Cyclic peptides for trapping interleukin-1β

Abstract

To provide additional, non-surgical therapeutic approaches beyond the standard of care cholesterol-lowering medications for slowing the progression of atherosclerosis and decreasing the risk of Major Adverse Cardiac Events (MACE).SOLUTION: The present disclosure provides cyclic peptides represented by a specific formula, which reduce inflammation by binding to an IL-1β cytokine and prevent binding to an IL-1 receptor, thereby inhibiting downstream pro-inflammatory signaling. These cyclic peptides can be pharmaceutically active compounds useful for the treatment of cardiovascular diseases and inflammatory disorders.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to specific cyclic peptides that capture interleukin-1β (IL-1β), pharmaceutical compositions containing such peptides, and methods of using such compounds to treat, inhibit, or ameliorate one or more cardiovascular disease conditions that may benefit from capturing IL-1β, such as atherosclerosis. The name of the XML file created on May 25, 2023 is 25545-WO-PCT_SL.XML and its size is 916,839 bytes.

[0002]

Background Art

[0003] Atherosclerosis is an arterial disease characterized by the accumulation of cholesterol plaques on the inner walls of arteries. As atherosclerosis progresses, the arteries become hardened and narrowed, increasing the risk of plaque rupture. When a plaque ruptures, cholesterol balls and other substances are released into the bloodstream, which can result in the inhibition of blood flow to the brain, heart, and other organs. Medically, these are known as major adverse cardiac events (MACE).

[0004] Risk factors for the development and progression of atherosclerotic cardiovascular disease (ASCVD) include high cholesterol, high blood pressure, a diet rich in saturated fat, smoking, obesity, diabetes, lack of exercise, and elevated levels of C-reactive protein (CRP), a marker of inflammation.

[0005] The first-line treatment for preventing the progression of ASCVD is a healthy diet and exercise, but ​​​​​​​​​​​The compliance rate is low. Pharmacological treatment of ASCVD has mainly focused on cholesterol-lowering drugs such as statins, cholesterol absorption inhibitors, and low density lipoprotein (LDL) receptor inhibitors. These drugs are highly effective in reducing the accumulation of fatty deposits and improving arterial health. Other drugs prescribed for ASCVD but not improving the condition include anticoagulants such as aspirin that prevent platelet aggregation in narrow arteries, and blood pressure drugs that reduce the risk and severity of heart attacks. Surgical options for more aggressive intervention when ASCVD has progressed include angioplasty, stent placement, endarterectomy (surgical removal of plaque), and bypass surgery. Cholesterol-lowering drugs have functioned as an important standard treatment for retarding the progression of atherosclerosis, but clinical data have supported that inflammation plays an even more important role in the progression of untreated ASCVD. Inflammatory biomarkers such as CRP are associated with an increased risk of cardiovascular events regardless of cholesterol levels. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. Canakinumab is a human monoclonal antibody against interleukin-1 β (IL-1β) approved for clinical use in rheumatic disorders. IL-1β is a pro-inflammatory cytokine that induces IL-6 and thereby raises the downstream inflammatory biomarker high-sensitivity CRP (hs CRP). Therefore, CANTOS demonstrated that a treatment targeting IL-1β

[0006] Cholesterol-lowering drugs have functioned as an important standard treatment for retarding the progression of atherosclerosis, but clinical data have supported that inflammation plays an even more important role in the progression of untreated ASCVD. Inflammatory biomarkers such as CRP are associated with an increased risk of cardiovascular events regardless of cholesterol levels. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. Cholesterol-lowering drugs have functioned as an important standard treatment for retarding the progression of atherosclerosis, but clinical data have supported that inflammation plays an even more important role in the progression of untreated ASCVD. Inflammatory biomarkers such as CRP are associated with an increased risk of cardiovascular events regardless of cholesterol levels. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. Inflammatory biomarkers such as CRP are associated with an increased risk of cardiovascular events regardless of cholesterol levels. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. Inflammatory biomarkers such as CRP are associated with an increased risk of cardiovascular events regardless of cholesterol levels. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first clinical trial to show that reducing vascular inflammation without simultaneously lowering lipids reduces the incidence of cardiovascular events. N Engl J Med 2017;377:1119-1131. Canakinumab is a human monoclonal antibody against interleukin-1 β (IL-1β) approved for clinical use in rheumatic disorders. IL-1β is a pro-inflammatory cytokine that induces IL-6 and thereby raises the downstream inflammatory biomarker high-sensitivity CRP (hs CRP). Therefore, CANTOS demonstrated that a treatment targeting IL-1β , to complement and potentially add to standard therapies that lower LDL, provide evidence that it may be possible to reduce the incidence of MAC E in certain patients.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] To slow the progression of atherosclerotic disease and reduce the risk of MACE, additional non-surgical therapies beyond standard cholesterol-lowering drugs are needed. Furthermore, patients suffering from inflammatory disorders are thought to benefit from oral medications that inhibit the same cytokine, IL-1β, as canakinumab.

Means for Solving the Problems

[0009] The present disclosure provides specific cyclic peptides that reduce inflammation by binding to the IL-1β cytokine and prevent the binding of IL-1 receptor, thereby inhibiting downstream inflammation-inducing signal transduction. These cyclic peptides can be pharmaceutically active compounds useful for the treatment of cardiovascular diseases and inflammatory disorders. In one embodiment, the present disclosure provides a compound of formula (I):

Chemical Formula

[0010] These compounds capture IL-1β, thereby potentially reducing downstream It can affect the inflammatory signaling pathways of the stream. Therefore, in another aspect wherein, the present invention provides a method for treating a subject in need of treatment by administering a therapeutically effective amount of a compound of the present disclosure to a method for treating cardiovascular diseases (e.g., atherosclerosis, vascular inflammation). In some embodiments, the administration includes oral administration of the compound.

[0011] The present disclosure further provides a method for producing a compound of the present disclosure, and a pharmaceutical composition comprising the compound of the present disclosure and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The compound of the present disclosure In one embodiment, the present disclosure R 1 is CH 3 C(O)NH-CH 2 CH 2 -O- or C 1 ; C 1 is (i) a 5- to 6-membered monocyclic aryl or heteroaryl [the heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S.]; or (ii) a 5- to 6-membered monocyclic or bicyclic, saturated cycloalkyl or heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; or (iii) a 5- to 6-membered monocyclic or bicyclic cycloalkyl ; wherein C 1 is unsubstituted or, independently, halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, carboxy, C 1 -C 3 alkoxy, and C 2 -C3 Acyl 1 to 3 Rs selected from the group consisting of C1 substituted by a substituent; R 2 is H, C 1 -C 3 alkyl, benzyl, or phenyl-CH 2 CH 2 -; R 3 is a 9- to 10-membered bicyclic aryl or heteroaryl, said heteroaryl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; wherein R 3 is unsubstituted or, independently, is selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, hydroxy, and C 1 -C 3 alkoxy; 1 to 3 Rs selected 3a substituted by a substituent; R 4 is C 1 -C 3 alkyl, HO 2 C-(CH 2 ) m -, H 2 NC(O)-(CH 2 ) m -, (CH 3 ) 2 NC(O)-(CH 2 ) m -, or tetrazolyl-(CH 2 ) m - ; R 5 is amino, H 2 N(CH 2 ) n -, H 2 NC(O)-(CH 2 ) n -, CH 3 C (O)NH-, CH 3 C(O)NH(CH 2 ) n -, C 5 、 or C 5 -CH 2 - and is C 5 is (i) a 5- to 6-membered monocyclic aryl or heteroaryl [said heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O , and S.]; (ii) a 9- to 10-membered bicyclic aryl or heteroaryl [said bicyclic heteroaryl - contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S.]; (iii) a 5- to 6-membered monocyclic or 9- to 10-membered heterocyclic alkyl [said heterocyclic alkyl is saturated or partially unsaturated and contains 1 to 2 hetero atoms selected from the group consisting of N, O, and S.]; (iv) a 5- to 6-membered monocyclic cycloalkyl; (v) 2,3-dihydroindolyl and; here, C 5 is unsubstituted or, independently, halo, amino, hydroxy , C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, H 2 N- (CH 2 ) k -, H 2 NC(O)-(CH 2 ) k -, H 2 C=CH-CH 2 O-, and phenyl selected from the group consisting of 1 to 3 R C5 substituents; R 6 is H, C 1 -C 5Alkyl, H 2 N(CH 2 ) p -, HOCH 2 (CH 3 ) 2 NCH 2 -, H 3 CO-(CH 2 ) q -, or C 6 -CH 2 -; C 6 is a 5-membered or 6-membered monocyclic saturated heterocyclic alkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S; where C 6 is unsubstituted or is independently substituted by 1 to 3 R 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, hydroxy, and C 1 -C 3 alkoxy selected from the group consisting of; C6 substituted by ; R 7 is H or C 1 -C 3 alkyl; R 8a is H, C 1 -C 5 alkyl, HOCH 2 (CH 2 N(CH 2 ) r (CH 3 ) 3 N + (CH 2 ) r -, or CH 3 C(O)NH(CH 2 ) r -; R 8b is H or C 1 -C 3 alkyl; R 9a is H or C1 -C 3 is alkyl; R 9b is H, C 1 -C 5 alkyl, C 9 -CH 2 -, or C 9 -CH 2 CH 2 -; ; C 9 is (i) a 5- to 6-membered monocyclic aryl or heteroaryl [the heteroaryl contains 1 to 2 heteroatoms selected from the group consisting of N, O , and S]; or (ii) a 5- to 6-membered monocyclic, saturated cycloalkyl or heterocycloalkyl [the heterocycloalkyl contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S]. ; ; wherein C 9 is unsubstituted or is independently selected from the group consisting of halo, amino, hydroxy, cyano, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, H 2 N-(CH 2 ) k -, H 2 NC(O)-(CH 2 ) k -, H 2 NCH 2 CH 2 O-, C H 3 C(O)NH-CH 2 CH 2 O-, and morpholinyl-CH 2 CH 2 O-; and is substituted by 1 to 3 R C9 substituents selected from this group; R 10 is H, halo, or C1 -C 3 is alkyl; R 11 is H, halo, or C 1 -C 3 is alkyl; in each case of subscript k is independently 1 or 2; subscript m is 1 or 2; subscript n is 1, 2, 3, or 4; subscript p is 1, 2, 3, or 4; subscript q is 1 or 2; subscript r is 1, 2, 3, or 4; X 1 X 2 and X 3 are independently C(H) or N; and, A 1 and A 2 are independently HO 2 C-, H 2 NC(O)-, CH 3 C(O)N(H)-, H 2 NS(O) 2 -, CH 3 S(O) 2 N(H)-, tetrazolyl, and 5-oxoox sadiazozolyl, and a pharmaceutically acceptable salt thereof having the above-shown structural formula (I). is provided.

[0013] In another embodiment, the disclosure is R 5 is amino, H 2 N(CH 2 ) n -, H 2 NC(O)-(CH 2 ) n -, C 5 or is C 5 -CH 2 -, and C 5 is (i) a 5- or 6-membered monocyclic aryl or heteroaryl [the heteroaryl is N, O contains one or two heteroatoms selected from the group consisting of N, O, and S. (ii) a 9- to 10-membered bicyclic aryl or heteroaryl [wherein the bicyclic heteroaryl contains one to three heteroatoms selected from the group consisting of N, O, and S]; (iii) a 5- to 6-membered monocyclic or 9- to 10-membered heterocyclic alkyl [wherein the heterocyclic alkyl is saturated or partially unsaturated and contains one or two heteroatoms selected from the group consisting of N, O, and S]; or (iv) 2,3-dihydroindolyl wherein C 5 is unsubstituted or is independently substituted by one to three R substituents selected from the group consisting of halo, amino, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, H 2 N-( CH 2 ) k -, H 2 NC(O)-(CH 2 ) k -, H 2 C=CH-CH 2 O-, and phenyl; R C5 is substituted by; R 6 is H, C 2 -C 5 alkyl, H 2 N(CH 2 ) p -, HOCH 2 -, (CH 3 ) 2 NCH 2 -, H 3 CO-(CH 2 ) q -, or C 6 -CH 2 -;​​ R 8a is H, C 1 -C 3 alkyl, HOCH 2 -, or H 2 N(CH 2 ) r -; ; R 9a is H; R 9b is H, C 1 -C 3 alkyl, C 9 -CH 2 -, or C 9 -CH 2 CH 2 -; ; R 10 is H; R 11 is H; subscript p is 1, 2, or 3; and, subscript r is 2, 3, or 4, a compound of formula (I) is provided.

[0014] In one embodiment, the compound of formula (I) has the following structural formula (IA).

Chemical formula

[0015] In another embodiment, the present disclosure C 1 is phenyl, pyrimidyl, or piperazinyl, where C 1 is unsubstituted or substituted by 1 to 2 RC 1 substituents; R 3 is naphthyl or indolyl, where R 3 is unsubstituted or substituted by 1 to 2 R 3a substituents; C 5is phenyl, pyridyl, pyrimidyl, naphthyl, indolyl, 7-azaindol yl, indazolyl, 2,3-dihydroindolyl, piperidinyl, tetrahydropyranyl , or cyclohexyl, where C 5 is unsubstituted or substituted by 1 to 2 R C5 ; C 6 is tetrahydropyranyl or morpholinyl; where C 6 is unsubstituted or substituted by 1 to 2 R ; C6 ; C 9a is H or methyl; C 9b is phenyl, pyridyl, cyclohexyl, morpholinyl, or piperidinyl and where C 9 is unsubstituted or substituted by 1 to 2 R C9 ; to provide a compound of formula (I).

[0016] In another embodiment, the present disclosure X 1 and X 2 are C(H); R 1 is phenyl substituted by carboxy, to provide a compound of formula (I).

[0017] In another embodiment, the present disclosure X 1 and X 2 are C(H); R 1 is CH 3 C(O)NH-CH 2 CH 2 -O- to provide a compound of formula (I) .

[0018] In another embodiment, the present disclosure is R 2To provide a compound of formula (I) wherein R is H.

[0019] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 3 is indolyl substituted by one halo .

[0020] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 3 is naphthyl. .

[0021] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 4 is HO 2 C-(CH 2 ) m -. To provide a compound of formula (I).

[0022] In another embodiment, the present disclosure provides a compound of formula (I) wherein X 3 is C(H). .

[0023] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 5 is H 2 N(CH 2 ) n -, indole, 7- azaindole, naphthyl or pyridyl.

[0024] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 5 is H 2 N(CH 2 ) n -, indole, naph thyl or pyridyl.

[0025] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 6 is H, HOCH 2 -, C 2 -C 5 alkyl or is H 2 N(CH 2) p - Provide a compound of formula (I) which is

[0026] In another embodiment, the present disclosure provides that R 6 is 2 -C 5 alkyl or H 2 N(CH 2 ) p - Provide a compound of formula (I) which is

[0027] In another embodiment, the present disclosure provides that R 7 is H, a compound of formula (I).

[0028] In another embodiment, the present disclosure provides R 8a is methyl or H 2 NCH 2 CH 2 - and; R 8b is H, a compound of formula (I).

[0029] In another embodiment, the present disclosure provides that R 9b is

Chemical formula

[0030] In another embodiment, the present disclosure provides that R 9b is

Chemical formula

[0031] In one embodiment, the present disclosure provides that A 1 is HO 2 C-, H 2 NC(O)-, CH 3 C( O)N(H)-, H 2 NS(O) 2 -, CH 3 S(O)2 N(H)-, tetrazolyl, and a compound of formula (I) selected from the group consisting of 5-oxooxadiazolyl is provided. Those skilled in the art will understand that such a moiety in its amino acid residue can be represented by the following substructure.

Chemical Structure

[0032] In one embodiment, the present disclosure provides a compound of formula (I) wherein A 2 is HO 2 C-, H 2 NC(O)-, CH 3 C( O)N(H)-, H 2 NS(O) 2 -, CH 3 S(O) 2 N(H)-, tetrazolyl, and a compound of formula (I) selected from the group consisting of 5-oxooxadiazolyl is provided. Those skilled in the art will understand that such a moiety in its amino acid residue can be represented by the following substructure.

[0033]

Chemical Structure

[0034] In another embodiment, the present disclosure provides a compound of formula (I) wherein R 10 is H; R 11 is H, F or Cl.

[0035] In another embodiment, the present disclosure provides a compound of formula (I) wherein both A 1 and A 2 are HO 2 C- (i.e., carboxy). ​​​

[0036] In some embodiments, the present disclosure R 1 is 4-CH 3 C(O)-piperazin-1-yl, CH 3 C(O)NH-CH 2 C H 2 -O-, 5-CO 2 H-pyrimidin-2-yl, or 4-CO 2 H-phenyl; ; R 2 is H, ethyl, benzyl, or phenyl-CH 2 CH 2 -; R 3 is naphthalen-1-yl, 4-fluoroindol-3-yl, or 4-chloroindol-3-yl; R 4 is methyl, HO 2 C-(CH 2 ) m -, or H 2 NC(O)-(CH 2 ) m -; R 5 is amino, H 2 N(CH 2 ) n -, naphthalen-1-yl, indol-3-yl, 7-aza-indol-3-yl, indazol-1-yl, 2,3-dihydroindol-1-yl, pyrid-3-yl, pyrid-4-yl, piperidin-4-yl, 3-aminomethylphenyl, 4-aminomethylphenyl, 3-aminophenyl, 4-aminophenyl, phenyl, pyrid-4-yl-CH -, pyrimidin-5-yl, tetrahydropyran-4-yl-, H NC(O)-(CH 2 -; 2 NC(O)-(CH 2 ) 2 -, 3-biphenyl, 3-CH 2 =CH​​​ -CH 2 O-phenyl, CH 3 C(O)NH-, CH 3 C(O)NH(CH 2 ) 3 -, or is cyclohexyl; R 6 is H, (CH 3 ) 2 CHCH 2 (CH 3 ) 3 CCH 2 -, H 2 N(CH 2 ) p -, HOCH 2 -, H 3 CCH 2 CH 2 -, morpholin-4-yl-CH 2 -, tetra hydropyran-4-yl-CH 2 (CH 3 ) 2 NCH 2 -, or H 3 CO-(CH 2 ) q -; R 7 is H or methyl; R 8a is H, methyl, HOCH 2 -, H 2 N(CH 2 ) r (CH 3 ) 3 NCH 2 CH 2 -, or CH 3 C(O)NH(CH 2 ) 4 -; R 8b is H or methyl; R 9a is H or methyl; R 9b is H, methyl, H 3 CCH 2 CH2 CH 2 -, 4-HO-phenyl-CH 2 C H 2 -, phenyl-CH 2 CH 2 -, cyclohexyl-CH 2 CH 2 -, 5-NC-pyr id-3-yl-CH 2 CH 2 -, 4-F 3 C-phenyl-CH 2 -, 3-F 3 C-phenyl -CH 2 -, 2-F 3 C-phenyl-CH 2 -, morpholin-4-yl-CH 2 CH 2 O-phenyl-CH 2 -, 4-aminophenyl-CH 2 -, 4,4-difluorocyclohe xyl-CH 2 -, 4-H 2 NCH 2 CH 2 O-phenyl-CH 2 -, 4-H 2 NCH 2 CH 2 O-pyrid-3-yl-CH 2 -, piperidin-4-yl-CH 2 -, or 4-C H 3 C(O)NH-CH 2 CH 2 O-phenyl-CH 2 -; R 10 is H, fluoro, or methyl; R 11 is H, fluoro, or chloro; A 1 and A 2 are both HO 2 C-; and, X 1 X 2 and X3 To provide a compound of formula (I) wherein C(H).

[0037] In certain embodiments, the present disclosure R 1 is 4-CH 3 C(O)-piperazin-1-yl, CH 3 C(O)NH-CH 2 C H 2 -O-, 5-CO 2 H-pyrimidin-2-yl, or 4-CO 2 H-phenyl; ; R 2 is H, ethyl, benzyl, or phenyl-CH 2 CH 2 -; R 3 is naphtha-1-yl, 4-fluoroindol-3-yl, or 4-chloroindol-3-yl; R 4 is methyl, HO 2 C-(CH 2 ) m -, or H 2 N(O)C-(CH 2 ) m -; ; R 5 is amino, H 2 N(CH 2 ) n -, naphtha-1-yl, indol-3-yl, 7-aza-indol-3-yl, indazol-1-yl, 2,3-dihydroindol-1-yl, pyrid-3-yl, pyrid-4-yl, piperidin-4-yl, 3-aminomethylphenyl, 4-aminomethylphenyl, 3-aminophenyl, 4-aminophenyl, phenyl, pyrid-4-yl-CH -, pyrimidin-5-yl, tetrahydropyran-4-yl-, H N(O)C-(CH 2 -; -; 2 N(O)C-(CH 2 )2 -, 3-biphenyl, or 3-CH 2 = CH-CH 2 is O-phenyl; R 6 is H, (CH 3 ) 2 CHCH 2 -, H 2 N(CH 2 ) p -, HOCH 2 -, H 3 CCH 2 CH 2 -, morpholin-4-yl-CH 2 -, tetrahydropyran-4-yl- CH 2 -, (CH 3 ) 2 NCH 2 -, or H 3 CO-(CH 2 ) q -; R 7 is H or methyl; R 8a is H, methyl, HOCH 2 -, or H 2 N(CH 2 ) r -; R 8b is H or methyl; R 9a is H; R 9b is H, methyl, 4-HO-phenyl-CH 2 CH 2 -, phenyl-CH 2 CH 2 -, 5-NC-pyrid-3-yl-CH 2 CH 2 -, 4-F 3 C-phenyl-CH 2 - , 3-F 3 C-phenyl-CH 2 , 2-F 3 C-phenyl-CH 2 , morpholin-4 -yl-CH 2 CH 2 O-phenyl-CH 2 -, 4-aminophenyl-CH 2 -, 4,4 -difluorocyclohexyl-CH 2 -, 4-H 2 NCH 2 CH 2 O-phenyl-CH 2 -, 4-H 2 NCH 2 CH 2 O-pyrid-3-yl-CH 2 -, piperidin-4-yl- CH 2 -, or 4-CH 3 C(O)NH-CH 2 CH 2 O-phenyl-CH 2 -; R 10 and R 11 are both H; and A 1 and A 2 are both HO 2 C-; a compound of formula (I) is provided.

[0038] In some embodiments, the present disclosure provides a compound of formula (I). The compound is selected from the group consisting of SEQ ID NOs: 1-215 set forth in Table 1. In certain embodiments, the present disclosure provides a compound of formula (I). The compound is selected from the group consisting of SEQ ID NOs: 1-173 set forth in Table 1.

[0039] In a specific embodiment, the present disclosure provides a compound of formula (I). The compound is selected from the group consisting of the following (SEQ ID NOs: 78, 71-72, 6 7, 65, 70, 69, 68, 66, 64, 77, 79, 209, 193, 215, 21 2, and 210 in order of appearance).

[0040]

Chem.

