091475, WO2015/113057, WO2015/147020, WO2016/021742, WO2016/088903, WO2017/014323, WO2017/066633, WO2 017/085198、WO2018/195123、WO2018/195123、WO2018/210987、WO2018/210988、WO2018/210992、WO2018/210994、WO2018/210995、WO2018/216640、WO2019/038156、WO2019/245590、WO2019/101171、WO2019/ 152982, WO2019/166022, CN108929281, WO2020/012305, WO2020/014465, WO2020/151566, WO2020/160075 or WO2020/161275.

The EP4 receptor antagonist used in the combination of the present invention is preferably a compound described in WO2016/ ₁₁₁₃₄₇ (including the compound represented by the general formula of the invention, the embodiment, its pharmaceutically acceptable salt or the hydrate thereof) , more preferably the compounds represented by general formula (I) and general formula (I-2) described in WO2016/111347, their pharmaceutically acceptable salts or hydrates thereof, more preferably the compounds described in WO2016/111347 The compounds described in Examples, their pharmaceutically acceptable salts, or their hydrates. Still more preferably the following compounds, their pharmaceutically acceptable salts or their hydrates: (1) 4-[4-cyano-2-({[(2'R,4S)-6-(form (aminoformyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4- {4-cyano-2-[({(2'R,4S)-6-[(cyclopropylmethyl)aminoformyl]-2,3-dihydrospiro[benzopyran-4, 1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (3) 4-{4-cyano-2-[({(2'R,4S)-6-[ (2-Methoxyethyl)aminoformyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl} Butyric acid, (4) 4-{4-cyano-2-[({(2'R,4S)-6-[(2-methyl-2-propionitrile)carbamoyl]-2,3 -Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (5) 4-[4-cyano-2-({ [(2'R,4S)-6-{[(2S)-1-Methoxy-2-propionitrile]carbamoyl}-2,3-dihydrospiro[benzopyran-4,1 '-Cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-{4-cyano-2-[({(2'R,4S)-6-[( 1-Methyl-1H-pyrazol-3-yl)aminoformyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amine base]phenyl}butanoic acid, (7) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclopropylaminoformyl)-2,3-dihydro Spiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl} Amino)phenyl]butanoic acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclopentylaminoformyl)-2,3-bis Hydrogenspiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{2-[({(2'R,4S )-6-[(2S)-2-Butylaminocarbamoyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amine Base]-4-cyanophenyl}butanoic acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[(trans-4-hydroxycyclohexyl) Carbamoyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-{ 4-cyano-2-[({(2'R,4S)-6-[(cis-4- Hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (13 ) 4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridylaminoformyl)-2,3-dihydrospiro[benzopyran-4, 1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (14) 4-[4-cyano-2-({[(2'R,4S)-6-( 3-pyridylcarbamoyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, ( 15) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclobutylaminoformyl)-2,3-dihydrospiro[benzopyran-4, 1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-{ [1-(2-Methyl-2-propionitrile)-1H-pyrazol-4-yl]aminoformyl}-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane ]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(tetrahydro-2H- Pyran-4-ylaminoformyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(propenylaminoformyl)-2,3-dihydrospiro[benzopyran-4, 1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-{4-cyano-2-[({(2'R,4S)-6-[ (2-ethoxyethyl)aminoformyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl} Butyric acid, or (20) 4-[4-cyano-2-({[(2'R,4S)-6-(ethylaminoformyl)-2,3-dihydrospiro[benzopiper Fran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (21) 4-[4-cyano-2-({[(1R,2R)-6 '-(Methylaminoformyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butanoic acid, (22) 4-{4-cyano-2-[({(1R,2R)-6'-[(2-methoxyethyl)aminoformyl]-2',3'-dihydrospiro[cyclopropane -1,1'-indene]-2-yl}carbonyl)amino]phenyl}butanoic acid, (23) 4-{4-cyano-2-[({(1R,2R)-6'-[ (1-Methyl-1H-pyrazol-4-yl)aminoformyl]-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl}carbonyl)amino ]phenyl}butanoic acid, (24) 4-[4-cyano-2- ({[(2'R,4S)-7-fluoro-6-(methylaminoformyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2 '-yl]carbonyl}amino)phenyl]butanoic acid, (25) 4-{4-cyano-2-[({(2'R,4S)-7-fluoro-6-[(2- Methoxyethyl)aminoformyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (26) 4-[4-cyano-2-({[(2'R,4S)-7-fluoro-6-(isopropylaminoformyl)-2,3-dihydrospiro[benzene and pyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (27) 4-[4-cyano-2-({[(2'R, 4S)-7-(Methylaminoformyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyl Acid, (28) 4-{4-cyano-2-[({(2'R,4S)-7-[(2-methoxyethyl)aminoformyl]-2,3-dihydro Spiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (29) 4-[4-cyano-2-({[(2 'R, 4S)-7-methoxy-6-(methylaminoformyl)-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl] Carbonyl}amino)phenyl]butanoic acid, (30) 4-{4-cyano-2-[({(2'R,4S)-7-methoxy-6-[(2-methoxy Ethyl)carbamoyl]-2,3-dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (31) 4-[4-cyano-2-({[(2'R,3S)-5-(methylaminoformyl)-2H-spiro[1-benzofuran-3,1'-cyclopropane] -2'-yl]carbonyl}amino)phenyl]butanoic acid, (32) 4-{4-cyano-2-[({(2'R,3S)-5-[(2-methoxy Ethyl)carbamoyl]-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (33) 4-[ 4-cyano-2-({[(1S,2R)-6'-[(2-methoxyethyl)aminoformyl]-3',3'-dimethyl-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butanoic acid, or (34) 4-[4-cyano-2-({[(1S ,2R)-3',3'-Dimethyl-6'-(methylaminoformyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl ]carbonyl}amino)phenyl]butanoic acid.

Alternatively, the EP4 antagonists are preferably the following compounds, their pharmaceutically acceptable salts or their hydrates: (1) 4-[4-cyano-2-({[(2'R,4S)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-2,3 -Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-[4-cyano-2-({[(2'R,4S)-6-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2, 3-Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (3) 4-[4-cyano-2-({[(2'R,4S)-6-(3-methyl-1,2,4-oxadiazol-5-yl)-2,3 -Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (4) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridyl)-2,3-dihydrospiro[benzopyran-4,1' -cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (5) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazol-1-yl)-2,3-dihydrospiro[benzopyran- 4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazol-5-yl)-2,3-dihydrospiro[benzopyran- 4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (7) 4-[4-cyano-2-({[(2'R,4S)-6-(4-pyridyl)-2,3-dihydrospiro[benzopyran-4,1 '-Cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano-2-({[(2'R,4S)-6-(2-oxo-1-pyrrolidinyl)-2,3-dihydrospiro[benzo pyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methoxy-3-pyridyl)-2,3-dihydrospiro[benzopiper Furan-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(1H-pyrazol-1-yl)-3-pyridyl]-2,3- Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(dimethylamino)-3-pyridyl]-2,3-dihydrospiro [Benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methyl-3-pyridyl)-2,3-dihydrospiro[benzopyran -4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (13) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(methylamino)-3-pyridyl]-2,3-dihydrospiro[ Benzopyran-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (14) 4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridyl)-2,3-dihydrospiro[benzopyran-4,1' -cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-thiazol-2-yl)-2,3-dihydrospiro[benzopyran -4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-azol-2-yl)-2,3-dihydrospiro[benzopiper Furan-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2, 3-Dihydrospiro[benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridyl)-2,3-dihydrospiro[benzopyran-4,1 '-Cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-[4-cyano-2-({[(2'R,3S)-5-(3-pyridyl)-2H-spiro[1-benzofuran-3,1'-cyclopropane ]-2'-yl]carbonyl}amino)phenyl]butanoic acid, or (20) 4-[4-cyano-2-({[(1S,2R)-3',3'-dimethyl-6'-(3-pyridyl)-2',3'-dihydro spiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butanoic acid.

The most preferred EP4 receptor antagonist used in the combination of the present invention is 4-[ ₄ -cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl} Amino)phenyl]butyric acid, its pharmaceutically acceptable salts or their hydrates.

Any one or a plurality of these EP ₄ antagonists can be used in combination with the disclosed compound (EP ₂ receptor antagonist) used in the present invention.

In the present invention, EP4 antagonists can be produced according to known methods, for example, the compounds described in _WO2016 /111347 are produced according to the methods described in WO2016/111347.

In the present invention, _EP4 antagonists are usually formulated together with pharmaceutically acceptable carriers such as various additives and solvents, and administered orally or parenterally systemically or locally. Here, the term "pharmaceutically acceptable carrier" refers to substances other than the active ingredients used in general pharmaceutical formulations. The pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the preparation, is harmless and does not hinder the therapeutic effect of the active ingredient. In addition, pharmaceutically acceptable carriers can also be used for the purpose of improving the usefulness of active ingredients and preparations, facilitating formulation, stabilizing quality, or improving usability. Specifically, it is only necessary to select the substances described in "Pharmaceutical Additives 2016" (compiled by Japan Association of Pharmaceutical Additives) published by Yakuji Daily in 2016 according to the appropriate purpose.

Dosage forms for administration include, for example, preparations for oral administration (for example, lozenges, capsules, granules, powders, oral liquids, syrups, oral gels, etc.), oral preparations (for example, , oral lozenges, oral sprays, oral semi-solid preparations, cough preparations, etc.), injection preparations (for example, injections, etc.), dialysis preparations (for example, dialysis preparations, etc.), inhalation preparations (for example: inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointment, etc.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nose drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enemas, etc.), vaginal preparations (e.g., vaginal lozenges, vaginal suppositories, etc.), and skin preparations (e.g., external solids, external liquids, sprays, ointments agents, creams, gels, patches, etc.) etc.

The dosage of the compound used in the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc. Usually, each adult is within the range of 0.1ng to 1000mg once a day. Or multiple times of oral administration, or each adult, within the range of 0.1ng to 100mg each time, once a day or multiple times of parenteral administration, or continuous intravenous administration within the range of 1 hour to 24 hours a day give. Of course, as mentioned above, the dose varies depending on various conditions, so there may be cases where a smaller dose than the above-mentioned dose is sufficient, and there may be cases where it must exceed the range. [toxicity]

Since the combination of the present invention has low toxicity, it can be safely used as medicine. [Applicability to pharmaceuticals]

The combinations of the present invention are useful for cancer therapy.

More specifically, cancers include, for example, breast cancer, ovarian cancer, colorectal cancer (such as colon cancer, etc.), lung cancer (such as non-small cell lung cancer, etc.), prostate cancer, head and neck cancer (such as oral squamous cell carcinoma, squamous head and neck cancer, etc.) Epithelial cancer, pharynx cancer, larynx cancer, tongue cancer, thyroid cancer, acoustic nerve sheath tumor, etc.), lymphoma (such as B-cell lymphoma, T-cell lymphoma, etc.), uveal melanoma, thymoma, mesothelioma, esophagus Cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis/urethral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (such as malignant melanoma, etc.), malignant bone tumors, soft tissue sarcoma, chondrosarcoma, leukemia (such as acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, etc.), myeloid dysplasia syndrome, brain tumor or multiple myeloma, etc. The cancer is preferably breast cancer, ovarian cancer, colon cancer, lung cancer or gastric cancer.

Among them, for example, for cancer patients whose treatment with immune checkpoint inhibitors, _EP4 receptor antagonists or EP2 _receptor antagonists alone is insufficient, it is particularly expected that the combination of the present invention can maximize its antitumor effect. Effect. Furthermore, by the combination of the present invention, it is possible to reduce the doses of individual medicines and administer them, and the reduction of side effects can be expected.

An aspect of the combination of the present invention can also be applied to the treatment of metastatic cancer and the inhibition of metastasis.

One aspect of the combination of the present invention is inhibition of relapse.

In the present disclosure, treating means producing at least one of the following: reduction of tumor size, inhibition of tumor growth (delay or cessation), inhibition of tumor metastasis (delay or cessation), inhibition of recurrence (prevention or delay), and alleviation and One or more symptoms related to cancer.

One aspect of the combination of the present invention is used in the treatment of breast cancer, ovarian cancer, colorectal cancer, lung cancer, pancreatic cancer or gastric cancer.

Concomitant administration in the combination of the present invention includes simultaneous administration of each drug in the same or different dosage form, or separate administration (for example, sequential administration) of each drug.

In this disclosure, the combination of the present invention can be further used in combination with other drugs (for example, known anticancer treatments) for the following situations (1) to (3): (1) Supplementation of therapeutic effects and/or Enhancement, (2) dynamic/absorption improvement, reduction in dosage, and/or (3) reduction in side effects.

Other agents used to supplement and/or enhance the cancer therapeutic effect of the combination of the present invention include, for example: alkylating agents, metabolic antagonists, anticancer antibiotics, botanical preparations, hormone agents, platinum compounds, topoisomers Enzyme inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteosome inhibitors, HDAC inhibitors, and immunomodulators, etc.

Other pharmaceuticals may be administered in combination of any two or more.

In addition, other agents that supplement and/or enhance the preventive and/or therapeutic effects of the compounds used in the present invention include not only those discovered so far but also those discovered in the future based on the above mechanism.

Unless otherwise defined, all technical and scientific terms and abbreviations used in this specification have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs.

In addition, in this specification, the contents of all patent documents and non-patent documents or reference documents explicitly cited are all incorporated herein as a part of this specification. [Synthesis Examples of Compounds Used in the Present Invention]

The position of separation by chromatography and the solvent in parentheses shown by TLC represent the eluting solvent or developing solvent used, and the ratio represents the volume ratio.

The solvent in parentheses shown in the position of NMR indicates the solvent used for the measurement.

The compound names used in this specification are generally named according to the computer program named according to the rules of IUPAC, ACD/Name (registered trademark), or using Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft Co., Ltd.), or named according to the IUPAC nomenclature .

LC-MS/ELSD was performed under the following conditions. Condition A; Column: Waters Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0mL/min; column temperature: 30°C; mobile phase (A ): 0.1% trifluoroacetic acid aqueous solution (hereinafter referred to as TFA); mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (mobile phase (A): record the ratio of mobile phase (B)): [0 points] 95: 5; [0.1 point] 95: 5; [1.2 point] 5: 95; [1.4 point] 5: 95; [1.41 point] 95: 5; [1.5 point] 95: 5; detector: UV ( PDA), ELSD, MS. Condition B; Column: Waters Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0mL/min; column temperature: 30°C; mobile phase (A ): 0.1% TFA; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (mobile phase (A): record mobile phase (B) ratio): [0 minutes] 95:5; [0.15 minutes] 95 : 5; [1.15 points] 5: 95; [2.80 points] 5: 95; [2.81 points] 95: 5; [3 points] 95: 5; detectors: UV (PDA), ELSD, MS. Condition C; column: ACQUITY UPLC BEH C ₁₈ (particle size: 1.7 x 10 ^-6 m; column length: 50 x 2.1 mm); flow rate: 0.6mL/min; column temperature: 35°C; mobile phase (A ): 0.1% TFA; mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (mobile phase (A): ratio of recorded mobile phase (B)): [0 points] 97: 3; [0.4 points] 97 : 3; [2.5 points] 2: 98; [3.5 points] 2: 98; [4.01 points] 97: 3; detectors: UV (PDA), ELSD, MS. Condition D; Column: Xbridge C ₁₈ (particle size: 3.5 x 10 ^-6 m); Flow rate: 1.000mL/min; Column temperature: 35°C; Mobile phase (A): 10mM ammonium bicarbonate aqueous solution; Mobile phase ( B): acetonitrile; Gradient (mobile phase (A): record mobile phase (B) ratio): [0 minutes] 95:5; [0.8 minutes] 95:5; [5 minutes] 2:98; [6 minutes ]2: 98; [8.01 points] 95: 5; detectors: UV (PDA), ELSD, MS. Condition E; column: ACQUITY UPLC BEH C ₁₈ (particle size: 1.7 x 10 ^-6 m; column length: 50 x 2.1 mm); flow rate: 0.6mL/min; column temperature: 35°C; mobile phase (A ): 0.05% TFA; mobile phase (B): 0.05% TFA-acetonitrile solution; gradient (mobile phase (A): ratio of recorded mobile phase (B)): [0 points] 97: 3; [0.4 points] 97 : 3; [2.5 points] 2: 98; [3.5 points] 2: 98; [3.8 points] 97: 3; detectors: UV (PDA), ELSD, MS. Condition F; column: ACQUITY UPLC BEH C ₁₈ (particle size: 1.7 x 10 ^-6 m; column length: 50 x 2.1 mm); flow rate: 0.6mL/min; column temperature: 35°C; mobile phase (A ): 0.07% TFA; mobile phase (B): 0.07% TFA-acetonitrile solution; gradient (mobile phase (A): ratio of recorded mobile phase (B)): [0 points] 97: 3; [0.4 points] 97 : 3; [2.5 minutes] 2: 98; [3.5 minutes] 2: 98; [3.8 minutes] 97: 3; detectors: UV (PDA), ELSD, MS.

Unless otherwise specified, the HPLC retention time means the retention time in Condition A described in the aforementioned LC-MS/ELSD.

As a microwave reaction apparatus, Initiator 60 EXP manufactured by Biotage Corporation was used.

Separation and purification by high-speed liquid chromatography (hereinafter abbreviated as HPLC) were carried out under the following conditions. Mobile phase A (0.1%TFA): mobile phase B (0.1%TFA/acetonitrile)=95:5→5:95

Reference Example 1: 5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester in 1H-pyrrole-2-carboxylic acid ethyl ester (CAS number: 2199-43-1, 2.50g) In N,N-dimethylacetamide (hereinafter referred to as DMA) (3mL) solution, add bicyclo[2.2.2]-2-heptene (hereinafter referred to as norcamphene) (CAS number: 498-66- 8, 3.40 g), potassium bicarbonate (5.40 g), bis(acetonitrile)dichloropalladium(II) (CAS number: 14592-56-4, 230 mg), degassed by ultrasound. 1-Bromo-3-phenylpropane (CAS number: 637-59-2, 7.20 g) was added to the reaction mixture, and stirred at 90° C. for 20 hours. The reaction solution was diluted with ethyl acetate:hexane (1:1), and filtered through Celite (trade name). The filtrate was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→3:1) to obtain the title compound (3.82 g) having the following physical property values. HPLC retention time (min): 1.12; MS (ESI, Pos.): 258 (M+H) ⁺ .

Reference Example 2: 1-(butan-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid ethyl ester in toluene of the compound (0.27 g) produced in Reference Example 1 (5mL) solution was added 2-butanol (0.78g) and cyanomethylene tributylphosphine (hereinafter referred to as CMBP) (CAS number: 157141-27-0, 0.76g), using a microwave device at 130 ° C Stir for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 → 9:1) to obtain the title having the following physical properties: Compound (0.24g). HPLC retention time (min): 1.34; MS (ESI, Pos.): 314 (M+H) ⁺ .

Reference example 3: 1-(butane-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid in 1,2 of the compound (0.24g) produced in reference example 2 - Add methanol (2 mL) and 50% potassium hydroxide aqueous solution (1 mL) to a solution of dimethoxyethane (hereinafter abbreviated as DME) (2 mL), and stir at 90° C. for 22 hours. After standing to cool the reaction solution, it was made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→4:1) to obtain the title compound (0.18 g) having the following physical properties. HPLC retention time (min): 1.13; MS (ESI, Pos.): 286 (M+H) ⁺ . Reference examples 3-1 to 3-2:

Using the corresponding alcohol instead of 2-butanol, the same reaction as in reference example 2→reference example 3 was carried out to obtain the title compound having the following physical property values. Reference Example 3-1: 1-[(2S)-butane-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carboxylic acid HPLC retention time (minutes): 1.10; MS (ESI, Pos.): 286(M+H) ⁺ . Reference Example 3-2: 5-(3-phenylpropyl)-1-(propan-2-yl)-1H-pyrrole-2-carboxylic acid HPLC retention time (minutes): 1.10; MS (ESI, Pos. ): 272(M+H) ⁺ .

Reference Example 4: Racemic mixture of ethyl rel-(1R,2S)-2-[3-amino-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate in 5-bromo-2- (Trifluoromethyl)aniline (CAS number: 703-91-3, 3g) in 1,4-dioxane (60mL) solution, add 2-(4,4,5,5-tetramethyl-1 , ethyl 3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (CAS number: 1215107-29-1, 3g), 2M potassium phosphate aqueous solution (18.8mL) and [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (CAS number: 95464-05-4, 1 g), stirred at 100°C for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.8 g) having the following physical property values. HPLC retention time (min): 1.03; MS (ESI, Pos.): 273 (M+H) ⁺ .

Reference Example 5: 5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(trifluoromethyl)aniline in 5-bromo-2 -(Trifluoromethyl)aniline (1g) and bis(neopentyl glycol)diboron (CAS number: 201733-56-4, 1.9g) in dimethylsulfoxide (hereinafter referred to as DMSO) (10mL) solution Add potassium acetate (1.2g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (340mg), and stir at 100°C 2 hours. The reaction solution was diluted with water, and extracted with 2-methoxy-2-methylpropane (hereinafter abbreviated as MTBE). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (1 g) having the following physical property values. ¹ H-NMR (CDCl ₃ ): δ 1.55, 3.76, 4.06-4.15, 7.16-7.21, 7.39-7.42.

Reference Example 6: Ethyl (1R,2S)-2-[3-amino-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate The compound (491 mg) produced in Reference Example 5 and (1S,2S)-2-Iodocyclopropanecarboxylic acid ethyl ester (CAS number: 1629125-76-3, 400mg) in 1,4-dioxane (10mL) solution, add 2M cesium carbonate aqueous solution (2.2mL) , Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl)(2'-aminobiphenyl-2-yl)palladium(II) (hereinafter referred to as XPhos Pd G2) (CAS number: 1310584-14-5, 236 mg), stirred at 100°C for 4.5 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (NH silica) (hexane:ethyl acetate=9:1→0:1) and silica gel column chromatography (hexane:ethyl acetate (ester=9:1→1:1) was purified to obtain the title compound (110 mg) having the following physical property values. HPLC retention time (min): 0.95; MS (ESI, Pos.): 274 (M+H) ⁺ .

