Classifications

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  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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Definitions

• the present invention relates to novel compounds having SF-1 antagonist activity, polyfunctional molecules containing a portion corresponding to said compounds, in particular SF-1 degradation inducers, and pharmaceutical compositions containing them, etc.
• SF1 or SF-1 Steroidogenic factor 1
• SF1 or SF-1 is a nuclear receptor expressed in the adrenal cortex, gonads, hypothalamus, and pituitary gland, and is an important molecule in the development of the adrenal glands and gonads.
• Non-Patent Document 2 Since mice overexpressing SF-1 have developed adrenal tumors (Non-Patent Document 2), and cases of overexpression of SF-1 protein in adrenal cortical cancer tissue have been reported (Non-Patent Document 3), it is believed that SF-1 contributes to the development and progression of adrenal tumors.
• Non-Patent Documents 4, 5 SF-1 controls the expression of steroid hormone synthesis enzymes such as CYP11A1 and CYP17A1 in the adrenal cortex and testis, and induces the production of steroid hormones such as androgens. Androgens are important for the development and growth of prostate cancer, and although its progression is suppressed by hormone therapy such as castration in the early stages of treatment, it progresses to castration-resistant prostate cancer, which is resistant to hormone therapy. It is known that the growth of castration-resistant prostate cancer depends on androgens derived from the adrenal gland (Non-Patent Document 6).
• TPD Targeted Protein Degradation
• TPD is one of the techniques that utilize such heterobifunctional molecules.
• TPD is a technique that induces degradation of a target protein. It uses heterobifunctional molecules in which a binder portion that binds to a target protein and a binder portion that binds to an E3 ligase are linked by a linker to induce the formation of a complex between the target protein and E3 ligase in cells, and induces the ubiquitination and degradation of the target protein, thereby exhibiting strong physiological activity.
• E3 ligases More than 600 types of E3 ligases have been identified, but only a limited number of them are used in TPD, in particular cereblon (CRBN) and Von Hippel-Lindau (VHL) (Non-Patent Document 8).
• CRBN cereblon
• VHL Von Hippel-Lindau
• Patent Documents 1-9, Non-Patent Document 9 A variety of proteins have been reported as targets of TPD, but no targeted protein degradation inducers targeting SF-1 have been reported to date.
• the object of the present invention is to provide a novel compound having SF-1 antagonist activity, a polyfunctional molecule containing a portion corresponding to the compound, in particular an SF-1 degrader.
• a further object of the present invention is to provide a composition for inhibiting SF-1, a composition for inducing the degradation of SF-1, or a pharmaceutical composition, which contains the compound or polyfunctional molecule.
• Another object of the present invention is to provide a method for treating a disease (in particular, cancer such as castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism) which comprises administering the compound or polyfunctional molecule.
• Yet another object of the present invention is to provide an intermediate that can be used in the production of the compound or polyfunctional molecule.
• a 3-phenylpropylamine derivative compound represented by the following formula (1) etc. has SF-1 antagonist activity, and further found that a multifunctional molecule containing a portion corresponding to the compound represented by the formula (1) etc. can degrade SF-1 protein and inhibit the proliferation of tumor cells, thereby completing the present invention. That is, the present invention relates to the following. [1] The following formula (1):
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• the alkylene and alkenylene are each independently unsubstituted or substituted with 1 to 3 halogens;
• Ring Q2 is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle, a C3-7 cycloalkane ring, a 3- to 7-membered heterocycloalkane ring, a C3-7 cycloalkene ring, a 3- to 7-membered heterocycloalkene ring, a C5-12 spirocycloalkane ring, or a 5- to 12-membered spir
• C 1-6 alkyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of carboxy, hydroxy and -O-C 1-6 alkyl, and n is an integer of 0 to 3, or a pharma- ceutically acceptable salt thereof.
• A is --O-- or --CR b R c --.
• n R1 's are each independently halogen, -O- C1-6 alkyl, -N(H) -C1-3 alkyl, -N( C1-3 alkyl) 2 , or 3- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl has 1 or 2 nitrogen atoms as ring member atoms.
• R 2 and R 3 are each independently hydrogen or C 1-6 alkyl, or a pharma- ceutically acceptable salt thereof.
• R 4 is C 1-6 alkyl, —C( ⁇ O)—R d , or 6- to 12-membered heteroaryl; Where: R d is C 1-6 alkyl; The C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogens or C 3-7 cycloalkyl, and the heteroaryl has 1 or 2 nitrogen atoms as ring member atoms.