[0041] In some embodiments, the present disclosure provides a compound of formula (I). The compound is selected from the group consisting of SEQ ID NO: 78, 71-72, 67, 65, 70, 69, 68, 66, 64, 77, and 79. SEQ ID NO: 78, 71-72, 67, 65, 70, 69, 68, 66, 64, 77, and 79 selected from the group consisting of.

[0042] Without being bound by any particular theory, Applicants believe that the compounds of the present disclosure capture interleukin-1β, block signal transduction via the IL-1 receptor, thereby reducing the downstream markers IL-6 and CRP. Accordingly, the compounds may be useful for the treatment of inflammatory components of cardiovascular diseases such as HFpEF with preserved ejection fraction and HFpEF. The compounds may also be useful for treating inflammatory disorders such as hidradenitis suppurativa (acne inversa), inflammatory bowel disease, and rheumatoid arthritis. 1β, block signal transduction via the IL-1 receptor, thereby reducing the downstream markers - IL-6 and CRP. Thus, the compound is useful for the treatment of inflammatory components of cardiovascular diseases such as HFpEF with preserved ejection fraction and HFpEF. The compound may also be useful for treating inflammatory disorders such as hidradenitis suppurativa (acne inversa), inflammatory bowel disease, and rheumatoid arthritis. useful for the treatment of inflammatory components of cardiovascular diseases such as HFpEF with preserved ejection fraction and HFpEF. The compound may also be useful for treating inflammatory disorders such as hidradenitis suppurativa (acne inversa), inflammatory bowel disease, and rheumatoid arthritis. arthritis.

[0043] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0044] As used throughout this disclosure, the terms "compounds of the disclosure," "compounds of the present disclosure," and "compounds disclosed herein" are used interchangeably and refer to the disclosed cyclic peptides and compounds of formula (I). As used throughout this disclosure, the terms "compounds of the disclosure," "compounds of the present disclosure," and "compounds disclosed herein" are used interchangeably and refer to the disclosed cyclic peptides and compounds of formula (I). It is understood to include compounds. References to compounds of formula (I) include compounds of other general formulas within the scope of formula (I) including (but not limited to) compounds of formula (IA). Compounds of formula (I) can form salts, which are also within the scope of this disclosure. References to the compounds of this disclosure (or compounds of formula (I)) in this specification are understood to include references to their salts, unless otherwise stated. As used herein, the term "salt" refers to acidic salts formed with inorganic acids and / or organic acids, as well as basic salts formed with inorganic bases and / or organic bases. Further, when a compound of formula (I) contains both a basic moiety such as an amino group, pyrrolidine, imidazole, etc. (not limited thereto) and an acidic moiety such as a carboxylic acid, etc. (not limited thereto), an amphoteric ion ("inner salt") may be formed and is included in the term "salt" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. The salts of the compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with a certain amount of an acid or base (e.g., equivalent) in a medium such as a medium in which the salt precipitates or in an aqueous medium, and then lyophilizing. "Acyl" means an alkyl-C(O)-group, where alkyl is as defined below. The bond to the parent group is through the carbon atom of the carbonyl group. "Alkyl" and other groups having the prefix "alk", such as alkoxy, are as specified and include (but are not limited to) straight-chain or branched-chain saturated hydrocarbon groups having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. are included. The term "alkyl" also includes cyclic saturated hydrocarbon groups having from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. The salts of the compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with a certain amount of an acid or base (e.g., equivalent) in a medium such as a medium in which the salt precipitates or in an aqueous medium, and then lyophilizing. Another embodiment, the salts are other than pharmaceutically acceptable salts. The salts of the compounds of formula (I) can be formed, for example, by reacting the compounds of formula (I) with a certain amount of acid or base (e.g., equivalent) in a medium such as a medium in which the salt precipitates or in an aqueous medium, and then freeze-drying. The compounds of formula (I) can form salts, which are also within the scope of this disclosure. References to the compounds of this disclosure (or compounds of formula (I)) in this specification are understood to include references to their salts, unless otherwise stated. As used herein, the term "salt" refers to acidic salts formed with inorganic acids and / or organic acids, as well as basic salts formed with inorganic bases and / or organic bases. Further, when a compound of formula (I) contains both a basic moiety such as an amino group, pyrrolidine, imidazole, etc. (not limited thereto) and an acidic moiety such as a carboxylic acid, etc. (not limited thereto), an amphoteric ion ("inner salt")

[0045] "Acyl" means an alkyl-C(O)-group, where alkyl is as defined below. The bond to the parent group is through the carbon atom of the carbonyl group. "Alkyl" and other groups having the prefix "alk", such as alkoxy, are as specified

[0046] and include (but are not limited to) straight-chain or branched-chain saturated hydrocarbon groups having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. For example, A carbon chain that can be linear, branched, or a combination thereof and contains a number of carbon atoms means. For example, C 1 -C 6 Alkyl means an alkyl group having from 1 (i.e., methyl) to a maximum of 6 (i.e., hexyl) carbon atoms. In certain embodiments, the straight chain alkyl group has 1 to 6 carbon atoms and the branched alkyl group has 3 to 7 carbon atoms . Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0047] "Alkoxy" and "alkyl-O-" are used interchangeably and refer to an alkyl group linked to oxygen.

[0048] "Amino" means an H 2 N-group. The bond to the parent group is through the nitrogen atom.

[0049] "Amino acid" refers to natural α-amino acids and their stereoisomers, as well as non-natural amino acids ( such as β-amino acids and substituted amino acids) and their stereoisomers. In the sequences given for the peptides (compounds) according to the present disclosure, the amino acid residues have their conventional meanings. Thus, "G" is glycine, "W" is tryptophan, "A" is alanine , "S" is serine, and so on. It should be understood that the "D" isomer is designated by attaching "d" before the one-letter code or the amino acid name. For example, dA is the D-isomer of L-alanine . Amino acid residues not included above have the definitions provided in the table in the Examples section below.

[0050] ​​​​​As used herein, "aryl" means a monocyclic 6-membered ring or bicyclic 10-membered ring system in which at least one ring is aromatic and all ring atoms are carbon.

[0051] "Bicyclic ring system" refers to two rings that are joined. The rings can be fused, i.e., they can share two adjacent atoms, or "spirocyclic," i.e., they can share only one atom.

[0052] "Carboxy" means a HO 2 C-group. The bond to the parent group is through the carbon atom of the carbonyl component.

[0053] "Cycloalkyl" means a saturated cyclic hydrocarbon group. In certain embodiments, the cycloalkyl group has 3 to 12 carbon atoms and forms 1 to 3 fused carbon rings . Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohe xyl, cycloheptyl, adamantyl, and the like.

[0054] "Fluoroalkyl" includes mono- and polyfluoro-substituted alkyl groups, perfluoro alkyl and lower substituted alkyl. For example, fluoromethyl, 1,1-difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included.

[0055] Unless otherwise indicated, "halogen" or "halo" includes fluorine (fluoro), chlorine (cl oro), bromine (bromo), and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0056] "Heterocyclic alkyl" means a non-aromatic monocyclic, bicyclic or tricyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, where one or more of the atoms in the ring system are elements other than carbon, for example, nitrogen, oxygen or sulfur, either alone or in combination. There are no adjacent oxygen atoms and / or sulfur atoms in the ring system. In some embodiments, heterocyclic alkyl contains about 5 to about 6 ring atoms. The prefixes aza, oxa or thia before the heterocyclic stem mean that at least nitrogen, oxygen or sulfur atoms are present as ring atoms, respectively. In some embodiments, the nitrogen or sulfur atoms of the heterocyclic alkyl may be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocycles include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, and the like.

[0057] "Heteroaryl" refers to aromatic monocyclic, bicyclic, and tricyclic ring structures in which one or more of the atoms (heteroatoms) within the ring are elements other than carbon. The heteroatoms are typically O, S, or N atoms. Examples of heteroaromatic groups include pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0058] If any variable element (e.g., R C1 ) appears more than once in any component of this specification or in formula (I) or any other general formula, its definition in each occurrence is independent of all other C1 occurrences and is defined as such in each occurrence. occurrences and is independent of all other is independent of its definition in the context of its occurrence. Combinations of substituents and / or variable elements are only permitted if such combinations result in stable compounds. When selecting the compounds of the present disclosure, one skilled in the art will recognize that the various substituents (e.g., RC should be selected according to known principles regarding the connectivity and stability of the chemical structure. Unless explicitly stated to the contrary, such ring substitutions are chemically acceptable and, if they result in stable compounds, substitution by the designated substituents is permitted at any atom within the ring (e.g., an aryl, heteroaryl, or saturated heteroaryl ring). A "stable" compound is one that can be prepared and isolated and whose structure and properties do not essentially change for a period sufficient to use the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). 9 ) of the chemical structure. For the purposes of the present disclosure, unless otherwise specified, a "substituted" group is considered to include the multiplicity of substitution by the designated substituents. When multiple substituent moieties are disclosed or claimed, the substituted compound can be substituted, singly or in combination, by one or more of the disclosed or claimed substituent moieties. Substituted independently means that the (two or more) substituents can be the same or different. Unless explicitly depicted or otherwise described, a variable element depicted with a "floating" bond in a structural formula is permitted at any available carbon atom within the ring to which the variable element is attached. In formula (I) or any of its embodiments, when a moiety is "optionally substituted", it is independent of its definition in the context of its occurrence. Combinations of substituents and / or variable elements are only permitted if such combinations result in stable compounds. When selecting the compounds of the present disclosure, one skilled in the art will recognize that the various substituents (e.g., RC should be selected according to known principles regarding the connectivity and stability of the chemical structure. Unless explicitly stated to the contrary, such ring substitutions are chemically acceptable and, if they result in stable compounds, substitution by the designated substituents is permitted at any atom within the ring (e.g., an aryl, heteroaryl, or saturated heteroaryl ring). A "stable" compound is one that can be prepared and isolated and whose structure and properties do not essentially change for a period sufficient to use the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). For the purposes of the present disclosure, unless otherwise specified, a "substituted" group is considered to include the multiplicity of substitution by the designated substituents. When multiple substituent moieties are disclosed or claimed, the substituted compound can be substituted, singly or in combination, by one or more of the disclosed or claimed substituent moieties. Substituted independently means that the (two or more) substituents can be the same or different. Unless explicitly depicted or otherwise described, a variable element depicted with a "floating" bond in a structural formula is permitted at any available carbon atom within the ring to which the variable element is attached. In formula (I) or any of its embodiments, when a moiety is "optionally substituted",

[0059] it is independent of its definition in the context of its occurrence. Combinations of substituents and / or variable elements are only permitted if such combinations result in stable compounds. When selecting the compounds of the present disclosure, one skilled in the art will recognize that the various substituents (e.g., RC should be selected according to known principles regarding the connectivity and stability of the chemical structure. Unless explicitly stated to the contrary, such ring substitutions are chemically acceptable and, if they result in stable compounds, substitution by the designated substituents is permitted at any atom within the ring (e.g., an aryl, heteroaryl, or saturated heteroaryl ring). A "stable" compound is one that can be prepared and isolated and whose structure and properties do not essentially change for a period sufficient to use the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). For the purposes of the present disclosure, unless otherwise specified, a "substituted" group is considered to include the multiplicity of substitution by the designated substituents. When multiple substituent moieties are disclosed or claimed, the substituted compound can be substituted, singly or in combination, by one or more of the disclosed or claimed substituent moieties. Substituted independently means that the (two or more) substituents can be the same or different. Unless explicitly depicted or otherwise described, a variable element depicted with a "floating" bond in a structural formula is permitted at any available carbon atom within the ring to which the variable element is attached. In formula (I) or any of its embodiments, when a moiety is "optionally substituted",

[0060] it is independent of its definition in the context of its occurrence. Combinations of substituents and / or variable elements are only permitted if such combinations result in stable compounds. When selecting the compounds of the present disclosure, one skilled in the art will recognize that the various substituents (e.g., RC should be selected according to known principles regarding the connectivity and stability of the chemical structure. Unless explicitly stated to the contrary, such ring substitutions are chemically acceptable and, if they result in stable compounds, substitution by the designated substituents is permitted at any atom within the ring (e.g., an aryl, heteroaryl, or saturated heteroaryl ring). A "stable" compound is one that can be prepared and isolated and whose structure and properties do not essentially change for a period sufficient to use the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). When described, it means that the formula (I) or its embodiment includes compounds containing the specified substituent(s) on that part thereof, and compounds not containing the specified substituent(s) on that part thereof. Including compounds containing the specified substituent(s) (or multiple substituents) on that part thereof, and compounds not containing the specified substituent(s) (or multiple substituents) on that part thereof.

[0061] The wavy line used in this specification:

Chemical Structure

[0062] Among the compounds described herein, there are some that may exist as tautomers with different hydrogen bonding points accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Individual tautomers and their mixtures are included in the compounds of the present disclosure. In the compounds of the present disclosure, atoms may exhibit natural isotope abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those predominantly found in nature. The present disclosure described and claimed herein is intended to include all suitable isotope variations of the compounds of the present disclosure and their embodiments. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also denoted as D herein). Protium is the predominant hydrogen isotope found in nature. Enriching deuterium can provide certain therapeutic advantages such as an extended in vivo half-life or a reduced dosing requirement, or may result in compounds useful as standards for characterizing biological samples. The isotope-enriched compounds of the present disclosure

[0063] 1 2 ​​​​​​​​​​ The substances can be produced without undue experimentation using suitable isotope enrichment reagents and / or intermediates by conventional techniques well known to those skilled in the art or by processes similar to those described in the figures and examples of this specification.

[0064] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds of the present disclosure are acidic (or have functional groups that can be anionic), their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic bases such as inorganic bases and organic bases. Examples of suitable inorganic cations include alkali metal ions such as Li , Li + , Na + , and K + etc., alkaline earth metal cations such as Ca 2+ and Mg 2+ etc., and other cations such as Al 3+ and Zn + etc., but are not limited thereto. Examples of suitable organic cations include ammonium ions ( i.e., NH 4 + ) and substituted ammonium ions etc., but are not limited thereto. Examples of suitable substituted ammonium ions include those derived from methylamine, ethylamine, diethylamine, triethylamine, and ethylenediamine. When the compounds of the present disclosure are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Examples of such acid addition salts include hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), formic acid, There are salts formed from acetic acid, capric acid, and citric acid, etc. Salts containing acetate, formate, capric acid, chloride, or sodium salt are representative ones used together with the compounds of the present disclosure. In some embodiments, the salts of the compounds of the present disclosure can be formed by anion exchange well-known to those skilled in the art, for example, by replacing trifluoroacetate ions with chloride ions.

[0065] Furthermore, the compounds of the present disclosure can exist in an amorphous form and / or one or more crystalline forms, and thus all amorphous and crystalline forms of the compounds of formula (I) including the examples, as well as their mixtures, are considered to be within the scope of the present disclosure. Additionally, some of the compounds of the present disclosure can form solvates with water (i.e., hydrates) or common organic solvents such as acetic acid or acetonitrile (however, not limited thereto). Such solvates and hydrates of the compounds, especially pharmaceutically acceptable solvates and hydrates, are likewise included within the scope of the present disclosure along with the non-solvated and anhydrous forms.

[0066] Pharmaceutically acceptable prodrug modifications of the compounds of the present disclosure that are converted to compounds within the scope of the present disclosure in vivo are also within the scope of the present disclosure.

[0067] The present invention also relates to a method for producing the compounds of formula (I) described in the following examples, from which the compounds of the present disclosure can be obtained.

[0068] "Treatment" and "treating" refer to all processes that can slow down, interrupt, prevent, control, or stop the progression of the diseases or disorders described in this document. These The term does not necessarily mean that all symptoms of a disease or disorder are completely eliminated. Rather.

[0069] As used herein, "prevent" or "prevention" means reducing the likelihood of contracting a disease or disorder described herein, or reducing the severity of a disease or disorder described herein. Or causing it to decrease. Refers to making it happen.

[0070] The terms "therapeutically effective (or effective) amount" and similar descriptions such as "amount effective for treatment" or "effective dose" mean the amount of a compound of the present disclosure that causes a biological or medical response in an organism, system, animal, or human that is sought by researchers, veterinarians, physicians, and other clinical practitioners. In a preferred embodiment, the term "therapeutically effective amount" means the amount of a compound of the present disclosure that reduces at least one clinical symptom in a human patient. The terms "prophylactically effective (or effective) amount" and similar descriptions such as "amount effective for prevention" mean the amount of a compound of the present disclosure that prevents or reduces the risk of occurrence of a biological or medical event that a researcher, veterinarian, physician, or other clinical practitioner is attempting to prevent in an organism, system, animal, or human. Or the amount of the compound of the present disclosure that reduces the risk of occurrence of a biological or medical event that a researcher, veterinarian, physician, or other clinical practitioner is attempting to prevent in an organism, system, animal, or human. Is what it means. In a preferred embodiment, the term "therapeutically effective amount" means the amount of a compound of the present disclosure that reduces at least one clinical symptom in a human patient. The terms "prophylactically effective (or effective) amount" and similar descriptions such as "amount effective for prevention" mean the amount of a compound of the present disclosure that prevents or reduces the risk of occurrence of a biological or medical event that a researcher, veterinarian, physician, or other clinical practitioner is attempting to prevent in an organism, system, animal, or human. Or the amount of the compound of the present disclosure that reduces the risk of occurrence of a biological or medical event that a researcher, veterinarian, physician, or other clinical practitioner is attempting to prevent in an organism, system, animal, or human. Is what it means. Or the amount of the compound of the present disclosure that reduces the risk of occurrence of a biological or medical event that a researcher, veterinarian, physician, or other clinical practitioner is attempting to prevent in an organism, system, animal, or human. Is what it means.

[0071] The dosage of the compound of the present disclosure The method of administration using the compound of the present disclosure is selected according to various factors including the type, species, age, weight, gender, and medical condition of the patient; the severity of the medical condition to be treated; the efficacy of the compound selected for administration; the route of administration; and the renal and hepatic functions of the patient. Considering these factors is within the purview of a clinical practitioner with ordinary skill in the art for the purpose of determining the therapeutically effective amount or prophylactically effective amount necessary to prevent, arrest, or stop the progression of the medical condition. The specific daily dosage ; the severity of the medical condition to be treated; the efficacy of the compound selected for administration; the route of administration; and the renal and hepatic functions of the patient. Considering these factors is within the purview of a clinical practitioner with ordinary skill in the art for the purpose of determining the therapeutically effective amount or prophylactically effective amount necessary to prevent, arrest, or stop the progression of the medical condition. The specific daily dosage ; the severity of the medical condition to be treated; the efficacy of the compound selected for administration; the route of administration; and the renal and hepatic functions of the patient. Considering these factors is within the purview of a clinical practitioner with ordinary skill in the art for the purpose of determining the therapeutically effective amount or prophylactically effective amount necessary to prevent, arrest, or stop the progression of the medical condition. The specific daily dosage ; the severity of the medical condition to be treated; the efficacy of the compound selected for administration; the route of administration; and the renal and hepatic functions of the patient. Considering these factors is within the purview of a clinical practitioner with ordinary skill in the art for the purpose of determining the therapeutically effective amount or prophylactically effective amount necessary to prevent, arrest, or stop the progression of the medical condition. The specific daily dosage Is within the purview of a clinical practitioner with ordinary skill in the art for the purpose of determining the therapeutically effective amount or prophylactically effective amount necessary to prevent, arrest, or stop the progression of the medical condition. The specific daily dosage For example, it is understood that it can be both a therapeutically effective amount for treating oncological symptoms and a prophylactically effective amount for preventing, for example, oncological symptoms.

[0072] Individual needs vary, but the determination of the optimal range of the effective amount of the compounds of the present disclosure is within the scope of the art. In the treatment or prophylactic treatment of the symptoms and disorders specified herein, in the administration to humans, for example, representative dosages of the compounds of the present disclosure can be from about 0.05 mg / kg / day to about 50 mg / kg / day. In some embodiments, the patient is administered from about 5 mg / day to about 120 mg / day, such as 10 mg / day, 20 mg / day, 30 mg / day , 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, mg / day , 90 mg / day, or 100 mg / day of the compounds of the present disclosure. In certain embodiments, the patient is administered from about 0.2 mg / kg to about 5 mg / kg, such as 0.5 mg / kg, 0. 75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, or 1.5 mg / kg of the compounds of the present disclosure. Such dosages can be administered as a single dose or divided into multiple doses.

[0073] Pharmaceutical Compositions The compounds of the present disclosure and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, particularly humans, as pharmaceuticals alone, in a mixture with each other, or in the form of a pharmaceutical composition. The terms "subject" or "patient" include animals, preferably mammals, particularly humans, to whom the active agents of the present invention are used for the prevention or treatment of medical conditions. Administration of the drug to a subject includes both self - administration and administration to the patient by others. The subject is already ​A subject who needs or desires treatment for an existing disease or medical condition, or who needs or desires prophylactic measures to prevent the occurrence of a disease or medical condition or to reduce the risk of its occurrence is also acceptable. As used herein, when a subject "needs" treatment or prophylactic measures for an existing condition, it includes both the determination of its necessity by a medical professional and the patient's desire for such treatment is also acceptable. As used herein, when a subject "needs" treatment or prophylactic measures for an existing condition, it includes both the determination of its necessity by a medical professional and the patient's desire for such treatment is also acceptable. As used herein, when a subject "needs" treatment or prophylactic measures for an existing condition, it includes both the determination of its necessity by a medical professional and the patient's desire for such treatment is also acceptable. As used herein, when a subject "needs" treatment or prophylactic measures for an existing condition, it includes both the determination of its necessity by a medical professional and the patient's desire for such treatment Both are included.

[0074] Accordingly, the present disclosure provides the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as medicaments, their use for modulating the activity of cytokine IL-1β, in particular their use in the treatment and prevention of the diseases or disorders described hereinafter, and their use for preparing medicaments for such purposes Accordingly, the present disclosure provides the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as medicaments, their use for modulating the activity of cytokine IL-1β, in particular their use in the treatment and prevention of the diseases or disorders described hereinafter, and their use for preparing medicaments for such purposes Accordingly, the present disclosure provides the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as medicaments, their use for modulating the activity of cytokine IL-1β, in particular their use in the treatment and prevention of the diseases or disorders described hereinafter, and their use for preparing medicaments for such purposes Accordingly, the present disclosure provides the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as medicaments, their use for modulating the activity of cytokine IL-1β, in particular their use in the treatment and prevention of the diseases or disorders described hereinafter, and their use for preparing medicaments for such purposes In some specific embodiments, the compounds of the present disclosure and pharmaceutically acceptable salts thereof capture IL-1β

[0075] Furthermore, the present disclosure provides a pharmaceutical composition comprising an effective dose of at least one compound of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives Furthermore, the present disclosure provides a pharmaceutical composition comprising an effective dose of at least one compound of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives Furthermore, the present disclosure provides a pharmaceutical composition comprising an effective dose of at least one compound of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives

[0076] Accordingly, the present disclosure provides, for example, the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as a pharmaceutical composition comprising an effective dose of the compounds of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier Accordingly, the present disclosure provides, for example, the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as a pharmaceutical composition comprising an effective dose of the compounds of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier Accordingly, the present disclosure provides, for example, the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as a pharmaceutical composition comprising an effective dose of the compounds of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier Accordingly, the present disclosure provides, for example, the compounds of the present disclosure and pharmaceutically acceptable salts thereof for use as a pharmaceutical composition comprising an effective dose of the compounds of the present disclosure and / or a pharmaceutically acceptable salt thereof as an active ingredient and a conventional pharmaceutically acceptable carrier the use of salts thereof that are permitted, and thereof for preparing a medicament for such purposes to provide the use.