Reference Example 7: Ethyl (1R,2S)-2-[5-amino-2-chloro-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate Compound produced in Reference Example 6 (50 mg) in DMF (1 mL) was added N-chlorosuccinimide (CAS number: 128-09-6, 37 mg), and stirred at 60° C. for 1 hour. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (13 mg) having the following physical properties. HPLC retention time (min): 1.02; MS (ESI, Pos.): 308 (M+H) ⁺ .

Reference Example 8: rel-(1R,2S)-2-[3-{[1-(butane-2-yl)-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amine Base}-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid ethyl ester racemic mixture in the compound (105 mg) produced in Reference Example 4 and the compound (100 mg) produced in Reference Example 3 Add N,N-diisopropylethylamine (hereinafter referred to as DIPEA) (CAS number: 7087-68-5, 135mg) and chlorine-N,N,N',N' to the solution of methyl chloride (1mL) - Tetramethylformamidine hexafluorophosphate (hereinafter abbreviated as TCFH) (CAS number: 94790-35-9, 147 mg), stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC to obtain the title compound (100 mg) having the following physical properties. HPLC retention time (min): 1.39; MS (ESI, Pos.): 541 (M+H) ⁺ .

於參考例8所製造的化合物(95mg)的四氫呋喃(以下簡稱為THF) (2.5mL)及甲醇(2.5mL)溶液中添加5N氫氧化鈉水溶液(0.5mL)，在室溫攪拌3.5小時。將反應液以5N鹽酸中和，以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮，藉此得到具有以下的物性值之標題化合物(82mg)。 HPLC保持時間(分鐘)：1.22； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.58-0.82, 1.34-1.53, 1.61-2.22, 2.54-2.81, 4.63-5.18, 5.93-6.04, 6.58-6.71, 7.07-7.13, 7.17-7.24, 7.28-7.35, 7.46-7.54, 7.86-7.97, 8.06-8.18。 Example 1: rel-(1R,2S)-2-[3-({[1-second butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)- 4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid racemic mixture

To a solution of the compound (95 mg) produced in Reference Example 8 in tetrahydrofuran (hereinafter abbreviated as THF) (2.5 mL) and methanol (2.5 mL) was added 5N aqueous sodium hydroxide solution (0.5 mL), and stirred at room temperature for 3.5 hours. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (82 mg) having the following physical properties. HPLC retention time (min): 1.22; MS (ESI, Pos.): 513 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.58-0.82, 1.34-1.53, 1.61-2.22, 2.54-2.81 , 4.63-5.18, 5.93-6.04, 6.58-6.71, 7.07-7.13, 7.17-7.24, 7.28-7.35, 7.46-7.54, 7.86-7.97, 8.06-8.18.

Reference Example 9: N-[5-bromo-2-(trifluoromethyl)phenyl]-1-[(2S)-butane-2-yl]-5-(3-phenylpropyl)-1H -Pyrrole-2-carboxamide Use 5-bromo-2-(trifluoromethyl)aniline to replace the compound produced in Reference Example 4, and use the compound produced in Reference Example 3-1 to replace the compound produced in Reference Example 3 The compound was subjected to the same reaction as in Reference Example 8, whereby the title compound having the following physical properties was obtained. HPLC retention time (min): 1.43; MS (ESI, Pos.): 507 (M+H) ⁺ .

Reference Example 10: 2-[3-({1-[(2S)-butane-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4 -(Trifluoromethyl)phenyl]cyclopropane-1-carboxylic acid ethyl ester 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborin was added to a 1,4-dioxane solution (2 mL) of the compound (200 mg) produced in Reference Example 9 Ethyl cyclopentan-2-yl)cyclopropanecarboxylate (94mg), 2M aqueous potassium phosphate solution (0.59mL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II)-Dichloromethane adduct (96 mg), stirred at 120° C. for 1 hour using a microwave device. This reaction solution was used directly in the subsequent reaction without purification.

於參考例10所得之反應液中添加5N氫氧化鈉水溶液(1mL)，在50℃攪拌2小時。以5N鹽酸使反應液成為酸性，以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮，並以HPLC進行精製，藉此得到具有以下的物性值之標題化合物(45mg)。 HPLC保持時間(分鐘)：1.22； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR(CDCl ₃)：δ 0.76, 1.36-1.45, 1.51, 1.62-1.72, 1.73-1.87, 1.90-2.14, 2.57-2.79, 4.58-5.27, 5.98, 6.65, 7.03, 7.17-7.24, 7.28-7.35, 7.47, 7.94, 8.22。 Example 2: rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrole-2- yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomer mixture

A 5N aqueous sodium hydroxide solution (1 mL) was added to the reaction liquid obtained in Reference Example 10, followed by stirring at 50° C. for 2 hours. The reaction solution was made acidic with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by HPLC to obtain the title compound (45 mg) having the following physical properties. HPLC retention time (min): 1.22; MS (ESI, Pos.): 513 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.76, 1.36-1.45, 1.51, 1.62-1.72, 1.73-1.87 , 1.90-2.14, 2.57-2.79, 4.58-5.27, 5.98, 6.65, 7.03, 7.17-7.24, 7.28-7.35, 7.47, 7.94, 8.22.

HPLC保持時間(分鐘)：1.36； MS (ESI, Pos.)：459(M+H) ⁺； ¹H-NMR(CDCl ₃)：δ 0.68-0.81, 1.31-1.39, 1.50, 1.61-1.87, 1.96-2.12, 2.26-2.30, 2.51-2.80, 4.21-5.10, 5.95, 6.61, 6.83, 7.11-7.36, 7.58。 實施例2-2：rel-(1R,2R)-2-{3-[({1-[(2S)-2-丁基]-5-(3-苯基丙基)-1H-吡咯-2-基}羰基)胺基]-5-甲基苯基}環丙烷羧酸 非鏡像異構物混合物

HPLC保持時間(分鐘)：1.38； MS (ESI, Pos.)：459(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.76, 1.36-1.47, 1.52, 1.57-1.66, 1.71-2.08, 2.31, 2.49-2.61, 2.65-2.81, 4.43-5.37, 5.95, 6.59, 6.65, 7.09-7.36, 7.49-7.57。 實施例2-3：rel-(1R,2S)-2-{5-[({1-[(2S)-2-丁基]-5-(3-苯基丙基)-1H-吡咯-2-基}羰基)胺基]-2-(三氟甲基)苯基}環丙烷羧酸 非鏡像異構物混合物

HPLC保持時間(分鐘)：1.41； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.73-0.80, 1.42-1.57, 1.95-2.09, 2.14-2.28, 2.61-2.87, 4.32-5.33, 5.97, 6.67, 7.17-7.36, 7.42, 7.54-7.59, 7.62-7.78。 實施例2-4：rel-(1R,2R)-2-{5-[({1-[(2S)-2-丁基]-5-(3-苯基丙基)-1H-吡咯-2-基}羰基)胺基]-2-(三氟甲基)苯基}環丙烷羧酸 非鏡像異構物混合物

HPLC保持時間(分鐘)：1.43； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.77, 1.47-1.57, 1.63-1.88, 1.90-2.08, 2.63-2.93, 4.26-5.25, 5.98, 6.66, 7.12-7.34, 7.39, 7.44-7.50, 7.57-7.62, 7.68。 Examples 2-1 to 2-4: Using the corresponding aniline derivatives to replace 5-bromo-2-(trifluoromethyl)aniline, using 2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) ethyl cyclopropanecarboxylate or the corresponding borate, carry out the same operation as Reference Example 9→Reference Example 10→Example 2, thereby obtaining The title compound having the following physical properties. Example 2-1: rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrole- 2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid diastereomer mixture

HPLC retention time (min): 1.36; MS (ESI, Pos.): 459 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.68-0.81, 1.31-1.39, 1.50, 1.61-1.87, 1.96 -2.12, 2.26-2.30, 2.51-2.80, 4.21-5.10, 5.95, 6.61, 6.83, 7.11-7.36, 7.58. Example 2-2: rel-(1R,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrole- 2-yl}carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid diastereomer mixture

HPLC retention time (min): 1.38; MS (ESI, Pos.): 459 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.76, 1.36-1.47, 1.52, 1.57-1.66, 1.71-2.08 , 2.31, 2.49-2.61, 2.65-2.81, 4.43-5.37, 5.95, 6.59, 6.65, 7.09-7.36, 7.49-7.57. Example 2-3: rel-(1R,2S)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrole- 2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomer mixture

HPLC retention time (min): 1.41; MS (ESI, Pos.): 513 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.73-0.80, 1.42-1.57, 1.95-2.09, 2.14-2.28 , 2.61-2.87, 4.32-5.33, 5.97, 6.67, 7.17-7.36, 7.42, 7.54-7.59, 7.62-7.78. Example 2-4: rel-(1R,2R)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrole- 2-yl}carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid diastereomer mixture

HPLC retention time (min): 1.43; MS (ESI, Pos.): 513 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.77, 1.47-1.57, 1.63-1.88, 1.90-2.08, 2.63 -2.93, 4.26-5.25, 5.98, 6.66, 7.12-7.34, 7.39, 7.44-7.50, 7.57-7.62, 7.68.

HPLC保持時間(分鐘)：1.19； MS (ESI, Pos.)：499(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.39-1.47, 1.52, 1.64-1.74, 1.96-2.13, 2.58-2.80, 5.00-5.21, 5.97, 6.65, 6.90-7.17, 7.17-7.24, 7.28-7.36, 7.48, 7.95, 8.26。 實施例3-2：(1R,2R)-2-[3-({[1-異丙基-5-(3-苯基丙基)-1H-吡咯-2-基]羰基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：1.21； MS (ESI, Pos.)：499(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.45-1.51, 1.54, 1.66-1.76, 1.96-2.09, 2.60-2.83, 5.05-5.18, 5.97, 6.65, 6.89, 7.18-7.24, 7.28-7.34, 7.51, 7.98, 8.17。 Examples 3-1 to 3-2: Use isopropanol to replace 2-butanol, use the corresponding borate ester to replace 2-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) ethyl cyclopropanecarboxylate, carry out the same reaction as Reference Example 2→Reference Example 3→Reference Example 9→Reference Example 10→Example 1, thereby obtaining The title compound with the stated physical properties. Example 3-1: (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (min): 1.19; MS (ESI, Pos.): 499 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.39-1.47, 1.52, 1.64-1.74, 1.96-2.13, 2.58 -2.80, 5.00-5.21, 5.97, 6.65, 6.90-7.17, 7.17-7.24, 7.28-7.36, 7.48, 7.95, 8.26. Example 3-2: (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (min): 1.21; MS (ESI, Pos.): 499 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.45-1.51, 1.54, 1.66-1.76, 1.96-2.09, 2.60 -2.83, 5.05-5.18, 5.97, 6.65, 6.89, 7.18-7.24, 7.28-7.34, 7.51, 7.98, 8.17.

Reference Example 11: 4-iodo-1-methoxy-2-nitrobenzene 1-fluoro-4-iodo-2-nitrobenzene (CAS number: 364-75-0, 3.2 g) in methanol (10 mL) A methanol solution (7.3 mL) of 28% sodium methoxide was added to the solution, followed by stirring at 50° C. for 15 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.3 g) having the following physical properties. HPLC retention time (min): 0.94; ¹ H-NMR (CDCl ₃ ): δ 3.95, 6.87, 7.81, 8.12.

Reference Example 12: 5-iodo-2-methoxyaniline Water (1 mL) and iron powder (1.4 g) were added to a solution of the compound (2.3 g) produced in Reference Example 11 in acetic acid (10 mL), and stirred at 50° C. 6 hours. The reaction solution was diluted with MTBE and hexane, and filtered with Celite ((trade name). The filtrate was washed with 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was Purification by silica gel column chromatography (NH silica) (hexane:ethyl acetate=9:1→1:1) gave the title compound (1.8 g) having the following physical properties. HPLC Retention time (min): 0.63; MS (ESI, Pos.): 250 (M+H) ⁺ .

Reference Example 13: 1-[(2S)-butane-2-yl]-N-(5-iodo-2-methoxyphenyl)-5-(3-phenylpropyl)-1H-pyrrole- 2-Carboxamide Use the compound produced in Reference Example 12 to replace the compound produced in Reference Example 4, use the compound produced in Reference Example 3-1 to replace the compound produced in Reference Example 3, and carry out the same procedure as in Reference Example 8 reaction to obtain the title compound having the following physical properties. HPLC retention time (min): 1.41; MS (ESI, Pos.): 517 (M+H) ⁺ .

Reference example 14: 1-[(2S)-butane-2-yl]-N-[5-(5,5-dimethyl-1,3,2-dioxaborinane-2- Base)-2-methoxyphenyl]-5-(3-phenylpropyl)-1H-pyrrole-2-carboxamide To a DMSO (1 mL) solution of the compound (50 mg) and bis(neopentyl glycol) diborane (43 mg) produced in Reference Example 13, potassium acetate (28 mg) and [1,1'-bis(diphenyl phosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (8mg), and stirred at 100°C for 1 hour. The reaction solution was diluted with MTBE, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (35 mg) having the following physical properties. HPLC retention time (min): 1.14.

Reference Example 15: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl} Carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylic acid ethyl ester A 2M cesium carbonate aqueous solution ( 0.17mL) and XPhos Pd G2 (11mg), stirred at 100°C for 30 minutes. The reaction solution was used directly in the subsequent reaction without purification.

於參考例15的反應液中添加甲醇(1mL)及5N氫氧化鈉水溶液(1mL)在50℃攪拌1小時。使反應液回至室溫，以5N鹽酸中和，以MTBE進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後減壓濃縮。將所得之殘渣藉由HPLC進行精製，藉此得到具有以下的物性值之標題化合物(3mg)。 HPLC保持時間(分鐘)：1.39； MS(ESI, Pos.)：475(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.72-0.81, 1.33-1.44, 1.48-1.55, 1.62-1.71, 1.75-2.16, 2.59-2.79, 3.83-3.87, 4.62-5.16, 5.93-5.99, 6.59-6.66, 6.75-6.81, 6.87-6.94, 7.14-7.24, 7.27-7.35, 8.17-8.27, 8.32-8.36。 Example 4: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl} Carbonyl)amino]-4-methoxyphenyl}cyclopropanecarboxylic acid

Methanol (1 mL) and 5N sodium hydroxide aqueous solution (1 mL) were added to the reaction liquid of Reference Example 15, and it stirred at 50 degreeC for 1 hour. The reaction solution was returned to room temperature, neutralized with 5N hydrochloric acid, and extracted with MTBE. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (3 mg) having the following physical property values. HPLC retention time (min): 1.39; MS (ESI, Pos.): 475 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.72-0.81, 1.33-1.44, 1.48-1.55, 1.62-1.71 , 1.75-2.16, 2.59-2.79, 3.83-3.87, 4.62-5.16, 5.93-5.99, 6.59-6.66, 6.75-6.81, 6.87-6.94, 7.14-7.24, 7.27-7.35, 8.17-8.27, 8.3.6

Reference Example 16: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl rel-(1R,2S)-2-[3-({1-[(2S)- Butane-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate diastereomer mixture To a solution of the compound (50 mg) produced in Example 2 in dichloromethane (1 mL) and acetonitrile (1 mL), DIPEA (63 mg), L-menthol (45 mg), 4-dimethylaminopyridine (hereinafter Abbreviated as DMAP) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (hereinafter referred to as CyCIU) (CAS number: 135540-11-3, 65mg), stirred at 70°C for 2 Hour. The reaction solution was concentrated for subsequent fractionation.

Reference Examples 16-1 to 16-2: Fractionation The mixture obtained in Reference Example 16 was purified by HPLC to obtain the title compound having the following physical property values. Reference Example 16-1: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl(1S,2R)-2-[3-({1-[(2S)- Butane-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate HPLC retention time (min): 1.67 (condition B); MS (ESI, Pos.): 651 (M+H) ⁺ . Reference Example 16-2: (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl(1R,2S)-2-[3-({1-[(2S)- Butane-2-yl]-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxylate HPLC retention time (min): 1.70 (condition B); MS (ESI, Pos.): 651 (M+H) ⁺ .

於參考例16-1所製造的化合物的甲醇(1mL)及THF(1mL)的溶液中添加5N氫氧化鈉水溶液(1mL)，在50℃攪拌1小時。將反應液以5N鹽酸中和，以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮，藉此得到具有以下的物性值之標題化合物(16mg)。 HPLC保持時間(分鐘)：1.29； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.72-0.81, 1.17-1.47, 1.48-1.54, 1.63-1.87, 1.92-2.16, 2.58-2.80, 4.38-4.84, 5.95-6.01, 6.62-6.68, 7.03-7.08, 7.17-7.24, 7.28-7.35, 7.44-7.51, 7.91-7.98, 8.19-8.24。 Example 5: (1S,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl} Carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

A 5N aqueous sodium hydroxide solution (1 mL) was added to a solution of the compound produced in Reference Example 16-1 in methanol (1 mL) and THF (1 mL), followed by stirring at 50° C. for 1 hour. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (16 mg) having the following physical properties. HPLC retention time (min): 1.29; MS (ESI, Pos.): 513 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.72-0.81, 1.17-1.47, 1.48-1.54, 1.63-1.87 , 1.92-2.16, 2.58-2.80, 4.38-4.84, 5.95-6.01, 6.62-6.68, 7.03-7.08, 7.17-7.24, 7.28-7.35, 7.44-7.51, 7.91-7.98, 8.19-8.24.

於參考例16-2所製造的化合物的甲醇(1mL)及THF(1mL)的溶液中添加5N氫氧化鈉水溶液(1mL)，在50℃攪拌1小時。將反應液以5N鹽酸中和，以乙酸乙酯進行萃取。將有機層以飽和食鹽水，以無水硫酸鈉乾燥後進行減壓濃縮，藉此得到具有以下的物性值之標題化合物(11mg)。 HPLC保持時間(分鐘)：1.29； MS (ESI, Pos.)：513(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.76, 1.37-1.46, 1.52, 1.62-1.72, 1.73-1.86, 1.89-2.17, 2.56-2.82, 4.34-5.29, 5.98, 6.65, 7.02, 7.17-7.24, 7.27-7.35, 7.47, 7.94, 8.22。 Example 6: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl} Carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

A 5N aqueous sodium hydroxide solution (1 mL) was added to a solution of the compound produced in Reference Example 16-2 in methanol (1 mL) and THF (1 mL), followed by stirring at 50° C. for 1 hour. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (11 mg) having the following physical properties. HPLC retention time (min): 1.29; MS (ESI, Pos.): 513(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.76, 1.37-1.46, 1.52, 1.62-1.72, 1.73-1.86 , 1.89-2.17, 2.56-2.82, 4.34-5.29, 5.98, 6.65, 7.02, 7.17-7.24, 7.27-7.35, 7.47, 7.94, 8.22.

使用5-溴-2-氯苯胺來取代參考例4所製造的化合物，進行與參考例9→參考例10→實施例1同樣的操作，藉此得到具有下述物性值之標題化合物。 HPLC保持時間(分鐘)：1.41； MS (ESI, Pos.)：479(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 0.62-0.69, 1.11-1.51, 1.63-2.12, 2.34-2.80, 4.58-5.26, 5.88-6.00, 6.83-6.88, 6.97-7.07, 7.12-7.41, 7.50-7.56, 9.20-9.24, 11.90。 Example 7: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl} Carbonyl)amino]-4-chlorophenyl}cyclopropanecarboxylic acid

Substituting 5-bromo-2-chloroaniline for the compound produced in Reference Example 4, the same procedure as Reference Example 9→Reference Example 10→Example 1 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.41; MS (ESI, Pos.): 479 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 0.62-0.69, 1.11-1.51, 1.63-2.12, 2.34 -2.80, 4.58-5.26, 5.88-6.00, 6.83-6.88, 6.97-7.07, 7.12-7.41, 7.50-7.56, 9.20-9.24, 11.90.

Reference Example 17: 5-[2-(Benzyloxy)ethyl]-1H-pyrrole-2-carboxylic acid ethyl ester in 1H-pyrrole-2-carboxylic acid ethyl ester (37g) and norbornene (50g ) in DMA (265 mL), potassium bicarbonate (80 g), 2-bromoethoxymethylbenzene (CAS number: 1462-37-9, 57 g) and bis(acetonitrile) dichloropalladium(II) ( 3.5 g), stirred at 100°C for 24 hours. Water was added to the reaction liquid, filtered with Celite (trade name), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→6:1). The resulting residue was dissolved in heptane, washed with a 1:1 mixture of methanol and water, and the heptane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→6:4) to obtain the title compound (11 g) having the following physical property values. TLC: Rf 0.34 (hexane:ethyl acetate=5:1); HPLC retention time (min): 1.04; MS (ESI, Pos.): 274(M+H) ⁺ .

Reference Example 18: 5-[2-(Benzyloxy)ethyl]-1-[(2S)-butane-2-yl]-1H-pyrrole-2-carboxylic acid ethyl ester in Reference Example 17 (R)-(-)-2-Butanol (CAS No.: 14898-79-4, 12 mL) and CMBP (12 mL) were added to a toluene (22 mL) solution of the produced compound (6 g), and heated at 130° C. using a microwave Stir for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), thereby obtaining the title compound (4.6 g). HPLC retention time (min): 1.32; MS (ESI, Pos.): 330 (M+H) ⁺ .