• [6] The compound according to any one of [1] to [5], or a pharma- ceutically acceptable salt thereof, wherein ring Q1 is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle, a C3-7 cycloalkane ring, or a C3-7 cycloalkene ring, and the aromatic heterocycle has 1 or 2 nitrogen atoms as ring member atoms.
• L 1 is a single bond, —O—, C 1-3 alkylene, or —C( ⁇ O)—, or a pharma- ceutically acceptable salt thereof.
• A is —O— or —CF 2 —;
• R 1 is halogen, —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, —N(H)—C 1-3 alkyl, —N(C 1-3 alkyl) 2 , or a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom;
• R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;
• Ring Q1 is a benzene ring optionally having
• A is -O-, R2 is methyl; R3 is methyl; R 4 is C 1-6 alkyl optionally substituted with 1 to 3 halogens, —C( ⁇ O)—C 1-6 alkyl optionally substituted with 1 to 3 halogens, or a 6-membered heteroaryl having 1 or 2 nitrogen atoms as ring members (the heteroaryl is optionally substituted with 1 halogen);
• Ring Q1 is a benzene ring optionally having one group selected from the group consisting of halogen and C1-3 alkyl, or a pyridine ring; L 1 is a single bond, —O—, or —C( ⁇ O)—, and ring Q 2 is a benzene ring, a C 4-7 cycloalkane ring, or a C 4-7 cycloalkene ring;
• R 1 is methoxy, and R 4 is 3,3,3-trifluoro-2,2-dimethylpropyl;
• [12] The following groups: trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid, 2-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)phenyl]propanoic acid, ⁇ trans-4-
• a polyfunctional molecule comprising a moiety corresponding to the compound according to any one of [1] to [12] or a pharma- ceutically acceptable salt thereof.
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• the alkylene and alkenylene are each independently unsubstituted or substituted with 1 to 3 halogens;
• Ring Q2 is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle, a C3-7 cycloalkane ring, a 3- to 7-membered heterocycloalkane ring, a C3-7 cycloalkene ring, a 3- to 7-membered heterocycloalkene ring, a C5-12 spirocycloalkane ring, or a 5- to 12-membered spir
• n R1s are each independently halogen, -O- C1-6 alkyl, -N(H) -C1-3 alkyl, -N( C1-3 alkyl) 2 , or 3- to 7-membered heterocycloalkyl, wherein the heterocycloalkyl has 1 or 2 nitrogen atoms as ring member atoms.
• R 4 is C 1-6 alkyl, —C( ⁇ O)—R d , or 6- to 12-membered heteroaryl; Where: R d is C 1-6 alkyl; The C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogens or C 3-7 cycloalkyl, and the heteroaryl has 1 or 2 nitrogen atoms as ring member atoms.
• R d is C 1-6 alkyl
• the C 1-6 alkyl is unsubstituted or substituted with 1 to 3 halogens or C 3-7 cycloalkyl, and the heteroaryl has 1 or 2 nitrogen atoms as ring member atoms.
• A is —O— or —CF 2 —;
• R 1 is halogen, —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, —N(H)—C 1-3 alkyl, —N(C 1-3 alkyl) 2 , or a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom;
• R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;
• Ring Q1 is a benzene ring optionally having
• R 6 is an E3 ligase binding moiety, or a pharma- ceutically acceptable salt thereof.
• R 6 is represented by the following formula:
• R 8 is hydrogen or C 1-6 alkyl
• W, X, Y, and Z each independently represent a nitrogen atom or a carbon atom optionally having one group selected from the group consisting of halogen, C 1-6 alkyl, and —O—C 1-6 alkyl
• l, m, and n each independently represent an integer of 0 to 3
• the wavy line represents the bonding position to L4 .
• the compound or pharma- ceutical acceptable salt thereof according to any one of [18] to [28].
• R 6 is represented by the following formula:
• R 8 is hydrogen or C 1-6 alkyl; V is a halogen, and the wavy line indicates the bonding position to L4 .
• R 1 is —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens;
• R 4 is C 1-6 alkyl optionally substituted by 1 to 3 halogens or C 3-6 cycloalkylmethyl optionally substituted by 1 trifluoromethyl;
• Ring Q 1 is a benzene ring optionally having 1 or 2 groups selected from the group consisting of halogen and C 1-6 alkyl, a 9- to 10-membered bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms, a C 4-7 cycloalkane ring, or a C 4-7 cycloalkene ring, and L 1 is a single bond or -O-;
• A is -O-, R 2 is methyl, and R 3 is methyl; The compound according to any one of [18] to [31], or a pharma- ceutically acceptable salt thereof.