[0077] The pharmaceutical compositions according to the present disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard gelatin capsules and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or can be administered rectally, for example, in the form of suppositories. Administration can also be parenterally, for example, subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or infusion.

[0078] Other suitable administration forms are, for example, ointments, tinctures, sprays or transdermal therapeutic systems or, for example, transdermal or topical administration in the form of microcapsules, implants or rods . Preferred administration forms are determined, for example, by the disease to be treated and its severity.

[0079] The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I). The compound of formula (I) can be used in combination with any suitable pharmaceutical carrier or excipient. Such a pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of formula (I), and a pharmaceutically acceptable excipient and / or carrier. Specific pharmaceutical compositions are adapted to the administration form. In certain embodiments, the pharmaceutically acceptable carrier can be water or a buffer solution.

[0080] The excipients included in the pharmaceutical composition have different purposes depending on, for example, the nature of the drug and the administration form . Examples of commonly used excipients include physiological saline, buffered physiological saline, dextrose solution, water for injection, glycerol, ethanol, and combinations thereof, stabilizers, solubilizers ​and surfactants, buffers and preservatives, isotonic agents, extenders, lubricants (such as talc or silica , and fats such as vegetable stearin, magnesium stearate or stearic acid) , emulsifiers, suspending or viscous agents, inert diluents, fillers (cellulose, dicalcium phosphate , vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol , calcium carbonate, and magnesium stearate, etc.), disintegrants (cross-linked polyvinylpyrro lidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose , etc.), binders (starch, gelatin, cellulose, methylcellulose or modified cellulose , such as microcrystalline cellulose, hydroxypropyl cellulose, sugars such as sucrose and lactose , or sugar alcohols such as xylitol, sorbitol or maltitol , polyvinylpyrrolidone, and polyethylene glycol), wetting agents, antibacterial agents, chelating agents, coating agents (cellulose film coating agents, synthetic polymers, shellac, corn m protein zein or other polysaccharides, gelatin, etc.), preservatives (vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, cysteine, methionine , citric acid and sodium citrate, and synthetic preservatives such as methylparaben and propylparaben are included), sweeteners, fragrances, flavoring agents, coloring agents, absorption promoters, administration aids, and combinations thereof, etc., but are not limited thereto.

[0081] A carrier is, in the context of a pharmaceutical composition, a compound and substance that improves and / or extends the delivery of the active ingredient to the subject. The carrier uses sustained release technology to extend the in-vivo or play a role in delaying the release of the drug in the subject. The carrier is the subject It can also reduce drug metabolism and / or reduce the toxicity of the drug in the subject. Carrier It can also be used to deliver the drug to specific cells or tissues in the subject. General burden Bodies (both hydrophilic and hydrophobic carriers) include fat emulsions, lipids, PEGylated phospholipids, PE Liposomes coated with cyclic RGD peptides via PEG spacers, P EGylated liposomes, liposomes and lipospheres, microspheres (such as those made of biodegradable polymers or albumin), polymer matrices, biocompatible polymers, tamp Protein-DNA complexes, protein complexes, red blood cells, vesicles, nanoparticles, and hydrocarbon sta Pull side chains, etc. The aforementioned carriers can also be used to enhance the cell membrane permeability of the compound of formula (I). In addition to use in the pharmaceutical compositions of the present disclosure, the carrier can be used in other applications such as in vitro (e.g., for delivery to cultured cells) and / or in vivo research applications compositions. For example, for delivery to cultured cells) and / or in other applications such as in vivo research applications compositions.

[0082] Pharmaceutical compositions suitable for oral administration can be provided as individual units such as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (aqueous or non-aqueous liquids, or as edible foams or whipped products, or as emulsions). Excipients suitable for tablets or hard gelatin capsules include lactose, corn starch or its derivatives, st earic acid or its salts, etc. Excipients suitable for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. In the case of preparing solutions and syrups, excipients that can be used include water, polyols, and sugars, etc. Susp In the case of preparing a turbid solution, an oil-in-water or water-in-oil suspension can be provided using an oil, such as vegetable oil. Excipients that promote absorption from the digestive tract, such as penetration enhancers such as sodium caprylate, can be included. In certain situations, a delayed-release formulation may be advantageous, and a composition capable of delivering the compounds of the present disclosure in a delayed-release or sustained-release manner can also be prepared. Since there is a problem of degradation by enzymes present in the stomach when staying in the stomach for a long time, enteric-coated capsules that release the active substance in the lower part of the digestive tract can also be prepared by standard techniques in the art. Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in close contact with the epidermis of the subject over a long period of time. For example, as described in Pharmaceutical Research, 3(6):318(1986), the active ingredient can be delivered from the patch by iontophoresis. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. In the case of preparing a turbid solution, an oil, such as vegetable oil, can be used to provide an oil-in-water or water-in-oil suspension. Excipients that promote absorption from the digestive tract, such as penetration enhancers such as sodium caprylate, can be included. In certain situations, a delayed-release formulation may be advantageous, and a composition capable of delivering the compounds of the present disclosure in a delayed-release or sustained-release manner can also be prepared. Since there is a problem of degradation by enzymes present in the stomach when staying in the stomach for a long time, enteric-coated capsules that release the active substance in the lower part of the digestive tract can also be prepared by standard techniques in the art. In the case of preparing a turbid solution, an oil, such as vegetable oil, can be used to provide an oil-in-water or water-in-oil suspension. Excipients that promote absorption from the digestive tract, such as penetration enhancers such as sodium caprylate, can be included. In certain situations, a delayed-release formulation may be advantageous, and a composition capable of delivering the compounds of the present disclosure in a delayed-release or sustained-release manner can also be prepared. Since there is a problem of degradation by enzymes present in the stomach when staying in the stomach for a long time, enteric-coated capsules that release the active substance in the lower part of the digestive tract can also be prepared by standard techniques in the art. In the case of preparing a turbid solution, an oil, such as vegetable oil, can be used to provide an oil-in-water or water-in-oil suspension. Excipients that promote absorption from the digestive tract, such as penetration enhancers such as sodium caprylate, can be included. In certain situations, a delayed-release formulation may be advantageous, and a composition capable of delivering the compounds of the present disclosure in a delayed-release or sustained-release manner can also be prepared. Since there is a problem of degradation by enzymes present in the stomach when staying in the stomach for a long time, enteric-coated capsules that release the active substance in the lower part of the digestive tract can also be prepared by standard techniques in the art. In the case of preparing a turbid solution, an oil, such as vegetable oil, can be used to provide an oil-in-water or water-in-oil suspension. Excipients that promote absorption from the digestive tract, such as penetration enhancers such as sodium caprylate, can be included. In certain situations, a delayed-release formulation may be advantageous, and a composition capable of delivering the compounds of the present disclosure in a delayed-release or sustained-release manner can also be prepared. Since there is a problem of degradation by enzymes present in the stomach when staying in the stomach for a long time, enteric-coated capsules that release the active substance in the lower part of the digestive tract can also be prepared by standard techniques in the art.

[0083] Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in close contact with the epidermis of the subject over a long period of time. For example, as described in Pharmaceutical Research, 3(6):318(1986), the active ingredient can be delivered from the patch by iontophoresis. Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in close contact with the epidermis of the subject over a long period of time. For example, as described in Pharmaceutical Research, 3(6):318(1986), the active ingredient can be delivered from the patch by iontophoresis. Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in close contact with the epidermis of the subject over a long period of time. For example, as described in Pharmaceutical Research, 3(6):318(1986), the active ingredient can be delivered from the patch by iontophoresis. Pharmaceutical compositions suitable for transdermal administration can be provided as individual patches intended to remain in close contact with the epidermis of the subject over a long period of time. For example, as described in Pharmaceutical Research, 3(6):318(1986), the active ingredient can be delivered from the patch by iontophoresis.

[0084] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes. Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. When formulated as an ointment, the active ingredient can be used with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions suitable for topical administration to the eye include eye drops in which the active ingredient is preferably dissolved or suspended in a suitable carrier, particularly an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges, troches, and mouthwashes.

[0085] A pharmaceutical composition suitable for rectal administration can be provided as a suppository or an enema.

[0086] Examples of pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size of, for example, 20 to 500 microns, which are administered by the method of taking a snuff, i.e., rapidly inhaling through the nasal cavity from a container of the powder held in the vicinity of the nose. Examples of suitable compositions for administration as a nasal spray or nasal drops in which the carrier is liquid include aqueous or oily solutions of the active ingredient. Examples of pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size of, for example, 20 to 500 microns, which are administered by the method of taking a snuff, i.e., rapidly inhaling through the nasal cavity from a container of the powder held in the vicinity of the nose. Examples of suitable compositions for administration as a nasal spray or nasal drops in which the carrier is liquid include aqueous or oily solutions of the active ingredient. Examples of pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size of, for example, 20 to 500 microns, which are administered by the method of taking a snuff, i.e., rapidly inhaling through the nasal cavity from a container of the powder held in the vicinity of the nose. Examples of suitable compositions for administration as a nasal spray or nasal drops in which the carrier is liquid include aqueous or oily solutions of the active ingredient. Examples of pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size of, for example, 20 to 500 microns, which are administered by the method of taking a snuff, i.e., rapidly inhaling through the nasal cavity from a container of the powder held in the vicinity of the nose. Examples of suitable compositions for administration as a nasal spray or nasal drops in which the carrier is liquid include aqueous or oily solutions of the active ingredient. Examples of pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size of, for example, 20 to 500 microns, which are administered by the method of taking a snuff, i.e., rapidly inhaling through the nasal cavity from a container of the powder held in the vicinity of the nose. Examples of suitable compositions for administration as a nasal spray or nasal drops in which the carrier is liquid include aqueous or oily solutions of the active ingredient.

[0087] Examples of pharmaceutical compositions suitable for inhalation administration include various metered-dose pressurized aerosols, fine particle dusts or mists that can be generated by a nebulizer or inhaler. Examples of pharmaceutical compositions suitable for inhalation administration include various metered-dose pressurized aerosols, fine particle dusts or mists that can be generated by a nebulizer or inhaler.

[0088] A pharmaceutical composition suitable for vaginal administration can be provided as a pessary, tampon, cream, gel, paste, foam, or spray formulation. A pharmaceutical composition suitable for vaginal administration can be provided as a pessary, tampon, cream, gel, paste, foam, or spray formulation.

[0089] Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes (which render the formulation substantially isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. Excipients that can be used in injection solutions include, for example, water for injection, alcohol, polyols, glycerin, and vegetable oils. The composition can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. (lyophilized) state that requires only the addition of a sterile liquid carrier (for example, water for injection or physiological saline) immediately before use. Solutions and suspensions for immediate injection are sterile powders. , can be prepared from granules and tablets. The pharmaceutical composition may contain a preservative, a solubilizer, a stabilizer, a wetting agent, an emulsifier, a sweetener, a coloring agent, a flavoring agent, a salt (the substance of the present disclosure itself may be provided in the form of a pharmaceutically acceptable salt), a buffering agent, a coating agent, or an antioxidant. It may also contain a therapeutic active agent in addition to the compounds of the present disclosure.

[0090] Method of using the disclosed compounds This application provides a method for IL-1-mediated cell signaling, which includes contacting cells with the compounds of the present disclosure or pharmaceutically acceptable salts thereof. Inhibition of IL-1-mediated cell signaling can be evaluated by detecting a decrease in the levels of downstream biomarkers IL-6 and CRP (e.g., hsCRP).

[0091] This application also provides a method of using the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or a pharmaceutical composition containing such compounds to treat symptoms (but not limited to) of diseases such as those involving IL-1β.

[0092] In some embodiments, the present disclosure provides a method for treating cardiovascular diseases, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the aforementioned pharmaceutical compositions containing the compounds of the present disclosure (or pharmaceutically acceptable salts thereof) or such compounds. In some embodiments, the cardiovascular disease is vascular inflammation. In some embodiments, the cardiovascular disease is atherosclerosis. In some embodiments the cardiovascular disease is heart failure with preserved ejection fraction (HFpEF). In other embodiments, the cardiovascular disease is heart failure with reduced ejection fraction (HFrEF).

[0093] In some embodiments, the present disclosure is a method for treating chronic kidney disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the aforementioned pharmaceutical compositions comprising such a compound. A method is provided.

[0094] In some embodiments, the present disclosure is a method for treating an inflammatory disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt thereof) or any of the aforementioned pharmaceutical compositions comprising such a compound. A method is provided. In certain embodiments, the inflammatory disorder is selected from the group consisting of hidradenitis suppurativa (acne inversa), inflammatory bowel disease, arthritis, and non-alcoholic steatohepatitis (NASH).

[0095] In some embodiments, the inflammatory disorder is hidradenitis suppurativa (opposite type acne).

[0096] In certain embodiments, the inflammatory disorder is inflammatory colitis, such as Crohn's disease and ulcerative colitis.

[0097] In some embodiments, the inflammatory disorder is arthritis, such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, or gouty arthritis.

[0098] In other embodiments, the inflammatory disorder is non-alcoholic steatohepatitis (NASH).

[0099] Combination Therapy One or more additional pharmacologically active agents may be administered in combination with a compound of the present disclosure. Further active agent(s) may be a prodrug that is converted to a pharmaceutically active form after administration, such as a​​​​ means a pharmaceutically active agent (or agents) that is active in the body and is different from the disclosed compounds and also includes the free acids, free bases and pharmaceutically acceptable salts of said further active agents. Generally, anti- hypertensive agents, anti-atherosclerotic agents such as lipid-modifying compounds, anti-diabetic drugs and / or anti-obesity drugs, anti-inflammatory drugs, etc. (but not limited to these) any suitable further active agent (or agents) can be used in any combination with the compounds of the present disclosure in a single formulation (fixed-dose drug combination), or administered to a subject in one or more separate formulations that allow for simultaneous or sequential administration of the active agents (simultaneous administration of separate drugs).

[0100] Examples of further active agents that can be used in the treatment of cardiovascular disorders include angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, cilapril, temocapril, ortrandopril), angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR® (registered trademark), valsartan (including combinations with sacubitril), candesartan, olmesartan, telmisartan, and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR® (registered trademark)); sGC activators (e.g., riociguat and vericiguat), PC SK9 inhibitors (e.g., evolocumab, alirocumab, MK-0616 and those disclosed in WO2019 / 246349), neutral endopeptidase inhibitors (e.g., thiorphan and phosphonamidon), aldosterone antagonists, aldosterone synthase inhibitors, le nin inhibitors, endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprikalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympathetic nerve blockers, β-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), α-adrenergic blockers (e.g., doxazosin, prazosin or methyldopa), central α-adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, e.g., lactone prodrugs in the form of and functioning as inhibitors after administration, HMG-CoA reductase inhibitors such as simvastatin and lovastatin marketed as ZOCOR® and MEVACOR®, and atorvastatin (particularly the calcium salt sold as LIPITOR®), rosuvastatin (particularly the calcium salt sold as CRESTOR®), pravastatin (particularly the sodium salt sold as PRAVACHOL®), fluvastatin (particularly the sodium salt sold as LESCOL®), crivastatin and dihydroxy open-ring acid HMG-CoA reductase inhibitors such as pitavastatin pharmaceutically Permissible salts; cholesterol absorption inhibitors such as ezetimibe (ZETIA®) agents, and any other lipid-lowering agent such as the above-mentioned HMG-CoA reductase inhibitors , particularly ezetimibe in combination with simvastatin (VYTORIN®) or atorvastatin calcium ; niacin in immediate release or sustained release form, and / or niacin in combination with an HMG-C oA reductase inhibitor; niacin receptor agonists such as acipimox and acifran , and niacin receptor partial agonists; insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), di peptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogli ptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers , for example (i) PPARy agonists, such as glitazones (e.g., pioglitazone, mito glitazone, lobeglitazone, rosiglitazone and balaglitazone), and other PPAR ligands, such as (1) PPARα / γ dual agonists (e.g., tiglitazone, muraglitaz ar, aleglitazar, sodagliptazar and navaglitazar); (2) PPARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPAR γ modulators (SPPARγMs), (e.g., those disclosed in WO02 / 060388, WO02 / 0 8188, WO2004 / 019869, WO2004 / 020409, WO2004 / 020408, and WO2004 / 066963, etc.); and (4) PPA Rγ partial agonist; (ii) biguanides such as metformin and pharmaceutically acceptable salts thereof, particularly metformin hydrochloride, and sustained-release preparations thereof such as Glumetza (trademark), Fortamet (trademark), and Glucophage XR (trademark); and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro, and inhalation preparations thereof); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glibide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide, and repaglinide); α-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol); glucagon receptor antagonists; incretin mimetics such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide including nasal administration preparations, transdermal preparations, and once-weekly preparations); bile acid metal ion sequestrants (e.g., cholestyramine, cholestimid, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran), acyl CoA:cholesterol acyltransferase inhibitors (e.g., avasimibe); anti-obesity compounds; aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and use in inflammatory conditions such as selective cyclooxygenase-2 or COX-2 inhibitors ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. ; and (iv) other agents useful for treating diabetes, obesity, and related metabolic disorders. Intended agent; glucokinase activator (GKA); 11β-hydroxysteroid de hydrogenase type 1 inhibitor (e.g., those disclosed in U.S. Patent No. 6,730,690 ); fructose 1,6-bisphosphatase inhibitor (e.g., U.S. Patent Nos. 6,054,58 7; 6,110,903; 6,284,748; 6,399,782; and those disclosed in 6,489,476, etc.); acetyl-CoA carboxylase-1 or 2 inhibitor (ACC1 or ACC2); AMP-activated protein kinase (AMPK) act ivator; other G protein-coupled receptor agonists: (i) GPR-109, (ii) GPR- 119, and (iii) GPR-40; SSTR3 antagonist (e.g., those disclosed in WO2009 / 0018 36, etc.); neuromedin U receptor agonist (e.g., those disclosed in WO2009 / 0420 53, etc., such as neuromedin S (MS), etc. (not limited thereto)); SCD regulator; GPR-105 antagonist (e.g., those disclosed in WO2009 / 000087 ); SGLT inhibitor (e.g., empagliflozin, dapagliflozin, cana gliflozin, ertugliflozin, remogliflozin, tofogliflozin, and ipra gliflozin); acyl-CoA:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2) inhibitor; fatty acid synthase inhibitor; acyl-CoA :monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGA T-2) inhibitor; TGR5 receptor (also referred to as GPBAR1, BG37, GPCR19, GPR13 1 and M-BAR) agonist; ileal bile acid transporter inhibitor; PACA ; and P, PACAP mimetics, and PACAP receptor 3 agonists; PPAR agonists; proteins Tyrosine phosphatase-1B (PTP-1B) inhibitors; IL-1β antibodies (e.g., gevokizumab mab and canakinumab); and bromocriptine mesylate and its immediate-release formulations, including metabolic modifiers, or, where chemically possible, the free acids, free bases, and pharmaceutically acceptable salt forms of the foregoing active agents, in combination with other drugs useful for the treatment of the foregoing symptoms or disorders and the like, but not limited thereto.

[0101] Examples of additional active agents that can be used in the treatment of inflammatory disorders include steroid and non-steroid anti-inflammatory agents, glucocorticoids, and therapeutic hormones, but not limited thereto In certain embodiments, in the treatment of hidradenitis suppurativa (opposite acne), the additional active agent can be an antibiotic, an injectable steroid, a therapeutic hormone, a TNF inhibitor (e.g., infliximab , adalimumab, etanercept, golimumab, certolizumab), an analgesic (e.g.: codeine, hydrocodone, morphine, pregabalin, gabapentin, intralesional triamcinolone , corticosteroid, naproxen, ketoprofen, diclofenac, ibuprofen , acetaminophen). In other embodiments, in the treatment of inflammatory bowel disease, the additional active agent can be methotrexate, a TNF inhibitor, an oral sphingosine 1-phosphate receptor modulator (e.g., fingolimod, siponimod, ozanimod, ponesimod ), or a selective JAK inhibitor (e.g., tofacitinib, baricitinib, upadacitinib ). In some embodiments, in the treatment of osteoarthritis, the additional active agent The agent can be an analgesic (the above example). In other embodiments, in the treatment of gouty arthritis, the additional active agent can be colchicine, a non-steroidal anti-inflammatory agent, or a glucocorticoid. The additional active agent can be colchicine, a non-steroidal anti-inflammatory agent, or a glucocorticoid. can be a glucocorticoid.

[0102] Method for producing the disclosed compounds The compounds described herein can be produced using appropriate materials according to the procedures of the following schemes and examples, and are further illustrated by the following specific examples. The examples also include methods for testing such compounds in cell assays. However, the compounds shown in the examples should not be construed as forming the only genus considered to be disclosed. The examples further illustrate details regarding the production of the compounds of the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. The examples further illustrate details regarding the production of the compounds of the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. The examples further illustrate details regarding the production of the compounds of the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure.

[0103] The examples further illustrate details regarding the production of the compounds of the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. Those skilled in the art will readily understand that these compounds can be produced using the conditions of the following production procedures and known variations of the processes. For example, in some cases, the order of performing the steps of the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure. The starting materials and intermediates of the final compounds can be purchased, produced by known procedures, or are as described in other forms. The examples are provided for the purpose of further illustration only and are not intended to be limiting to the present disclosure.

[0104] The NMR data was obtained on a 300 MHz or 400 MHz instrument in CDCl 3 , DMSO-d 6 or is methanol-d 4 and the chemical shifts are reported as relative values to the tetramethylsilane standard. The resonance signals are reported using the following abbreviations: s = singlet, d = doublet and the resonance signals are reported using the following abbreviations: s = singlet, d = doublet , t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlapping of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[0105] Throughout the synthetic schemes and examples, unless otherwise indicated, abbreviations and acronyms can be used with the following meanings.

[0106] Abbreviation

Table 1

[0107] Intermediate synthesis: Synthetic Scheme 1

Chem.