Reference Example 19: 5-[2-(Benzyloxy)ethyl]-1-[(2S)-butane-2-yl]-1H-pyrrole-2-carboxylic acid produced in Reference Example 18 A 50% potassium hydroxide aqueous solution (2.7 mL) was added to a solution of compound (3 g) in 1-methylpyrrolidone (hereinafter abbreviated as NMP) (8 mL) and methanol (2.7 mL), followed by stirring at 85° C. for 1 hour. MTBE was added to the reaction solution, and after cooling with ice, the pH was adjusted to 5 with a 10% phosphoric acid aqueous solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.7 g) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 0.69-0.80, 1.45-1.55, 1.74-1.92, 1.96-2.08, 2.91-3.11, 3.69-3.78, 4.53-4.59, 5.16-5.92, 5.95-6.02, 7.09-7.15, 7.27-7.40.

Reference Example 20: (1R,2S)-2-{3-[({5-[2-(Benzyloxy)ethyl]-1-[(2S)-2-butyl]-1H-pyrrole -2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid ethyl ester Using the compound produced in Reference Example 19 to replace the compound produced in Reference Example 3, use Reference Example The compound produced in 6 was replaced with the compound produced in Reference Example 4, and the same operation as in Reference Example 8 was carried out to obtain the title compound (305 mg) having the following physical properties. HPLC retention time (min): 1.27; MS (ESI, Pos.): 557 (M+H) ⁺ .

使用參考例20所製造的化合物來取代參考例8所製造的化合物，進行與實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.13； MS (ESI, Pos.)：529(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.61-0.70, 1.05-1.31, 1.33-1.46, 1.80-2.03, 2.20-2.39, 2.93-3.02, 3.69-3.75, 4.53-4.57, 4.64-4.95, 5.94-5.98, 6.61-6.66, 7.13-7.39, 7.41-7.48, 7.57-7.64, 7.80-7.87。 Example 8: (1R,2S)-2-{3-[({5-[2-(Benzyloxy)ethyl]-1-[(2S)-2-butyl]-1H-pyrrole -2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

Using the compound produced in Reference Example 20 instead of the compound produced in Reference Example 8, the same operation as in Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (min): 1.13; MS (ESI, Pos.): 529 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.61-0.70, 1.05-1.31, 1.33-1.46, 1.80-2.03 , 2.20-2.39, 2.93-3.02, 3.69-3.75, 4.53-4.57, 4.64-4.95, 5.94-5.98, 6.61-6.66, 7.13-7.39, 7.41-7.48, 7.57-7.64, 7.80-7.87.

Reference Example 21: 1-[(2S)-butane-2-yl]-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylic acid ethyl ester Palladium hydroxide (CAS number: 12135-22-7, 300 mg) was added to an ethyl acetate (30 mL) solution of the compound (1.5 g) produced in Reference Example 18, and stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite (trade name), and concentrated under reduced pressure. The obtained residue was directly used in the subsequent reaction without purification.

Reference Example 22: 1-[(2S)-butane-2-yl]-5-{2-[(2-fluoropyridin-4-yl)oxy]ethyl}-1H-pyrrole-2-carboxylic acid Add CMBP (2.2 g) to the toluene (15 mL) solution of the reaction mixture prepared in Reference Example 21 and 2-fluoropyridin-4-ol (CAS number: 22282-69-5, 1 g), and stir at 90° C. 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1), thereby obtaining the following physical properties: The title compound (0.95g). HPLC retention time (min): 1.20; MS (ESI, Pos.): 335 (M+H) ⁺ .

Reference Example 23: 1-[(2S)-butane-2-yl]-5-{2-[(2-fluoropyridin-4-yl)oxy]ethyl}-1H-pyrrole-2-carboxylic acid A 5N aqueous sodium hydroxide solution (5 mL) was added to an NMP (15 mL) solution of the compound (0.95 g) produced in Reference Example 22, followed by stirring at 80° C. for 2 hours. After the reaction solution was washed with MTBE, the aqueous layer was neutralized with a 5% phosphoric acid aqueous solution, and extracted with MTBE. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) and silica gel (manufactured by Fuji Silysia, Inc., Chromatorex DIOL60) was purified by column chromatography to obtain the title compound (0.19 g) having the following physical properties. HPLC retention time (min): 0.95; MS (ESI, Pos.): 307 (M+H) ⁺ .

使用參考例23所製造的化合物來取代參考例3所製造的化合物，進行與參考例8→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.11； MS (ESI, Pos.)：534(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 0.70, 1.20-1.28, 1.32-1.39, 1.42-1.57, 1.71-1.87, 2.04-2.12, 2.63-2.74, 3.12-3.20, 4.35-4.41, 4.68-5.27, 6.05, 6.81, 6.92-6.96, 7.29, 7.36-7.41, 7.61, 8.04, 9.44, 11.98。 Example 9: rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-fluoro-4-pyridyl)oxy Base]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid diastereomer mixture

Using the compound produced in Reference Example 23 instead of the compound produced in Reference Example 3, the same operation as in Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (min): 1.11; MS (ESI, Pos.): 534(M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 0.70, 1.20-1.28, 1.32-1.39, 1.42-1.57 , 1.71-1.87, 2.04-2.12, 2.63-2.74, 3.12-3.20, 4.35-4.41, 4.68-5.27, 6.05, 6.81, 6.92-6.96, 7.29, 7.36-7.41, 7.61, 8.04, 1.494, .

Reference Example 24: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(2-hydroxyethyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylate to a solution of the compound (220mg) produced in Reference Example 20 in dichloromethane (10mL) was added 1M Tris A solution of boron bromide in dichloromethane (CAS number: 10294-33-4, 0.6 mL) was stirred at room temperature for 2.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:9→0:1) to obtain the title compound (140 mg) having the following physical properties. HPLC retention time (min): 1.02; MS (ESI, Pos.): 467 (M+H) ⁺ .

Reference Example 25: (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-chloro-6-fluoro-4-pyridyl )oxyl] ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid ethyl ester in reference example 24 manufactured compound (0.8g ) in toluene (20 mL) were added 2-chloro-6-fluoropyridin-4-ol (CAS number: 1807206-99-0, 0.3 g) and CMBP (0.5 g), and stirred at 90° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3:97→1:1), thereby obtaining the following physical properties: The title compound (0.9 g). HPLC retention time (min): 1.43; MS (ESI, Pos.): 596 (M+H) ⁺ .

於參考例25所製造的化合物(900mg)的1,4-二噁烷(10mL)溶液中添加硫酸(2mL)，在100℃攪拌48小時。將反應液以乙酸乙酯稀釋，以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣藉由HPLC進行精製，藉此得到具有以下的物性值之標題化合物(300mg)。 HPLC保持時間(分鐘)：1.31； MS (ESI, Pos.)：568(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 0.67-0.73, 1.21-1.29, 1.33-1.41, 1.43-1.50, 1.51-1.58, 1.71-1.84, 2.03-2.20, 2.63-2.73, 3.10-3.19, 4.39-4.45, 4.94-5.44, 6.02-6.07, 6.77-6.84, 6.87-6.93, 7.15-7.20, 7.25-7.31, 7.37-7.40, 7.61, 9.42-9.46, 11.98。 Example 10: (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-chloro-6-fluoro-4-pyridyl )oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

Sulfuric acid (2 mL) was added to a 1,4-dioxane (10 mL) solution of the compound (900 mg) produced in Reference Example 25, followed by stirring at 100° C. for 48 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (300 mg) having the following physical properties. HPLC retention time (min): 1.31; MS (ESI, Pos.): 568(M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 0.67-0.73, 1.21-1.29, 1.33-1.41, 1.43 -1.50, 1.51-1.58, 1.71-1.84, 2.03-2.20, 2.63-2.73, 3.10-3.19, 4.39-4.45, 4.94-5.44, 6.02-6.07, 6.77-6.84, 6.87-6.93, 7.15-7.25, , 7.37-7.40, 7.61, 9.42-9.46, 11.98.

Examples 10-1 to 10-3: Using the corresponding alcohol body instead of 2-chloro-6-fluoropyridin-4-ol, the same operation as that of Reference Example 25→Example 10 was carried out to obtain the following physical properties value of the title compound. Example 10-1: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2-chloro-3,5-difluorobenzene Oxy)ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid HPLC retention time (minutes): 1.37; MS (ESI, Pos .): 585(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.83, 1.42-1.53, 1.61, 1.68-1.80, 1.83-1.97, 2.02-2.16, 2.63-2.77, 3.26-3.33, 4.22 -4.30, 4.71-5.33, 6.07-6.14, 6.47-6.62, 6.65-6.70, 7.11-7.16, 7.50-7.56, 7.90-7.97, 8.14-8.20. Example 10-2: (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2,4-difluorophenoxy)ethyl Base]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid HPLC retention time (minutes): 1.32; MS (ESI, Pos.): 551 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.82, 1.41-1.52, 1.59, 1.69-1.77, 1.83-1.95, 1.98-2.25, 2.61-2.76, 3.16-3.29, 4.27, 4.69-5.28 , 6.08, 6.67, 6.74-6.98, 7.12, 7.48-7.55, 7.94, 8.18. Example 10-3: (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(1-methyl-1H-pyrazole- 4-yl)oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.14; MS (ESI, Pos.): 519(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.82, 1.40-1.51, 1.58, 1.67-1.75, 1.78-1.92, 1.95-2.21, 2.60-2.74, 3.15 , 3.84, 4.14, 4.66-5.21, 6.03, 6.66, 7.06-7.16, 7.48-7.56, 7.94, 8.19.

Reference Example 26: Methyl 2,6-dimethyl-4-(2-phenylethoxy)benzoate in methyl 4-hydroxy-2,6-dimethylbenzoate (CAS number: 83194-70 -1, 2.5g) in DMF (10mL) in potassium carbonate (5.8g) and 2-bromoethylbenzene (CAS number "103-63-9, 7.7g), stirred at 80°C for 15 hours. Then, additional 2-Bromoethylbenzene (1.4g) and potassium carbonate (1g) were stirred overnight. The reaction solution was diluted with ethyl acetate and hexane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to obtain the title compound (3.3 g).HPLC retention time (minutes): 1.15; MS (ESI, Pos.): 285 ( _M ⁺ H) ⁺ ; 7.46.

Reference Example 27: 2,6-Dimethyl-4-(2-phenylethoxy)benzoic acid Add 50% potassium hydroxide aqueous solution to the NMP (2 mL) solution of the compound (2 g) produced in Reference Example 26 (4 mL), stirred at 120°C for 3 hours. The reaction liquid was washed with ethyl acetate and hexane, made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to obtain the title compound (0.83 g) having the following physical property values. HPLC retention time (min): 0.98; MS (ESI, Pos.): 271 (M+H) ⁺ .

使用參考例27所製造的化合物來取代參考例3所製造的化合物，進行與參考例8→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.15； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.47, 1.66-1.77, 2.11-2.22, 2.35, 2.62-2.74, 3.10, 4.17, 6.60, 7.14, 7.21-7.37, 7.43-7.54, 8.27。 Example 11: rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-( Trifluoromethyl)phenyl]cyclopropanecarboxylic acid racemic mixture

Using the compound produced in Reference Example 27 instead of the compound produced in Reference Example 3, the same operation as in Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (min): 1.15; MS (ESI, Pos.): 498(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.47, 1.66-1.77, 2.11-2.22, 2.35, 2.62-2.74 , 3.10, 4.17, 6.60, 7.14, 7.21-7.37, 7.43-7.54, 8.27.

HPLC保持時間(分鐘)：2.28(條件C)； MS (ESI, Pos.)：484(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 0.95-1.02, 1.21-1.29, 1.70-1.79, 2.04-2.13, 2.40, 3.05, 4.24, 6.83-6.89, 7.20-7.27, 7.29-7.43, 7.44-7.52, 9.76。 實施例11-2：(1R,2S)-2-[3-{[2-氯-4-(2-苯基乙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.31(條件C)； MS (ESI, Pos.)：504(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.36-1.41, 1.51-1.59, 2.07-2.15, 2.64-2.75, 3.05, 4.29, 7.02-7.07, 7.05, 7.21-7.28, 7.29-7.37, 7.42-7.52, 7.65, 10.06, 12.01。 實施例11-3：(1R,2S)-2-[3-{[4-(2-苯基乙氧基)-2-(三氟甲基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.32(條件C)； MS (ESI, Pos.)：538(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.30-1.38, 1.45-1.56, 2.02-2.13, 2.56-2.69, 3.08, 4.35, 7.20-7.41, 7.55-7.67, 10.19, 12.01。 Examples 11-1 to 11-3: Use the corresponding phenol body to replace methyl 4-hydroxy-2,6-dimethylbenzoate, use the compound produced in Reference Example 6 to replace the compound produced in Reference Example 4 , and the same operation as in Reference Example 26→Reference Example 27→Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. Example 11-1: (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform base) phenyl] cyclopropane carboxylic acid

HPLC retention time (minutes): 2.28 (condition C); MS (ESI, Pos.): 484 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 0.95-1.02, 1.21-1.29, 1.70 -1.79, 2.04-2.13, 2.40, 3.05, 4.24, 6.83-6.89, 7.20-7.27, 7.29-7.43, 7.44-7.52, 9.76. Example 11-2: (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl ) phenyl] cyclopropane carboxylic acid

HPLC retention time (minutes): 2.31 (condition C); MS (ESI, Pos.): 504 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.36-1.41, 1.51-1.59, 2.07 -2.15, 2.64-2.75, 3.05, 4.29, 7.02-7.07, 7.05, 7.21-7.28, 7.29-7.37, 7.42-7.52, 7.65, 10.06, 12.01. Example 11-3: (1R,2S)-2-[3-{[4-(2-phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.32 (condition C); MS (ESI, Pos.): 538 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.30-1.38, 1.45-1.56, 2.02 -2.13, 2.56-2.69, 3.08, 4.35, 7.20-7.41, 7.55-7.67, 10.19, 12.01.

Reference Example 28: Methyl 2,6-dimethyl-4-[(1E)-3-phenylprop-1-en-1-yl]benzoate in 4-bromo-2,6-dimethylbenzene Add allylbenzene (CAS number: 300-57-2, 0.73g), palladium acetate (CAS number: 3375- 31-3, 46mg), tri-2-tolylphosphine (CAS number: 6163-58-2, 0.19g) and DIPEA (1.6g), stirred at 90°C for 6 hours and at 120°C respectively under nitrogen atmosphere 3 hours. Aqueous saturated ammonium chloride was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→2:3) to obtain the title compound (1.1 g) having the following physical property values. HPLC retention time (min): 1.27; MS (ESI, Pos.): 281 (M+H) ⁺ .

Reference Example 29: Methyl 2,6-dimethyl-4-(3-phenylpropyl)benzoate Add palladium hydroxide to a solution of the compound (180 mg) produced in Reference Example 28 in ethyl acetate (1 mL) (45 mg), stirred at room temperature under hydrogen for 1.5 hours. The reaction solution was filtered through Celite (trade name), and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5) to obtain the title compound (160 mg) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 1.87-1.97, 2.29, 2.57, 2.64, 3.90, 6.85, 7.15-7.23, 7.25-7.32.

Reference Example 30: 2,6-Dimethyl-4-(3-phenylpropyl)benzoic acid was added to the NMP (2 mL) solution of the compound (160 mg) produced in Reference Example 29 by adding water (2 mL) and hydrogenation Potassium (600mg), stirred at 120°C for 21 hours. 1N hydrochloric acid was added to the reaction solution to make it acidic, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (210 mg) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 1.89-1.97, 2.40, 2.59, 2.65, 6.88, 7.15-7.24, 7.26-7.33.

Reference Example 31: 4-(acetyloxy)-2,6-dimethylbenzoic acid in 4-hydroxy-2,6-dimethylbenzoic acid (CAS number: 75056-97-2, 3g) Acetic anhydride (2 mL) and pyridine (1.8 mL) were added to the ethyl acetate (18 mL) suspension, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with hexane and ethyl acetate to obtain the title compound (2.9 g) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 2.30, 2.45, 6.82.

Reference Example 32: Benzyl 4-hydroxy-2,6-dimethylbenzoate Potassium carbonate (50 g) and benzyl bromide were added to a solution of the compound (50 g) produced in Reference Example 31 in DMF (175 mL) (43 g), stirred at room temperature for 3 hours. Methanol (125 mL) and potassium carbonate (50 g) were added to the reaction liquid, and it stirred at room temperature for 1 hour. The reaction solution was diluted with 5N hydrochloric acid and water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to obtain the title compound (57 g) having the following physical property values. TLC: Rf 0.60 (hexane:ethyl acetate=2:1); ¹ H-NMR (DMSO-d ₆ ): δ 2.13, 3.32, 5.27, 6.44, 7.31-7.48, 9.63.

Reference Example 33: Benzyl 4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoate To a THF (10 mL) solution of the compound (1.6 g) produced in Reference Example 32 were added 2-(2,4-difluorophenyl)ethanol (CAS number: 81228-02-6, 1 g), triphenylphosphine (2.5 g) and a toluene solution (2.2 M, 4.3 mL) of diethyl azodicarboxylate (hereinafter abbreviated as DEAD), and stirred at room temperature for 5 hours. Then a solution of DEAD in toluene (2.2M, 2 mL) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5→75:25) to obtain the title having the following physical properties: Compound (1.8 g). TLC: Rf 0.79 (hexane:ethyl acetate=3:1).

Reference Example 34: 4-[2-(2,4-Difluorophenyl)ethoxy]-2,6-dimethylbenzoic acid in methanol (20 mL) of the compound (1.8 g) produced in Reference Example 33 10% palladium/carbon (0.6 g) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure to obtain the title compound (1.4 g) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 2.40, 3.08, 4.15, 6.57, 6.76-6.88, 7.17-7.28.

Reference Example 35: (1R,2S)-2-{3-[2,6-Dimethyl-4-(3-phenylpropyl)benzamide]-4-(trifluoromethyl)phenyl }Ethyl cyclopropane-1-carboxylate To a toluene (1 mL) suspension of the compound (23 mg) produced in Reference Example 30 was added thionyl chloride (0.01 mL), followed by stirring at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in acetonitrile (1 mL). The compound (20 mg) produced in Reference Example 6 was added to the reaction liquid, and stirred at room temperature for 21 hours. The reaction solution was concentrated for use in subsequent reactions.

使用參考例35所製造的化合物來取代參考例8所製造的化合物，進行與實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.32； MS (ESI, Pos.)：496(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.46-1.54, 1.67-1.79, 1.89-2.00, 2.16-2.24, 2.36, 2.56-2.74, 6.90, 7.15-7.23, 7.26-7.32, 7.46-7.57, 8.17。 Example 12: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl base) phenyl] cyclopropane carboxylic acid

Using the compound produced in Reference Example 35 instead of the compound produced in Reference Example 8, the same operation as in Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (min): 1.32; MS (ESI, Pos.): 496 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.46-1.54, 1.67-1.79, 1.89-2.00, 2.16-2.24 , 2.36, 2.56-2.74, 6.90, 7.15-7.23, 7.26-7.32, 7.46-7.57, 8.17.

HPLC保持時間(分鐘)：1.27； MS (ESI, Pos.)：534(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ1.46-1.56, 1.75, 2.15-2.27, 2.35, 2.66-2.78, 3.09, 4.15, 6.59, 6.76-6.89, 7.16-7.32, 7.46-7.57, 8.23。 Example 13: (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amine Base)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid using the compound produced in Reference Example 34 to replace the compound produced in Reference Example 30, the same operation as in Reference Example 35→Example 12 was carried out, and This gave the title compound having the following physical property values.

HPLC retention time (min): 1.27; MS (ESI, Pos.): 534 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ1.46-1.56, 1.75, 2.15-2.27, 2.35, 2.66- 2.78, 3.09, 4.15, 6.59, 6.76-6.89, 7.16-7.32, 7.46-7.57, 8.23.

Reference Example 36: Ethyl 2-(2,3-dichloro-4-fluorophenyl)cyclopropane-1-carboxylate in 1-bromo-2,3-dichloro-4-fluorobenzene (CAS number: 1093092 -14-8, 200mg) in 1,4-dioxane (6mL) solution, add 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) ethyl cyclopropanecarboxylate (197 mg), 2M aqueous potassium phosphate solution (1.2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride - Dichloromethane adduct (134mg), stirred at 100°C for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→3:1) to obtain a mixture (150 mg) containing the title compound having the following physical properties . HPLC retention time (min): 1.12, 1.17; MS (ESI, Pos.): 277 (M+H) ⁺ .

Reference Example 37: Ethyl 2-(2,3-dichloro-4-fluoro-5-nitrophenyl)cyclopropane-1-carboxylate To a concentrated sulfuric acid (0.15 mL) solution of the mixture (150 mg) produced in Reference Example 36, a mixture of concentrated sulfuric acid (0.15 mL) and fuming nitric acid (0.07 mL) was added dropwise under ice-cooling, and stirred at room temperature for 1 hour. The reaction solution was poured into ice, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was directly used in the subsequent reaction without purification.

Reference Example 38: Ethyl 2-(5-amino-2,3-dichloro-4-fluorophenyl)cyclopropane-1-carboxylate Using the compound produced in Reference Example 37 instead of the compound produced in Reference Example 11, the same operation as in Reference Example 12 was carried out to obtain a mixture containing the title compound.