• R 1 is methoxy, and R 4 is 3,3,3-trifluoro-2,2-dimethylpropyl; The compound according to any one of [18] to [32], or a pharma- ceutically acceptable salt thereof.
• Ring Q1 is a benzene ring optionally having one halogen atom; L 1 is a single bond, and ring Q 2 is a cyclohexene ring. The compound according to any one of [18] to [33], or a pharma- ceutically acceptable salt thereof.
• a composition for inhibiting Steroidogenic Factor 1, comprising the compound according to any one of [1] to [12] or a pharma- ceutical acceptable salt thereof, the polyfunctional molecule according to any one of [13] to [17], or the compound according to any one of [18] to [42-6] or a pharma-ceutical acceptable salt thereof, or a crystal thereof.
• a composition for inducing degradation of Steroidogenic Factor 1, comprising the polyfunctional molecule according to any one of [13] to [17], or the compound according to any one of [18] to [42-6], or a pharma- ceutically acceptable salt thereof, or a crystal thereof.
• a pharmaceutical composition comprising the compound according to any one of [1] to [12] or a pharma- ceutical acceptable salt thereof, the polyfunctional molecule according to any one of [13] to [17], or the compound according to any one of [18] to [42-6] or a pharma-ceutical acceptable salt thereof, or a crystal thereof.
• the pharmaceutical composition according to [45] for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism.
• a method for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, breast cancer, Cushing's syndrome, or primary aldosteronism comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of [1] to [12] or a pharmacologic acceptable salt thereof, a polyfunctional molecule according to any one of [13] to [17], or a compound according to any one of [18] to [42-6] or a pharmacologic acceptable salt thereof, or a crystal thereof.
• a method for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, Cushing's syndrome, or primary aldosteronism comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of [1] to [12] or a pharmacologic acceptable salt thereof, a polyfunctional molecule according to any one of [13] to [17], or a compound according to any one of [18] to [42-6] or a pharmacologic acceptable salt thereof, or a crystal thereof.
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof has SF-1 antagonist activity, and therefore can be used as an SF-1 antagonist or SF-1 inhibitor.
• SF-1 is known to be involved in the development and progression of various diseases such as adrenal cortical carcinoma and castration-resistant prostate cancer
• the compound represented by formula (1) of the present invention or a pharma-ceutically acceptable salt thereof can be used in the treatment of such diseases.
• the compound represented by formula (1) of the present invention or a pharma-ceutically acceptable salt thereof has SF-1 antagonist activity, it can be used as a partial structure in a larger molecule (e.g., a multifunctional molecule) by combining it with another functional moiety.
• the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof specifically binds to SF-1, and therefore can be used as an SF-1 binder.
• the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof can be combined with other functional moieties to be used as an SF-1 binding moiety in a larger molecule (e.g., a polyfunctional molecule).
• a polyfunctional molecule containing a moiety corresponding to the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof and an E3 ligase binding moiety, particularly a compound represented by formula (2) of the present invention or a pharma- ceutically acceptable salt thereof, or a crystal thereof can degrade SF-1 protein and inhibit the proliferation of tumor cells, and therefore can be used as an SF-1 inhibitor and an SF-1 degrader, and can also be used for the treatment of SF-1-related diseases such as adrenocortical carcinoma and castration-resistant prostate cancer.
• the vertical axis of the figure shows the diffraction intensity in counts/second (cps), and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
• the vertical axis of the figure shows the diffraction intensity in counts/second (cps), and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
• the vertical axis of the figure shows the diffraction intensity in counts/second (cps), and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
• 1 is a powder X-ray diffraction pattern of the crystals obtained in Example CL1.
• the vertical axis of the figure indicates the diffraction intensity in counts/second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
• 1 is a powder X-ray diffraction pattern of the crystals obtained in Example CM1.
• the vertical axis of the figure indicates the diffraction intensity in counts/second (cps), and the horizontal axis indicates the value of the diffraction angle 2 ⁇ .
• the vertical axis of the figure shows the diffraction intensity in counts/second (cps), and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
• Powder X-ray diffraction pattern of the crystal obtained in Example CO1.
• the vertical axis of the figure shows the diffraction intensity in counts/second (cps), and the horizontal axis shows the value of the diffraction angle 2 ⁇ .