[0108] Step 2: To the resulting solution, Na in THF (150 mL) at 0 °C 2 CO 3 (21.5 5 g, 2.0 equivalents) and Fmoc-OSu (37.68 g, 1.1 equivalents) were added. The solution was stirred at 25 °C for 2 hours. The progress of the reaction was monitored by HPLC-MS. The solution was adjusted to pH 3 with hydrogen chloride (6 M). The solution was extracted with EtOAc (3 times with 500 mL). The organic layers were combined and washed with H O (2 times with 1 liter) and NaCl (1 time with 1 liter 2 ) and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was slurried with D CM (15 volumes) and the solid was recovered by filtration. HPLC-MS: (E SI, m / z): 428 [M + H] + . 1 H NMR: (400 MHz, DMSO-d6, ppm): δ 13.08 (s , 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.87 (dt, J = 7.7, 1.0 Hz, 2H), 7.81 - 7.71 (m, 2H), 7.71 - 7.65 (m, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7 .41 (dtd, J = 6.0, 4.4, 4.3, 3.2 Hz, 2H), 7.40 - 7.33 (m, 1H), 7.36 - 7.24 (m, 1 ​H), 7.29 - 7.20 (m, 1H), 7.16 - 7.08 (m, 1H), 4.83 - 4.65 (m, 2H), 4.61 - 4.51 ( m, 1H), 4.22 - 4.06 (m, 3H).

[0109] Synthesis Scheme 2 [Chemical Formula] TIFF2025084920000023.tif29133 (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(indolin-1-yl)propanoic acid Step 1: In a 10 - liter three - necked round - bottom flask, at 25°C, indoline (125 g, 1.05 mol, 1.00 equivalent), DMSO (625 mL), pH 8 0.2 M potassium phosphate buffer (5625 mL), and PLP (778.32 mg, 2.94 mmol), L - serine (115.75 g, 1.10 mol, 1.05 equivalents), and PfTrpB - 4D11 (12 .50 g) were added. The resulting solution was stirred at 65°C for 4 hours under nitrogen. The progress of the reaction was monitored by H PLC - MS.

[0110] Step 2: To the above - mentioned solution, at 0°C, Na 2 CO 3 (129 g, 2.00 equivalents), Fmoc - OS u(306 g, 1.50 equivalents), and THF (2.5 liters) were added. The reaction mixture was stirred at 25°C for 3 hours under nitrogen. The solution was acidified to pH 3 with 6 M HCl. The mother liquor was recovered by filtration and extracted with EtOAc (3 times with 1 liter each). The organic layers were combined, washed with H O (2 times with 800 mL each) and NaCl (1 time with 800 mL), dehydrated with Na SO 2 O, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1). 2 SO 4 and dehydrated, and concentrated under reduced pressure. The residue was eluted with PE / EtOAc (3:1) on silica gel Purification by gel chromatography gave the crude product. Next, the crude product was subjected to preparative H PLC reverse phase (C18) elution with acetonitrile / water + 0.05% TFA (gradient from 50% to 70% in 30 minutes). The mixture was concentrated at 20 °C under reduced pressure to remove MeCN, extracted with EtOAc (3 times with 1 liter each), dehydrated with Na SO 2 and concentrated under reduced pressure. 4 The pure product was slurried in hexane (1 liter) for 30 minutes. The solid was collected by filtration to give (2S)-3-(2,3-dihydroindol-1-yl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoic acid. HPLC-MS: (ESI, m / z): 429 [M+H] + . 1 H NMR : (400 MHz, DMSO-d6, ppm) δ 7.89 (d, J = 7.5 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 - 7.25 (m, 2H), 7.00 (ddd, J = 17.4, 7.5, 1.3 Hz, 2H) , 6.61 - 6.48 (m, 2H), 4.35 - 4.18 (m, 4H), 3.47 - 3.28 (m, 4H), 2.87 (t, J = 8. 2 Hz, 2H).

[0111] Synthesis Scheme 3

Chemical Structure

[0112] Step 2: The mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.696 g, 3.17 mmol) and 1,10-phenanthroline (0.571 g, 3.17 mm ol) in DMA (2 mL) was heated at 50 °C for 0.5 hour. 1-(4-(5-b romopyridin-2-yl)piperazin-1-yl)ethan-1-one (4.5 g, 15. 84 mmol), tert-butyl (R)-2-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)-3-bromopropanoate (7.78 g, 17.42 mmol) and tetrabutylammonium iodide (5.85 g, 15.84 mmol) in DMA (2 mL) were added at 25 °C. Then, zinc powder (2.071 g, 31.7 ​​(mmol) was added. The resulting mixture was stirred at 50 °C for 1 hour. The resulting mixture was poured into water ( 300 mL), and extracted with EtOAc (3 times with 300 mL). The organic layer was washed with water (10 0 mL) and brine (2 times with 80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM-MeOH (10:1) to give tert-butyl (S)-2-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-acetyl piperazin-1-yl)pyridin-3-yl)propanoate. MS ESI: C H 33 H 39 N 4 O 5 [M+H] + Calculated value: 571.28, Found: 571.40.

[0113] Step 3: To a solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy carbonyl)amino)-3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)propanoate (7.3 g, 12.79 mmol) in DCM (70 mL) under argon at room temperature was added TFA (70 mL, 909 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in THF (20 mL), and the resulting mixture was purified by reverse phase Combi-Flash under the following conditions: column C18 silica gel column (3 30 g), 20 - 35 μm; mobile phase A: 5 mM aqueous TFA solution; mobile phase B: MeCN; ( gradient: hold at 0% B for 10 minutes, to 42.3% B in 35 minutes, hold at 42.3% B for 3.2 minutes; to 95% B in 2 minutes, hold at 95% B for 10 minutes); flow rate: 60 mL / min; detector: UV254&2 54 nm; fraction collector: automated; injection volume: 2 mL) to give (S)-2- 10 nm; purified by RT: 35.32 minutes. The product-containing fraction was collected and concentrated under reduced pressure to obtain (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)propanoic acid. MS ESI: C H N O 29 H 31 N 4 O 5 [M+H] + Calculated value: 515.22 , Measured value: 515.15. 1 H NMR (300 MHz, methanol-d4) δ 7.87 - 7.79 (m, 4H), 7.62 - 7.55 (m, 2H), 7.42 - 7.27 (m, 4H), 7.11 - 7.09 (m, 1H), 4.51 - 4.46 (m, 1 H), 4.32 - 4.09 (m, 3H), 3.65 - 3.54 (m, 8H), 3.29 - 3.20 (m, 1H), 2.94 - 2.89 ( m, 1H), 2.12 (s, 3H).

[0114] Synthesis Scheme 4

Chemical Structure

[0115] Step 2: Nickel(II) chloride ethylene glycol dimethyl ether complex (1.187 g, 5.40 mmol) and 1,10-phenanthroline (0.974 g, 5.40 mmol) A mixture of N-(2-((5 ol) in DMA (70 mL) was heated at 50° C. for 0.5 h. -Bromopyridin-2-yl)oxy)ethyl)acetamide (7 g, 27.0 mmol ), tert-butyl(R)-2-((((9H-fluoren-9-yl)methoxy)carbamate (13.26 g, 29.7 mmol) and and tetrabutylammonium iodide (9.98 g, 27.0 mmol) were subjected to DMA (70 m The mixture was added with 1.5 mL of zinc powder (3.53 g, 54.0 mmol) at 25° C. The resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was diluted with 300 mL of EtOAc. Dilute with saturated NaHCO 3 Wash with aqueous solution (80 mL x 3) and brine (80 mL). , Na 2 SO 4 The mixture was dried at 40° C. and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with 10% Purified by silica gel column chromatography eluting with 20% DCM / MeOH The fractions containing the desired product were combined and concentrated under reduced pressure to give tert-butyl (S)- 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6 -(2-acetamidoethoxy)pyridin-3-yl)propanoate. MS E SI: C 31 H 36 N 3 O 6 [M+H] + Calculated: 546.25, Found: 546.4 0.

[0116] Step 3: To a mixture of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy carbonyl)amino)-3-(6-(2-acetamidoethoxy)pyridin-3-yl)propanoate (8 g, 14.66 mmol) in DCM (80 mL) was added TFA (80 mL, 1038 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by RP flash column chromatography under the following conditions: column: C18 silica gel column ( 330 g), 20 - 35 μm; mobile phase A: 5 mM NH CO 4 aqueous solution; mobile phase B: Me 3 CN; (gradient: hold at 0% B for 5 minutes, 45% B in 20 minutes, hold at 45% B for 10 minutes; 95% B in 15 minutes and hold at 95% B for 10 minutes); flow rate: 60 mL / min; detector: UV254 & 21 0 nm; RT: 35.32 minutes. The product-containing fractions were collected and concentrated under reduced pressure to give (S)-2-((((9H-fluoro ren-9-yl)methoxy)carbonyl)amino)-3-(6-(2-acetamidoethoxy)pyridin-3-yl)propanoic acid. MS ESI: C The fractions containing the product were collected and concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(2-acetamidoethoxy)pyridin-3-yl)propanoic acid. MS ESI: C -(2-acetamidoethoxy)pyridin-3-yl)propanoic acid was obtained. MS ESI: C -(2-acetamidoethoxy)pyridin-3-yl)propanoic acid was obtained. MS ESI: C27 H 28 N 3 O 6 M+H] + Calculated value: 490.19, measured value: 490.10. 1 H NMR (400 MHz, methanol -d4) δ 8.02 - 8.00 (m, 1H), 7.79 - 7.77 (m, 2H), 7.67 - 7.64 (m, 1H), 7.61 - 7.57 (m, 2H), 7.40 - 7.36 (m, 2H), 7.31 - 7.27 (m, 2H), 6.82 - 6.80 (m, 1H), 4 .42 - 4.39 (m, 1H), 4.33 - 4.22 (m, 4H), 4.16 - 4.13 (m, 1H), 3.53 - 3.51 (m, 2H ), 3.20 - 3.15 (m, 1H), 2.93 - 2.87 (m, 1H), 1.92 (s, 3H).

[0117] Synthesis Scheme 5

Chemical Structure

[0118] Step 2: To a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridin-3-yl)propanoate (5 g, 10.48 mmol) in DCM (5 mL) was added TFA (10 mL ) at room temperature. The solution was stirred at 25 °C for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by RP-flash under the following conditions: column: flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; (gradient: 5% B held for 5 minutes, increased to 30% B in 15 minutes, held at 30% B for 5 minutes; increased to 95% B in 2 0 minutes, held at 95% B for 10 minutes); flow rate: 90 mL / min; detector: UV210 nm; RT = 40 minutes. The product-containing fractions were collected, and and The solvent was distilled off under reduced pressure to obtain (S)-2-((((9H-fluoren-9-yl)methoxy) carbonyl)amino)-3-(6-chloropyridin-3-yl)propanoic acid. MS ESI:C 23 H 20 ClN 2 O 4 [M+H] + Calculated value: 423.10, measured value: 4 23.10.

[0119] Step 3: To a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) amino)-3-(6-chloropyridin-3-yl)propanoic acid (3 g, 7.09 mmol ) in THF (25 mL) and water (5 mL) was added (4-(t ert-butoxycarbonyl)phenyl)boronic acid (1.890 g, 8.51 mmol) and K 3 PO 4 (7.53 g, 35.5 mmol) at 25 °C under nitrogen. The resulting solution was stirred at 25 °C for 1 0 minutes. Pd(dtbpf)Cl 2 (0.694 g, 1.064 mmol) was dissolved in the solution, and the mixture was stirred at 60 °C for 16 hours. The reaction solution was cooled to room temperature, and the reaction was quenched with H 2 O (2 00 mL), and extracted with EtOAc (twice with 500 mL). The combined organic layers were washed with brine (thrice with 200 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified under the following conditions: column: flash C18 (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; (gradient: hold 5% B for 5 minutes, increase to 6 0% B in 15 minutes, hold 60% B for 15 minutes; increase to 95% B in 10 minutes, hold 95% B for 10 minutes); flow rate : 90 mL / min; Detector: UV 210 nm; Purified by RP-flash at RT = 55 min The product-containing fraction was collected, and the solvent was distilled off under reduced pressure to obtain (S)-2-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(tert -butoxycarbonyl)phenyl)pyridin-3-yl)propanoic acid. MS E SI: C 34 H 33 N 2 O 6 [M + H] + Calculated value: 565.23, Measured value: 565.1 5; 1 H NMR (400 MHz, methanol-d4) δ 8.66 (d, J = 1.9 Hz, 1H), 8.12 - 8.07 (m, 3H), 7.99 - 7.92 (m, 3H), 7.77 (d, J = 7.5 Hz, 2H), 7.59 - 7.56 (m, 2H), 7.37 - 7.33 (m, 2H), 7.30 - 7.22 (m, 2H), 4.60 - 4.56 (m, 1H), 4.29 - 4.27 (m, 2H), 4. 14 - 4.10 (m, 1H), 3.45 - 3.41 (m, 1H), 3.14 - 3.10 (m, 1H), 1.62 (s, 9H).

[0120] Synthesis Scheme 6

Chemical Structure

[0121] Step 2: Under a nitrogen atmosphere, in a 500 mL two-necked flask, I 2 (22.17 g, 87 mmo 2 l) was added to a solution of PPh (17.19 g, 65.5 mmol) and 1H-imidazole (4.4 3 6 g, 65.5 mmol) in dry CH Cl 2 (100 mL) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 15 min. A solution of benzyl ((benzyloxy)carbonyl)-L-homoserinate (15 g, 43.7 mmol) in CH 2 Cl (100 mL) was added over 10 min, and the mixture was stirred at room temperature for 2 h. The mixture was washed with saturated Na S 2 O 2 solution (3 times with 200 mL) and then with brine (3 times with 50 mL). The organic layer was dried over Na SO 2 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 40% Et 2 O 3 and concentrated under reduced pressure. The residue was washed with saturated Na S 2 O 4 solution (3 times with 200 mL) and then with brine (3 times with 50 mL). The organic layer was dried over Na Purified by silica gel chromatography eluting with OAc / PE to give benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-iodobutanoate MS ESI: C 19 H 21 INO 4 [M+H] + Calculated value: 454.04, measured value : 454.05. 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 - 7.31 (m, 10H), 5.37 - 5.35 (m, 1H), 5.19 - 5.15 (m, 2H), 5.11 (s, 2H), 4.48 - 4.41 (m, 1H), 3.15 - 3.10 (m, 2H ), 2.46 - 2.44 (m, 1H), 2.25 - 2.20 (m, 1H).

[0122] Step 3: To a stirred mixture of benzyl (S)-2-(((benzyloxy carbonyl)amino)-4-iodobutanoate (13.6 g, 30.0 mmol) in THF (140 mL) was added morpholine (20.91 g, 240 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0% to 80% EtOAc / PE to recover the product containing fractions, which were concentrated under reduced pressure to give 23 benzyl (S)-2-(((benzyloxy 29 carbonyl)amino)-4-morpholinobutanoate. MS ESI: C 23 H 29 N 2 O 5 [M+H] + Calculated value: 413.21, measured value: 413.35. 1 H NMR (40 0 MHz, CDCl 3 ) δ 7.36 - 7.34 (m, 10H), 6.67 (s, 1H), 5.24 - 5.02 (m, 4H), 4.52 - 4.47 (m, 1H), 3.67 - 3.52 (m, 4H), 2.38 - 2.51 (m, 6H), 2.15 - 1.81 (m, 2H).

[0123] Step 4: Benzyl (S)-2-(((benzyloxy)carbonyl)amino)-4-morpholinobutanoate (6.5 g, 15.76 mmol) was dissolved in EtOH (65 mL), and the resulting mixture was evacuated and placed under a nitrogen atmosphere at ambient temperature. Next, Pd-C (2.6 g, dry, 20 wt%) was added under a nitrogen atmosphere. The suspension was degassed under reduced pressure and purged several times with H and the reaction solution was stirred at 25 °C for 5 h under 1 atm H . The suspension was filtered and the filtrate was concentrated under reduced pressure to obtain crude (S)-2-amino-4-morpholinobutanoic acid. MS ESI : C 2 H N 2 O [M+H] calculated value: 189.12, measured value: 189.25. 8 H 17 N 2 O 3 [M+H] + of: 189.12, found: 189.25.

[0124] Step 5: To a solution of (S)-2-amino-4-morpholinobutanoic acid (2.97 g, 15.76 mmol) in THF (25 mL) and water (25 mL) was added NaHCO (6.6 3 3 g, 79 mmol) and Fmoc-OSu (4.85 g, 14.20 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. When complete, the pH of the solution was adjusted to 3 with 1 M HCl . The mixture was then under the following conditions: C18 column (120 g); mobile phase A: water (0. (1 M HCl ); mobile phase B: acetonitrile; gradient: 0 - 100% B in 30 min; flow rate: 10 mL / min; detection wavelength: 254 nm. The product was eluted and collected, and then concentrated under reduced pressure to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-morpholinobutanoic acid. MS ESI 05% TFA), mobile phase B: MeCN; (gradient: hold 5% B for 5 min, reach 38% B in 30 min, hold 38% B for 2.6 min; reach 95% B in 2 min, hold 95% B for 5 min); flow rate: 60 mL / min; detector: UV 210 nm; purified by reverse-phase flash chromatography at RT = 31 min. The product-containing fraction was collected and concentrated under reduced pressure to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-morpholinobutanoic acid. MS ESI: C H N O [M-H] calculated value: 411.19, measured 23 H 27 N 2 O 5 [M-H] - value: 411.30. H NMR (300 MHz, methanol-d4) δ 7.81 - 7.79 (m, 2H), 7.68 - 1 7.65 (m, 2H), 7.42 - 7.37 (m, 2H), 7.33 - 7.29 (m, 2H), 4.48 - 4.45 (m, 2H), 4. 42 - 4.23 (m, 2H), 4.01 - 3.77 (m, 4H), 3.33 - 3.30 (m, 2H), 3.29 - 3.14 (m, 4H) , 2.45 - 2.05 (m, 2H). Synthetic Scheme 7

[0125]

Chemical Structure

Figure

[0126] Synthesis Scheme 8

Chemical formula

[0127] Step 2: PPh 3 (12.67 g, 48.3 mmol) and 1H-imidazole (4. 38 g, 64.4 mmol) in a stirred solution of DCM (200 mL) under a nitrogen atmosphere at room temperature, I 2 (12.26 g, 48.3 mmol) was added. The mixture was stirred at room temperature for 10 minutes . tert-Butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L -homoserinate (12.8 g, 32.2 mmol) was added to the mixture and stirred at 25 °C for 2 hours . The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0% to 18% EtOAc / PE to give tert-butyl (S)-2-(( ((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutano ate. MS ESI: C H 23 H 26 INO 4 Na [M+Na] + Calculated value: 53 0.09, found: 530.20. 1 1H NMR (300 MHz, CDCl 3 ) δ 7.83 - 7.71 (m, 2H), 7.65 - 7.56 (m, 2H), 7.47 - 7.36 (m, 2H), 7.36 - 7.28 (m, 2H), 5.35 (d, J = 8.3 Hz, 1H), 4.52 - 4.35 (m, 2H), 4.34 - 4.16 (m, 2H), 3.21 - 3.04 (m, 2H), 2.52 - 2 .32 (m, 1H), 2.28 - 2.07 (m, 1H), 1.48 (s, 9H).

[0128] Step 3: To a stirred solution of 1,10-phenanthroline (1.083 g, 6.01 mmol) in DMA ( 300 mL) was added NiCl 2 -glyme (1.3 21 g, 6.01 mmol) at room temperature under an argon atmosphere. The mixture was stirred at 50 °C for 1 hour and then cooled to room temperature. Next, tert-butyl (S)-2-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)-4-iodobutanoate (15.25 g, 30.1 m mol), 5-bromonicotinonitrile (5.5 g, 30.1 mmol), TBAI (1 5.25 g, 30.1 mmol) and zinc (3.93 g, 60.1 mmol) were added to the mixture at room temperature and stirred at 35 °C for 2.5 hours. The mixture was cooled to room temperature and diluted with water (500 mL ) and EtOAc (800 mL). The solid was filtered off and the organic layer was separated. The organic layer was washed with brine (3 times with 150 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with 0% to 40% EtOAc / PE to give tert-butyl (S)-2-((((9 H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-cyanopyridin -3-yl)butanoate. MS ESI:C 29 H 30 N 3 O 4 [M+H] + Calculated value: 484.22, measured value: 484.20. 1 H NMR (300 MHz, CDCl 3 ) δ 8.75 (s , 1H), 8.66 (s, 1H), 7.87 - 7.71 (m, 3H), 7.61 (d, J = 7.4 Hz, 2H), 7.47 - 7.28 (m, 4H), 5.40 (d, J = 7.8 Hz, 1H), 4.55 - 4.37 (m, 2H), 4.36 - 4.18 (m, 2H), 2.8 5 - 2.59 (m, 2H), 2.26 - 2.08 (m, 1H), 2.02 - 1.82 (m, 1H), 1.49 (s, 9H).

[0129] Step 4: To a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy carbonyl)amino)-4-(5-cyanopyridin-3-yl)butanoate (7. 5 g, 15.51 mmol) in DCM (50 mL) was added TFA (10 0 mL) at room temperature. The solution was stirred at 25 °C for 3 h and then concentrated under reduced pressure. The residue was purified by RP-flash on the following conditions: C18 column, 330 g, 5% - 5% for 10 min, 5% to 55% for 40 min, 55% - 55% for 10 min, with MeCN / H2O (0.05% TFA) to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino )-4-(5-cyanopyridin-3-yl)butanoic acid. MS ESI: C H )-4-(5-cyanopyridin-3-yl)butanoic acid. MS ESI: C 25 H 2 2 N 3 O 4 [M+H] + Calculated value: 428.15, measured value: 428.05. 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (br, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 7.92 - 7.90 (m, 2H), 7.76 - 7.73 (m, 3H), 7.44 - 7.33 (m, 4H), 4.39 - 4.20 (m, 3H), 3 .94 - 3.89 (m, 1H), 2.79 - 2.67 (m, 2H), 2.09 - 1.89 (m, 2H).

[0130] Synthesis Scheme 9 [Chemical Formula] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(4-(4-acetylpiperazin-1-yl)phenyl)propanoic acid Step 1: To a stirred solution of (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (6 g, 17.43 mmol) in toluene (180 mL) was added XPhos Pd G (2.057 g, 2.61 mmol ) at 25 °C under nitrogen. The resulting solution was stirred at 100 °C for 10 minutes. 1-(Piperazin-1-yl 2 )ethan-1-one (2.234 g, 17.43 mmol) and Cs CO (5.04 2 CO 3 (5.04 g, 26.1 mmol) were added and the resulting solution was stirred at 110 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with H O (500 mL), extracted with EtOAc (2 × 500 m 2 L). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous Na SO 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0% to 60% EtOAc / PE to give (S)-3-(4- (4-Acetylpiperazin-1-yl)phenyl)-2-((tert-butoxycarbonyl amino)propanoic acid was obtained. MS ESI: C 20 H 30 N 3 O 5 [M+H] + of Calculated value: 392.21, Measured value: 392.25. 1 H NMR (400 MHz, methanol-d4) δ 7 .12 (d, J = 8 Hz, 2H), 6.89 (d, J = 8 Hz, 2H), 4.16 - 4.13 (m, 1H), 3.72 - 3.65 (m, 4H), 3.14 - 3.04 (m, 4H), 2.93 - 2.81 (m, 2H), 2.13 (s, 3H), 1.38 - 1.29 (m, 9H).