HPLC保持時間(分鐘)：1.31； MS (ESI, Pos.)：516(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.53-1.60, 1.69-1.77, 2.23-2.31, 2.34, 2.57-2.66, 3.10, 4.18, 6.60, 7.20-7.37, 7.39-7.43, 8.37。 實施例14-2：rel-(1R,2R)-2-(2,3-二氯-5-{[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯基]胺基}-4-氟苯基)環丙烷羧酸 消旋混合物

HPLC保持時間(分鐘)：1.32； MS (ESI, Pos.)：516 (M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.50-1.62, 1.68-1.81, 1.85-1.94, 2.33, 2.74-2.87, 3.10, 4.18, 6.61, 7.21-7.38, 7.44, 8.25。 Examples 14-1 to 14-2: The compound produced in Reference Example 27 was used to replace the compound produced in Reference Example 30, and the compound produced in Reference Example 38 was used to replace the compound produced in Reference Example 6. Example 35→Example 1 After the same operation, it was separated and purified by HPLC to obtain the title compound having the following physical properties. Example 14-1: rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl Base]amino}-4-fluorophenyl)cyclopropanecarboxylic acid racemic mixture

HPLC retention time (min): 1.31; MS (ESI, Pos.): 516 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.53-1.60, 1.69-1.77, 2.23-2.31, 2.34, 2.57 -2.66, 3.10, 4.18, 6.60, 7.20-7.37, 7.39-7.43, 8.37. Example 14-2: rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl Base]amino}-4-fluorophenyl)cyclopropanecarboxylic acid racemic mixture

HPLC retention time (min): 1.32; MS (ESI, Pos.): 516 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.50-1.62, 1.68-1.81, 1.85-1.94, 2.33, 2.74 -2.87, 3.10, 4.18, 6.61, 7.21-7.38, 7.44, 8.25.

Reference Example 39: (1R,2S)-2-{2-Chloro-5-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro To ethyl methyl)phenyl}cyclopropane-1-carboxylate, DIPEA (4 mg) was added to a solution of the compound (8 mg) produced in Reference Example 27 and the compound (6 mg) produced in Reference Example 7 in acetonitrile (0.5 mL) and phosphorus oxychloride (3mg), stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 → 4:1) to obtain the following physical properties: The title compound (6 mg). HPLC retention time (min): 1.25; MS (ESI, Pos.): 560 (M+H) ⁺ .

於參考例39所製造的化合物(6mg)的甲醇(0.3mL)溶液中添加5N氫氧化鈉水溶液(0.05mL)，在室溫攪拌17小時。於反應液追加5N氫氧化鈉水溶液(0.05mL)並攪拌3小時。添加DME(0.1mL)並攪拌1小時。於反應液追加5N氫氧化鈉水溶液(0.1mL)並攪拌22小時。將反應液以5N鹽酸中和，以乙酸乙酯進行萃取。將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮，藉此得到包含具有以下的物性值之標題化合物的混合物(4mg)。 HPLC保持時間(分鐘)：1.12； MS (ESI, Pos.)：532(M+H) ⁺； ¹H-NMR (CDCl ₃：δ 1.54-1.62, 1.67-1.76, 2.22-2.37, 2.59-2.66, 3.10, 4.16-4.20, 6.59, 7.18-7.37, 7.45, 7.59, 8.30。 Example 15: (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

A 5N aqueous sodium hydroxide solution (0.05 mL) was added to a methanol (0.3 mL) solution of the compound (6 mg) produced in Reference Example 39, followed by stirring at room temperature for 17 hours. A 5N aqueous sodium hydroxide solution (0.05 mL) was added to the reaction solution, followed by stirring for 3 hours. DME (0.1 mL) was added and stirred for 1 hour. A 5N aqueous sodium hydroxide solution (0.1 mL) was added to the reaction solution, followed by stirring for 22 hours. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture (4 mg) containing the title compound having the following physical properties. HPLC retention time (min): 1.12; MS (ESI, Pos.): 532 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ : δ 1.54-1.62, 1.67-1.76, 2.22-2.37, 2.59-2.66, 3.10, 4.16-4.20, 6.59, 7.18-7.37, 7.45, 7.59, 8.30.

使用5-溴-2-氯苯胺來取代參考例4所製造的化合物，並使用參考例27所製造的化合物來取代參考例3所製造的化合物，進行與參考例8→參考例14→參考例15→參考例35→實施例1同樣的操作，藉此得到具有下述物性值之標題化合物。 MS (ESI, Pos.)：464(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.21-1.27, 1.30-1.36, 1.42-1.49, 2.00-2.07, 2.28-2.32, 2.99-3.05, 4.19, 6.67, 7.06-7.10, 7.19-7.24, 7.28-7.34, 7.36-7.41, 7.49, 9.90, 11.94。 Example 16: (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl ) Cyclopropane carboxylic acid

Use 5-bromo-2-chloroaniline to replace the compound produced in Reference Example 4, and use the compound produced in Reference Example 27 to replace the compound produced in Reference Example 3, and proceed with Reference Example 8→Reference Example 14→Reference Example 15→Reference Example 35→Example 1 In the same manner, the title compound having the following physical properties was obtained. MS (ESI, Pos.): 464(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.21-1.27, 1.30-1.36, 1.42-1.49, 2.00-2.07, 2.28-2.32, 2.99-3.05, 4.19, 6.67, 7.06-7.10, 7.19-7.24, 7.28-7.34, 7.36-7.41, 7.49, 9.90, 11.94.

HPLC保持時間(分鐘)：1.30； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.44-1.69, 2.32, 2.56-2.70, 3.07-3.12, 4.13-4.19, 6.58, 7.20-7.38, 7.91。 實施例17-2：rel-(1R,2R)-2-(2,3-二氯-5-{[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯基]胺基}苯基)環丙烷羧酸 消旋混合物

HPLC保持時間(分鐘)：1.32； MS(ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.39-1.49, 1.67-1.73, 1.81-1.88, 2.32, 2.73-2.90, 3.10, 4.17, 6.59, 7.19-7.42, 7.72。 Examples 17-1 to 17-2: Using 3-bromo-4,5-dichloronitrobenzene instead of the compound produced in Reference Example 11, and using the compound produced in Reference Example 27 instead of the compound produced in Reference Example 30 Compounds using the corresponding boronic esters to replace ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxy The ester was separated and purified by HPLC in the same manner as in Reference Example 12→Reference Example 35→Reference Example 10→Example 1 to obtain the title compound having the following physical properties. Example 17-1: rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl base]amino}phenyl)cyclopropanecarboxylic acid racemic mixture

HPLC retention time (min): 1.30; MS (ESI, Pos.): 498(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.44-1.69, 2.32, 2.56-2.70, 3.07-3.12, 4.13 -4.19, 6.58, 7.20-7.38, 7.91. Example 17-2: rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl base]amino}phenyl)cyclopropanecarboxylic acid racemic mixture

HPLC retention time (min): 1.32; MS (ESI, Pos.): 498 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.39-1.49, 1.67-1.73, 1.81-1.88, 2.32, 2.73 -2.90, 3.10, 4.17, 6.59, 7.19-7.42, 7.72.

Reference Example 40: N-[5-bromo-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide in Reference Example 27 DIPEA (0.72 g) and phosphorus oxychloride (0.62 g) were added to an acetonitrile solution (10 mL) of the produced compound (1 g) and 5-bromo-2-(trifluoromethyl)aniline (1.1 g), and the °C and stirred for 12 hours. Phosphorus oxychloride (0.12 g) was added to the reaction liquid, followed by stirring for 6 hours. The reaction solution was returned to room temperature, 1N aqueous sodium hydroxide solution (10 mL) was added and stirred for 10 minutes. The precipitated precipitate was filtered off and washed with hexane to obtain the title compound (1.5 g) having the following physical properties. HPLC retention time (min): 1.26; MS (ESI, Pos.): 492 (M+H) ⁺ .

Reference Example 41: N-[5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-(trifluoromethyl)phenyl]- 2,6-Dimethyl-4-(2-phenylethoxy)benzamide In a DME (5 mL) solution of the compound (500 mg) produced in Reference Example 40, bis(neopentyl glycol) diborane (459 mg) and potassium acetate (300 mg) were degassed, and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (83 mg), stirred at 88°C for 1.5 hours. The reaction solution was diluted with MTBE, and filtered with Celite (trade name). The filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:4) to obtain the title compound (508 mg) having the following physical properties. HPLC retention time (min): 1.03.

Reference Example 42: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Ethyl}cyclopropane-1-carboxylate To a solution of the compound (488 mg) produced in Reference Example 41 in 1,4-dioxane (5.4 mL) was added (1S,2S)-2-iodocyclopropanecarboxylic acid Ethyl ester (185 mg) and 2M cesium carbonate aqueous solution (1.2 mL) were degassed, XPhos Pd G2 (122 mg) was added, and stirred at 100° C. for 1.5 hours. The reaction solution was diluted with MTBE, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→0:1) to obtain the title compound (316 mg) having the following physical properties. HPLC retention time (min): 1.20; MS (ESI, Pos.): 526 (M+H) ⁺ .

於參考例42所製造的化合物(500mg)的THF(1.5mL)及甲醇(1.5mL)溶液中，在冰冷下添加5N氫氧化鈉水溶液(1.5mL)，在50℃攪拌1小時。於反應液添加水，以己烷洗淨。於水層添加5N鹽酸進行中和，以MTBE進行萃取。將所得之有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯=95：5→1：1)進行精製，藉此得到具有以下的物性值之標題化合物(395mg)。 HPLC保持時間(分鐘)：1.06； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR(CDCl ₃)：δ 1.39-1.51, 1.64-1.75, 2.09-2.21, 2.34, 2.62-2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24。 Example 18: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

To a THF (1.5 mL) and methanol (1.5 mL) solution of the compound (500 mg) produced in Reference Example 42 was added 5N aqueous sodium hydroxide solution (1.5 mL) under ice-cooling, followed by stirring at 50° C. for 1 hour. Water was added to the reaction liquid, followed by washing with hexane. The aqueous layer was neutralized by adding 5N hydrochloric acid, and extracted with MTBE. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1) to obtain the title compound (395 mg) having the following physical properties. HPLC retention time (min): 1.06; MS (ESI, Pos.): 498 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.39-1.51, 1.64-1.75, 2.09-2.21, 2.34, 2.62 -2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24.

使用對應的碘化合物來取代(1S,2S)-2-碘環丙烷羧酸乙酯，進行與參考例42→實施例18同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.08； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.43-1.53, 1.68-1.77, 2.10-2.21, 2.34, 2.63-2.76, 3.10, 4.17, 6.59, 7.17, 7.22-7.36, 7.47-7.58, 8.22。 Example 19: (1S,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

Substituting the corresponding iodine compound for ethyl (1S,2S)-2-iodocyclopropanecarboxylate, the same procedure as in Reference Example 42→Example 18 was carried out to obtain the title compound having the following physical properties. HPLC retention time (min): 1.08; MS (ESI, Pos.): 498(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.43-1.53, 1.68-1.77, 2.10-2.21, 2.34, 2.63 -2.76, 3.10, 4.17, 6.59, 7.17, 7.22-7.36, 7.47-7.58, 8.22.

Reference Example 43: (1R,2S)-2-{3-[4-(Acetyloxy)-2,6-dimethylbenzamide]-4-(trifluoromethyl)phenyl} Ethyl cyclopropane-1-carboxylate To a toluene (5 mL) suspension of the compound (914 mg) produced in Reference Example 31 were added thionyl chloride (0.4 mL) and DMF (42 mg), and stirred at 75° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and an acetonitrile solution of the compound (1 g) produced in Reference Example 6 was added to the obtained residue, followed by stirring at 55° C. for 2 hours. The reaction solution was diluted with hexane and MTBE, washed with 1N aqueous sodium hydroxide solution, 5N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to obtain the title compound (1.4 g) having the following physical property values. HPLC retention time (min): 1.03; MS (ESI, Pos.): 464 (M+H) ⁺ .

Reference Example 44: (1R,2S)-2-[3-(4-Hydroxy-2,6-dimethylbenzamide)-4-(trifluoromethyl)phenyl]cyclopropane-1-carboxy Ethyl acetate Potassium carbonate (1.3 g) was added to an ethanol (40 mL) solution of the compound (1.4 g) produced in Reference Example 43, followed by stirring at room temperature for 22 hours. The reaction solution was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1) to obtain the title compound (1.1 g) having the following physical property values. HPLC retention time (min): 0.94; MS (ESI, Pos.): 422 (M+H) ⁺ .

於參考例44所製造的化合物(20mg)的甲苯(0.5mL)溶液中添加2-(1-甲基-1H-吡唑-4-基)乙醇(CAS編號：176661-75-9，12mg)及CMBP (17mg)，在80℃攪拌2小時。於反應液追加CMBP(17mg)並攪拌1.5小時。將反應液濃縮，使所得之殘渣溶解於甲醇(0.3mL)，添加5N氫氧化鈉水溶液(0.05mL)並攪拌14小時。將反應液以5N鹽酸中和，使用HPLC進行精製，藉此得到具有以下的物性值之標題化合物(4mg)。 HPLC保持時間(分鐘)：1.05； MS (ESI, Pos.)：502(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.45-1.53, 1.71-1.78, 2.15-2.23, 2.36, 2.64-2.76, 2.93, 3.87, 4.04-4.11, 6.61, 7.18, 7.27, 7.40, 7.48, 7.53, 8.29。 Example 20: (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzene Formyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

To a solution of the compound (20 mg) produced in Reference Example 44 in toluene (0.5 mL) was added 2-(1-methyl-1H-pyrazol-4-yl)ethanol (CAS number: 176661-75-9, 12 mg) and CMBP (17mg), stirred at 80°C for 2 hours. CMBP (17 mg) was added to the reaction solution, followed by stirring for 1.5 hours. The reaction solution was concentrated, and the resulting residue was dissolved in methanol (0.3 mL), and a 5N aqueous sodium hydroxide solution (0.05 mL) was added thereto, followed by stirring for 14 hours. The reaction solution was neutralized with 5N hydrochloric acid and purified by HPLC to obtain the title compound (4 mg) having the following physical properties. HPLC retention time (min): 1.05; MS (ESI, Pos.): 502 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.45-1.53, 1.71-1.78, 2.15-2.23, 2.36, 2.64 -2.76, 2.93, 3.87, 4.04-4.11, 6.61, 7.18, 7.27, 7.40, 7.48, 7.53, 8.29.