• steroidogenic factor 1 means the protein encoded by the NR5A1 gene, and may be abbreviated or abbreviated as SF-1, hSF-1, SF1, Ad4BP, AD4BP, ELP, FTZ1, TZF1, POF7, SPGF8, SRXX4, or SRXY3.
• SF-1 antagonist refers to a substance that reduces, interferes with, or neutralizes the action, activity, or effect of SF-1.
• halogen means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I).
• alkyl refers to straight-chain or branched-chain alkyl.
• C 1-6 alkyl refers to alkyl having 1 to 6 carbon atoms
• C 1-3 alkyl refers to alkyl having 1 to 3 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
• alkylene refers to straight-chain or branched-chain alkylene.
• C 1-6 alkylene refers to alkylene having 1 to 6 carbon atoms
• C 1-3 alkylene refers to alkylene having 1 to 3 carbon atoms.
• alkylene include, but are not limited to, methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene, n-hexylene, and the like.
• alkenyl refers to straight-chain or branched-chain alkenyl.
• C 2-6 alkenyl refers to alkenyl having 2 to 6 carbon atoms
• C 2-5 alkenyl refers to alkenyl having 2 to 5 carbon atoms.
• alkenyl include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, buta-2,3-dienyl, pentenyl, hexenyl, and the like.
• alkenylene refers to straight-chain or branched-chain alkenylene.
• C2-3 alkenylene refers to alkenylene having 2 to 3 carbon atoms.
• alkenylene include, but are not limited to, ethenylene (vinylene), 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, buta-2,3-dienylene, pentenylene, hexenylene, and the like.
• haloalkyl means an alkyl substituted with one or more halogens
• C1-3 haloalkyl means a C1-3 alkyl substituted with one or more halogens.
• haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, pentafluoroethyl, tetrafluoroethyl, monofluoroethyl, trifluoroethyl, trichloromethyl, and the like.
• aromatic hydrocarbon ring refers to a monocyclic or polycyclic hydrocarbon ring in which at least one of the rings is an aromatic ring.
• aryl refers to a group derived from an aromatic hydrocarbon ring.
• C 6-12 aryl refers to an aryl containing 6 to 12 carbon atoms as ring member atoms
• C 6-12 monocyclic or bicyclic aromatic hydrocarbon ring refers to a monocyclic or bicyclic aromatic hydrocarbon ring containing 6 to 12 carbon atoms as ring member atoms.
• aromatic hydrocarbon ring examples include, but are not limited to, benzene, indene, naphthalene, anthracene, and the like.
• aryl examples include, but are not limited to, phenyl, indenyl, naphthyl, anthryl, and the like.
• aromatic heterocycle means a monocyclic or polycyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur as ring member atoms, and at least one of the rings is an aromatic ring.
• heteroaryl means a group derived from an aromatic heterocycle.
• 6- to 12-membered heteroaryl means a heteroaryl consisting of 6 to 12 ring member atoms
• 6- to 12-membered monocyclic or bicyclic aromatic heterocycle means a monocyclic or bicyclic aromatic heterocycle consisting of 6 to 12 ring member atoms.
• aromatic heterocycle examples include, but are not limited to, thiophene, pyrrole, pyrazole, triazole, oxazole, oxadiazole, thiazole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, quinoxaline, benzothiophene, benzimidazole, benzotriazole, benzofuran, etc.
• heteroaryl examples include, but are not limited to, thienyl, pyrrolyl, pyrazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, quinolyl, quinoxalyl, benzothiophenyl, benzimidazolyl, benzotriazolyl, and benzofuranyl.
• examples of "6-membered heteroaryl having one or two nitrogen atoms as ring atoms” include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.
• examples of the "6- to 12-membered monocyclic or bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring atoms" include pyridine, pyrazine, pyrimidine, 7-membered rings such as azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine; 8-membered rings such as azocine; 9-membered rings such as azonine; 6/5-membered fused rings such as indole, isoindole, indazole, benzimidazole, imidazopyridine (including imidazo[1,2-a]pyridine); and 6/6-membered fused rings such as quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline.
• examples of the "9- to 10-membered bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring atoms include, but are not limited to, 6/5-membered fused rings such as indole, isoindole, indazole, benzimidazole, and imidazopyridine (including imidazo[1,2-a]pyridine); and 6/6-membered fused rings such as quinoline, isoquinoline, quinazoline, quinoxaline, and cinnoline.
• a "cycloalkane ring” refers to a hydrocarbon ring that does not contain an unsaturated bond.