[0131] Step 2: To a stirred solution of (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (10 g, 25.5 mmol) in DCM (30 mL) at room temperature was added TFA (30 mL). The solution was stirred at 25 °C for 1 h and concentrated under reduced pressure. The crude (S)-3-(4-(4-acetylpiperazin -1-yl)phenyl)-2-aminopropanoic acid was used directly in the next step without further purification. MS ESI: C 15 H 22 N 3 O 3 [M+H] + Calculated value: 292.16, Actual Measured value: 292.20.

[0132] Step 3: (S)-3-(4-(4-acetylpiperazin-1-yl)phenyl)-2- (carboxyamino)propanoic acid (7 g, 20.87 mmol) in THF (25 mL) and To the stirred solution in water (25 mL) under nitrogen at 25 °C was added Fmoc-OSu (6.34 g, 1 8.79 mmol), and then NaHCO 3 (8.77 g, 104 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The pH was adjusted to 5 with 1 N HCl, and the mixture was extracted with EtO Ac (2 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL ), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel (330 g); mobile phase A: water (0.1% TFA), mobile phase B: MeCN; (gradient: hold 5% B for 5 min, reach 55% B in 15 min, hold 55% B for 5 min ; reach 95% B in 20 min, hold 95% B for 5 min); flow rate: 90 mL / min; detector: UV 21 0 nm; RT = 45 min. The product-containing fractions were collected and concentrated under reduced pressure to give (S)-2-((((9H-fluoren-9-yl methoxy)carbonyl)amino)-3-(4-(4-acetylpiperazin-1-yl )phenyl)propanoic acid. MS ESI: C H N O 30 H 32 N 3 O 5 [M + H] + calculated value: 514.23, found: 514.30. H NMR (400 MHz, methanol-d4) δ 7.7 1 8 - 7.76 (m, 2H), 7.61 - 7.52 (m, 2H), 7.40 - 7.37 (m, 2H), 7.32 - 7.22 (m, 4H), 7.08 - 6.98 (m, 2H), 4.47 - 4.43 (m, 1H), 4.33 - 4.31 (m, 1H), 4.14 - 4.02 (m, 1H), 2H), 3.68 - 3.63 (m, 4H), 3.23 - 3.08 (m, 5H), 2.91 - 2.85 (m, 1H), 2.11 (s, 3H) .

[0133] Synthesis Scheme 10

Chem.

[0134] Step 2: To a mixture of tert-butyl 2-chloropyrimidine-5-carboxylate (4 g, 18 .64 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was added (S)-3-(4-boronophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (8.64 g, 28.0 mmol), PdCl under argon at room temperature (dppf 2 (dppf )(1.364 g, 1.864 mmol) and K 2 CO 3 (7.73 g, 55.9 mmol l) was added. The resulting mixture was stirred at 80 °C for 3 hours, then the pH was adjusted to 4 with 1N HCl and extracted with EtOAc (2 times with 300 mL). The combined organic layers were washed with brine (3 times with 50 mL), dried over anhydrous Na SO 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure . The residue was purified by silica gel chromatography eluting with 0% to 100% EtOAc / PE to give (S)-2-((tert-butoxycarbonyl)amino)-3 -(4-(5-(tert-butoxycarbonyl)pyrimidin-2-yl)phenyl)propanoic acid. MS ESI: C H N 23 H 30 N 3 O 6 [M+H] + calculated: 444. 21, found: 444.35. 1 H NMR (400 MHz, CDCl 3 ) δ 9.27 (s, 2H), 8.42 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 4.69 - 4.68 (m, 1H), 3.29 - 3.24 (m, 2H ), 1.63 (s, 9H), 1.44 (s, 9H).

[0135] Step 3: To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5 -(tert-butoxycarbonyl)pyrimidin-2-yl)phenyl)propanoic acid (7 g, 15.78 mmol) in DCM (70 mL) was added TFA (14 mL, 182 mmol) under argon at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated to give (S ) - 2 - Amino - 3 - (4 - (5 - (tert - butoxycarbonyl)pyrimidin - 2 - yl)phenyl)propanoic acid was obtained. MS ESI: C 18 H 22 N 3 O 4 [M + H] + Calculated value: 344.15, Measured value: 344.20.

[0136] Step 4: To a mixture of (S) - 2 - amino - 3 - (4 - (5 - (tert - butoxycarbonyl)p yrimidin - 2 - yl)phenyl)propanoic acid (4 g, 11.65 mmol) in THF (4 0 mL) and H 2 O (40 mL), under argon at room temperature, NaHCO 3 (4.8 9 g, 58.2 mmol) and Fmoc - OSu (3.54 g, 10.48 mmol) were added. After stirring at room temperature for 1 hour, the pH was adjusted to 4 with 1N HCl, and the solution was extracted with EtOAc (2 times with 300 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 4, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP - flash under the following conditions: column : C18 column (330 g); mobile phase A: water (0.05% TFA); mobile phase B: MeCN ; (gradient: hold at 0% B for 5 minutes, reach 73% B in 30 minutes, hold at 73% B for 10 minutes; reach 95% B in 4 minutes, hold at 95% B for 10 minutes); flow rate: 60 mL / min; detector: UV254 & 210 nm ; RT: 35.32 minutes to give (S) - 2 - ((((9 H - fluoren - 9 - yl)methoxy)carbonyl)amino) - 3 - (4 - (5 - (te rt - butoxycarbonyl)pyrimidin - 2 - yl)phenyl)propanoic acid. MS ESI: C 33 H32 N 3 O 6 [M+H] + Calculated value: 566.22, measured value: 566 .35。 1 H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 9.24 (s, 2H), 8.37 (d, J = 8 .0 Hz, 2H), 7.88 - 7.79 (m, 3H), 7.66 - 7.14 (m, 8H), 4.30 - 4.14 (m, 4H), 3.22 - 3.16 (m, 1H), 3.05 - 2.82 (m, 1H), 1.59 (s, 9H).

[0137] Synthesis Scheme 11

Chem.

[0138] Step 2: To a mixture of 1-(tert-butyl) 2-methyl (2S,4R)-4-((4-nitrophenyl)sulfonamido)pyrrolidine-1,2-dicarboxylate (17 g, 39.6 mmol) in DCM (60 mL) was added TFA (30 mL, 389 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to obtain methyl (2 S,4R)-4-((4-nitrophenyl)sulfonamido)pyrrolidine-2-carboxylate. MS ESI: C H 12 N 16 O 3 S[M + H] 6 N + O 3 S[M + H] 2 Calculated value: 330 .07, Measured value: 330.10.

[0139] Step 3: To a solution of methyl (2S,4R)-4-((4-nitrophenyl)sulfonamido)pyrrolidine-2-carboxylate (18.5 g, 39.3 mmol) in THF (150 mL ​​) and in a solution in water (150 mL), at ambient temperature, NaHCO 3 (16.52 g, 197 mmol ) and Alloc-OSu (5.46 mL, 35.4 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 h, then diluted with water (100 mL) and extracted with EtOAc (25 0 mL, 3 times). The combined organic layers were washed with brine (150 mL, 2 times), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc / PE from 0 % to 55% to give 1- allyl 2-methyl(2S,4R)-4-((4-nitrophenyl)sulfonamido)pyrro lidine-1,2-dicarboxylate. MS ESI: C 16 H 20 N 3 O 8 S M+H] + calculated: 414.09, found: 413.95. 1 H NMR (300 MHz, CDCl 3 ) δ 8.18 - 8.15 (m, 1H), 7.91 - 7.88 (m, 1H), 7.82 - 7.77 (m, 2H), 5.84 - 5.70 (m , 1H), 5.30 - 5.16 (m, 2H), 4.58 - 4.52 (m, 2H), 4.50 - 4.48 (m, 1H), 4.47 - 4.1 5 (m, 1H), 3.78 - 3.73 (m, 4H), 3.32 - 3.28 (m, 1H), 2.30 - 2.19 (m, 2H).

[0140] Step 4: 1-Allyl 2-methyl(2S,4R)-4-((4-nitrophenyl)sulfon amido)pyrrolidine-1,2-dicarboxylate (8.1 g, 19.59 mmol) To a solution of [compound] in DMF (100 mL) at ambient temperature was added (bromomethyl)benzene (4.02 g, 23.51 mmol) and K 2 CO 3 (8.12 g, 58.8 mmol). The reaction mixture was stirred at ambient temperature for 4 h, then quenched with water (100 mL) and extracted with EtOAc (3 times with 250 mL). The combined organic layers were washed with brine (4 times with 200 mL), dried over anhydrous Na SO 2 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc / 4 PE from 0% to 55% to give 1-allyl 2-methyl (2S,4R)-4-((N-benzyl-4-nitrophenyl )sulfonamido)pyrrolidine-1,2-dicarboxylate. MS ESI: C H N 23 H 26 N 3 O 8 S [M+H] + calculated: 504.14, found: 504.20. 1 H NMR (300 MHz, CDCl 3 ) δ 7.88 - 7.84 (m, 1H), 7.68 - 7.67 (m, 2H), 7.66 - 7.55 ( m, 1H), 7.29 - 7.23 (m, 5H), 5.85 - 5.75 (m, 1H), 5.25 - 5.18 (m, 2H), 4.19 - 4. 15 (m, 6H), 3.73 - 3.25 (m, 5H), 2.23 - 2.15 (m, 2H).

[0141] Step 5: 1-allyl 2-methyl (2S,4R)-4-((N-benzyl-4-nitrophenyl )sulfonamido)pyrrolidine-1,2-dicarboxylate (9.3 g, 18. To a solution of 4-methoxybenzenethiol (3.11 g, 22.16 mmol) and K 2 CO 3 (7.66 g, 55.4 mmol ) in DMF (40 mL) at ambient temperature was added . The reaction mixture was stirred at ambient temperature for 1 h, then diluted with water (100 mL) and extracted with EtO Ac (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL ), dried over anhydrous Na 2 SO 4 and filtered. The residue was purified by RP-flash under the following conditions: column: silica C18 (330 g); mobile phase A: water (0.05% TFA), mobile phase B: MeCN; ( gradient: hold at 5% B for 5 min, 32% B in 15 min, hold at 32% B for 6 min; 95% B in 5 min ), hold at 95% B for 5 min ); flow rate: 90 mL / min; detector: UV 210 nm; RT = 36 min . The product-containing fractions were collected and concentrated under reduced pressure to afford 1-allyl 2-methyl (2S,4R)-4-(benzylamino)pyrrolidine-1,2-dicar boxylate. MS ESI: calculated for C 17 H 23 N 2 O 4 [M+H] + 319.16, found 319.10. 1 H NMR (300 MHz, CDCl 3 ) δ 7.39 - 7.34 (m, 5H) , 5.90 - 5.85 (m, 1H), 5.32 - 5.17 (m, 2H), 4.60 - 4.36 (m, 3H), 3.96 - 3.57 (m, 8H), 2.07 - 1.99 (m, 2H).

[0142] Step 6: 1-allyl 2-methyl (2S,4R)-4-(benzylamino)pyrrolidine- 2 CO 3 2 SO 4 17 H 23 N 2 O 4 + + 1 3

[0142] In DCM (40 mL) of 1,2-dicarboxylate (4.5 g, 12.72 mmol) to the solution, Boc 2 O (4.16 g, 19.08 mmol) and TEA (5.3 2 mL, 38.2 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 h, then quenched with water (30 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na SO 2 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc / PE from 0% to 40% to give 1-allyl 2-methyl (2S,4R)-4 4 -(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-1,2-dicarboxylate. MS ESI: C H N O [M+H] 22 calculated: 419 31 .21, found: 419.15. 2 H NMR (300 MHz, CDCl 6 ) δ 7.34 - 7.15 (m, 5H), 5. + 90 - 5.85 (m, 1H), 5.25 - 5.18 (m, 2H), 4.58 - 4.32 (m, 6H), 3.74 - 3.44 (m, 5H) .21, found: 419.15. 1 H NMR (300 MHz, CDCl 3 ) δ 7.34 - 7.15 (m, 5H), 5. 90 - 5.85 (m, 1H), 5.25 - 5.18 (m, 2H), 4.58 - 4.32 (m, 6H), 3.74 - 3.44 (m, 5H) , 2.49 - 2.38 (m, 1H), 2.12 - 1.99 (m, 1H), 1.42 (s, 9H).

[0143] Step 7: 1-allyl 2-methyl (2S,4R)-4-(benzyl(tert-butoxy carbonyl)amino)pyrrolidine-1,2-dicarboxylate (3 g, 5.73 mmo To a mixture of 11.47 mL of LiOH (11.47 m The reaction was stirred at ambient temperature for 2 hours and then diluted with aqueous HCl. The mixture was acidified to pH 3-4 and extracted with EtOAc (150 mL x 3). Then, wash with brine (2 x 80 mL) and add anhydrous Na 2 SO 4 The filtrate was dried at 40°C and filtered. The mixture was concentrated under reduced pressure to give (2S,4R)-1-((allyloxy)carbonyl)-4-(aryloxy) To obtain 3-phenyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid, MS ESI:C 21 H 29 N 2 O 6 [M+H] + Calculated value: 405.19, Measured value: 4 05.30. 1 H NMR (300 MHz, CDCl 3 ) δ 7.35 - 7.14 (m, 5H), 5.89 - 5.75 (m, 1H), 5.14 - 5.19 (m, 2H), 4.61 - 4.30 (m, 6H), 3.82 - 3.32 (m, 2H), 2.47 - 2.18 (m, 2H), 1.42 (s, 9H).

[0144] Step 8: (2S,4R)-1-((allyloxy)carbonyl)-4-(benzyl(t (ert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (2.6 g, 5.4 To a mixture of 6 mmol) in DCM (150 mL) was added AcOH (0.751 mL) at ambient temperature. , 13.11 mmol) and Pd(Ph 3 P) 4 (0.126g, 0.109mmol) Then, add Bu 3 SnH (1.749 g, 6.01 mmol) was added. Reaction The liquid was stirred at ambient temperature for 4 h, then concentrated under reduced pressure to give (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C 17 H 25 N 2 O 4 [M+H] + Calculated value: 321.17, found: 3 21.15.

[0145] Step 9: To a mixture of (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (3.2 g, 4.99 mmol) in THF (50 mL) and water (50 mL) was added NaHCO (2.098 g, 24.97 mmol) to adjust the pH to 8 - 9, then Fmoc-OSu (1.516 g, 4.49 mmol) was added to the reaction solution. The resulting mixture was stirred at ambient temperature for 4 h, then acidified with aqueous HCl to 3 pH 3 - 4 and extracted with EtOAc (3 times with 200 mL). The combined organic layers were washed with brine (2 times with 100 mL), dried over anhydrous Na SO and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The residue was purified under the following conditions: column: flash C18 (330 2 g); mobile phase A: water (0.05% TFA), mobile phase B: MeCN; (gradient: hold 5% B for 5 4 min, increase to 70% B in 25 min, hold 70% B for 8 min; increase to 95% B in 2 min, hold 95% B for 5 min ); flow rate: 90 mL / min; detector: UV210 nm; RT = 45 min by RP-flash chromatography. The product-containing fractions were collected and concentrated under reduced pressure to give (2S,4R)-1- ((((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyl(ter (((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. t-Butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid was obtained. MS ESI: C 32 H 35 N 2 O 6 [M+H] + Calculated value: 543.24, actual value: 543.20. 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 2H), 7.88 (d, J = 7.6 Hz, 2H), 7.61 - 7.57 (m, 2H), 7.43 - 7.18 (m, 9H), 4.43 - 4.15 (m, 8H), 3.53 - 3.25 (m, 2H), 2.51 - 2 .50 (m, 1H), 2.03 - 1.92 (m, 1H), 1.37 (s, 2H).

[0146] Synthesis scheme 12 [ka] TIFF2025084920000035.tif41136 (2S,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)- 4-(phenethylamino)pyrrolidine-2-carboxylic acid Step 1: 1-Allyl 2-methyl(2S,4R)-4-((4-nitrophenyl)sulfonate amide)pyrrolidine-1,2-dicarboxylate (7.2 g, 17.42 mmol) , DIAD (5.08 mL, 26.1 mmol), and PPh 3 (6.85g, 26.1 A mixture of 10 mmol of 2-phenylethane-1-ol in THF (70 mL) was added at ambient temperature. The reaction was stirred at ambient temperature for 4 hours and then The reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 250 mL). Combine, wash with brine (4 x 200 mL), and add anhydrous Na 2 SO 4 Dehydrated and filtered The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 55% EtOAc / PE to give 1-allyl 2-methyl (2S, 4R)-4-((4-nitro-N-phenethylphenyl)sulfonamido)pyrrolidine- 1,2-dicarboxylate. MS ESI:C 24 H 28 N 3 O 8 S [M+H] + Calculated value: 518.15, Found: 518.20.

[0147] Step 2: To a mixture of 1-allyl 2-methyl (2S,4R)-4-((4-nitro-N-phenethyl phenyl)sulfonamido)pyrrolidine-1,2-dicarboxylate (7.2 g, 13 .91 mmol) in DMF (80 mL) was added 4-methoxybenzylthiol (1.950 g, 13.91 mmol) and K 2CO 2 CO 3 (1.923 g, 13.9 1 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h and then diluted with water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na 2SO 4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by RP-flash under the following conditions: column: flash C18 (330 g); mobile phase A: water (0.05% 2 TFA), mobile phase B: MeCN; (gradient: hold at 5% B for 5 min, 32% B in 15 min, hold at 32 4 % B for 6 min; 95% B in 5 min, hold at 95% B for 5 min); flow rate: 90 mL / min; detector : UV 210 nm; RT = 36 min. The product-containing fraction was collected and concentrated under reduced pressure to give the title compound. % B for 6 min; 95% B in 5 min, hold at 95% B for 5 min); flow rate: 90 mL / min; detector : UV210nm; RT=36min by RP - flash chromatography and the product-containing fraction The painting was recovered and concentrated under reduced pressure to obtain 1-allyl 2-methyl (2S,4R)-4-(phenethyl amino)pyrrolidine-1,2-dicarboxylate. MS ESI:C 18 H 2 5 N 2 O 4 [M+H] + Calculated value: 333.17, measured value: 333.25.

[0148] Step 3: To a mixture of 1-allyl 2-methyl (2S,4R)-4-(phenethylamino)pyrrolidine -1,2-dicarboxylate (4 g, 12.03 mmol) in DCM (40 mL), Boc O (3.93 g, 18.04 mmol) and TEA (3.3 2 5 mL, 24.07 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 4 hours, then quenched with water (3 0 mL) and extracted with EtOAc (3 times with 200 mL). The combined organic layers were washed with brine (2 times with 100 mL), dried over anhydrous Na SO 2 and filtered. The filtrate was 4 concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of EtOAc / PE from 0% to 40% to obtain 1-allyl 2-methyl (2S,4R)- 4-((tert-butoxycarbonyl)(phenethyl)amino)pyrrolidine-1,2- dicarboxylate. MS ESI:C 4-((tert-butoxycarbonyl)(phenethyl)amino)pyrrolidine-1,2- dicarboxylate. MS ESI:C 23 H 33 N 2 O 6 [M+H] + Calculated value : 433.23, measured value: 433.25.

[0149] Step 4: 1-allyl 2-methyl (2S,4R)-4-((tert-butoxycarbonyl ((Phenethyl)amino)pyrrolidine-1,2-dicarboxylate (3.84 g, 8 .88 mmol) in a mixture of THF (30 mL) was added with LiOH (17.76 mL, 17.76 mmol, 1 M aqueous solution) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 hours, and then made acidic to pH 3 - 4 with aqueous H Cl solution and extracted with EtOAc (3 times with 150 mL). The combined organic layers were washed with brine (2 times with 80 mL), dried over anhydrous Na 2 SO 4 and filtered . The filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step without further purification. . MS ESI: C 22 H 31 N 2 O 6 [M + H] + Calculated value: 419.21, Measured value: 419.35.

[0150] Step 5: (2S,4R)-1-((allyloxy)carbonyl)-4-((tert- butoxycarbonyl)(phenethyl)amino)pyrrolidine-2-carboxylic acid (7 g, 16 .73 mmol) in a mixture of DCM (150 mL) was added with AcOH (2.411 g, 40.1 mmol) and Pd(Ph 3 P) 4 (3.87 g, 3.35 mmol) at ambient temperature, and then Bu SnH (5.36 g, 18.40 mmol) was added to the reaction mixture. 3 The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure. The crude product was used directly in the next step without further purification. MS ESI: C H 18 H 27 N 2 O 4 [M + H] + Calculated value: 335 .19, Measured value: 335.25.

[0151] Step 6: (2S,4R)-4-((tert-butoxycarbonyl)(phenethyl)a (amino)pyrrolidine-2-carboxylic acid (5.4 g, 16.15 mmol) in THF (50 mM L) and water (50 mL) at room temperature. 3 (8.56g, 81mmol) Then, Fmoc-OSu (4.89 g, 14.54 mmol) was added. After stirring at ambient temperature for 4 h, it was acidified to pH 3-4 with aqueous HCl and diluted with EtO The organic layers were combined and washed with brine (200 mL). 2 times), anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure. The residue was Conditions: Column: Flash C18 (330 g); Mobile phase A: Water (0.05% TFA). , Mobile phase B: MeCN; (Gradient: 5% B hold for 5 min, to 70% B in 25 min, hold at 70% B 8 min; 2 min to 95% B, hold 95% B for 5 min); Flow rate: 90 mL / min; Detector: UV2 Purified by RP-flash at 10 nm; RT=45 min. Product-containing fractions were collected. and concentrated under reduced pressure to give (2S,4R)-1-(((9H-fluoren-9-yl)meth 4-((tert-butoxycarbonyl)(phenethyl)amino) Pyrrolidine-2-carboxylic acid was obtained. MS ESI:C 33 H 37 N 2 O 6 Na[M+N a] + Calculated value: 579.26, actual value: 579.25. 1 H NMR (300 MHz, methanol- d4) δ 7.78 - 7.76 (m, 2H), 7.63 - 7.57 (m, 2H), 7.44 - 7.24 (m, 6H), 7.20 - 7.1 7 (m, 3H), 4.51 - 4.28 (m, 4H), 4.25 - 4.15 (m, 1H), 3.60 - 3.41 (m, 1H), 3.39 - 3.31 (m, 3H), 2.82 - 2.77 (m, 2H), 2.45 - 2.44 (m, 1H), 1.98 - 1.94 (m, 1H), 1. 46 (s, 9H).