HPLC保持時間(分鐘)：1.24； MS (ESI, Pos.)：462(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.09-0.17, 0.47-0.53, 0.77-0.91, 1.44-1.55, 1.65-1.78, 2.20, 2.36, 2.63-2.75, 4.04, 6.62, 7.20, 7.46-7.58, 8.18。 實施例20-2：(1R,2S)-2-{3-[(2,6-二甲基-4-丙氧基苯甲醯基)胺基]-4-(三氟甲基)苯基}環丙烷羧酸 HPLC保持時間(分鐘)：1.19； MS (ESI, Pos.)：436(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.04, 1.45-1.53, 1.66-1.87, 2.11-2.26, 2.35, 2.62-2.74, 3.93, 6.60, 7.20, 7.44-7.58, 8.17。 實施例20-3：(1R,2S)-2-[3-{[4-(己基氧基)-2,6-二甲基苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.14； MS (ESI, Pos.)：478(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 0.86-0.98, 1.04-1.16, 1.03-1.55, 1.72-1.83, 1.84-1.95, 2.19-2.31, 3.95, 6.53, 7.07-7.14, 7.31-7.39, 7.46-7.57, 7.67-7.76。 實施例20-4：(1R,2S)-2-[3-{[4-(苯甲基氧基)-2,6-二甲基苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.22； MS (ESI, Pos.)：484(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.43-1.55, 1.73, 2.14-2.27, 2.36, 2.65-2.76, 5.07, 6.69, 7.20, 7.31-7.46, 7.49-7.59, 8.17。 實施例20-5：(1R,2S)-2-[3-{[4-(2-甲氧基乙氧基)-2,6-二甲基苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.07； MS (ESI, Pos.)：452(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.35-1.43, 1.49-1.59, 2.05-2.15, 2.30, 2.63-2.79, 3.30, 3.60-3.68, 4.08, 6.67, 7.27-7.34, 7.44, 7.58-7.68, 9.95, 12.03。 實施例20-6：(1R,2S)-2-[3-({2,6-二甲基-4-[2-(四氫-2H-哌喃-2-基)乙氧基]苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.21； MS (ESI, Pos.)：506(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.22-1.76, 1.80-1.96, 2.15-2.24, 2.35, 2.63-2.77, 3.35-3.60, 3.91-4.18, 6.62, 7.19, 7.46-7.57, 8.19。 實施例20-7：(1R,2S)-2-[3-({4-[2-(2-呋喃基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.20； MS (ESI, Pos.)：488(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.45-1.55, 1.69-1.76, 2.16-2.23, 2.35, 2.62-2.77, 3.13, 4.22, 6.15, 6.32, 6.61, 7.20, 7.29-7.40, 7.44-7.59, 8.18。 實施例20-8：(1R,2S)-2-[3-({4-[2-(2-氯苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.30； MS (ESI, Pos.)：532(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.43-1.53, 1.67-1.78, 2.18, 2.34, 2.61-2.74, 3.24, 4.20, 6.61, 7.14-7.26, 7.32-7.42, 7.44-7.50, 7.50-7.56, 8.22。 實施例20-9：(1R,2S)-2-[3-({4-[2-(3-氯苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.30； MS (ESI, Pos.)：532(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.44-1.55, 1.67-1.77, 2.16-2.24, 2.35, 2.65-2.74, 3.07, 4.17, 6.59, 7.14-7.31, 7.45-7.55, 8.20。 實施例20-10：(1R,2S)-2-[3-({4-[2-(1H-咪唑-1-基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：0.84； MS (ESI, Pos.)：488(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.46-1.55, 1.69-1.78, 2.17-2.27, 2.33, 2.65-2.74, 4.28-4.34, 4.52-4.59, 6.55, 7.19-7.30, 7.37, 7.48, 7.53-7.57, 8.18, 8.96。 實施例20-11：(1R,2S)-2-[3-({4-[2-(2,6-二氟苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.26； MS (ESI, Pos.)：534(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.45-1.56, 1.67-1.79, 2.15-2.26, 2.34, 2.65-2.76, 3.18, 4.16, 6.60, 6.83-6.94, 7.14-7.25, 7.45-7.57, 8.19。 實施例20-12：(1R,2S)-2-[3-({4-[2-(3,5-二氟苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.27； MS (ESI, Pos.)：534(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.57-1.58, 1.70-1.79, 2.15-2.28, 2.36, 2.68-2.78, 3.07, 4.17, 6.60, 6.65-6.73, 6.78-6.88, 7.17-7.23, 7.50, 7.55, 8.23。 實施例20-13：(1R,2S)-2-[3-{[4-(1H-吲唑-5-基甲氧基)-2,6-二甲基苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.09； MS (ESI, Pos.)：524(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.35-1.47, 1.51-1.60, 2.32, 2.65-2.74, 5.21, 6.79, 7.31-7.36, 7.40-7.48, 7.54-7.60, 7.65,7.84, 8.09, 9.95, 12.62-13.37。 實施例20-14：(1R,2S)-2-[3-{[2,6-二甲基-4-(1,2,3,4-四氫-1-萘基甲氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.33； MS (ESI, Pos.)：538(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.34-1.46, 1.49-1.58, 1.62-2.02, 2.04-2.20, 2.28-2.35, 2.65-2.80, 3.16-3.28, 3.99-4.10, 4.15-4.22, 6.73, 7.07-7.19, 7.29-7.37, 7.46, 7.61-7.70, 9.94, 12.1。 實施例20-15：(1R,2S)-2-[3-({2,6-二甲基-4-[2-(3-吡啶基)乙氧基]苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：0.89； MS (ESI, Pos.)499：(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.35-1.46, 1.50-1.58, 2.04-2.20, 2.31, 2.62-2.77, 3.21, 4.29, 6.68, 7.31-7.39, 7.45, 7.66, 7.81, 8.27-8.30, 8.70, 8.80  9.93, 11.48-12.44。 實施例20-16：(1R,2S)-2-[3-({2,6-二甲基-4-[2-(4-吡啶基)乙氧基]苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：0.88； MS (ESI, Pos.)：499(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.38-1.43, 1.50-1.59, 2.07-2.18, 2.31, 2.66-2.75, 3.16-3.19, 4.31, 6.68, 7.34 ,7.45, 7.60, 7.66, 8.63, 9.94, 11.70-12.35。 實施例20-17：(1R,2S)-2-[3-({2,6-二甲基-4-[2-(2-吡啶基)乙氧基]苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：0.90； MS (ESI, Pos.)：499(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.34-1.44, 1.49-1.59, 2.05-2.17, 2.31, 2.66-2.79, 3.36, 4.40, 6.67, 7.30-7.38, 7.45, 7.66, 7.73-7.85, 8.09-8.36, 8.73, 9.93, 12.03。 實施例20-18：(1R,2S)-2-[3-({4-[2-(2-氯-1H-咪唑-1-基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.05； MS (ESI, Pos.)：522(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.33-1.47, 1.50-1.59, 2.05-2.18, 2.31, 2.67-2.75, 4.25-4.31, 4.33-4.39, 6.66, 6.91-6.96, 7.30-7.37, 7.38-7.41, 7.44-7.48, 7.65, 9.95。 實施例20-19：(1R,2S)-2-[3-({4-[2-(2-氟苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.25； MS (ESI, Pos.)：516(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.33-1.45, 1.48-1.59, 2.10-2.16, 2.31, 2.63-2.77, 3.08, 4.21, 6.68, 7.12-7.23, 7.25-7.38, 7.39-7.49, 7.65, 9.95, 12.10。 實施例20-20：(1R,2S)-2-[3-({4-[2-(3-氟苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.24； MS (ESI, Pos.)：516(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.34-1.46, 1.48-1.60, 2.05-2.19, 2.31, 2.64-2.78, 3.07, 4.22, 6.69, 7.02-7.10, 7.15-7.24, 7.30-7.40, 7.45, 7.65, 9.95, 12.10。 實施例20-21：(1R,2S)-2-[3-({4-[2-(4-氟苯基)乙氧基]-2,6-二甲基苯甲醯基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.23； MS (ESI, Pos.)：516(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.38-1.45, 1.50-1.61, 2.08-2.17, 2.31, 2.64-2.73, 3.03, 4.19, 6.68, 7.11-7.19, 7.29-7.42, 7.45, 7.65, 9.94, 12.06。 實施例20-22：(1R,2S)-2-[3-{[2,6-二甲基-4-(3,3,3-三氟丙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.17； MS (ESI, Pos.)：490(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.38-1.46, 1.50-1.58, 2.07-2.17, 2.33, 2.68-2.74, 2.74-2.85, 4.22, 6.72, 7.34, 7.46, 7.66, 9.98, 12.02。 實施例20-23：(1R,2S)-2-[3-{[2,6-二甲基-4-(3,3,3-三氟-2-甲基丙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸 HPLC保持時間(分鐘)：1.20； MS (ESI, Pos.)：504(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.21, 1.36-1.48, 1.50-1.62, 2.07-2.18, 2.33, 2.64-2.74, 2.82-3.02, 4.03-4.19, 6.72, 7.30-7.37, 7.46, 7.66, 9.97, 11.99。 Examples 20-1 to 20-23: Using the corresponding alcohol body to replace 2-(1-methyl-1H-pyrazol-4-yl)ethanol, perform the same operation as in Example 20, thereby obtaining the following The physical properties of the title compound. Example 20-1: (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (min): 1.24; MS (ESI, Pos.): 462(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.09-0.17, 0.47-0.53, 0.77-0.91, 1.44-1.55 , 1.65-1.78, 2.20, 2.36, 2.63-2.75, 4.04, 6.62, 7.20, 7.46-7.58, 8.18. Example 20-2: (1R,2S)-2-{3-[(2,6-Dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)benzene Hydroxycyclopropanecarboxylic acid HPLC retention time (minutes): 1.19; MS (ESI, Pos.): 436 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.04, 1.45-1.53, 1.66-1.87 , 2.11-2.26, 2.35, 2.62-2.74, 3.93, 6.60, 7.20, 7.44-7.58, 8.17. Example 20-3: (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl ) phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.14; MS (ESI, Pos.): 478 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.86-0.98, 1.04-1.16 , 1.03-1.55, 1.72-1.83, 1.84-1.95, 2.19-2.31, 3.95, 6.53, 7.07-7.14, 7.31-7.39, 7.46-7.57, 7.67-7.76. Example 20-4: (1R,2S)-2-[3-{[4-(Benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.22; MS (ESI, Pos.): 484 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.43-1.55, 1.73 , 2.14-2.27, 2.36, 2.65-2.76, 5.07, 6.69, 7.20, 7.31-7.46, 7.49-7.59, 8.17. Example 20-5: (1R,2S)-2-[3-{[4-(2-methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.07; MS (ESI, Pos.): 452 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.35-1.43, 1.49-1.59, 2.05-2.15, 2.30, 2.63-2.79, 3.30, 3.60-3.68, 4.08, 6.67, 7.27-7.34, 7.44, 7.58-7.68, 9.95, 12.03. Example 20-6: (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzene Formyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.21; MS (ESI, Pos.): 506 (M+H) ⁺ ; ¹ H -NMR (CDCl ₃ ): δ 1.22-1.76, 1.80-1.96, 2.15-2.24, 2.35, 2.63-2.77, 3.35-3.60, 3.91-4.18, 6.62, 7.19, 7.46-7.57, 8.19. Example 20-7: (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.20; MS (ESI, Pos.): 488 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.45-1.55, 1.69-1.76, 2.16-2.23, 2.35, 2.62-2.77, 3.13, 4.22, 6.15, 6.32, 6.61, 7.20, 7.29-7.40, 7.44-7.59, 8.18. Example 20-8: (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.30; MS (ESI, Pos.): 532 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ) : δ 1.43-1.53, 1.67-1.78, 2.18, 2.34, 2.61-2.74, 3.24, 4.20, 6.61, 7.14-7.26, 7.32-7.42, 7.44-7.50, 7.50-7.56, 8.22. Example 20-9: (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.30; MS (ESI, Pos.): 532 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ) : δ 1.44-1.55, 1.67-1.77, 2.16-2.24, 2.35, 2.65-2.74, 3.07, 4.17, 6.59, 7.14-7.31, 7.45-7.55, 8.20. Example 20-10: (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl} Amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 0.84; MS (ESI, Pos.): 488 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ). Example 20-11: (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.26; MS (ESI, Pos.): 534 (M+H) ⁺ ; ¹ H-NMR ( CDCl ₃ ): δ 1.45-1.56, 1.67-1.79, 2.15-2.26, 2.34, 2.65-2.76, 3.18, 4.16, 6.60, 6.83-6.94, 7.14-7.25, 7.45-7.57, 8.19. Example 20-12: (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.27; MS (ESI, Pos.): 534 (M+H) ⁺ ; ¹ H-NMR ( CDCl ₃ ): δ 1.57-1.58, 1.70-1.79, 2.15-2.28, 2.36, 2.68-2.78, 3.07, 4.17, 6.60, 6.65-6.73, 6.78-6.88, 7.17-7.23, 7.50, 7.55, 8.2. Example 20-13: (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino} -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.09; MS (ESI, Pos.): 524 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.35-1.47, 1.51-1.60, 2.32, 2.65-2.74, 5.21, 6.79, 7.31-7.36, 7.40-7.48, 7.54-7.60, 7.65,7.84, 8.09, 9.95, 12.62-13.37. Example 20-14: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(1,2,3,4-tetrahydro-1-naphthylmethoxy)benzene Formyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.33; MS (ESI, Pos.): 538(M+H) ⁺ ; ¹ H -NMR (DMSO-d ₆ ): δ 1.34-1.46, 1.49-1.58, 1.62-2.02, 2.04-2.20, 2.28-2.35, 2.65-2.80, 3.16-3.28, 3.99-4.10, 4.15-4.22, 6.73, 7.07- 7.19, 7.29-7.37, 7.46, 7.61-7.70, 9.94, 12.1. Example 20-15: (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(3-pyridyl)ethoxy]benzoyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 0.89; MS (ESI, Pos.) 499: (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.35-1.46, 1.50-1.58, 2.04-2.20, 2.31, 2.62-2.77, 3.21, 4.29, 6.68, 7.31-7.39, 7.45, 7.66, 7.81, 8.27-8.30, 8.70, 8.34, 1.80 1.9 Example 20-16: (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(4-pyridyl)ethoxy]benzoyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 0.88; MS (ESI, Pos.): 499 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.38-1.43, 1.50-1.59, 2.07-2.18, 2.31, 2.66-2.75, 3.16-3.19, 4.31, 6.68, 7.34 ,7.45, 7.60, 7.66, 8.63, 9.94, 11.70-12.35. Example 20-17: (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(2-pyridyl)ethoxy]benzoyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 0.90; MS (ESI, Pos.): 499 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.34-1.44, 1.49-1.59, 2.05-2.17, 2.31, 2.66-2.79, 3.36, 4.40, 6.67, 7.30-7.38, 7.45, 7.66, 7.73-7.85, 8.09-8.36, 8.733, 1.9.9 Example 20-18: (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzene Formyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (min): 1.05; MS (ESI, Pos.): 522(M+H) ⁺ ; ¹ H -NMR (DMSO-d ₆ ): δ 1.33-1.47, 1.50-1.59, 2.05-2.18, 2.31, 2.67-2.75, 4.25-4.31, 4.33-4.39, 6.66, 6.91-6.96, 7.30-7.37, 7.38-7.41, 7.44-7.48, 7.65, 9.95. Example 20-19: (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.25; MS (ESI, Pos.): 516 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.33-1.45, 1.48-1.59, 2.10-2.16, 2.31, 2.63-2.77, 3.08, 4.21, 6.68, 7.12-7.23, 7.25-7.38, 7.39-7.49, 7.65, 9.95, 12.10. Example 20-20: (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.24; MS (ESI, Pos.): 516 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ). Example 20-21: (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.23; MS (ESI, Pos.): 516 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.38-1.45, 1.50-1.61, 2.08-2.17, 2.31, 2.64-2.73, 3.03, 4.19, 6.68, 7.11-7.19, 7.29-7.42, 7.45, 7.65, 9.94, 12.06. Example 20-22: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino} -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.17; MS (ESI, Pos.): 490 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.38-1.46, 1.50-1.58, 2.07-2.17, 2.33, 2.68-2.74, 2.74-2.85, 4.22, 6.72, 7.34, 7.46, 7.66, 9.98, 12.02. Example 20-23: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl Base]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid HPLC retention time (minutes): 1.20; MS (ESI, Pos.): 504 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.21, 1.36-1.48, 1.50-1.62, 2.07-2.18, 2.33, 2.64-2.74, 2.82-3.02, 4.03-4.19, 6.72, 7.30-7.37, 7.46, 7.66, 9.997, 1

Reference Example 45: (1R,2S)-2-[3-{4-[(6-Chloropyrazin-2-yl)oxy]-2,6-dimethylbenzamide}-4-( Ethyl trifluoromethyl)phenyl]cyclopropane-1-carboxylate 2,6-Dichloropyrazine (CAS number: 4774-14-5, 21 mg) and potassium carbonate (25 mg) were added to a DMF (1 mL) solution of the compound (50 mg) produced in Reference Example 44, and stirred at 50°C 2 hours. The reaction solution was diluted with MTBE, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification.

於參考例45所製造的粗生成物的1,4-二噁烷(0.2mL)溶液中添加水(0.2mL)及濃硫酸(0.05mL)，在100℃攪拌15小時。將反應液以乙酸乙酯稀釋，以水洗淨，以無水硫酸鈉乾燥後進行減壓濃縮。將所得之殘渣藉由HPLC進行精製，藉此得到具有以下的物性值之標題化合物(30mg)。 HPLC保持時間(分鐘)：1.16； MS (ESI, Pos.)：506(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.46-1.55, 1.70-1.77, 2.16-2.24, 2.41, 2.66-2.76, 6.89, 7.21, 7.53-7.59, 8.20, 8.31, 8.32。 Example 21: (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

Water (0.2 mL) and concentrated sulfuric acid (0.05 mL) were added to a 1,4-dioxane (0.2 mL) solution of the crude product produced in Reference Example 45, and stirred at 100° C. for 15 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (30 mg) having the following physical properties. HPLC retention time (min): 1.16; MS (ESI, Pos.): 506(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.46-1.55, 1.70-1.77, 2.16-2.24, 2.41, 2.66 -2.76, 6.89, 7.21, 7.53-7.59, 8.20, 8.31, 8.32.

HPLC保持時間(分鐘)：1.21； MS (ESI, Pos.)：539(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.37-1.47, 1.52-1.61, 2.09-2.19, 2.37, 2.66-2.80, 6.98, 7.27-7.43, 7.48, 7.68, 8.02-8.27, 10.22, 12.05。 實施例21-2：(1R,2S)-2-[3-{[2,6-二甲基-4-(吡唑并[1,5-a]嘧啶-5-基氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：1.06； MS (ESI, Pos.)：511(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.39-1.46, 1.52-1.59, 2.10-2.17, 2.39, 2.69-2.81, 6.38, 6.83, 7.03, 7.36, 7.49, 7.68, 8.08, 9.08, 10.27, 12.16。 Examples 21-1 to 21-2: Substituting the corresponding chlorine form for 2,6-dichloropyrazine, the same operation as that of Reference Example 45→Example 21 was carried out to obtain the title compound having the following physical properties . Example 21-1: (1R,2S)-2-{3-[(2,6-Dimethyl-4-{[6-(trifluoromethyl)-2-pyridyl]oxy}benzyl Acyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid

HPLC retention time (min): 1.21; MS (ESI, Pos.): 539 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.37-1.47, 1.52-1.61, 2.09-2.19, 2.37 , 2.66-2.80, 6.98, 7.27-7.43, 7.48, 7.68, 8.02-8.27, 10.22, 12.05. Example 21-2: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzyl Acyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (min): 1.06; MS (ESI, Pos.): 511(M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.39-1.46, 1.52-1.59, 2.10-2.17, 2.39 , 2.69-2.81, 6.38, 6.83, 7.03, 7.36, 7.49, 7.68, 8.08, 9.08, 10.27, 12.16.

Reference Example 46: (1R,2S)-2-[3-{2,6-Dimethyl-4-[(trifluoromethanesulfonyl)oxy]benzamide}-4-(trifluoroform 1,1,1-trifluoro-N-(trifluoromethylsulfonyl) to a solution of the compound (100 mg) produced in Reference Example 44 in THF (3 mL) Acyl)methanesulfonamide (CAS number: 37595-74-7, 127mg) and triethylamine (72mg), stirred at room temperature for 88 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→1:1) to obtain the title compound (120 mg) having the following physical properties. HPLC retention time (min): 1.14; MS (ESI, Pos.): 554 (M+H) ⁺ .

Reference Example 47: (1R,2S)-2-{3-[4-(6-fluoropyridin-3-yl)-2,6-dimethylbenzamide]-4-(trifluoromethyl) To ethyl phenyl}cyclopropane-1-carboxylate, 2-fluoro-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS No.: 444120-95-0, 127 mg), 2M aqueous cesium carbonate solution (0.08 mL) and XPhos Pd G2 (8mg), stirred at 100°C for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to obtain the title compound having the following physical property values. HPLC retention time (min): 1.07; MS (ESI, Pos.): 501 (M+H) ⁺ .

於參考例47所製造的化合物的甲醇(1mL)溶液中添加5N氫氧化鈉水溶液(0.3mL)，在50℃攪拌17小時。將反應液以5N鹽酸中和，以乙酸乙酯進行萃取。將有機層進行減壓濃縮，以HPLC進行精製，藉此得到具有以下的物性值之標題化合物(12mg)。 HPLC保持時間(分鐘)：1.13； MS (ESI, Pos.)：473(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.46-1.58, 1.71-1.80, 2.16-2.28, 2.47, 2.66-2.78, 7.01-7.09, 7.18-7.27, 7.52-7.61, 7.94-8.03, 8.21, 8.43。 Example 22: (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridyl)-2,6-dimethylbenzoyl]amino}-4-(tri Fluoromethyl)phenyl]cyclopropanecarboxylic acid

A 5N aqueous sodium hydroxide solution (0.3 mL) was added to a methanol (1 mL) solution of the compound produced in Reference Example 47, followed by stirring at 50° C. for 17 hours. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by HPLC to obtain the title compound (12 mg) having the following physical properties. HPLC retention time (min): 1.13; MS (ESI, Pos.): 473 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.46-1.58, 1.71-1.80, 2.16-2.28, 2.47, 2.66 -2.78, 7.01-7.09, 7.18-7.27, 7.52-7.61, 7.94-8.03, 8.21, 8.43.

Reference Example 48: 2-{4-[(4-methoxybenzyl)oxy]phenyl}ethanol in 4-(2-hydroxyethyl)phenol (CAS number: 501-94-0, 2g) Potassium carbonate (3 g) and 4-methoxybenzyl chloride (CAS number: 824-94-2, 2.5 g) were added to a solution of DMF (10 mL) in a solution, and stirred at 50° C. for 14 hours. Water was added to the reaction solution, and the precipitated precipitate was filtered off. The obtained crude product was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.4 g) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 2.81, 3.75-3.90, 4.97, 6.85-6.98, 7.11-7.19, 7.33-7.38.

Reference Example 49: (1R,2S)-2-{3-[4-(2-{4-[(4-methoxyphenyl)methoxy]phenyl}ethoxy)-2,6- Dimethylbenzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid The compound (25 mg) and CMBP (17 mg) produced in Reference Example 48 were added to a toluene (0.5 mL) solution of the compound (20 mg) produced in Reference Example 44, and stirred at 80° C. for 27 hours. The reaction solution was concentrated under reduced pressure, methanol (0.3 mL), THF (0.3 mL) and 5N aqueous sodium hydroxide solution (0.05 mL) were added to the residue, and the mixture was stirred at 50°C for 2 hours and at room temperature for 21 hours. The reaction solution was neutralized with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was used in the subsequent reaction without purification.

將參考例49所得之粗生成物的乙酸(1mL)溶液使用微波反應裝置在150℃加熱攪拌15分鐘。將反應液進行減壓濃縮，將所得之殘渣藉由氧化矽凝膠管柱層析(Fuji Silysia公司製，Chromatorex DIOL60，己烷：乙酸乙酯=9：1→0：1)進行精製，藉此得到具有以下的物性值之標題化合物(18mg)。 HPLC保持時間(分鐘)：1.13； MS (ESI, Pos.)：514(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.43-1.51, 1.64-1.75, 2.17, 2.34, 2.63-2.72, 3.02, 4.13, 6.59, 6.75-6.82, 7.08-7.20, 7.45-7.49, 7.50-7.55, 8.16-8.24。 Example 23: (1R,2S)-2-[3-({4-[2-(4-Hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)- 4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

A solution of the crude product obtained in Reference Example 49 in acetic acid (1 mL) was heated and stirred at 150° C. for 15 minutes using a microwave reactor. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (manufactured by Fuji Silysia, Chromatorex DIOL60, hexane: ethyl acetate = 9:1 → 0:1). This gave the title compound (18 mg) having the following physical properties. HPLC retention time (min): 1.13; MS (ESI, Pos.): 514(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.43-1.51, 1.64-1.75, 2.17, 2.34, 2.63-2.72 , 3.02, 4.13, 6.59, 6.75-6.82, 7.08-7.20, 7.45-7.49, 7.50-7.55, 8.16-8.24.

Reference Example 50: (2E)-3-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl} Ethyl prop-2-enoate Ethyl acrylate (18 mg), DIPEA (24 mg), tetrakis(triphenylphosphine)palladium(0) (CAS No.: 14221-01-3, 14 mg), stirred overnight at 100°C. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:1), and the obtained title compound was used in the subsequent reaction.

Reference Example 51: (2E)-3-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl} prop-2-enoic acid A 2N aqueous sodium hydroxide solution (0.5 mL) was added to a THF/methanol (1 mL) solution of the compound produced in Reference Example 50, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was directly used in the subsequent reaction without purification.

於參考例51所得之殘渣的THF(1mL)溶液添加氫氧化鈀(3mg)，在氫環境下於室溫攪拌1小時。將反應液以Celite(商品名)過濾，進行減壓濃縮。將所得之殘渣藉由HPLC進行精製，藉此得到具有以下的物性值之標題化合物(0.62mg)。 HPLC保持時間(分鐘)：1.20； MS (ESI, Pos.)：486(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 2.30, 2.56-2.62, 2.92, 3.02, 4.19, 6.66, 7.19-7.25, 7.28-7.34, 7.34-7.37, 7.41, 7.67, 9.92, 12.11-12.32。 Example 24: 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl] propionic acid

Palladium hydroxide (3 mg) was added to a THF (1 mL) solution of the residue obtained in Reference Example 51, followed by stirring at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.62 mg) having the following physical property values. HPLC retention time (min): 1.20; MS (ESI, Pos.): 486(M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 2.30, 2.56-2.62, 2.92, 3.02, 4.19, 6.66 , 7.19-7.25, 7.28-7.34, 7.34-7.37, 7.41, 7.67, 9.92, 12.11-12.32.

HPLC保持時間(分鐘)：1.23； MS (ESI, Pos.)：500(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.24, 2.30, 2.55-2.63, 2.96-3.05, 3.20-3.29, 4.19, 6.66, 7.17-7.25, 7.28-7.35, 7.38-7.43, 7.66-7.69, 9.91, 12.06-12.24。 實施例24-2：3-[3-{[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]-2-甲基丙酸

HPLC保持時間(分鐘)：1.23； MS(ESI, Pos.)：500(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.08, 2.29, 2.64-2.78, 2.94-3.04, 4.15-4.23, 6.66, 7.18-7.25, 7.27-7.36, 7.39, 7.67, 9.92, 12.25。 Examples 24-1 to 24-2: Using ethyl crotonate or ethyl methacrylate instead of ethyl acrylate, the same operation as Reference Example 50→Reference Example 51→Example 24 was carried out to obtain the following compounds: The title compound of physical properties. Example 24-1: 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)benzene base] butyric acid

HPLC retention time (min): 1.23; MS (ESI, Pos.): 500(M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.24, 2.30, 2.55-2.63, 2.96-3.05, 3.20 -3.29, 4.19, 6.66, 7.17-7.25, 7.28-7.35, 7.38-7.43, 7.66-7.69, 9.91, 12.06-12.24. Example 24-2: 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)benzene base]-2-methylpropionic acid

HPLC retention time (min): 1.23; MS (ESI, Pos.): 500 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.08, 2.29, 2.64-2.78, 2.94-3.04, 4.15 -4.23, 6.66, 7.18-7.25, 7.27-7.36, 7.39, 7.67, 9.92, 12.25.

Reference Example 52: Use of N-[5-iodo-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide Reference Example 27 The produced compound was used to replace the compound produced in Reference Example 31, and 5-iodo-2-(trifluoromethyl)aniline (CAS No.: 1544-89-4) was used to replace the compound produced in Reference Example 6, and In the same manner as in Reference Example 43, the title compound (1.45 g) having the following physical property values was obtained. HPLC retention time (min): 1.25; MS (ESI, Pos.): 540 (M+H) ⁺ .

Reference Example 53: 2-methyl-2-propyl [1-(dimethylamino)-1-oxo-3-phenyl-2-propyl]carbamate In 2-({[(2-methyl-2-propyl)oxy]carbonyl}amino)-3-phenylpropanoic acid (CAS number: 13734-34-4, 6.6g), 1-hydroxybenzene In dichloromethane (200mL) solution of triazole (CAS number: 2592-95-2, 3.4g) and dimethylamine hydrochloride (CAS number: 506-59-2, 4.5g), under ice-cooling Add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (CAS number: 25952-53-8, 5.7g) and DIPEA (10mL), stir at room temperature for 1 Hour. The reaction solution was washed with 10% citric acid aqueous solution and saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification.

Reference Example 54: 2-Amino-N,N-dimethyl-3-phenylpropanamide hydrochloride The crude product produced in Reference Example 53 was dissolved in 4N hydrochloric acid ethyl acetate solution (25 mL), Stir at room temperature for 5 minutes. A solution of 4N hydrochloric acid in ethyl acetate (10 mL) was added, followed by stirring at room temperature for 3 hours. The precipitate was collected by filtration to obtain the title compound (1.45 g) having the following physical property values. HPLC retention time (min): 0.49; ¹ H-NMR (DMSO-d ₆ ): δ2.63, 2.79, 2.88-3.00, 3.00-3.10, 4.50-4.61, 7.14-7.24, 7.27-7.42, 8.24.

Reference Example 55: Add (2S)-N1,N1-dimethyl-3-phenyl-1,2-propanediamine to a suspension of lithium aluminum hydride (0.94g) in THF (20mL) dropwise under ice-cooling A THF (30 mL) suspension of the compound (3 g) produced in Reference Example 54 was stirred at 50° C. for 2 hours. The reaction solution was ice-cooled, and purified water (1 mL), 4N aqueous sodium hydroxide solution (1 mL) and purified water (3 mL) were added thereto, followed by stirring at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction solution, stirred at room temperature for 15 minutes, filtered through Celite (trade name), and concentrated under reduced pressure to obtain the title compound (2.2 g) having the following physical properties. HPLC retention time (minutes): 0.34; MS (ESI, Pos.): 179 (M+H) ⁺ ;

Reference Example 56: Dichloromethane of the compound (2.1 g) produced in Reference Example 55 by N-[(2S)-1-(dimethylamino)-3-phenyl-2-propyl]acetamide (20 mL), acetyl chloride (1 mL) was added under ice-cooling, stirred at room temperature for 5 minutes, and the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in MTBE, washed with 5N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to obtain the title compound (1.5 g) having the following physical property values. HPLC retention time (min): 0.50; MS (ESI, Pos.): 221(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.97, 2.12-2.23, 2.26-2.36, 2.72-2.90, 2.93 -3.04, 4.08-4.27, 5.50-5.65, 7.11-7.40.

於參考例52所製造的化合物(50mg)的1,1,1,3,3,3-六氟-2-丙醇(CAS編號：29463-77-2，0.5mL)溶液中添加環丁烷羧酸(CAS編號：3721-95-7，19mg)、碳酸銀(25mg)、碳酸鈉(15mg)、參考例56所製造的化合物(4mg)及乙酸鈀(25mg)，在85℃攪拌20小時。將反應液藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯=97：3→0：1)進行精製，藉此得到具有以下的物性值之標題化合物(10mg)。 HPLC保持時間(分鐘)：1.12； MS (ESI, Pos.)：512(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 2.22-2.48, 2.58-2.74, 3.10, 3.58-3.70, 4.03-4.24, 6.60, 7.18, 7.23-7.39, 7.47, 7.57, 8.14。 Example 25: (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclobutanecarboxylic acid

Cyclobutane was added to a solution of the compound (50 mg) produced in Reference Example 52 in 1,1,1,3,3,3-hexafluoro-2-propanol (CAS number: 29463-77-2, 0.5 mL) Carboxylic acid (CAS number: 3721-95-7, 19 mg), silver carbonate (25 mg), sodium carbonate (15 mg), the compound produced in Reference Example 56 (4 mg) and palladium acetate (25 mg), stirred at 85°C for 20 hours . The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→0:1) to obtain the title compound (10 mg) having the following physical properties. HPLC retention time (min): 1.12; MS (ESI, Pos.): 512 (M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 2.22-2.48, 2.58-2.74, 3.10, 3.58-3.70, 4.03 -4.24, 6.60, 7.18, 7.23-7.39, 7.47, 7.57, 8.14.

使用1-甲基環丙烷-1-羧酸(CAS編號：6914-76-7)來取代環丁烷羧酸，進行與實施例25同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：1.30； MS (ESI, Pos.)：512(M+H) ⁺； ¹H-NMR (CDCl ₃)：δ 1.23-1.30, 1.52, 1.92-2.00, 2.35, 2.41-2.49, 3.10, 4.18, 6.60, 7.12-7.20, 7.20-7.37, 7.44-7.54, 8.13。 Example 26: (1R,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]-1-methylcyclopropanecarboxylic acid

Using 1-methylcyclopropane-1-carboxylic acid (CAS number: 6914-76-7) instead of cyclobutanecarboxylic acid, the same operation as in Example 25 was carried out to obtain the title compound having the following physical properties . HPLC retention time (min): 1.30; MS (ESI, Pos.): 512(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 1.23-1.30, 1.52, 1.92-2.00, 2.35, 2.41-2.49 , 3.10, 4.18, 6.60, 7.12-7.20, 7.20-7.37, 7.44-7.54, 8.13.

使用5-溴-2-甲基苯胺(CAS編號：39478-78-9)來取代5-溴-2-(三氟甲基)苯胺，進行與參考例40→參考例4→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：2.19(條件B)； MS (ESI, Pos.)：444(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.20-1.45, 1.75-2.02, 2.21, 2.31, 3.03, 4.20, 6.68, 6.94-6.99, 7.05-7.11, 7.20-7.37, 9.65。 Example 27: rel-(1R,2S)-2-(3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methanol phenyl)cyclopropanecarboxylic acid racemic mixture

Use 5-bromo-2-methylaniline (CAS number: 39478-78-9) to replace 5-bromo-2-(trifluoromethyl)aniline, and proceed in the same manner as in Reference Example 40→Reference Example 4→Example 1 According to the operation, the title compound having the following physical property values was obtained. HPLC retention time (minutes): 2.19 (condition B); MS (ESI, Pos.): 444 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.20-1.45, 1.75-2.02, 2.21 , 2.31, 3.03, 4.20, 6.68, 6.94-6.99, 7.05-7.11, 7.20-7.37, 9.65.

Reference Example 57: DMF solution of methyl 4-(phenylmethyloxy)-2-bromobenzoate in methyl 2-bromo-4-hydroxybenzoate (CAS number: 101085-03-4, 4.0 g) ( Potassium carbonate (4.78 g) and benzyl bromide (2.1 mL) were added to 20 mL), and the mixture was stirred at 70° C. for 3 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification. HPLC retention time (min): 2.38; (Condition E) MS (ESI, Pos.): 321 (M+H) ⁺ .

Reference Example 58: Methyl 4-(benzyloxy)-2-isopropenylbenzoate A solution of the compound produced in Reference Example 57 in ethanol (15 mL) and water (3.6 mL) was degassed, and 2-isopropenylbenzoate was added. Propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS No.: 126726-62-3, 2.64g), 2,6-di- Tributyl-4-methylphenol (CAS number: 128-37-0, 0.58g), palladium acetate (0.44g), tricyclohexylphosphine (CAS number: 2622-14-2, 0.37g), potassium phosphate (8.32 g), stirred at 90°C for 16 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3 g) having the following physical properties. HPLC retention time (min): 2.46; (Condition E) MS (ESI, Pos.): 283 (M+H) ⁺ .

Reference Example 59: Methyl 4-(phenylmethyloxy)-2-isopropylbenzoate Add platinum oxide (CAS number: 1314-15- 4, 10 mg), stirred at room temperature under hydrogen for 16 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification. HPLC retention time (min): 2.56; (Condition E) MS (ESI, Pos.): 285 (M+H) ⁺ .

Reference Example 60: 4-(Benzyloxy)-2-isopropylbenzoic acid was added to a solution of the compound produced in Reference Example 59 in methanol (0.5 mL), THF (0.5 mL), and water (0.5 mL) Lithium hydroxide hydrate (CAS number: 1310-66-3, 88 mg), stirred at 60°C for 16 hours. The reaction solution was made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification. HPLC retention time (min): 2.20; (Condition E) MS (ESI, Pos.): 271 (M+H) ⁺ .

使用參考例60所製造的化合物來取代實施例3所製造的化合物，進行與參考例8→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：2.36(條件C)； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.20, 1.31-1.40, 1.51-1.59, 2.03-2.12, 2.62-2.71, 3.33-3.45, 5.17, 6.93-6.96, 7.01, 7.30-7.51, 7.63, 9.91, 12.02。 Example 28: (1R,2S)-2-[3-{[4-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)benzene base] cyclopropane carboxylic acid

Using the compound produced in Reference Example 60 instead of the compound produced in Example 3, the same operation as in Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (minutes): 2.36 (condition C); MS (ESI, Pos.): 498 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.20, 1.31-1.40, 1.51-1.59 , 2.03-2.12, 2.62-2.71, 3.33-3.45, 5.17, 6.93-6.96, 7.01, 7.30-7.51, 7.63, 9.91, 12.02.

HPLC保持時間(分鐘)：2.42(條件C)； MS (ESI, Pos.)：512(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.20, 1.30-1.38, 1.49-1.56, 2.01-2.13, 2.55-2.66, 3.06, 3.33-3.45, 4.25, 6.83-6.94, 7.20-7.27, 7.29-7.45, 7.62, 9.89。 實施例28-2：(1R,2S)-2-[3-{[2-異丙基-4-(3-苯基丙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.52(條件C)； MS (ESI, Pos.)：526(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.19, 1.32-1.41, 1.51-1.59, 1.99-2.14, 2.60-2.72, 2.77, 3.34-3.49, 4.04, 6-83-6.89, 6.93, 7.16-7.46, 7.64, 9.91, 11.83。 Examples 28-1 to 28-2 Use the corresponding bromine compound to replace the benzyl bromide, and perform the same operations as Reference Example 57→Reference Example 58→Reference Example 59→Reference Example 60→Reference Example 8→Example 1 , whereby the title compound having the following physical property values was obtained. Example 28-1: (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.42 (condition C); MS (ESI, Pos.): 512 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.20, 1.30-1.38, 1.49-1.56 , 2.01-2.13, 2.55-2.66, 3.06, 3.33-3.45, 4.25, 6.83-6.94, 7.20-7.27, 7.29-7.45, 7.62, 9.89. Example 28-2: (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.52 (condition C); MS (ESI, Pos.): 526 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.19, 1.32-1.41, 1.51-1.59 , 1.99-2.14, 2.60-2.72, 2.77, 3.34-3.49, 4.04, 6-83-6.89, 6.93, 7.16-7.46, 7.64, 9.91, 11.83.

HPLC保持時間(分鐘)：4.96(條件D)； MS (ESI, Pos.)：498(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.17-1.55, 1.91-2.04, 2.40-2.59, 3.11-3.25, 5.18, 6.97, 7.15, 7.21-7.53, 7.59, 10.02。 實施例29-2：(1R,2S)-2-[3-{[2-異丙基-3-(2-苯基乙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.42(條件C)； MS (ESI, Pos.)：512(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.21, 1.25-1.34, 1.45-1.53, 2.00-2.09, 2.51-2.62, 3.07-3.27, 4.26, 6.93, 7.08, 7.19-7.43, 7.60, 8.47, 9.97。 實施例29-3：(1R,2S)-2-[3-{[2-異丙基-3-(3-苯基丙氧基)苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.52(條件C)； MS (ESI, Pos.)：526(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.33-1.42, 1.51-1.62, 2.03-2.15, 2.61-2.87, 3.22-3.30, 4.00, 6.95, 7.03, 7.18-7.36, 7.44, 7.64, 10.02, 11.73。 Examples 29-1 to 29-3 use methyl 2-bromo-3-hydroxybenzoate (CAS number: 1260783-82-1) to replace methyl 2-bromo-4-hydroxybenzoate, and use benzyl Bromide or corresponding bromine compound replaces benzyl bromide, carries out the same operation as reference example 57→reference example 58→reference example 59→reference example 60→reference example 8→embodiment 1, thereby obtains having following Physical properties of the title compound. Example 29-1: (1R,2S)-2-[3-{[3-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl ) phenyl] cyclopropane carboxylic acid

HPLC retention time (minutes): 4.96 (condition D); MS (ESI, Pos.): 498 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.17-1.55, 1.91-2.04, 2.40 -2.59, 3.11-3.25, 5.18, 6.97, 7.15, 7.21-7.53, 7.59, 10.02. Example 29-2: (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.42 (condition C); MS (ESI, Pos.): 512 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.21, 1.25-1.34, 1.45-1.53 , 2.00-2.09, 2.51-2.62, 3.07-3.27, 4.26, 6.93, 7.08, 7.19-7.43, 7.60, 8.47, 9.97. Example 29-3: (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.52 (condition C); MS (ESI, Pos.): 526 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.33-1.42, 1.51-1.62, 2.03 -2.15, 2.61-2.87, 3.22-3.30, 4.00, 6.95, 7.03, 7.18-7.36, 7.44, 7.64, 10.02, 11.73.

Reference Example 61: Solution of 4-bromo-2,3,6-trimethylphenol in 2,3,6-trimethylphenol (CAS number: 2416-94-6, 4.0 g) in dichloromethane (60 mL) A solution of bromine (1.6 mL) in dichloromethane (30 mL) was added, and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, sodium thiosulfate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.9 g) having the following physical properties. ¹ H-NMR (CDCl ₃ ): δ 2.19, 2.21, 2.34, 4.56, 7.18.

Reference Example 62: 1-Bromo-2,3,5-trimethyl-4-(2-phenylethoxy)benzene was added to a THF (20 mL) solution of the compound (2.0 g) produced in Reference Example 61 2-Phenylethanol (1.36g), triphenylphosphine (4.87g). Then DEAD (3.23 g, 40% toluene solution) was added dropwise, and stirred at room temperature for 16 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=9:1) to obtain the title compound (1.5 g) having the following physical property values. ¹ H-NMR (CDCl ₃ ): δ 2.11, 2.14, 2.30, 3.09, 3.89, 7.20-7.22, 7.27-7.32.

Reference Example 63: Add 2,3,5-trimethyl-4-(2-phenylethoxy)benzoic acid to a THF (6 mL) solution of the compound (0.3 g) produced in Reference Example 62 at -78°C A hexane solution of n-butyllithium (2.5 mol/L, 0.46 mL) was stirred at -78°C for 15 minutes. Carbon dioxide gas was flowed through the reaction liquid at -78°C for 5 minutes, and stirred at -78°C for 20 minutes. Hydrochloric acid was added to the reaction solution to stop the reaction, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification. HPLC retention time (min): 2.59 (condition F); MS (ESI, Pos.): 285 (M+H) ⁺ .

使用參考例66所製造的化合物來取代參考例3所製造的化合物，進行與參考例8→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：2.42(條件C)； MS (ESI, Pos.)：512(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.31-1.36, 1.50-1.56, 2.04-2.13, 2.23, 2.55-2.66, 3.07, 3.93, 7.12, 7.22-7.26, 7.30-7.39, 7.42, 7.62, 9.90。 Example 30: (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl base]amino}phenyl]cyclopropanecarboxylic acid

Using the compound produced in Reference Example 66 instead of the compound produced in Reference Example 3, the same operation as in Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. HPLC retention time (minutes): 2.42 (condition C); MS (ESI, Pos.): 512 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.31-1.36, 1.50-1.56, 2.04 -2.13, 2.23, 2.55-2.66, 3.07, 3.93, 7.12, 7.22-7.26, 7.30-7.39, 7.42, 7.62, 9.90.

Reference Example 64: (1) 3-isopropyl-1-(3-phenylpropyl)-1H-pyrazole-4-carboxylic acid methyl ester, and (2) 5-isopropyl-1-(3 -Phenylpropyl)-1H-pyrazole-4-carboxylic acid methyl ester in 3-isopropyl-1H-pyrazole-4-carboxylic acid methyl ester (CAS number: 1186537-97-2, 0.4g) Potassium carbonate (0.985 g) and 1-bromo-3-phenylpropane (1.42 g) were added to a DMF (5 mL) solution, followed by stirring at 60° C. for 16 hours. The reaction liquid was cooled to room temperature, ice water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=88:12) to obtain the title compound (0.41 g, mixture) having the following physical properties. MS (ESI, Pos.): 287 (M+H) ⁺ .

HPLC保持時間(分鐘)：2.26(條件C)； MS (ESI, Pos.)：500(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.15-1.21, 1.31-1.42, 1.50-1.58, 2.04-2.13, 2.55-2.73, 3.44-3.53, 4.09, 7.16-7.41, 7.62, 8.26, 9.37, 12.00。 實施例31-2：(1R,2S)-2-[3-({[5-異丙基-1-(3-苯基丙基)-1H-吡唑-4-基]羰基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸

HPLC保持時間(分鐘)：2.25(條件C)； MS (ESI, Pos.)：500(M+H) ⁺； ¹H-NMR (DMSO-d ₆)：δ 1.16-1.32, 1.38-1.48, 1.90-2.09, 2.38-2.51, 2.59-2.68, 4.15, 7.15-7.25, 7.26-7.37, 7.56, 7.95, 9.53。 Examples 31-1 to 31-2 Using the compound produced in Reference Example 64 instead of the compound produced in Reference Example 26, the same operation as in Reference Example 27→Example 11 was carried out to obtain titles having the following physical properties compound. Example 31-1: (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.26 (condition C); MS (ESI, Pos.): 500 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.15-1.21, 1.31-1.42, 1.50 -1.58, 2.04-2.13, 2.55-2.73, 3.44-3.53, 4.09, 7.16-7.41, 7.62, 8.26, 9.37, 12.00. Example 31-2: (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

HPLC retention time (minutes): 2.25 (condition C); MS (ESI, Pos.): 500 (M+H) ⁺ ; ¹ H-NMR (DMSO-d ₆ ): δ 1.16-1.32, 1.38-1.48, 1.90 -2.09, 2.38-2.51, 2.59-2.68, 4.15, 7.15-7.25, 7.26-7.37, 7.56, 7.95, 9.53.

Reference Example 65: (1R,2S)-2-[3-({[2,6-Dimethyl-4-(2-phenylethoxy)phenyl]thiocarbonyl}amino)-4-( Trifluoromethyl)phenyl]cyclopropanecarboxylate, to the benzene (CAS number: 71-43-2, 2mL) solution of the compound (50 mg) produced in Reference Example 42, was added 5 phosphorus sulfide (CAS No.: 1314-80-3, 42mg), stirred at 60°C for 16 hours. The reaction liquid was cooled to room temperature, ice water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was used for subsequent reaction without purification. HPLC retention time (minutes): 2.93 (condition F); MS (ESI, Pos.): 542 (M+H) ⁺ ;

使用參考例65所製造的化合物來取代參考例42所製造的化合物，進行與實施例18同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：2.39(條件F)； MS (ESI, Pos.)：514(M+H) ⁺； ¹H-NMR(DMSO-d6)：δ 1.21-1.34, 1.66-1.82, 2.28, 2.32-2.61, 3.01, 4.13, 6.45, 6.81-6.92, 7.05-7.14, 7.19-7.27, 7.29-7.36。 Example 32: (1R,2S)-2-[3-({[2,6-Dimethyl-4-(2-phenylethoxy)phenyl]thiocarbonyl}amino)-4-( Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

Using the compound produced in Reference Example 65 instead of the compound produced in Reference Example 42, the same operation as in Example 18 was carried out to obtain the title compound having the following physical property values. HPLC retention time (minutes): 2.39 (condition F); MS (ESI, Pos.): 514 (M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 1.21-1.34, 1.66-1.82, 2.28, 2.32-2.61, 3.01, 4.13, 6.45, 6.81-6.92, 7.05-7.14, 7.19-7.27, 7.29-7.36.

使用實施例20-1的中間體之(1R,2S)-2-[3-{[4-(2-環丙基乙氧基)-2,6-二甲基苯甲醯基]胺基}-4-(三氟甲基)苯基]環丙烷羧酸乙酯來取代參考例42所製造的化合物，進行與參考例65→實施例18同樣的操作，藉此得到具有以下的物性值之標題化合物。 HPLC保持時間(分鐘)：2.36(條件F)； MS (ESI, Pos.)：478(M+H) ⁺； ¹H-NMR (DMSO-d6)：δ 0.10-0.15, 0.41-0.47, 0.78-0.89, 1.37-1.44, 1.51-1.56, 1.59-1.66, 2.10-2.15, 2.34, 2.35, 2.67-2.75, 4.03, 6.68, 7.38-7.44, 7.68-7.73, 11.73, 12.02。 Example 33: (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]thiocarbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

Using the (1R,2S)-2-[3-{[4-(2-cyclopropylethoxy)-2,6-dimethylbenzoyl]amino group of the intermediate of Example 20-1 }-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid ethyl ester to replace the compound produced in reference example 42, carry out the same operation as reference example 65 → embodiment 18, thereby obtain the following physical property values The title compound. HPLC retention time (minutes): 2.36 (condition F); MS (ESI, Pos.): 478 (M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 0.10-0.15, 0.41-0.47, 0.78- 0.89, 1.37-1.44, 1.51-1.56, 1.59-1.66, 2.10-2.15, 2.34, 2.35, 2.67-2.75, 4.03, 6.68, 7.38-7.44, 7.68-7.73, 11.73, 12.02.

Reference Example 66: Ethyl 2-2-butyl-1H-pyrrole-3-carboxylate in ethyl 4-methyl-3-oxohexanoate (CAS number: 98192-72-4, 1.0 g) and Ammonia (28% NH ₃ aqueous solution, 3.2mL) and water (3.2mL) were added to the mixture of 2-chloroacetaldehyde aqueous solution (CAS number: 107-20-0, 50wt%, 0.815mL), stirred at 70°C for 20 Hour. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (300 mg) having the following physical properties. LC-MS m/z 196(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.91, 1.28, 1.37, 1.58-1.70, 3.65-3.73, 4.24-4.33, 6.58-6.61, 6.61-6.63, 8.19.