[0152] Synthesis Scheme 13

Chemical formula

[0153] Step 2: 1-Allyl 2-methyl(2S,4R)-4-((N-ethyl-4-nitrophen nyl)sulfonamido)pyrrolidine-1,2-dicarboxylate (5.5 g, 12.4 6 mmol) and K 2 CO 3 (5.17 g, 37.4 mmol) in DMF (80 mL) To the stirred mixture, 4-methoxybenzenethiol (3.49 g, 24.92 mmo l) was added at room temperature. After the mixture was stirred at room temperature for 1 hour, it was quenched with water (200 mL) and extracted with EtOAc (3 times with 200 mL). The combined organic layers were washed with brine (3 times with 100 mL), dried over anhydrous Na SO 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure , and the residue was purified by silica gel column chromatography eluting with 0% to 3% MeOH / DCM to give 1-allyl 2-methyl(2S,4R)-4-(ethylamino) Pyrrolidine-1,2-dicarboxylate was obtained. MS ESI: C 12 H 21 N 2 O 4 [M+H] + Calculated value: 257.14, Measured value: 257.15. 1 H NMR (300 MHz, CDCl 3 ) δ 6.02 - 5.76 (m, 1H), 5.40 - 5.11 (m, 2H), 4.68 - 4.38 (m, 3H), 3.91 - 3.77 (m, 1H), 3.77 - 3.67 (m, 3H), 3.61 - 3.42 (m, 1H), 3.42 - 3.21 (m, 1H), 2.68 (q, J = 7.2 Hz, 2H), 2.28 - 2.00 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0154] Step 3: 1-Allyl 2-methyl (2S,4R)-4-(ethylamino)pyrrolidine-1 ,2-dicarboxylate (2.9 g, 11.31 mmol) and TEA (3.15 mL , 22.63 mmol) in DCM (50 mL) was stirred at room temperature, and Boc 2 O (3. 94 mL, 16.97 mmol) was added. The resulting solution was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 30% EtOAc / PE to give 1-allyl 2-methyl (2S,4R)- 4-((tert-butoxycarbonyl)(ethyl)amino)pyrrolidine-1,2-dicar boxylate. MS ESI: C 17 H 29 N 2 O 6 [M+H] + Calculated value: 3 57.19, Measured value: 357.30.1 H NMR (400 MHz, CDCl 3 ) δ 6.01 - 5.79 (m, 1H) , 5.37 - 5.14 (m, 2H), 4.70 - 4.40 (m, 4H), 3.85 - 3.75 (m, 1H), 3.73 (d, J = 7. 8 Hz, 3H), 3.49 - 3.36 (m, 1H), 3.28 - 3.06 (m, 2H), 2.53 - 2.38 (m, 1H), 2.22 - 2.07 (m, 1H), 1.46 (s, 9H), 1.11 (t, J = 7.0 Hz, 3H).

[0155] Step 4: To a stirred solution of 1-allyl 2-methyl(2S,4R)-4-((tert-butoxycarbonyl)(ethyl)amino)pyrrolidine-1,2-dicarboxylate (3.8 g, 10.6 6 mmol) in THF (50 mL) was added LiOH (32 mL, 32. 0 mmol, 1 N aqueous solution) at room temperature. After the solution was stirred at 25 °C for 2 h, the pH of the solution was adjusted to 3 with 1 N HCl and then extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na SO 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give (2S,4R)-1-((allyloxy)carbonyl)-4-((t ert-butoxycarbonyl)(ethyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C H 16 H 27 N 2 O 6 [M+H] + calculated: 343.18, found: 3 43.30.

[0156] Step 5: (2S,4R)-1-((allyloxy)carbonyl)-4-((tert- (Butoxycarbonyl)(ethyl)amino)pyrrolidine-2-carboxylic acid (3.4 g, 9. 93 mmol), AcOH (1.431 g, 23.83 mmol) and Pd(Ph 3 P) 4 (2.295 g, 1.986 mmol) in a stirred solution of DCM (150 mL) at room temperature was added Bu 3 SnH (3.18 g, 10.92 mmol) dropwise. The resulting solution was stirred at 25 °C for 1 hour and then concentrated under reduced pressure to give (2S,4R)-4-((tert-butoxy carbonyl)(ethyl)amino)pyrrolidine-2-carboxylic acid. MS ESI: C 12 H 23 N 2 O 4 [M+H] + Calculated value: 259.16, measured value: 259.30.

[0157] Step 6: (2S,4R)-4-((tert-Butoxycarbonyl)(ethyl)amino )pyrrolidine-2-carboxylic acid (2.5 g, 9.68 mmol) and Na 2 CO 3 (3. 08 g, 29.0 mmol) in a stirred solution of THF (60 mL) and water (60 mL) was added Fmoc-OSu (3.26 g, 9.68 mmol) at room temperature. The resulting mixture was stirred at 25 °C for 16 hours, then the pH was adjusted to 3 with 1N HCl and then extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine (2 times with 50 mL), anhydrous Na 2 SO 4 dried. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified under the following conditions: 33 0 g C18 column, 5%-5% for 5 minutes, 40 minutes from 5% to 65% MeCN / water (0.05 Purified by RP-flash with %TFA) to obtain (2S,4R)-1-(((9H- fluoren-9-yl)methoxy)carbonyl)-4-((tert-butoxycarbonyl (ethyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C 27 H 3 3 N 2 O 6 [M+H] + Calculated value: 481.23, measured value: 481.10. 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (br, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.68 - 7.64 (m, 2H), 7.44 - 7.41 (m, 2H), 7.35 - 7.31 (m, 2H), 4.43 - 4.18 (m, 5H), 3.60 - 3.56 (m, 1 H), 3.29 - 3.22 (m, 1H), 3.16 - 3.12 (m, 2H), 2.42 - 2.38 (m, 1H), 2.08 - 2.01 ( m, 1H), 1.40 (s, 9H), 1.05 - 1.00 (m, 3H).

[0158] Synthesis Scheme 14

Chemical Structure

[0159] Step 2: A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (0.693 g, 3.16 mmol) and 1,10-phenanthroline (0.569 g, 3.16 mm ol) in DMA (50 mL) was heated at 50 °C for 0.5 h. 1-(4-(5 -bromopyrimidin-2-yl)piperazin-1-yl)ethan-1-one (4.5 g, 15.78 mmol), tert-butyl (R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-iodopropanoate (11.68 g, 2 DMA (50mM, 3.67mmol) and TBAI (5.83g, 15.78mmol) L) was added at 25° C. Then, Zn (2.064 g, 31.6 mmol) was added. The resulting mixture was stirred at 30° C. for 24 h, after which the reaction mixture was filtered and washed with DCM. The organic layer was concentrated under reduced pressure, and the residue was purified using the following conditions: column: C18 column (330 g); Mobile phase A: Water (0.05% TFA); Mobile phase B: MeCN; (Gradient: 0% B hold 5 min, 3 0 min to 82% B, hold at 82% B for 6 min; 2 min to 95% B, hold at 95% B for 3 min); Volume: 60mL / min; Detector: UV254&210nm; RT: RP-Flash at 35min The compound was purified by filtration to give tert-butyl(S)-2-((((9H-fluorene-9-isopropyl) (2-(4-acetylpiperazin-1-yl)phenyl)methoxy)carbonyl)amino)-3-(2-(4-acetylpiperazin-1-yl) ) pyrimidin-5-yl) propanoate was obtained. MS ESI:C 32 H 38 N 5 O 5 [M+H] + Calculated value: 572.28, actual value: 572.30. 1 H NMR (300 MHz, CDCl 3 ) δ 8.19 (s, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.63 - 7.52 (m, 2H), 7.46 - 7.26 (m , 4H), 4.48 - 4.42 (m,2H), 4.35 - 4.30 (m, 1H), 4.22 - 4.17 (m, 1H), 3.89 - 3.81 (m, 4H), 3.71 - 3.68 (m, 2H), 3.56 - 3.52 (m, 2H), 3.08 - 3.02 (m, 1H), 2.92 - 2.87 (m, 1H), 2.17 (s, 3H), 1.48 (s, 9H).

[0160] Step 3: tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy )carbonyl)amino)-3-(2-(4-acetylpiperazin-1-yl)pyrimidin -5-yl)propanoate (4.6 g, 8.05 mmol) in DCM (40 mL) To the mixture, TFA (80 mL, 1038 mmol) was added at room temperature under argon. The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified by the following conditions: column: C18 gel column (330 g); mobile phase A: water (0.05% TFA); mobile phase B: MeCN; (gradient: 0% B held for 5 min, 72% B in 30 min, 72% B held for 6 min; 95% B in 2 min, 95% B held for 10 min); flow rate: 60 mL / min; detector: UV254&210 nm; RT: 35 min by RP-flash to give (S)-2-((((9H-fluoren -9-yl)methoxy)carbonyl)amino)-3-(2-(4-acetylpiperazin- 1-yl)pyrimidin-5-yl)propanoic acid. MS ESI: C H 28 H 30 N 5 O 5 [M+H] + Calculated value: 516.22, found: 516.35. 1 H NMR (300 MHz, D MSO-d6) δ 8.31 (s, 2H), 7.89 (d, J = 7.5 Hz, 2H), 7.81 (d, J = 8.6 Hz, 1H), 7.7 4 - 7.62 (m, 2H), 7.59 - 7.22 (m, 4H), 4.29 - 4.09 (m, 4H), 3.74 - 3.60 (m, 4H), 3.47 - 3.46 (m, 4H), 2.98 - 2.92 (m, 1H), 2.76 - 2.68 (m, 1H), 2.03 (s, 3H).

[0161] Synthesis Scheme 15 [Chemical formula] (2S,3S)-2-Amino-3-(4-fluoro-1H-indol-3-yl)but anoic acid In a 1 L three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-fluoro-1H-indole (10 g, 1.00 equivalent), L-threonine (10.6 g, 1 .20 equivalents), DMSO (100 mL), potassium phosphate buffer (0.2 M, 300 mL , pH = 7.4) were added. The reaction mixture was heated to 65 °C and then PfTrpB-7E 6 (2.5 g, 25 wt%) and 3-hydroxy-2-methyl-5-([phosphonooxy methyl)-4-pyridinecarboxaldehyde (0.078 g, 0.004 equivalent) were added . The resulting solution was stirred at 65 °C overnight. The mixture was cooled to room temperature and used directly in the next step .

[0162] To the above reaction mixture, at 0 °C, THF (100 mL), sodium carbonate (23.56 g, 3 .0 equivalents) and 2,5-dioxopyrrolidin-1-yl 9H-fluoren-9-ylmethyl carbonate (29.96 g, 1.20 equivalents) were added. The resulting solution was stirred at room temperature overnight. The pH was adjusted to 4 with 3 M HCl and the solid precipitate was filtered off. The resulting solution was extracted with EtOAc (3 times with 500 mL). The organic fractions were combined, washed with brine (1 liter ), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was MeOH:DC ​​Purified using a silica gel column with M = 1:5. HPLC-MS: (ES, m / z): [M + 1]: 459. 1 H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 11.15 (s, 1H), 7 .87 (d, J = 7.6 Hz, 2H), 7.76 - 7.49 (m, 3H), 7.47 - 7.34 (m, 2H), 7.34 - 7.16 ( m, 4H), 7.03 (td, J = 7.9, 5.0 Hz, 1H), 6.73 (dd, J = 11.8, 7.7 Hz, 1H), 4.36 (t , J = 8.5 Hz, 1H), 4.31 - 4.02 (m, 3H), 3.51 (q, J = 7.4 Hz, 1H), 1.31 (d, J = 7 .0 Hz, 4H), 0.78 (s, 1H).

[0163] Synthesis Scheme 16

Chemical formula

[0164] Synthesis Scheme 17

Chemical Structure

[0165] Step 2: In a three - necked round - bottom flask, under an inert atmosphere of nitrogen, (2S,3R) - benzyl 2 - ( (((9H - fluoren - 9 - yl)methoxy)carbonyl)amino) - 3 - hydroxy butanoate (125 g, 1.00 equivalent) and DCE (750 mL) were added. The reaction solution was cooled to 0 °C, and then NIS (195 g, 3.00 equivalents) and PPh 3 (228 g, 3 .00 equivalents) were added. The temperature was raised to 50 °C, and the reaction mixture was stirred for 3 hours. The reaction solution was poured into ice H 2 O (500 mL), and extracted with DCM (twice with 500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40 °C. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 0 / 1). 1 1H NMR (400 MH z, CDCl 3 3): δ 7.78 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.2 Hz, 2H), 7.33 - 7.43 (m, 9H), 5.27 - 5.68 (m, 1H), 5.21 - 5.23 (m, 2H), 4.39 - 4.52 (m, 3H), 4.25 - 4.38 (m, 1H), 1.91 - 1.95 (m, 3H).

[0166] Step 3: In a three - necked round - bottom flask, 2 - ((((9H - fluoren - 9 - yl)methoxy) (Carbonyl)amino)-3-iodobutanoate, 1-iodonaphthalene (42.2 g, 1.20 equivalents), TBAI (76.7 g, 1.50 equivalents), Zn (19.0 g, 2.10 equivalents) and DMA (750 mL) were added. To a second three-necked round-bottom flask, picolyl imidamide·2HCl (42.2 g, 1.20 equivalents), NiCl 2 ·glyme (7.6 1 g, 0.25 equivalents) and DMA (750 mL) were added. Under argon, the contents of the second flask were added to the first flask. The resulting mixture was stirred at 25 °C for 12 hours. The reaction solution was poured into ice H 2 O (3 liters) and extracted with EtOAc (twice with 1 liter). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40 °C. The crude product was purified by reverse-phase HPLC (MeCN:H 2 O). HPLC-MS: [M+23]: 564. 1 H N MR (400 MHz, CDCl 3 ) δ: 8.17 - 8.24 (m, 1H), 8.15 - 8.17 (m, 1H), 7.77 - 7.87 (m, 2H), 7.76 - 7.77 (m, 4H), 7.30 - 7.41 (m, 10H), 5.30 - 5.38 (m, 1H), 4.96 - 5.04 (m, 3H), 4. 85 - 4.87 (m, 1H), 4.30 - 4.34 (m, 1H), 4.18 - 4.26 (m, 4H), 1.43 - 1.45 (m, 3H).

[0167] Step 4: 143 g of (2S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalen-1-yl)butanoate was separated by SFC. The organic layer was concentrated under reduced pressure at 35 °C.

[0168] Peak 1: (2S,3R)-Benzyl 2-((((9H-Fluoren-9-yl)meth oxy)carbonyl)amino)-3-(naphthalen-1-yl)butanoate. 1 H NMR (40 0 MHz, DMSO-d6): δ 8.11-8.12 (m, 2H), 8.10-8.11 (m, 1H), 7.88-7.90 (m, 2H), 7.5 4-7.88 (m, 1H), 7.44-7.53 (m, 2H), 7.42-7.44 (m, 4H), 7.33-7.42 (m, 3H), 7.27-7. 33 (m, 6H), 7.08-7.09 (m, 2H), 4.91-4.94 (m, 1H), 4.79- 4.82 (m, 1H), 4.58 (t, J = 8.0 Hz), 4.17-4.25 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). Peak 2: (2S,3S) -Benzyl 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino) -3-(naphthalen-1-yl)butanoate. 1 H NMR (400 MHz, DMSO-d6): δ 7.92-8 .15 (m, 1H), 7.86-7.92 (m, 1H), 7.84-7.86 (m, 1H), 7.57-7.84 (m, 2H), 7.56-7.57 (m, 1H), 7.41-7.54 (m, 4H), 7.30-7.38 (m, 4H), 7.27-7.30 (m, 7H), 5.08-5.14 (m, 2H), 4.65 (t, J = 8.0 Hz), 4.23-4.26 (m, 1H), 4.05-4.18 (m, 3H), 1.30 (d, J = 6. 8 Hz, 3H).

[0169] Step 5: In a three-necked round-bottom flask, (2S,3S)-benzyl 2-((((9H-fluoren (N-9-yl)methoxy)carbonyl)amino)-3-(naphthalen-1-yl)butano Ethyl (40.0 g, 1.00 equivalent) and THF (200 mL) were added. 10% wet Pd / C (7.00 g) was added, and the reaction mixture was purged with H 2 three times, and then with H 2 (about 0.103 MPa ( 15 psi)) and stirred at 25 °C for 12 hours. The reaction mixture was filtered through a celite layer and concentrated under reduced pressure at 35 °C. The crude product was triturated with PE at 25 °C for 1 hour. After filtration, the filter cake was dissolved in MeCN (100 mL) and concentrated under reduced pressure at 35 °C to remove the residual solvent. HPLC-MS: [M + 23]: 474. 1 H NMR (400 MHz, DMSO-d6) δ 12. 78 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 7.86 - 7.88 (m, 1H), 7.80 - 7.86 (m, 2H), 7.61 -7.80 (m, 2H), 7.55 - 7.59 (m, 4H), 7.481 - 7.55 (m, 1H), 7.40 - 7.48 (m, 3H), 7.27 - 7. 29 (m, 2H), 4.28 - 4.60 (m, 1H), 4.24 - 4.28 (m, 1H), 4.17 - 4.24 (m, 2H), 4.04 - 4.15 ( m, 1H), 1.36 (d, J = 6.8 Hz, 3H).

[0170] Synthesis Scheme 18

Chemical Structure

[0171] Step 2: Methyl (S)-3-(4-(2-(((benzyloxy)carbonyl)amino ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (16.0 g, 33.9 mmol) and acetic anhydride (6.39 mL, 67.7 mmol ​To the stirred solution in THF (200 mL) under a nitrogen atmosphere at room temperature was added Pd / C (3.60 g , 33.9 mmol, dry product, 10 wt%). The mixture was degassed three times with hydrogen and stirred at 20 °C for 4 h. DIPEA (17.74 mL, 102 mmol) was added to the mixture and stirred at 20 °C for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 3% MeOH / DCM. MS ESI: C 19 H 28 N 2 O 6 [M+Na] + calculated: 403.19, found: 403.10; 1 H NMR (300 MHz, CDCl 3 ) δ 7.05 (d, J = 8.4 Hz, 2H), 6.85 - 6.80 ( m, 2H), 5.99 (br, 1H), 5.32 (br, 1H), 4.99 - 4.97 (m, 1H), 4.02 (t, J = 5.0 Hz, 2H), 3.72 (s, 3H), 3.69 - 3.63 (m, 2H), 3.10 - 2.89 (m, 2H), 2.02 (s, 3H), 1.42 (s, 9H).

[0172] Step 3: To the stirred solution of methyl (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-( (tert-butoxycarbonyl)amino)propanoate (12.5 g, 32.9 mmol) in THF (100 mL) at room temperature was added lithium hydroxide (65.7 mL, 65.7 mmol, 1 N aqueous solution). The solution was stirred at 20 °C for 2 h. The pH of the solution was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with EtOAc (2 × 250 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and filtered. It was then concentrated under reduced pressure.

[0173] MS ESI [M+H] + : 367.10.

[0174] Step 4: To a stirred solution of (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (12.5 g, 30.7 mmol) in HF (20 mL) was added 4N HCl / dioxane (200 mL) at room temperature. The solution was stirred at 20 °C for 1 hour. The solvent was concentrated under reduced pressure. MS ESI [M+H + : 267.05.

[0175] Step 5: To a stirred mixture of (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-aminopropanoic acid hydrochloride (9.50 g, 25.1 mmol) and NaHCO (10.54 g, 1 3 (126 mmol) in THF (100 mL) and water (100 mL) was added Fmoc-OSu (7.62 g, 22.59 mmol) at room temperature. The mixture was stirred at 20 °C for 1 hour. The pH value of the solution was adjusted to 3 with 1N HCl. The aqueous layer was extracted with EtOAc (2 times with 500 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium bicarbonate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from EtOAc (200 mL). The solid was collected by filtration and dried in vacuo. MS ESI [M+H (500 mL twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium bicarbonate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from EtOAc (200 mL). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium bicarbonate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from EtOAc (200 mL). L). The solid was collected by filtration and dried in vacuo. MS ESI [M+H (500 mL twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium bicarbonate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from EtOAc (200 mL). + : 489.05; 1 H NMR (300 MHz, methanol-d4) δ 7.79 (d, J = 7.6 Hz, 2H), ​​7.62 - 7.57 (m, 2H), 7.42 - 7.26 (m, 4H), 7.17 - 7.14 (m, 2H), 6.83 (d, J = 8.4 Hz, 2 H), 4.41 - 4.31 (m, 2H), 4.29 - 4.10 (m, 2H), 3.96 (t, J = 4.8 Hz, 2H), 3.51 (t, J = 5.4 Hz, 2H), 3.19 - 3.13 (m, 1H), 2.92 - 2.84 (m, 1H), 1.94 (s, 3H).

[0176] Synthesis Scheme 19

Chem.

[0177] Step 2: tert-Butyl (S)-2-((tert-butoxycarbonyl)amino) -3-(4-(2-morpholinoethoxy)phenyl)propanoate (525 mg, 1. 165 mmol) was dissolved in DCM (3 mL) at ambient temperature. TFA (3 mL) was added, and the mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and used next as the crude product . MW: 294.351, found: MSESI [M+H] + : 295.1.

[0178] Step 3: (S)-2-Amino-3-(4-(2-morpholinoethoxy)phenyl)pro panoic acid (354 mg, 1.203 mmol) was dissolved in tetrahydrofuran (3 mL) and water (3 mL) at ambient temperature. The reaction mixture was cooled to 0 °C. Sodium carbonate (382 m g, 3.61 mmol) was added and the solution was stirred at 0 °C for 5 min. (9H-Fluoren-9 -yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (406 mg, 1.203 mmol) was added and the mixture was stirred for 2 h. THF was removed under reduced pressure. The aqueous solution was acidified to pH 3 with 1 N HCl. The reaction mixture was extracted with EtOAc, washed with water, dried over sodium sulfate , filtered, and concentrated. The crude product was purified by reverse-phase column chromatography using a 50 g C18 prepacked column on an Isco eluting with a gradient of 10% to 10 0% TFA-adjusted MeCN / TFA-adjusted water over a 30 min period to give the product as multiple fractions. These fractions were combined, frozen in a -78 °C dry ice / acetone bath, lyophilized, and the product was obtained. MW: 516.94, found: MSESI [M+H] + : 517.2.

[0179] Synthetic Scheme 20 [Chemical formula] (R)-2,4-Diamino-2-methylbutanal Step 1: To a stirred solution of (R)-2-amino-2-methylpent-4-enoic acid (1.3 g, 10.07 mmol) and DIPEA (5.27 mL, 30.2 mmol) in dioxane (20 mL ) and water (20 mL) at room temperature was added Fmoc-OSu (3.73 g, 11.0 7 mmol). The resulting solution was stirred at 25 °C for 16 h. The pH was adjusted to 3 with 1N HCl, and the solution was purified by reverse-phase flash column chromatography under the following conditions: C18 column, 330 g, 5% - 5% for 5 min, 30 min at 5% to 50%, 98% - 98% for 5 min, MeCN / water (0.05% TFA) to obtain (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpent-4-enoic acid. MS ESI: C H NO Na [M+Na] calculated value: 374.15, found 21 H 21 NO 4 Na [M+Na] + value: 374.05. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 7.5 Hz, 2H), 7.61 (d , J = 7.5 Hz, 2H), 7.48 - 7.29 (m, 4H), 5.71 (s, 1H), 5.48 (s, 1H), 5.20 - 5.16 (m, 2H), 4.44 - 4.40 (m, 2H), 4.25 (t, J = 6.7 Hz, 1H), 2.82 - 2.71 (m, 2H).