Reference Example 67: 2-Second-butyl-1-(3-phenylpropyl)-1H-pyrrole-3-carboxylic acid ethyl ester The compound (110 mg) produced in Reference Example 66 and (3-bromopropyl ) cesium carbonate (0.184 g) was added to a DMF (1 mL) solution of benzene (123 mg), followed by stirring at 80° C. for 20 hours. The reaction solution was cooled to room temperature, and purified by silica gel column chromatography (hexane:ethyl acetate=8:2) to obtain the title compound (98 mg) having the following physical properties. LC-MS m/z 314(M+H) ⁺ ; ¹ H-NMR (CDCl ₃ ): δ 0.82, 1.32-1.40, 1.74, 1.88, 2.00-2.12, 2.68, 3.23, 3.84-3.97, 4.25, 6.46, 6.59, 7.16-7.21, 7.21-7.27, 7.31-7.36.

Reference Example 68: THF/methanol (1:1, 1 mL) solution was added 10N NaOH aqueous solution (0.1 mL), and stirred at 80° C. for 20 hours. The reaction solution was cooled to room temperature, and acetic acid (0.2 mL) was added. Then dichloromethane (5 mL) and water (5 mL) were added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (90 mg) having the following physical properties. LC-MS m/z 286(M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 0.71, 1.25, 1.63, 1.80, 1.89-2.06, 2.61, 3.20-3.39, 3.93, 6.37, 6.66, 7.18 -7.26, 7.31.

使用參考例68所製造的化合物來取代參考例3所製造的化合物，進行與參考例8→實施例1同樣的操作，藉此得到具有以下的物性值之標題化合物。 LC-MS m/z 513(M+H) ⁺； ¹H-NMR (DMSO-d6)：δ 0.72, 1.16-1.31, 1.38, 1.47-1.58, 1.58-1.69, 1.78, 1.88-2.03, 2.03-2.20, 2.59-2.75, 3.32, 3.94, 6.54, 6.73, 7.19-7.28, 7.28-7.34, 7.50, 7.60, 8.94。 Example 34: (1R,2S)-2-[3-({[2-Second-butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)- 4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

Using the compound produced in Reference Example 68 instead of the compound produced in Reference Example 3, the same operation as in Reference Example 8→Example 1 was carried out to obtain the title compound having the following physical property values. LC-MS m/z 513(M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 0.72, 1.16-1.31, 1.38, 1.47-1.58, 1.58-1.69, 1.78, 1.88-2.03, 2.03-2.20 , 2.59-2.75, 3.32, 3.94, 6.54, 6.73, 7.19-7.28, 7.28-7.34, 7.50, 7.60, 8.94.

LC-MS m/z 499(M+H) ⁺； ¹H-NMR (DMSO-d6)：δ 1.27, 1.38, 1.51-1.56, 1.97, 2.07-2.13, 2.58-2.71, 3.35-3.59, 3.95, 6.52, 6.70, 7.18-7.28, 7.28-7.34, 7.51, 7.60, 8.95。 實施例34-2：(1R,2S)-2-[3-({[2-(2-甲基-2-丙基)-1-(3-苯基丙基)-1H-吡咯-3-基]羰基}胺基)-4-(三氟甲基)苯基]環丙烷羧酸

LC-MS m/z 513(M+H) ⁺； ¹H-NMR (DMSO-d6)：δ 1.30-1.35, 1.38, 1.49, 1.98-2.16, 2.57-2.63, 2.70, 3.99-4.16, 6.09, 6.76, 7.20-7.25, 7.25-7.31, 7.31-7.37, 7.42, 7.60, 9.39。 [藥理實驗例] 藥理實驗例1：使用前列腺素受體(prostanoid receptor)表現細胞的EP ₂拮抗活性測定實驗 Examples 34-1 to 34-2 Use corresponding compounds to replace ethyl 4-methyl-3-side oxyhexanoate, proceed with reference example 66 → reference example 67 → reference example 68 → reference example 8 → embodiment 1, the title compound having the following physical property values was obtained by the same operation. Example 34-1: (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino) -4-(Trifluoromethyl)phenyl]cyclopropanecarboxylic acid

LC-MS m/z 499(M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 1.27, 1.38, 1.51-1.56, 1.97, 2.07-2.13, 2.58-2.71, 3.35-3.59, 3.95, 6.52 , 6.70, 7.18-7.28, 7.28-7.34, 7.51, 7.60, 8.95. Example 34-2: (1R,2S)-2-[3-({[2-(2-methyl-2-propyl)-1-(3-phenylpropyl)-1H-pyrrole-3 -yl]carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid

LC-MS m/z 513(M+H) ⁺ ; ¹ H-NMR (DMSO-d6): δ 1.30-1.35, 1.38, 1.49, 1.98-2.16, 2.57-2.63, 2.70, 3.99-4.16, 6.09, 6.76 , 7.20-7.25, 7.25-7.31, 7.31-7.37, 7.42, 7.60, 9.39. [Pharmacological Experiment Example] Pharmacological Experiment Example 1: EP ₂ Antagonistic Activity Measurement Experiment Using Prostanoid Receptor Expressing Cells

According to the method of Nishigaki et al. (FEBS Letters, vol. 364, pp. 339-341, 1995), CHO cells expressing the human EP ₂ receptor were prepared and prepared in CELLBANKER2 (manufactured by Zenyaku Kogyo Co., Ltd.). The knots saved at 1.5x10 ⁷ cells/mL/vial were used for experiments. The cells were lysed and suspended in an assay medium (D-PBS containing 1 mmol/L IBMX, 2 μmol/L Diclofenac) at 5× ^{10 5} cells/mL. To the cell suspension (10 μL), PGE ₂ at a final concentration of 10 nmol/L was added alone, or a solution (10 μL) containing both PGE ₂ and the test compound was added to start the reaction, and after reacting at room temperature for 1 hour, according to cAMP Gs Dynamic The amount of cAMP in cells was quantified by the method described in the kit (manufactured by CISBIO).

In addition, the antagonistic action (IC ₅₀ value) of the test compound was calculated as the inhibition rate of the reaction at 10 nM, which is the concentration at which PGE ₂ alone exhibits a submaximal cAMP production action, and the IC ₅₀ was obtained. value.

It can be seen from the above pharmacological experiments that the compounds used in the present invention have strong EP ₂ receptor antagonistic activity. For example, the _IC50 values of several compounds are shown in Table 1 below.

[Table 1]

The EP ₂ receptor antagonistic activity of the compound of Example 43 described in Patent Document 1 was >10000 nM. Pharmacological Experiment 2: Anti-tumor effect in the allograft model of mouse colorectal cancer cell line CT26

The anti-tumor effect of the compound (compound A) used in the present invention was evaluated by using the CT26 homograft model of the mouse colorectal cancer cell line. CT26 was cultured in RPMI-1640 medium containing 10vol% inactivated fetal bovine serum (Fetal Bovine Serum; FBS), 100 units/mL of penicillin (Penicillin) and 100 μg/mL of streptomycin (Streptomycin) in CO ₂ Cultivate in the box. On the day of transplantation, the culture supernatant was removed, and CT26 was recovered after being washed with phosphate buffered solution (hereinafter abbreviated as PBS). The recovered CT26 was suspended in PBS and used as cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right back of female Balb/C mice (Charles River Japan Co., Ltd.). Four days after the transplantation, the mice were equally divided into 2 groups of 10 each according to the vehicle group and the compound A group. For the vehicle and compound A, 10 mg/kg of the compound used in the present invention was repeatedly administered to the mice once on the 4th day of transplantation, and twice a day from the 5th day to the 25th day of transplantation. Tumor volume (mm ³ ) was measured by using an electronic caliper to measure the short axis and long axis of the tumor, and the tumor volume was calculated according to the following formula. In addition, during the administration period, mice with ulcers formed on tumors were excluded from the subsequent evaluation at that time point. Tumor volume = [(short diameter) ² × long diameter] /2

As a result, the compounds used in the present invention have an inhibitory effect on tumor growth. For example, when the compound of Example 18 was selected as compound A, the tumor volume of the compound A-administered group on the 25th day of transplantation was favorably smaller than that of the medium-administered group, as shown in Fig. 1 . Pharmacological Experiment Example 3: In the allograft model of mouse colorectal cancer cell line MC38, the combined effect of the compound (EP ₂ receptor antagonist) used in the present invention and anti-PD-1 antibody

The compound used in the present invention (compound A: EP2 receptor antagonist) and anti-PD- 1 Effect of combined use of antibodies. MC38 was cultured in a CO ₂ incubator using DMEM medium containing 10vol% FBS, 100 units/mL of penicillin (Penicillin) and 100 μg/mL of streptomycin (Streptomycin). On the day of transplantation, after removing the culture supernatant, MC38 was washed with PBS and recovered. The recovered MC38 were suspended in PBS and used as cells for transplantation. Under anesthesia, 200,000 cells for transplantation were subcutaneously transplanted into the right abdomen of female C57BL/6 mice. Nine days after the transplantation, the mice were equally divided into 3 groups of 10 cases each according to the vehicle group, the anti-mouse PD-1 antibody alone group, and the combination group (compound A and anti-mouse PD-1 antibody). Compound A was orally administered at 100 mg/kg once on the 9th day of transplantation, and twice a day from the 10th day to the 29th day of transplantation, to the compound A co-administered mice repeatedly orally. The anti-mouse PD-1 antibody system was administered at a dose of 20 mg/kg on the 9th day of transplantation, and at a dose of 10 mg/kg on the 15th, 21st, and 27th day of transplantation, against mouse PD-1 antibody alone group and combined group of mice Administered intraperitoneally. In addition, distilled water and compound A were repeatedly orally administered to the mice of the vehicle group and the anti-mouse PD-1 antibody group for the same period. In addition, PBS and the anti-mouse PD-1 antibody were intraperitoneally administered at the same time period to the mice of the vehicle group and compound A group. Tumor volume (mm ³ ) was measured by using an electronic caliper to measure the short axis and long axis of the tumor, and the tumor volume was calculated according to the following formula. Tumor volume = [(short diameter) ² × long diameter] /2

As a result, the combined use of the compound used in the present invention and the anti-PD-1 antibody showed a stronger inhibitory effect on tumor growth than when the anti-PD-1 antibody was used alone. For example, when the compound of Example 18 is selected as Compound A and the anti-PD-1 antibody 4H2 is used as the anti-PD-1 antibody, the time-dependent shift of the tumor volume of each group is shown in Figure 2, and the results of tumor disappearance are shown in Table 2.

In addition, anti-PD-1 antibody 4H2 can be obtained according to the method described in WO2006/121168.

[Table 2] cast group Tumor disappeared cases/number of cases medium 0/10 anti-mouse PD-1 1/10 Compound A (100mg/kg) and anti-mouse PD-1 5/10

From the above results, it was confirmed that the compound used in the present invention represented by Example 18 having an EP ₂ antagonistic effect in combination with an anti-PD-1 antibody can exert a strong antitumor effect. Pharmacological Experiment Example 4: Combined Effects of Compounds Used in the Present Invention (EP ₂ Receptor Antagonists) and EP ₄ Receptor Antagonists in the Allograft Model of Mouse Colorectal Cancer Cell Line MC38

The compound (EP2 receptor antagonist) used in the present invention and EP4 were evaluated by the following method in the homograft model of mouse colorectal cancer cell line MC38 (Cancer Res. (1975), 35(9), _p2434-9 ) Combination effect of 2 doses of receptor antagonists. MC38 was cultured in a CO ₂ incubator using DMEM medium containing 10vol% FBS, 100 units/mL of penicillin (Penicillin) and 100 μg/mL of streptomycin (Streptomycin). On the day of transplantation, after removing the culture supernatant, MC38 was washed with PBS and recovered. The recovered MC38 were suspended in PBS as cells for transplantation. Under anesthesia, 200,000 cells for transplantation were subcutaneously transplanted into the right abdomen of female C57BL/6 mice. Eight days after transplantation, the mice were treated according to the vehicle group, the compound (compound A: EP2 _receptor antagonist) used in the present invention alone group, the _EP4 receptor antagonist (compound B) alone group and the EP2 _receptor antagonist group. And EP4 receptor antagonists and 4 groups of 8 cases were divided equally. EP ₂ receptor antagonists and EP ₄ receptor antagonists were repeatedly orally administered to the concomitant group of mice once on the 8th day of transplantation and twice a day from the 9th day to the 11th day of transplantation. . Also, to the rats of the vehicle group, distilled water was orally administered repeatedly during the same period. Tumor volume (mm ³ ) was measured by using an electronic caliper to measure the short axis and long axis of the tumor, and the tumor volume was calculated according to the following formula. The body weight of the mice was measured more than 3 times a week, and the observation of the general state was carried out more than 5 times a week. Tumor volume = [(short diameter) ² × long diameter] /2

As a result, the combined use of the compound used in the present invention and an EP ₄ receptor antagonist exhibited a stronger tumor growth inhibitory effect than that of each compound alone. For example, the compound of Example 18 is selected as the compound (4-[4-cyano-2-({(2'R, 4S)-6-[( Propan-2-yl)aminoformyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid) When the _EP4 receptor antagonist (compound B) was used, the time-dependent shift of the tumor volume of each group is shown in Fig. 3 .

From the above results, it was confirmed that the compound used in the present invention represented by Example 18 having an EP ₂ antagonistic activity in combination with an EP ₄ receptor antagonist exerts a strong antitumor effect. Pharmacological experiment example 5: Effects of combined use of EP ₂ receptor antagonists, EP ₄ receptor antagonists and anti-mouse PD-1 antibody in the allograft model of mouse colorectal cancer cell line MC38

According to the combination effect of the compound (Compound A: EP2 receptor antagonist), EP4 receptor antagonist and anti-PD-1 antibody used in the present invention, it is possible to use, for example, MC38 (Cancer Res. (1975), 35(9), p2434-9) and were evaluated as follows. MC38 was cultured in a CO ₂ incubator using DMEM medium containing 10vol% FBS, 100 units/mL of penicillin (Penicillin) and 100 μg/mL of streptomycin (Streptomycin). On the day of transplantation, after removing the culture supernatant, MC38 was washed with PBS and recovered. The recovered MC38 were suspended in PBS and used as cells for transplantation. Under anesthesia, 200,000 cells for transplantation were subcutaneously transplanted into the right abdomen of female C57BL/6 mice. Thirteen days after transplantation, the mice were treated with medium group, anti-mouse PD-1 antibody alone group, anti-mouse PD-1 antibody and EP4 receptor antagonist group, and anti-mouse PD-1 antibody, EP4 receptor antagonist and The EP2 receptor antagonist group was equally divided into 12 cases in each of the 4 groups. EP ₂ receptor antagonists and EP ₄ receptor antagonists were administered orally once a day on the 13th day of transplantation, and twice a day from the 14th day to the 34th day of transplantation, and repeatedly administered orally to the mice in the combined group . The anti-mouse PD-1 antibody system was administered at a dose of 20 mg/kg on the 13th day of transplantation, and at a dose of 10 mg/kg on the 19th, 25th, and 31st day of transplantation, intraperitoneally of the mice of the anti-mouse PD-1 antibody alone group and the combined group cast. Also, distilled water and EP ₂ receptor antagonists were orally administered repeatedly for the same period of time to the mice of the vehicle group and the anti-mouse PD-1 antibody group. In addition, PBS and the anti-mouse PD-1 antibody were intraperitoneally administered for the same period of time to the mice of the vehicle group and the EP2 _receptor antagonist group. The tumor volume (mm ³ ) was calculated by the following formula after measuring the short axis and long axis of the tumor using an electronic caliper. The body weight of the mice was measured more than 3 times a week, and the observation of the general state was carried out more than 5 times a week. After the evaluation, use 10vol% buffered formalin solution to fix/preserve the stomach, small intestine (duodenum, jejunum, ileum), Peyer's plaque (ileum), large intestine (cecum, colon, rectum) and macroscopically abnormal parts for tissue evaluation. Pathological examination. Tumor volume = [(short diameter)2 × long diameter] /2 Pharmacological experiment example 6: Effects of combined use of EP ₂ receptor antagonists and EP ₄ receptor antagonists in the allograft model of mouse colorectal cancer cell line CT26

The combined effects of the compound (EP ₂ receptor antagonist) used in the present invention and the EP ₄ receptor antagonist were evaluated in the mouse colorectal cancer cell line CT26 homograft model. The CT26 system uses RPMI-1640 medium containing 10vol% deactivated fetal bovine serum (Fetal Bovine Serum; FBS), 100units/mL penicillin (Penicillin) and 100μg/mL streptomycin (Streptomycin) in CO ₂ Cultivate in an incubator. On the day of transplantation, the culture supernatant was removed, and CT26 was recovered after being washed with Hanks' balanced salt solution (hereinafter referred to as HBSS). The recovered CT26 was suspended in HBSS and used as cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right back of female Balb/C mice (Charles River Japan Co., Ltd.). After 7 days of transplantation, the mice were divided equally among the three groups according to the vehicle group, the _EP4 receptor antagonist (compound B) alone group, and the EP2 _receptor antagonist (compound A) and _EP4 receptor antagonist group. 10 cases. Medium, EP ₂ receptor antagonists and EP ₄ receptor antagonists were administered once a day on the 7th and 28th days of transplantation, twice a day from the 8th day to the 27th day of transplantation, and repeated oral administration to the mice give. Tumor volume (mm ³ ) was measured by using an electronic caliper to measure the short axis and long axis of the tumor, and the tumor volume was calculated according to the following formula. In addition, during the administration period, mice with ulcers formed on tumors were excluded from the subsequent evaluation at that time point. Tumor volume = [(short diameter)2 × long diameter]/2

As a result, the combined use of the compound used in the present invention and an EP ₄ receptor antagonist showed a stronger tumor growth inhibitory effect than that of each compound alone. For example, the compound of Example 18 is selected as the compound (4-[4-cyano-2-({(2'R,4S)-6-[( Propan-2-yl)aminoformyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid) When the _EP4 receptor antagonist (compound B) was used, the time-dependent shift of the tumor volume of each group is shown in Fig. 4 .

From the above results, it was confirmed that the compound used in the present invention represented by Example 18 having an EP ₂ antagonistic activity in combination with an EP ₄ receptor antagonist exerts a strong antitumor effect.

Dynamic Experiment Example 1: Liver Microsome Stability Test (1) Preparation of test substance solution A DMSO solution (10 mmol/L; 5 μL) of the test substance was diluted with 50% acetonitrile aqueous solution (195 μL) to prepare a 250 μmol/L solution of the test substance. (2) Preparation of standard sample (sample immediately after the reaction starts) In the reaction vessel that has been preheated to 37°C in a water bath, add NADPH-Co-Factor (BD-Bioscience Co.) and 0.1 mol/L phosphate buffer ( pH7.4) 245 μL, pre-incubated for 5 minutes. 5 µL of the previous test substance solution was added thereto to start the reaction (final concentration: 1 µmol/L). Immediately after the start of the reaction, 20 μL of the reaction solution was collected, and this solution was added to 180 μL of acetonitrile (containing an internal standard substance, Candesartan) to stop the reaction. The solution (20 μL; the sample solution immediately after starting the reaction) after the reaction was stopped was stirred with 50% acetonitrile (180 μL) on a flat filter for protein removal, and then subjected to suction filtration, and the filtrate was used as a standard sample. (3) Preparation of reaction sample (sample after 60 minutes of reaction) After the previous reaction solution was incubated at 37° C. for 60 minutes, 20 μL of the reaction solution was collected and added to 180 μL of acetonitrile (containing the internal standard substance candesartan) to stop the reaction. The solution (20 μL; sample solution after 60 minutes of reaction) after the reaction was stopped was stirred with 50% acetonitrile (180 μL) on a flat filter for protein removal, and then subjected to suction filtration, and the filtrate was used as a reaction sample. (4) Evaluation method Using the peak area obtained by LC-MS/MS, the residual rate of the test substance is calculated from the test substance mass (X) of the standard sample and the test substance mass (Y) of the reaction sample according to the following formula (%). Survival rate (%) = (Y/X) x100 X: The mass of the tested substance in the standard sample (Ratio=spectral peak area of the tested substance/spectrum peak area of the internal standard substance) Y: The amount of the tested substance in the reaction sample (Ratio=spectral peak area of the tested substance/spectral peak area of the internal standard substance) (5) Results It was found that the compounds used in the present invention have high stability to human liver microsomes.

Dynamic experiment example 2: Solubility determination test (1) Preparation of calibration curve solution The calibration curve solution was prepared by diluting the DMSO solution (10 mmol/L) of the test substance with acetonitrile and adding acetonitrile containing an internal standard substance (Nicardipine) to 5, 20 and 100 nmol/L. (2) Preparation of sample solution The sample solution was prepared in the following manner: add a DMSO solution (10 mmol/L; 5 μL) of the substance to be tested to 495 μL of Pharmacopoeia II solution, stir at room temperature for 5 hours, then transfer the solution to a filter plate for solubility and perform suction filtration. 10 µL of the filtrate was diluted with acetonitrile, and acetonitrile containing an internal standard substance (nicardipin) was added. (3) Evaluation 5 μL of the calibration curve solution and the sample solution were injected into LC-MS (Q Exactive Focus manufactured by Thermo Scientific Co., Ltd.) for quantification (quantitative range 5 to 100 nmol/L). Solubility is calculated by setting the quantitative value as 1000 times. The solubility when the value below the quantitative range is obtained is set as <5 μmol/L, and the solubility when the value above the quantitative range is obtained is set as 100 μmol/L. (4) Results The compounds used in the present invention are known to have good solubility. (industrial availability)

The combination of the present invention is useful for cancer therapy because it exerts a strong antitumor effect.

none

Fig. 1 is a graph showing the antitumor effect of the compounds used in the present invention in the allograft model of mouse colorectal cancer cell line CT26. In the figure, compound A is the compound of Example 18. Figure 2 shows the combined effect of the compound used in the present invention (compound A: EP ₄ receptor antagonist) and anti-PD-1 antibody in the allograft model of mouse colorectal cancer cell line MC38. In the figure, the combination represents the combination group of Compound A (the compound of Example 18) and the anti-mouse PD-1 antibody 4H2. Fig. 3 shows the combined effect of the compound (compound A: EP ₂ receptor antagonist) and EP ₄ receptor antagonist (compound B) used in the present invention in the allograft model of mouse colorectal cancer cell line MC38. In the figure, compound A is the compound of Example 18, and compound B is the compound described in Example 2-13 of WO2016/111347. Fig. 4 shows the combined effect of the compound (compound A: EP ₂ receptor antagonist) and EP ₄ receptor antagonist (compound B) used in the present invention in the allograft model of mouse colorectal cancer cell line CT26. In the figure, the X-axis represents the tumor volume, and the Y-axis represents the days after transplantation. Compound A is the compound of Example 18, and Compound B is the compound described in Example 2-13 of WO2016/111347.

none.

Claims (26)

A cancer therapeutic agent administered in combination with an immune checkpoint inhibitor and/or an _EP4 receptor antagonist, and containing a compound represented by general formula (IA), a pharmaceutically acceptable salt thereof, or a hydrate thereof ,

In the formula, L ¹ represents (CR ³⁸ R ³⁹ )-(CR ⁴⁰ R ⁴¹ )-, R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ independently represent (1) a hydrogen atom, (2) a halogen atom, or ( 3) C1-4 alkyl, the C1-4 alkyl in R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ can be independently substituted by at least one halogen atom, from R ³⁸ , R ³⁹ , R ⁴⁰ and R ⁴¹ When the two selected substituents are C1-4 alkyl groups, they can form a C3-6 saturated carbocyclic ring together with the carbon atom to be bonded, and L ² represents (1) bonded bond, (2) C1-8 alkylene , (3) C2-8 alkenyl, or (4) C2-8 alkynyl, 1 to 2 of the C1-8 alkylene, C2-8 alkenyl, and C2-8 alkynylene -CH ₂ -can be substituted by -O-, -S-, -SO-, or -SO ₂ -, the C1-8 alkylene, C2-8 alkenyl, and C2-8 alkynyl can be substituted by 1 to 8 halogen atoms, Y represents (1) a bond, (2) an oxygen atom, or (3) an oxidizable sulfur atom, R ¹ represents (1)-COOR ¹⁰ , (2)-SO ₃ H , (3)-SO ₂ NHR ¹¹ , (4)-CONHSO ₂ R ¹² , (5)-SO ₂ NHCOR ¹³ , (6)-CONR ¹⁴ R ¹⁵ , (7) tetrazolyl, or (8) hydroxylamic acid R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ independently represent (1) hydrogen atom or (2) C1-4 alkyl, R ² represents (1) hydrogen atom or (2) C1-4 alkyl, R ³ represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy Base, (6) 3-6 membered cyclic group, (7) (3-6 membered cyclic group) -O-, or (8) (3-6 membered cyclic group) - (C1-4 alkylene )-, (2) to (8) in R ³ may be substituted by 1 to 9 R ¹⁶ , when R ³ is plural, the plurality of R ³ may be the same or different, R ¹⁶ represents (1) a halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7) -NR ¹⁷ When R ¹⁸ and R ¹⁶ are plural, the plurality of R ¹⁶ may be the same or different, R ¹⁷ and R ¹⁸ each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group, and R ⁴ represents (1) Halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy, (6) 3-6 membered cyclic group , (7) (3-6 membered cyclic group)-O-, or (8) (3-6 membered cyclic group)-(C1-4 alkylene)-, ( ² ) to ( 8) Can be substituted by 1 to 9 R ¹⁹ , when R ⁴ is plural, the plural R ⁴ can be the same or different, R ¹⁹ represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl, (6) hydroxyl, or (7)-NR ²⁰ R ²¹ , R ²⁰ and R ²¹ represent independently (1) hydrogen atom or (2) C1-4 alkyl group, when R ¹⁹ is plural, the plurality of R ¹⁹ can be the same or different, R ⁵ represents (1) hydrogen atom, (2) C3-10 carbocycle, Or (3) 3-10 membered heterocyclic ring, the C3-10 carbon ring and 3-10 membered heterocyclic ring can be substituted by 1 to 5 R ²² , however, when L ² is a bonding bond, R ⁵ is not a hydrogen atom , R ²² represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) C3-6 cycloalkyl, (5) C1-6 alkoxy , (6) C3-6 cycloalkoxy, (7) C2-6 acyl, (8) C2-6 acyloxy, (9) C1-6 alkylthio, (10) C3-6 cycloalkane Thio, (11) C1-6 alkylsulfinyl, (12) C3-6 cycloalkylsulfinyl, (13) C1-6 alkylsulfinyl, (14) C3-6 cycloalkane Sulfonyl, (15) C1-6 alkoxycarbonyl, (16) 5-6 member cyclic group, (17) (5-6 member cyclic group) - (C1-4 alkylene) -, (18) (5-6 membered cyclic group)-(C1-4 alkylene)-O-, (19) (5-6 membered cyclic group)-C1-4 acyl group, (20) halogen atom, (21) hydroxyl, (22) nitro, (23) cyano, (24)-NR ²³ R ²⁴ , (25)-CONR ²⁵ R ²⁶ or (26)-SO ₂ NR ²⁷ R ²⁸ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ independently represent (1) hydrogen atom, (2) C1-6 alkyl, (3) C2-6 acyl or (4) C1-6 alkylsulfonate Acyl group, the groups (1) to (19) in R ²² can be substituted by 1 to 9 R ²⁹ , when R ²² is plural, the plurality of R ²² can be the same or different, R ²⁹ represents (1) C1 -4 alkyl, (2) C1-4 alkoxy, (3) C2-6 acyl, (4) C3-6 cycloalkyl, (5) hydroxyl, (6) -NR ³⁰ R ³¹ or (7 ) halogen atom, R ³⁰ and R ³¹ independently represent (1) hydrogen atom or (2) C1-4 alkyl, when R ²⁹ is plural, the plurality of R ²⁹ can be the same or different, Q represents (1) Oxygen atom or (2) sulfur atom, X represents (1) CR ⁶ or (2) NR ⁷ , R ⁶ represents (1) halogen atom, (2) C1-6 alkyl, (3) C2-6 alkenyl, (4) C2-6 alkynyl, (5) C1-6 alkoxy Base, (6) 3-6 membered cyclic group, (7) (3-6 membered cyclic group) -O-, or (8) (3-6 membered cyclic group) - (C1-4 alkylene )-, (2) to (8) in R ⁶ can be substituted by 1 to 9 R ³² , R ³² represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy group, (4) C2-6 acyl group, (5) C3-6 cycloalkyl group, (6) hydroxyl group, or (7)-NR ³³ R ³⁴ , R ³³ and R ³⁴ independently represent (1) hydrogen atom Or (2) C1-4 alkyl, when R ³² is plural, the plurality of R ³² can be the same or different, R ⁷ represents (1) C1-6 alkyl, (2) C2-6 alkenyl, (3 ) C2-6 alkynyl group, (4) 3-6 membered cyclic group, or (5) (3-6 membered cyclic group)-(C1-4 alkylene)-, R ⁷ can pass through 1 to 9 R ³⁵ is substituted, R ³⁵ represents (1) halogen atom, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) C2-6 acyl, (5) C3-6 cycloalkyl ^{. _ _ _ _ 35} can be the same or different respectively, ring A represents (1) benzene ring, or (2) 5-6 membered nitrogen-containing aromatic heterocycle, in ring A

Represents a single bond or a double bond, n represents an integer from 1 to 4, m represents an integer from 0 to 3, but excludes 3-[3-[(2,6-dimethoxybenzoyl)amino]- 4-propoxyphenyl]propanoic acid, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2 -Chlorophenyl]propionic acid methyl ester, 3-[5-({[1-tert-butyl-5-(4-fluorophenyl-1H-pyrazol-4-yl]carbonyl}amino-2- Chlorophenyl]propanoic acid, α-ethyl-3-[N-(1'-phenyl-5'-methyl-1',2',3'-triazolecarbonyl)]amino-2,4 ,6-triiodohydrocinnamic acid, and α-ethyl-3-{N-(1'-(4"-iodophenyl)-5'-methyl-1,2,3-triazolecarbonyl]} Amino-2,4,6-triiodohydrocinnamic acid. The cancer therapeutic agent as described in claim 1 is administered in combination with an immune checkpoint inhibitor. The cancer therapeutic agent as described in Claim 1 is administered in combination with an _EP4 receptor antagonist. The cancer therapeutic agent as described in Claim 1 is administered in combination with an immune checkpoint inhibitor and an _EP4 receptor antagonist. A cancer therapeutic agent administered in combination with the compound represented by the general formula (I-A) described in Claim 1, its pharmaceutically acceptable salt, or a hydrate thereof, and comprising an immune checkpoint inhibitor. A cancer therapeutic agent administered in combination with the compound represented by the general formula (IA) described in Claim 1, its pharmaceutically acceptable salt, or a hydrate thereof, and comprising an EP ₄ receptor antagonist. The cancer therapeutic agent according to any one of claims 1 to 6, wherein the compound represented by the general formula (IA) is a compound represented by the following general formula (I-1),

In the formula, p represents an integer from 1 to 4, and other symbols have the same meanings as those described in Claim 1. The cancer therapeutic agent according to any one of claims 1 to 6, wherein the compound represented by general formula (I-A) is: (1) rel-(1R,2S)-2-[3-({[1-second butyl-5-(3-phenylpropyl)-1H-pyrrole-2-carbonyl]amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (2) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (3) rel-(1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (4) rel-(1R,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-5-methylphenyl}cyclopropanecarboxylic acid, (5) rel-(1R,2S)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (6) rel-(1R,2R)-2-{5-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl }carbonyl)amino]-2-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (7) (1S,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2R)-2-[3-({[1-isopropyl-5-(3-phenylpropyl)-1H-pyrrol-2-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-methoxyphenyl}cyclopropanecarboxylic acid, (10) (1S,2R)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (11) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (12) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-(3-phenylpropyl)-1H-pyrrol-2-yl}carbonyl )amino]-4-chlorophenyl}cyclopropanecarboxylic acid, (13) (1R,2S)-2-{3-[({5-[2-(Benzyloxy)ethyl]-1-[(2S)-2-butyl]-1H-pyrrole- 2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (14) rel-(1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-fluoro-4-pyridyl)oxy ]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(2-chloro-6-fluoro-4-pyridyl) Oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (16) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2-chloro-3,5-difluorophenoxy) Ethyl]-1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (17) (1R,2S)-2-{3-[({1-[(2S)-2-butyl]-5-[2-(2,4-difluorophenoxy)ethyl]- 1H-pyrrol-2-yl}carbonyl)amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[(1-[(2S)-2-butyl]-5-{2-[(1-methyl-1H-pyrazol-4-yl )oxy]ethyl}-1H-pyrrol-2-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (19) rel-(1R,2S)-2-[3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(tri Fluoromethyl)phenyl]cyclopropanecarboxylic acid, (20) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3-phenylpropyl)benzoyl]amino}-4-(trifluoromethyl ) phenyl] cyclopropane carboxylic acid, (21) (1R,2S)-2-[3-({4-[2-(2,4-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (22) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}-4-fluorophenyl)cyclopropanecarboxylic acid, (23) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}-4-fluorophenyl)cyclopropanecarboxylic acid, (24) (1R,2S)-2-[2-chloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-(4-chloro-3-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amino}phenyl) Cyclopropane carboxylic acid, (26) rel-(1R,2S)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}phenyl)cyclopropanecarboxylic acid, (27) rel-(1R,2R)-2-(2,3-dichloro-5-{[2,6-dimethyl-4-(2-phenylethoxy)benzoyl]amine Base}phenyl)cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform Base) phenyl] cyclopropane carboxylic acid, (29) (1S,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform Base) phenyl] cyclopropane carboxylic acid, (30) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(1-methyl-1H-pyrazol-4-yl)ethoxy]benzyl Acyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (31) (1R,2S)-2-[3-{[4-(2-Cyclopropylethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (32) (1R,2S)-2-{3-[(2,6-Dimethyl-4-propoxybenzoyl)amino]-4-(trifluoromethyl)phenyl} ring propane carboxylic acid, (33) (1R,2S)-2-[3-{[4-(hexyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (34) (1R,2S)-2-[3-{[4-(Benzyloxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (35) (1R,2S)-2-[3-{[4-(2-Methoxyethoxy)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (36) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(tetrahydro-2H-pyran-2-yl)ethoxy]benzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (37) (1R,2S)-2-[3-({4-[2-(2-furyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (38) (1R,2S)-2-[3-({4-[2-(2-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (39) (1R,2S)-2-[3-({4-[2-(3-chlorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (40) (1R,2S)-2-[3-({4-[2-(1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl}amino) -4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (41) (1R,2S)-2-[3-({4-[2-(2,6-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (42) (1R,2S)-2-[3-({4-[2-(3,5-difluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino )-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (43) (1R,2S)-2-[3-({4-[(6-chloro-2-pyrazinyl)oxy]-2,6-dimethylbenzoyl}amino)- 4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (44) (1R,2S)-2-[3-{[4-(6-fluoro-3-pyridyl)-2,6-dimethylbenzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (45) (1R,2S)-2-[3-({4-[2-(4-hydroxyphenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (46) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]propane acid, (47) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]butyl acid, (48) 3-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl]- 2-Methylpropionic acid, (49) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform base) phenyl] cyclobutane carboxylic acid, or (50) (1R,2R)-2-[3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoroform base) phenyl]-1-methylcyclopropanecarboxylic acid. The cancer therapeutic agent according to any one of claims 1 to 6, wherein the compound represented by general formula (I-A) is: (1) (1R,2S)-2-[3-{[2-methyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)benzene Base] cyclopropane carboxylic acid, (2) (1R,2S)-2-[3-{[2-chloro-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (3) (1R,2S)-2-[3-{[4-(2-Phenylethoxy)-2-(trifluoromethyl)benzoyl]amino}-4-(trifluoro Methyl)phenyl]cyclopropanecarboxylic acid, (4) (1R,2S)-2-[3-{[4-(1H-indazol-5-ylmethoxy)-2,6-dimethylbenzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (5) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(1,2,3,4-tetrahydro-1-naphthylmethoxy)benzoyl ]amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (6) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(3-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (7) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(4-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (8) (1R,2S)-2-[3-({2,6-Dimethyl-4-[2-(2-pyridyl)ethoxy]benzoyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (9) (1R,2S)-2-[3-({4-[2-(2-chloro-1H-imidazol-1-yl)ethoxy]-2,6-dimethylbenzoyl }amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (10) (1R,2S)-2-[3-({4-[2-(2-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (11) (1R,2S)-2-[3-({4-[2-(3-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (12) (1R,2S)-2-[3-({4-[2-(4-fluorophenyl)ethoxy]-2,6-dimethylbenzoyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (13) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (14) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(3,3,3-trifluoro-2-methylpropoxy)benzoyl]amine Base}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (15) (1R,2S)-2-{3-[(2,6-Dimethyl-4-{[6-(trifluoromethyl)-2-pyridyl]oxy}benzoyl) Amino]-4-(trifluoromethyl)phenyl}cyclopropanecarboxylic acid, (16) (1R,2S)-2-[3-{[2,6-Dimethyl-4-(pyrazolo[1,5-a]pyrimidin-5-yloxy)benzoyl] Amino}-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (17) rel-(1R,2S)-2-(3-{[2,6-Dimethyl-4-(2-phenylethoxy)benzoyl]amino}-4-methyl Phenyl)cyclopropanecarboxylic acid, (18) (1R,2S)-2-[3-{[4-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (19) (1R,2S)-2-[3-{[2-isopropyl-4-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (20) (1R,2S)-2-[3-{[2-isopropyl-4-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (21) (1R,2S)-2-[3-{[3-(Benzyloxy)-2-isopropylbenzoyl]amino}-4-(trifluoromethyl)phenyl ]cyclopropanecarboxylic acid, (22) (1R,2S)-2-[3-{[2-isopropyl-3-(2-phenylethoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (23) (1R,2S)-2-[3-{[2-isopropyl-3-(3-phenylpropoxy)benzoyl]amino}-4-(trifluoromethyl) Phenyl] cyclopropane carboxylic acid, (24) (1R,2S)-2-[4-(trifluoromethyl)-3-{[2,3,5-trimethyl-4-(2-phenylethoxy)benzoyl ]amino}phenyl]cyclopropanecarboxylic acid, (25) (1R,2S)-2-[3-({[3-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (26) (1R,2S)-2-[3-({[5-isopropyl-1-(3-phenylpropyl)-1H-pyrazol-4-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (27) (1R,2S)-2-[3-({[2,6-Dimethyl-4-(2-phenylethoxy)phenyl]thiocarbonyl}amino)-4-(three Fluoromethyl)phenyl]cyclopropanecarboxylic acid, (28) (1R,2S)-2-[3-({[4-(2-cyclopropylethoxy)-2,6-dimethylphenyl]thiocarbonyl}amino)-4-( Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (29) (1R,2S)-2-[3-({[2-second butyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4 -(trifluoromethyl)phenyl]cyclopropanecarboxylic acid, (30) (1R,2S)-2-[3-({[2-isopropyl-1-(3-phenylpropyl)-1H-pyrrol-3-yl]carbonyl}amino)-4- (Trifluoromethyl)phenyl]cyclopropanecarboxylic acid, or (31) (1R,2S)-2-[3-({[2-(2-methyl-2-propyl)-1-(3-phenylpropyl)-1H-pyrrol-3-yl] Carbonyl}amino)-4-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid. The cancer therapeutic agent according to any one of claims 1, 2, 4, 5 and 7 to 9, wherein the immune checkpoint inhibitor is selected from CTLA-4, PD-1, PD-L1, PD-L2 Immune checkpoints in the group consisting of , LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDO1, Arginase I, TIGIT and CD115 molecular inhibitors. The cancer therapeutic agent according to any one of claims 1, 2, 4, 5, and 7 to 10, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. The cancer therapeutic agent according to any one of claims 1, 3, 4, and 6 to 9, wherein the EP ₄ receptor antagonist is a compound described in general formula (I) described in WO2016/111347, its pharmaceutical salts or their hydrates. The cancer therapeutic agent according to any one of claims 1, 3, 4, 6 to 9 and 12, wherein the EP ₄ receptor antagonist is 4-[4-cyano-2-({(2'R ,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-phenylpropyran-4,1'-cyclopropane]]-2'-carbonyl} Amino)phenyl]butyric acid, pharmaceutically acceptable salts thereof, or hydrates thereof. The cancer therapeutic agent according to any one of Claims 1 to 13, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, uveal melanoma, thymoma, mesenchymal Skin tumor, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, kidney cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer, malignant Bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, brain tumor, or multiple myeloma. The cancer therapeutic agent according to any one of claims 1 to 14, wherein the cancer is breast cancer, ovarian cancer, colon cancer, lung cancer, pancreatic cancer or gastric cancer. A medicine that antagonizes the compound represented by the general formula (IA) described in Claim 1, its pharmaceutically acceptable salt, or their hydrates with immune checkpoint inhibitors and/or _EP4 receptors A combination of medicines. A cancer treatment method comprising administering an effective amount of the compound represented by the general formula (IA) described in claim 1, its pharmaceutically acceptable salt, or a hydrate thereof to a patient in need of cancer treatment separately or simultaneously substances, and an effective amount of immune checkpoint inhibitors and/or _EP4 receptor antagonists. A cancer treatment method comprising administering an effective amount of the compound represented by the general formula (IA) described in claim 1, its pharmaceutically acceptable salt, or a hydrate thereof to a patient in need of cancer treatment, the The cancer treatment method further includes administering an effective amount of an immune checkpoint inhibitor and/or an EP ₄ receptor antagonist. A cancer treatment method comprising administering an effective amount of an immune checkpoint inhibitor to a patient in need of cancer treatment, the cancer treatment method further comprising administering an effective amount of the formula (I-A) described in Claim 1 Compounds, their pharmaceutically acceptable salts or their hydrates. A cancer treatment method comprising administering an effective amount of _EP4 receptor antagonists to a patient in need of cancer treatment, the cancer treatment method further comprising administering an effective amount of the general formula (IA) described in Claim 1 compounds, their pharmaceutically acceptable salts or their hydrates. A compound represented by the general formula (IA) described in Claim 1, its pharmaceutically acceptable salts or their hydrates are administered in combination with immune checkpoint inhibitors and/or _EP4 receptor antagonists for use in cancer treatment. An immune checkpoint inhibitor, which is used in cancer treatment in combination with the compound represented by the general formula (I-A) described in claim 1, its pharmaceutically acceptable salt, or its hydrate. An EP ₄ receptor antagonist, which is used in combination with the compound represented by the general formula (IA) described in claim 1, its pharmaceutically acceptable salt or their hydrates for cancer treatment. A use of the compound represented by the general formula (IA) described in claim 1, its pharmaceutically acceptable salt, or the hydrate thereof is used to manufacture a cancer therapeutic agent, and the cancer therapeutic agent is related to an immune test Point inhibitors and/or _EP4 receptor antagonists are administered in combination. The use of an immune checkpoint inhibitor is used to manufacture a cancer therapeutic agent, which is a compound represented by the general formula (I-A) described in claim 1, a pharmaceutically acceptable salt thereof, or the like The hydrate combination administration. The application of an _EP4 receptor antagonist is to manufacture a cancer therapeutic agent, and the cancer therapeutic agent is a compound represented by the general formula (IA) described in claim 1, a pharmaceutically acceptable salt thereof, or the compound shown in the formula (IA). Etc. hydrate combination administration.

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