[0180] Step 2: (R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl) (Amino)-2-methylpenta-4-enoic acid (3 g, 8.54 mmol) and N-methylmorpholine N-oxide (2.2 g, 9.39 mmol, 50% aqueous solution) in acetone (6 0 mL) of the stirred solution, at room temperature, OsO (2.170 g, 0.854 mmol, 10% 4 (aqueous solution) was added. The resulting solution was stirred at 25 °C for 4 hours. Sodium periodate (2.00 g, 9.39 mmol) in aqueous solution (20 mL of water) was added to the solution, and the resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 times with 200 mL). The combined organic layers were washed with brine (2 times with 100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give (R)-2-(( ((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-4- oxobutanoic acid. MS ESI: C H ((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-methyl-4- oxobutanoic acid. MS ESI: C 20 H 20 NO 5 [M + H] + Calculated value: 35 4.13, Found: 354.00.

[0181] Step 3: (R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl) amino)-2-methyl-4-oxobutanoic acid (3 g, 6.79 mmol) in toluene (1 20 mL) of the stirred solution, at room temperature, tert-butyl carbamate (4.77 g, 40. 8 mmol) and TFA (2.32 g, 20.38 mmol) were added. The resulting solution was stirred at 25 °C for 2 hours. The solution was concentrated under reduced pressure to give (R,Z)-2-((((9H-F luoren-9-yl)methoxy)carbonyl)amino)-4-((tert-butoxycarb onyl)imino)-2-methylbutanoic acid. MS ESI: C25 H 27 N 2 O 6 [M-H] + Calculated value: 451.19, measured value: 450.90.

[0182] Step 4: (R,Z)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl amino)-4-((tert-butoxycarbonyl)imino)-2-methylbutanoic acid (3.1 g, 5.48 mmol) and dimethyl(phenyl)silane (1.87 g, 13. 7 mmol) in a stirred solution of toluene (120 mL) at room temperature were added tris(pentafluoro phenyl)borane (0.281 g, 0.548 mmol). The solution was stirred at 25 °C for 16 hours. The solvent was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography under the following conditions: 330 g C18 column, 5%-5% for 5 minutes, 5% to 55% for 30 minutes, 98%-98% for 5 minutes, MeCN / water (0.0 5% TFA), RT = 35 minutes to give (R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)- 4-((tert-butoxycarbonyl)amino)-2-methylbutanoic acid. MS ESI: C 25 H 31 N 2 O 6 [M+H] + Calculated value: 455.21, measured value: 455. 10; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.48 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H), 7.54 (s, 1H), 7.44 - 7.41 (m, 2H), 7.36 - 7.32 (m, 2H), 6. 78 (s, 1H), 4.25 - 4.23 (m, 3H), 2.92 - 2.91 (m, 2H), 1.99 - 1.93 (m, 1H), 1.87 - 1.81 (m, 1H), 1.37 - 1.34 (m, 9H).

[0183] Synthesis Scheme 21

Chem.

[0184] Step 2: To a mixture of (R)-3-((tert-butoxycarbonyl)amino)-3-carboxy -N,N,N-trimethylpropan-1-aminium iodide (15 g, 23.18 mmol ) in DCM (60 mL) was added TFA (30 mL, 389 mmol ) was added. The reaction solution was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure to obtain (R)-3-amino-3-carboxy-N,N,N-trimethylpropane-1-aminium 2,2,2-trifluoroacetate. MS ESI: C H F 9 H 17 F 3 N 2 O 4 [M - CF 3 C OO] + Calculated value: 161.13, Observed value: 161.30.

[0185] Step 3: To a mixture of (R)-3-amino-3-carboxy-N,N,N-trimethylpropane-1-aminium 2,2,2-trifluoroacetate (11.5 g, 20.97 mmol) in THF (40 mL) and water (40 mL), NaHCO (8.81 g, 10 5 mmol) and Fmoc-OSu (6.37 g, 18.87 mmol) were added. The reaction 3 (8.81 g, 10 5 mmol) and Fmoc-OSu (6.37 g, 18.87 mmol) were added. The reaction solution was stirred at ambient temperature for 2 hours, acidified to pH 3 - 4 with aqueous HCl solution, and filtered to obtain a crude product. The crude product was purified by reverse-phase column chromatography under the following conditions: 330 g C18 column; mobile phase A: water (0.0 5% TFA), mobile phase B: MeCN; (gradient: 0% B held for 5 minutes, 33% B by 19 minutes, held at 38% B for 7 minutes; 95% B by 5 minutes, held at 95% B for 5 minutes); flow rate: 80 mL / min. The product-containing fractions were collected and lyophilized to obtain (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino )-3-carboxy-N,N,N-trimethylpropane-1-aminium 2,2,2-trifluoroacetate. MS ESI: C H F H )-3-carboxy-N,N,N-trimethylpropane-1-aminium 2,2,2-trifluoroacetate. MS ESI: C H 24 H 27 F 3 N 2 O6 [M-CF 3 C OO] + Calculated value: 383.20, measured value: 383.25. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.91 (d, J = 7.2 Hz, 2H), 7.79 - 7.71 (m, 3H), 7.46 - 7.41 (m, 2H), 7.37 - 7. 32 (m, 2H), 4.42 - 4.22 (m, 3H), 4.07 - 4.01 (m, 1H), 3.99 - 3.41 (m, 1H), 3.33 - 3.28 (m, 1H), 3.07 (s, 9H), 2.21 - 2.16 (m, 1H), 2.08 - 2.04 (m, 1H). 19 F-NMR (282 MHz, DMSO-d 6 ) δ 73.931.

[0186] Synthesis Scheme 22 [Chemical formula] 3-[4-[(S)-2-Amino-2-carboxyethyl]phenyl]bicyclo[1. 1.1]pentane-1-carboxylic acid Step 1: A stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodo phenyl)propanoic acid (3.91 g, 10 mmol) in DMF (40 mL) was added with 3-bromoprop-1-ene (3.63 g, 30.0 mmol) and NaHCO (0.840 g, 10.00 mmol) at 0 °C under an argon atmosphere. The resulting 3 mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature and quenched with water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Washed with [solvent] (3 times with 100 mL), dehydrated with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with 0% to 40% EtOAc / PE). The product-containing fractions were collected and the solvent was evaporated under reduced pressure to give allyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl) propanoate. MS ESI: C 27 H 25 INO 4 [M+H] + calculated value : 554.08, found: 554.20.

[0187] Step 2: To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (8 g, 47.0 mmol) in DCM (100 mL) was added tert- butyl (Z)-N,N'-diisopropylcarbodiimidate (37.7 g, 188 mmol) at room temperature. The resulting solution was stirred at 40 °C for 2 h. The mixture was then cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 3-methyl bicyclo[1.1.1]pentane-1,3-dicarboxylate. 1 H NMR (400 MH z, DMSO-d 6 ) δ 3.61 (s, 3H), 2.17 (s, 6H), 1.39 (s, 9H).

[0188] Step 3: To a stirred solution of 1-(tert-butyl) 3-methylbicyclo[1.1.1]pentane-1, 3-dicarboxylate (15 g, 39.8 mmol) in THF (150 mL) was added LiOH (119 mL, 119 mmol, 1 N aqueous solution) at room temperature. The resulting solution was obtained The resulting solution was stirred at 25 °C for 5 h. The pH of the solution was adjusted to 3 with 1 N HCl and extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine (2 times with 50 mL ), dried over anhydrous sodium sulfate, and filtered. Next, the filtrate was concentrated under reduced pressure to obtain 3-(tert -butoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid . MS ESI: C 11 H 15 O 4 [M−H] - calculated value: 211.10, found: 21 1.10.

[0189] Step 4: To a stirred solution of 3-(tert-butoxycarbonyl)bicyclo[1.1.1]pentane-1 -carboxylic acid (10 g, 28.3 mmol), 2-hydroxyisoindoline-1,3- dione (6.00 g, 36.7 mmol), and DMAP (0.345 g, 2.83 mmo l) in DCM (100 mL) at room temperature was added N,N′-dicyclohexylcarbodi imide (6.42 g, 31.1 mmol). The resulting mixture was stirred at 25 °C for 16 h . The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 40% EtO Ac / PE to give 1-(tert -butyl) 3-(1,3-dioxoisoindolin-2-yl)bicyclo[1.1.1 pentane-1,3-dicarboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d d, J = 5.5, 3.1 Hz, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 2.50 (s, 6H), 1.47 (s, 9H).

[0190] Step 5: NiBr 2 ·3H 2 O (0.791 g, 2.90 mmol) in DMA (80 m L) was added to the stirred solution at room temperature under a nitrogen atmosphere with 4,4′-di-tert-butyl-2,2′ -dipyridine (0.973 g, 3.63 mmol). The resulting mixture was stirred at 50 °C for 30 minutes and then cooled to room temperature. 1-(tert-Butyl) 3-(1, 3-dioxoisoindolin-2-yl) bicyclo[1.1.1]pentane-1,3-di carboxylate (4.8 g, 12.09 mmol), allyl (S)-2-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-iodophenyl ) propanoate (6.69 g, 12.09 mmol), trimethylsilyl chloride (0.1 31 g, 1.209 mmol), and zinc (3.95 g, 60.4 mmol) were added to the above mixture at room temperature. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was quenched with brine (150 mL) and extracted with EtOAc (3 times with 100 mL). The combined organic layers were washed with brine (3 times with 100 mL), dried over anhydrous sodium sulfate, and filtered. Next, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0% to 40% EtOAc / PE to give tert-butyl (S)-3-(4-(2-((( (9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(allyloxy (9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(allyloxy )-3-oxopropyl)phenyl) bicyclo[1.1.1]pentane-1-carboxylate. MS ESI: C rate was obtained. MS ESI: C 37 H 40 NO 6 [M+H] + Calculated value: 594.28 , found: 594.30.

[0191] Step 6: tert-Butyl (S)-3-(4-(2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-(allyloxy)-3-oxopropyl) phenyl)bicyclo[1.1.1]pentane-1-carboxylate (2.3 g, 1.5 5 mmol) and phenylsilane (0.335 g, 3.10 mmol) in THF (30 m L) of the stirred solution, under a nitrogen atmosphere at room temperature, Pd(Ph 3 P) 4 (0.090 g, 0.0 77 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure, The residue was purified by reverse-phase column chromatography under the following conditions: C18 column, 330 g, 5% - 5% for 5 minutes, 5% to 70% MeCN / water (0.05% TFA) for 40 minutes to give (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino )-3-(4-(3-(tert-butoxycarbonyl)bicyclo[1.1.1]penta n-1-yl)phenyl)propanoic acid. MS ESI: C H 34 H 34 NO 6 [M - H] - Calculated value: 552.25, Measured value: 552.30. 1 H NMR (400 MHz, methanol- d4) δ 7.80 - 7.77 (m, 2H), 7.67 - 7.65 (m, 2H), 7.48 - 7.23 (m, 4H), 7.19 - 7.1 7 (m, 2H), 7.10 - 7.07 (m, 2H), 4.45 - 4.44 (m, 1H), 4.42 - 4.41 (m, 1H), 4.34 - 4.29 (m, 2H), 3.24 - 3.18 (m, 1H), 2.94 - 2.86 (m, 1H), 2.12 (s, 6H), 1.45 (s, 9H).

[0192] Composite diagram 23 [ka] TIFF2025084920000048.tif35137 (1R,4s)-4-(4-((S)-2-Amino-2-carboxyethyl)phenyl )cyclohexane-1-carboxylic acid Step 1: tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Saborolan-2-yl)cyclohex-3-ene-1-carboxylate (29.5 g, To a mixture of (S)-2-((tert-butyl)phenyl ether (96 mmol) in THF (30 mL) at room temperature, t-Butoxycarbonyl)amino)-3-(4-iodophenyl)propanoate (15 0.5g, 38.2mmol), and Pd(Ph 3 P) 4 (2.21g, 1.91mmol The reaction mixture was then warmed to 60° C. for 4 hours. The resulting solution was diluted with water (1 The reaction was quenched with 100 mL of ethyl acetate and extracted with EtOAc (300 mL x 3). The organic layers were combined. The filtrate was washed twice with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The residue was concentrated under reduced pressure to give the crude product. 5%) gradient to give tert- Butyl 4'-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy C1-3-oxopropyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl] MS ESI:C 26 H 38 NO6 Na[M+Na] + Calculated value: 482.26, measured value: 482.10.

[0193] Step 2: In a mixture of tert-butyl 4'-((S)-2-((tert-butoxycarbonyl) imino)-3-methoxy-3-oxopropyl)-2,3,4,5-tetrahydro-[1 ,1'-biphenyl]-4-carboxylate (16 g, 34.8 mmol) in methanol (160 mL), Pd-C (10% carbon supported, moistened with about 55% water, 5.3 g, 4.98 mmol) was added at room temperature. The solution was degassed 2 with H 2 three times and stirred under an H atmosphere (1.5 atm) at room temperature for 1 hour. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (S)-4-(4-(2-((tert-butoxycarbonyl )amino)-3-methoxy-3-oxopropyl)phenyl)cyclohexane-1-car 26 H 41 NO 6 [M+H] + Calculated value: 462 .28, measured value: 462.30.

[0194] Step 3: To a stirred solution of tert-butyl (S)-4-(4-(2-((tert-butoxycarbonyl l)amino)-3-methoxy-3-oxopropyl)phenyl)cyclohexane-1-car boxylate (15 g, 32.5 mmol) in THF (300 mL), LiOH (65.0 mL, 65.0 mmol) was added at room temperature. The solution was stirred at 20 °C for 1 hour. The pH of the solution was adjusted to 3 with 1N HCl. The reaction mixture was concentrated under reduced pressure to obtain (S) -2-((tert-Butoxycarbonyl)amino)-3-(4-(4-(tert-but oxycarbonyl)cyclohexyl)phenyl)propanoic acid was obtained. MS ESI:C 2 5 H 38 NO 6 Na[M+Na] + Calculated value: 470.26, Measured value: 470.30.

[0195] Step 4: (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(4 -(tert-Butoxycarbonyl)cyclohexyl)phenyl)propanoic acid (14 g, 31.3 mmol) was separated by preparative supercritical fluid chromatography under the following conditions: Column: CHIRAL ART Cellulose -SB, 3×25 cm, 5 μm; Mobile phase A: CO 2 , Mobile phase B: MeOH (0.1% 2M NH 3 -MeOH); Flow rate: 80 mL / min; Gradient: 10% B; 220 nm; Retention time of peak 1 : 7.45; Retention time of peak 2: 8.38. The first eluting peak (S)-2-((tert-Butoxycarbonyl amino)-3-(4-((1s,4R)-4-(tert-Butoxycarbonyl )cyclohexyl)phenyl)propanoic acid was obtained. MS ESI:C H 25 H 38 NO 6 Na[M +Na] + Calculated value: 470.26, Measured value 470.30. 1H NMR (300 MHz, CDCl 3 ) δ 7.11 (d, J = 3.0 Hz, 4H), 4.27 (s, 1H), 3.18 - 3.12 (m, 1H), 2.91 (s, 1H), 2. 60 (s, 1H), 2.49 (s, 1H), 2.20 (d, J = 10.9 Hz, 2H), 1.78 - 1.52 (m, 6H), 1.49 ( d, J = 0.7 Hz, 9H), 1.36 (s, 9H); And the second eluting peak, (S)-2-((tert-butoxycarbonyl)amino )-3-(4-((1r,4S)-4-(tert-butoxycarbonyl)cyclohe xyl)phenyl)propanoic acid. MS ESI: C 25 H 38 NO 6 Na [M+Na] + of Calculated value: 470.26, Measured value: 470.30. 1H NMR (300 MHz, CDCl 3 ) δ 7.14 - 7. 06 (m, 4H), 4.25 (s, 1H), 3.14 (d, J = 12.3 Hz, 1H), 2.88 (s, 1H), 2.49 - 2.41 ( m, 1H), 2.29 - 2.15 (m, 1H), 2.05 (d, J = 12.2 Hz, 2H), 1.90 (d, J = 12.1 Hz, 2H ), 1.69 - 1.47 (m, 2H), 1.47 (s, 11H), 1.34 (s, 9H). was obtained.

[0196] Step 5: To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(( 1s,4R)-4-(tert-butoxycarbonyl)cyclohexyl)phenyl)prop anoic acid (8.3 g, 18.54 mmol) in THF (80 mL) was added dropwise HCl (9.27 mL, 18.54 mmol) little by little at room temperature. The reaction solution was concentrated under reduced pressure to obtain (S)-2-amino-3-(4-((1s,4R)-4-(tert-butoxycarbonyl (R)-Cyclohexyl(phenyl)propanoic acid was obtained. MS ESI: C 20 H 30 NO 4 [M+H] + Calculated value: 348.21, Measured value: 348.25.

[0197] Step 6: (S)-2-Amino-3-(4-((1S,4R)-4-(tert-butoxy carbonyl)cyclohexyl)phenyl)propanoic acid (6 g, 17.27 mmol) and NaHCO 3 (7.25 g, 86 mmol) in THF (60 mL) and water (60.0 m L) in a stirred solution, Fmoc-OSu (5.24 g, 15.54 mmol) was added. The mixture was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 3 with 1N HCl. The aqueous layer was extracted with Et OAc (200 mL twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase ca ram chromatography to give (S)-2-((((9H-Fluoren-9 -yl)methoxy)carbonyl)amino)-3-(4-((1S,4R)-4-(ter t-butoxycarbonyl)cyclohexyl)phenyl)propanoic acid. MS ESI :C 35 H 41 NO 6 [M+H] + Calculated value: 570.28, Measured value: 570.15. 1 H NMR (300 MHz, methanol-d 4 ) δ 7.81 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.43 - 7.27 (m, 4H), 7.16 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 4. 45 - 4.33 (m, 2H), 4.22 - 4.06 (m, 2H), 3.26 - 3.14 (m, 1H), 2.96 - 2.88 (m, 1H), 2.59 (s, 1H), 2.48 (s, 1H), 2.15 (s, 2H), 1.61 (d, J = 5.5 Hz, 6H), 1.49 (s, 9H) .

[0198] Synthesis Scheme 24

Chem.

[0199] Step 2: To a stirred solution of (S)-2-amino-3-(4-((1r,4S)-4-(tert-butoxy carbonyl)cyclohexyl)phenyl)propanoic acid (2 g, 5.76 mmol) in THF (20 mL) and water (20 mL) were added (1 .748 g, 5.18 mmol) and NaHCO 3 (2.418 g, 28.8 mmol) at room temperature, followed by Fmoc-OSu (1​ .748 g, 5.18 mmol) was added. The mixture was stirred at 20 °C for 1 hour. 1N H Cl was used to adjust the pH of the solution to 3. The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino )-3-(4-((1r,4S)-4-(tert-butoxycarbonyl)cyclohe xyl)phenyl)propanoic acid. MS ESI: C 35 H 41 NO 6 [M+H] + of Calculated: 570.28, Found: 570.35. 1 H NMR (300 MHz, methanol-d 4 ) δ 7 .81 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.34 - 7 .27 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.8 Hz, 2H), 4.47 - 4.43 (m, 1H), 4.35 - 4.30 (m, 1H), 4.21 - 4.02 (m, 2H), 3.24 - 3.18 (m, 1H), 2.94 - 2.87 (m, 1H), 2.40 (s, 1H), 2.17 (d, J = 11.9 Hz, 1H), 1.96 (s, 3H), 1.82 - 1.55 (m, 2H), 1.47 (s, 13H).

[0200] Preparation of the final compound: A. General Procedure for the Synthesis of Linear Peptide Precursors The peptides in Table 1 were synthesized using standard solid-phase synthesis with Fmoc / tBu chemistry as exemplified in Chan, W.C.; White, P.D. “Fmo c Solid-Phase Synthesis: a Practical App roach”, Oxford University Press, Oxford, 2000; Steward, J.; Young, J. “Solid Phase Peptide Synthesis”, Pierce Chemical Com pany, Rockford, 1984.; Benoiton, N.L. “Ch emistry of Peptide Synthesis”, CRC Press , New York, 2006; and Lloyd-Williams, P. ; Albericio, F.; Giralt, E. “Chemical Appr oaches to the Synthesis of Peptides and Proteins”, CRC Press, New York, 1997. The peptides were synthesized using standard solid-phase synthesis with Fmoc / tBu chemistry as exemplified in the above references.

[0201] During the elongation of the peptide chain, the α-amino group of each amino acid was protected with a 9H-fluoren-9-ylmeth oxycarbonyl group (Fmoc). To avoid side reactions during the chain elongation step, the reactive amino acid side chains also carried acid-labile protecting groups, which effectively masked the reactive groups until they were removed by strong acid treatment. After completion of each coupling step, the Fmoc group of the N-terminal amino acid was removed with pi peridine or 4-methylpiperidine, and the resin was thoroughly washed in preparation for the subsequent ca ppling of the Fmoc-protected amino acid derivative.

[0202] The side-chain protecting groups used were S, hY, Bip4CO​​2 H, Phe4COOH, F4pcC For CA, F4ptCCA, F4bcpA, tert-butyl (tBu); for Dap, dDa b, dK, dOrn, K, Prot4NH 2 , for dDap, daMeDab, tert- butoxycarbonyl (Boc); for D, β-methylpentyl ester (OMpe) was used.

[0203] Fmoc-protected amino acids were typically obtained from suppliers such as Sigma-Aldrich, Novabioc hem, Chem-Impex, and Combi-Block.

[0204] B. Synthetic procedures used to produce cyclic peptides Synthesis Scheme 25

Chemical formula

[0205] Peptide solid-phase synthesis protocol A Using the standard solid-phase synthesis using the Fmoc / tBu chemistry summarized above in Scheme 25, the peptide was synthesized using a Liberty Blue (trademark) synthesizer from CEM Corporation. N, N'-diisopropylcarbodiimide (DIC) and cyano(hydroxyimino)acetic acid ethyl ester (Oxyma) were used as coupling agents to form amide bonds between the free amino terminus of the resin-bound protected peptide and the carboxylic acid of the Fmoc-protected amino acid. 2-Chlorotrityl resin (200 - 400 mesh, 0.79 mmol / g loading, 1% cross-linked polystyrene, Novabiochem) loaded with H-Gly was used for the synthesis.

[0206] All amino acids were dissolved in DMF (N,N-dimethylformamide) at a concentration of 0.2 M and used. . The amino acid was activated with an equimolar amount of Oxyma solution (solution in 0.5 M DMF) and a two-fold molar excess of DIC solution (solution in 1.0 M DMF). Alternatively, the amino acid was dissolved in DM F (N,N-dimethylformamide) at a concentration of 0.125 M. The amino acid was activated with an equimolar amount of Oxyma Pure solution (solution in 0.125 M DMF; containing 0.05 M DI EA) and a two-fold molar excess of DIC solution (solution in 0.25 M DMF). The reaction was typically carried out on a 25 μmol scale.

[0207] Each synthesis cycle included deprotection of the Fmoc amino acid with a solution of 20% piperidine in DMF (microwave heating at 90 °C, 2 minutes), and coupling with Fmoc-protected amino acid / DIC / Oxyma ( 5, 5, and 10 equivalents respectively, microwave heating at 90 °C, 2 minutes or 4 minutes) ( repeated twice in case of difficult coupling). The cycle of Fmoc deprotection and coupling of Fmoc-protected amino acids was repeated with the desired monomers until the full-length linear peptide was formed.

[0208] Solid-phase synthesis protocol B for peptides Alternatively, peptides were synthesized using a Biotage (registered trademark) Syro II peptide synthesizer using the standard solid-phase synthesis summarized above in Scheme 25 using Fmoc / tBu chemistry. HATU and DIPEA were used as coupling agents to form an amide bond between the free amino terminus of the resin-bound protected peptide and the carboxylic acid of the Fmo c-protected amino acid. 2-Chlorotrityl resin (200 - 400 mesh, 0.7 9 mmol / g loading, 1% cross-linked polystyrene, Novabiochem) loaded with H-Gly was used for the synthesis. It was. All amino acids were dissolved at a concentration of 0.2 M in 1:1 DMF:NMP. The reaction was typically carried out on a 12 μmol scale.

[0209] Each synthesis cycle included the following: (1) coupling with Fmoc-protected amino acid / H ATU / DIPEA (4, 4, and 8 equivalents respectively; room temperature; 15 minutes) (2 repeated). The mixture was filtered and the peptidyl resin was washed with DMF (twice with 1 mL) ; (2) Fmoc deprotection (repeated 3 times): 20% solution of 4-methylpiperidine in DMF (1 mL; room temperature; 3 minutes). The mixture was filtered and the peptidyl resin was washed with DMF (4 times with 1 mL) . The cycle of Fmoc deprotection and Fmoc-protected amino acid coupling was repeated with the desired monomers until the full-length linear peptide was formed.

[0210] Selective cleavage and macrolactamization of the protected peptide For cleavage of the protected linear peptide from the solid support, the peptidyl resin (about 16 m g) was treated with a solution of 25% hexafluoroisopropanol (HFIP) in D CM at room temperature for 20 minutes, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMF (5 m L). HATU (0.44 equivalent) and DIPEA (2.5 equivalents) were added. The mixture was stirred at room temperature for 5 minutes. Then, an additional 0.66 equivalent of HATU was added. When macrolactamization, monitored by UPLC -MS, was complete, the solvent was removed under reduced pressure.

[0211] Final side-chain deprotection A solution of TFA / H 2 O / TIS (90 / 8 / 2, volume ratio, 1 mL) was added to the crude protected cyclic peptide In addition to the do, the mixture was stirred at room temperature for 10 minutes. Cold diethyl ether (15 mL) was added to the solution. The peptide was precipitated by centrifugation (3200 rpm, -10 °C). The precipitate was washed with diethyl ether (twice with 10 mL) and dried under vacuum overnight to obtain the crude deprotected cyclic peptide as a solid.

[0212] HPLC purification Purification was carried out by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) using a Waters MS-Directed AutoPurification HPLC / MS system with a Waters X-Bridge Prep C 18 OBD Prep column (130 Å, 5 pm, column size 19 × 100 mm). Mobile phase: (A) 0.16% TFA / HPLC water and (B) 0.16% TFA / HPLC acetonitrile; flow rate: 25 mL / min; UV wavelength λ = 215 nm; gradient: 25% to 50% B over 5 minutes. Alternatively, purification was carried out using an Agilent 1290 infinity II preparative LC system and an LC-MSD XT mass spectrometer with a Waters CSH-C18 column (19 × 250 mm, 5 μM). Mobile phase: (A) 0.1% formic acid / HPLC water and (B) 0.1% formic acid / HPLC acetonitrile; flow rate: 25 mL / min; UV wavelength λ = 215 nm; gradient: 20% B for 2.5 minutes, 55% B from 2.5 to 20 minutes. The UV-absorbing fractions containing the target m / z ions were collected, and the fractions containing the product were confirmed by LC / MS. The identification and purity evaluation of the final compound were performed by UPLC-MS measured on a reverse-phase Waters Acquity UPLC-M S system. Column: Waters XSel

[0213] The identification and purity evaluation of the final compound were performed by UPLC-MS measured on a reverse-phase Waters Acquity UPLC-M S system. Column: Waters XSel Ect CSH C18 column (130 Å, 2.5 μm, column size 2.1×50 mm ). Mobile phase: (A) 0.05% TFA / HPLC water and (B) 0.05% TFA / HPL C acetonitrile; injection volume: 1 μL; flow rate: 1 mL / min; UV wavelength λ = 215 nm; gradient elution: from 5% to 100% B in 5 minutes. The fractions containing pure peptide were combined and lyophilized to obtain the final cyclized product as a powder.

[0214] Biological assay: Procedure for IL-6 assay in MRC5 cells The inhibition of IL-1β-induced IL-6 secretion was evaluated in MRC5 cells. 2×EC 80 concentration of recombinant human IL-1β (BioLegend 579404) was prepared in seeding medium, EMEM (ATCC 30-2003), containing 0.025% BSA (Sigma A9576), 1× penicillin / streptomycin (Gibco 15 070-063), 1× NEAA (Gibco 11140-050), 1× Gluta Max (Gibco 35050-061), and 1× sodium pyruvate (Gibc o 11360-070). 20 μL of IL-1β was added to a 384-well collagen-coated plate (Co rning 354664) and dispensed using an ECHO555 liquid handler and incubated for 1 hour at ambient temperature with 200 nL of compound. Human lung fibroblast MR C5 cells (ATCC CCL-171) were added at a density of 3000 cells / 20 μL / well. In a collagen-coated T175 flask (Greiner 661950), 10% fetal bovine serum (Gibco 16140-071), 1× penicillin / strept omycin were added. Tomycin (Gibco 15070-063), 1×NEAA (Gibco 1114 0-050), 1×GlutaMax (Gibco 35050-061), and 1X sodium pyruvate (Gibco 11360-070) containing growth medium EMEM (AT CC 30-2003) to subculture the cells three times to prepare the cells, and collect them in the inoculation medium 5 minutes after digestion with 0.25% trypsin- EDTA (Gibco 25200-056). A 384-well collagen-coated plate containing a final volume of 40 μL was incubated overnight at 37°C, 5% CO 2 2. According to the manufacturer's protocol, for the detection of IL-6 using the human AlphaLISA IL-6 kit (PerkinElmer AL223F), 5 μL of the conditioned medium was transferred to a 384-well AlphaLISA plate (PerkinEl mer 6005350). 20 μL of the acceptor beads / biotinylated antibody mix was added to the 384-well AlphaLISA plate and incubated for 1 hour at ambient temperature . Protect the donor beads mix from light and add 25 μL to the plate and incubate for 30 minutes at ambient temperature . The AlphaLISA plate was read using an EnVision multimode plate reader (PerkinElmer model 2104) with AlphaScree n settings (laser excitation at 680 nm and emission at 570 nm) . The dose-response curve and IC values were analyzed using a four-parameter logistic equation in Spotfire software (Tibco, Palo Alto, CA) . . 50 .

[0215] The amino acid sequences of Examples Nos. 1 to 215 (SEQ ID NOs: 1 to 215), biological activities (MRC I C 50 ), monoisotopic mass calculated values, molecular formulas, molecular weight calculated values, and mass spectrum data ([M+H]+ or [M+2H] / 2+) are provided in Table 1 below.

[0216] Table 1

Table 2

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R １ is CH ３ C(O)NH-CH ２ CH ２ -O- or C １ and C １ teeth, (i) 5-6 membered monocyclic aryl or heteroaryl, wherein the heteroaryl is N, O, and S; (ii) 5 to 7 alkyl groups each containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S. 6-membered monocyclic or bicyclic, saturated cycloalkyl or heterocyclic alkyl; or (iii) 5- to 6-membered monocyclic or bicyclic cycloalkyl and Here, C １ is unsubstituted or independently halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, carboxy, C １ -C ３ Alkoxy, and C ２ -C ３ Acyl One to three R selected from the group consisting of Ｃ１ is substituted by a substituent; R ２ is H, C １ -C ３ Alkyl, benzyl, or phenyl-CH ２ CH ２ - and R ３ is a 9-10 membered bicyclic aryl or heteroaryl, contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S; Here, R ３ is unsubstituted or independently halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, hydroxy and C １ -C ３ Selected from the group consisting of alkoxy 1 to 3 R ３ａ is substituted by a substituent; R ４ is C １ -C ３ Alkyl, HO ２ C-(CH ２ ) ｍ -, H ２ NC(O)-(CH ２ ) ｍ -, (CH ３ ) ２ NC(O)-(CH ２ ) ｍ -, or tetrazolyl-(CH ２ ) ｍ - and R ５ is amino, H ２ N (CH ２ ) ｎ -, H ２ NC(O)-(CH ２ ) ｎ -, CH ３ C (O) NH-, CH ３ C(O)NH(CH ２ ) ｎ -, C ５ , or C ５ -CH ２ - and C ５ teeth, (ii) 5-6 membered monocyclic aryl or heteroaryl, wherein the heteroaryl is N, Contains 1 to 2 heteroatoms selected from the group consisting of O, and S. (ii) 9-10 membered bicyclic aryl or heteroaryl [the bicyclic heteroaryl The ring contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S. (iii) 5- to 6-membered monocyclic or 9- to 10-membered heterocyclic alkyl, wherein the heterocyclic alkyl is , saturated or partially unsaturated, and 1 to 2 hetero atoms selected from the group consisting of N, O, and S. Contains a molybdenum atom. (iv) 5-6 membered monocyclic cycloalkyl; (v) 2,3-dihydroindolyl and Here, C ５ is unsubstituted or independently selected from halo, amino, hydroxy , C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy, H ２ N- (CH ２ ) ｋ -, H ２ NC(O)-(CH ２ ) ｋ -, H ２ C=CH-CH ２ O- and F 1 to 3 R selected from the group consisting of phenyl Ｃ５ is substituted by a substituent; R ６ is H, C １ -C ５ Alkyl, H ２ N (CH ２ ) ｐ - , HOCH ２ -, (CH ３ ) ２ NCH ２ -, H ３ CO-(CH ２ ) ｑ - or C ６ -CH ２ - and C ６ is a 5-membered ring containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S. or a 6-membered monocyclic saturated heterocyclic alkyl; ６ is not replaced or or independently halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, hydroxy and C １ -C ３ 1 to 3 R selected from the group consisting of alkoxy Ｃ６ Substituted by a substituent It is; R ７ is H or C １ -C ３ is alkyl; R ８ａ is H, C １ -C ５ Alkyl, HOCH ２ -, H ２ N (CH ２ ) ｒ -, (CH ３ ) ３ N ＋ (CH ２ ) ｒ - or CH ３ C(O)NH(CH ２ ) ｒ - and R ８ｂ is H or C １ -C ３ is alkyl; R ９ａ is H or C １ -C ３ is alkyl; R ９ｂ is H, C １ -C ５ Alkyl, C ９ -CH ２ - or C ９ -CH ２ CH ２ -Yes the law of nature; C ９ teeth, (i) 5-6 membered monocyclic aryl or heteroaryl, wherein the heteroaryl is N, O and S; (ii) 5- to 6-membered monocyclic, saturated cycloalkyl or heterocyclic alkyl [the heterocyclic alkyl The alkyl group contains 1 to 2 heteroatoms selected from the group consisting of N, O, and S. and Here, C ９ is unsubstituted or independently selected from halo, amino, hydroxy, Cyano, C. １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy, H ２ N-(CH ２ ) ｋ -、H ２ NC(O)-(CH ２ ) ｋ -、H ２ NCH ２ CH ２ O-、C H ３ C(O)NH-CH ２ CH ２ O-, and morpholinyl-CH ２ CH ２ The group consisting of O- One to three R selected from Ｃ９ is substituted by a substituent; R １０ is H, halo, or C １ -C ３ is alkyl; R １１ is H, halo, or C １ -C ３ is alkyl; each occurrence of subscript k is independently 1 or 2; The subscript m is 1 or 2; The subscript n is 1, 2, 3, or 4; subscript p is 1, 2, 3, or 4; The subscript q is 1 or 2; The subscript r is 1, 2, 3, or 4; X １ , X ２ , and X ３ is independently C(H) or N; and A １ and A ２ is independently HO ２ C-, H ２ NC(O)-, CH ３ C(O)N(H)-, H ２ N.S. (O) ２ -, CH ３ S (O) ２ N(H)-, tetrazolyl, and 5-oxoxa and diazolyl.

2. R ５ But, Amino, H ２ N (CH ２ ) ｎ -, H ２ NC(O)-(CH ２ ) ｎ -, C ５ ,also is C ５ -CH ２ - and C ５ but, (i) 5-6 membered monocyclic aryl or heteroaryl, wherein the heteroaryl is N, O and S. (ii) 9-10 membered bicyclic aryl or heteroaryl [the bicyclic heteroaryl The ring contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S. (iii) 5- to 6-membered monocyclic or 9- to 10-membered heterocyclic alkyl, It is saturated or partially unsaturated and has 1 to 2 heteroatoms selected from the group consisting of N, O, and S. including the atom; or (iv) 2,3-dihydroindolyl and Here, C ５ are unsubstituted or independently selected from halo, amino, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy, H ２ N-( CH ２ ) ｋ -, H ２ NC(O)-(CH ２ ) ｋ -, H ２ C=CH-CH ２ O- and Phen 1 to 3 R selected from the group consisting of nyl Ｃ５ is substituted by a substituent; R ６ But, H, C ２ -C ５ Alkyl, H ２ N (CH ２ ) ｐ - , HOCH ２ -, (CH ３ ) ２ NCH ２ -, H ３ CO-(CH ２ ) ｑ - or C ６ -CH ２ - and R ８ａ But, H, C １ -C ３ Alkyl, HOCH ２ - or H ２ N (CH ２ ) ｒ - and ； R ９ａ is H; R ９ｂ But, H, C １ -C ３ Alkyl, C ９ -CH ２ - or C ９ -CH ２ CH ２ -Yes the law of nature; R １０ is H; R １１ is H; the subscript p is 1, 2, or 3; and The compound of claim 1 or a pharma- ceutically acceptable salt thereof, wherein the subscript r is 2, 3, or 4. Rusono salt.

3. C １ is phenyl, pyrimidyl, or piperazinyl, where C １ is replaced No, or 1-2 R Ｃ１ is substituted by a substituent; R ３ is naphthyl or indolyl, where R ３ is not replaced, or , 1 to 2 R ３ａ is substituted by a substituent; C ５ Phenyl, pyridyl, pyrimidyl, naphthyl, indolyl, 7-azaindolyl indole, indazolyl, 2,3-dihydroindolyl, piperidinyl, tetrahydropyranyl or cyclohexyl, where C ５ is unsubstituted or has 1 to 2 R Ｃ５ is replaced by; C ６ is tetrahydropyranyl or morpholinyl; ６ is replaced None or 1-2 R Ｃ６ is replaced by; C ９ａ is H or methyl; C ９ｂ is phenyl, pyridyl, cyclohexyl, morpholinyl, or piperidinyl; where C ９ is unsubstituted or is substituted with 1 to 2 R Ｃ９ Replaced by 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

4. X １ and X ２ is C(H); and R １ is phenyl substituted by carboxy. A physiologically acceptable salt thereof.

5. X １ and X ２ is C(H); and R １ CH ３ C(O)NH-CH ２ CH ２ The compound according to claim 1, A pharma- ceutically acceptable salt thereof.

6. R ２ or a pharma- ceutically acceptable salt thereof.

7. R ３ is indolyl substituted by one halo; or A pharma- ceutically acceptable salt thereof.

8. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is naphthyl.

9. R ４ HO ２ C-(CH ２ ) ｍ -, or a pharma- ceutically acceptable salt thereof, The salt that can be used.

10. X ３ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

11. R ５ But, H ２ N (CH ２ ) ｎ -, indole, 7-azaindole, naphthyl or pyridyl 2. The compound of claim 1, which is dihydropyridine, or a pharma- ceutically acceptable salt thereof.

12. R ５ But, H ２ N (CH ２ ) ｎ -, indole, naphthyl or pyridyl. or a pharma- ceutically acceptable salt thereof.

13. R ６ But, H, HOCH ２ -, C ２ -C ５ Alkyl or H ２ N (CH ２ ) ｐ - is, please 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

14. R ６ But, C ２ -C ５ Alkyl or H ２ N (CH ２ ) ｐ The compound according to claim 13, or a pharma- ceutically acceptable salt thereof.

15. R ７ or a pharma- ceutically acceptable salt thereof.

16. R ８ａ is methyl or H ２ NCH ２ CH ２ - and R ８ｂ or a pharma- ceutically acceptable salt thereof.

17. R ９ｂ but 【Chemistry 2】 2. The compound of claim 1, wherein:

18. R ９ｂ but 【Chemistry 3】 2. The compound of claim 1, wherein:

19. R １０ is H; and R １１ is H, F or Cl, or a pharma- ceutically acceptable salt thereof. Salt.

20. A １ and A ２ Both are HO ２ C- or a pharma- ceutically acceptable The salt that will be used.

21. R １ But 4-CH ３ C(O)-piperazin-1-yl, CH ３ C(O)NH-CH ２ C H ２ -O-, 5-CO ２ H-pyrimidin-2-yl, or 4-CO ２ H-phenyl ； R ２ is H, ethyl, benzyl, or phenyl-CH ２ CH ２ - and R ３ naphth-1-yl, 4-fluoroindol-3-yl, or 4-chloroindol-3-yl. dol-3-yl; R ４ Methyl, HO ２ C-(CH ２ ) ｍ - or H ２ NC(O)-(CH ２ ) ｍ -in can be; R ５ But, Amino, H ２ N (CH ２ ) ｎ -, naphth-1-yl, indol-3-yl, 7-Aza-indol-3-yl, indazol-1-yl, 2,3-dihydroindole pyrid-1-yl, pyrid-3-yl, pyrid-4-yl, piperidin-4-yl, 3-amino aminomethylphenyl, 4-aminomethylphenyl, 3-aminophenyl, 4-aminophenyl phenyl, pyrid-4-yl-CH ２ -, pyrimidin-5-yl, tetrahydropyra N-4-yl-, H ２ NC(O)-(CH ２ ) ２ -, 3-biphenyl, 3-CH ２ =CH -CH ２ O-phenyl, CH ３ C(O)NH-, CH ３ C(O)NH(CH ２ ) ３ -,also is cyclohexyl; ( ６ が、(、(). ３ ) ２ |||| ２ 、(C) ３ ) ３ || ２ 、H ２ !!(|) ２ ) ｐ - , HOCH ２ -, H ３ CCH ２ CH ２ -, morpholin-4-yl-CH ２ - Tetra Hydropyran-4-yl-CH ２ -, (CH ３ ) ２ NCH ２ - or H ３ CO-(CH ２ ) ｑ - and R ７ is H or methyl; R ８ａ H, methyl, HOCH ２ -, H ２ N (CH ２ ) ｒ -, (CH ３ ) ３ NCH ２ CH ２ - or CH ３ C(O)NH(CH ２ ) ４ - and R ８ｂ is H or methyl; R ９ａ is H or methyl; R ９ｂ But H, methyl, H ３ CCH ２ CH ２ CH ２ -, 4-HO-phenyl-CH ２ C H ２ -, phenyl-CH ２ CH ２ -, cyclohexyl-CH ２ CH ２ -, 5-NC-pyridine Do-3-yl-CH ２ CH ２ -, 4-F ３ C-Phenyl-CH ２ -, 3-F ３ C-Feni Ru-CH ２ -, 2-F ３ C-Phenyl-CH ２ -, morpholin-4-yl-CH ２ CH ２ O-Phenyl-CH ２ -, 4-aminophenyl-CH ２ -,4,4-difluorocyclo Xyl-CH ２ -, 4-H ２ NCH ２ CH ２ O-Phenyl-CH ２ -, 4-H ２ NCH ２ CH ２ O-Pyrid-3-yl-CH ２ -, piperidin-4-yl-CH ２ - or 4-C H ３ C(O)NH-CH ２ CH ２ O-Phenyl-CH ２ - and R １０ is H, fluoro, or methyl; R １１ is H, fluoro, or chloro; A １ and A ２ But both are HO ２ C-; and X １ , X ２ , and X ３ is C(H), or The salt that can be used.

22. A compound or pharma- ceutical according to claim 1 selected from the group consisting of SEQ ID NOs: 1 to 215. Acceptable salts thereof.

23. Selected from the group consisting of the following (SEQ ID NOs: 78, 71-7, respectively, in order of appearance): ２、６７、６５、７０、６９、６８、６６、６４、７７、７９、２０９、１９３、２１５ , 212, and 210), the compound of claim 1 or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】 【change】 【change】 【change】

24. A compound according to any one of claims 1 to 23 or a pharma- ceutically acceptable salt thereof, and A pharmaceutical composition comprising a physiologically acceptable carrier.

25. A method for treating atherosclerosis comprising administering to a subject in need of treatment a therapeutically effective amount of Administering a compound according to any one of claims 1 to 23 or a pharma- ceutically acceptable salt thereof The method includes:

26. A method for treating vascular inflammation comprising administering to a subject in need of treatment a therapeutically effective amount of any one of claims 1 to 4.

23. The method of claim 1, further comprising administering a compound according to claim 23 or a pharma- ceutically acceptable salt thereof. method.

27. A method for treating an inflammatory disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of the compound according to claim 1.

23. The method of claim 1, further comprising administering a compound according to claim 1 or a pharma- ceutical acceptable salt thereof to a patient having a pulmonary circulation. How to do it.

28. orally administering to a subject the effective amount of the compound or a pharma- ceutically acceptable salt thereof.

28. The method according to item 25, 26 or 27.

29. A compound according to any one of claims 1 to 23 or a pharma- ceutically acceptable salt thereof in a therapeutic method. Use of that salt.

30. A compound according to any one of claims 1 to 23 for treating atherosclerosis. or a pharma- ceutically acceptable salt thereof.

31. A compound or pharma- ceutical agent according to any one of claims 1 to 23 for the treatment of vascular inflammation. Acceptable uses of its salts.

32. A compound or pharmaceutical composition according to any one of claims 1 to 23 for the treatment of inflammatory disorders. Use of salts thereof that are acceptable for.

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