• a "cycloalkyl” refers to a monovalent group derived from a cycloalkane ring.
• a "cycloalkane ring” may be a monocyclic cycloalkane, a fused bicyclic cycloalkane, a spiro ring, or a bridged cycloalkane in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.
• a "C 3-7 cycloalkane ring” and a “C 4-7 cycloalkane ring” refer to a cycloalkane ring having 3 to 7 and 4 to 7 carbon atoms, respectively
• a "C 3-7 cycloalkyl” and a “C 3-6 cycloalkyl” refer to a cycloalkyl having 3 to 7 and 3 to 6 carbon atoms, respectively
• a "C 5-12 spirocycloalkane ring” refers to a spirocycloalkane ring having 5 to 12 carbon atoms.
• Examples of the "cycloalkane ring” include cyclobutane, cyclopentane, cyclohexane, and cycloheptane.
• cycloalkylene refers to a divalent group derived from a cycloalkane ring.
• C 3-6 cycloalkylene refers to a cycloalkylene having 3 to 6 carbon atoms. Examples of “cycloalkylene” include, but are not limited to, cyclobutylene, cyclopentylene, cyclohexylene, and the like.
• a "cycloalkene ring” refers to a hydrocarbon ring containing at least one carbon-carbon double bond.
• a "cycloalkene ring” may be a monocyclic cycloalkene, a fused bicyclic cycloalkene, or a bridged cycloalkene in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.
• C 3-7 cycloalkene ring refers to a cycloalkene ring having 3 to 7 carbon atoms
• C 4-7 cycloalkene ring refers to a cycloalkene ring having 4 to 7 carbon atoms
• cycloalkene rings include, but are not limited to, cyclobutene, cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptene, 1,3-cycloheptadiene, 1,4-cycloheptadiene, cycloheptatriene, and the like.
• heterocycloalkane ring refers to a saturated ring containing, as ring member atoms, one or more heteroatoms selected from atoms other than carbon, e.g., nitrogen, oxygen, and sulfur.
• a heterocycloalkyl refers to a monovalent group derived from a heterocycloalkane ring.
• heterocycloalkane ring may be a monocyclic heterocycloalkane, a fused bicyclic heterocycloalkane, a spiro ring, or a bridged heterocycloalkane in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.
• the term "3- to 7-membered heterocycloalkane ring” refers to a heterocycloalkane ring having a total of 3 to 7 carbon atoms and heteroatoms as ring member atoms
• the term "5- to 12-membered spiroheterocycloalkane ring” refers to a spiroheterocycloalkane ring having a total of 5 to 12 carbon atoms and heteroatoms as ring member atoms
• the term "3- to 7-membered heterocycloalkyl” refers to a heterocycloalkyl having a total of 3 to 7 carbon atoms and heteroatoms as ring member atoms.
• heterocycloalkyl examples include oxiranyl, thiaarnyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1,4-dithia ...
• nyl piperazinyl, 1,4-azathiyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, 1,4-azaphosphinanyl, 1,4-diazepanyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1, 2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, chromanyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl,
• a “heterocycloalkene ring” refers to a ring containing one or more heteroatoms other than carbon, such as nitrogen, oxygen, and sulfur, and containing at least one double bond.
• a “heterocycloalkene ring” may be a monocyclic heterocycloalkene, a fused bicyclic heterocycloalkene, a spiro ring, or a bridged heterocycloalkene in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms.
• a "3- to 7-membered heterocycloalkene ring” refers to a heterocycloalkene ring having a total of 3 to 7 carbon atoms and heteroatoms as ring member atoms.
• heterocycloalkene rings include, but are not limited to, imidazoline, tetrahydropyridine, dihydropyridine, pyran, thiopyran, dihydropyran, dihydrofuran, dihydropyrazine, octahydroquinoline, octahydroisoquinoline, dihydrothiophene, dihydropyrroline, and the like.
• stereochemical symbols with * e.g., R * , S * , etc.
• * indicate the relative configuration of the asymmetric center.
• pharmaceutical acceptable means that it has no significant toxicity and can be used as a pharmaceutical composition. Therefore, in this specification, “pharmaceutical acceptable salt” means that it has no significant toxicity and can be used as a pharmaceutical composition.
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• the alkylene and alkenylene are each independently unsubstituted or substituted with 1 to 3 halogens;
• Ring Q2 is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle, a C3-7 cycloalkane ring, a 3- to 7-membered heterocycloalkane ring, a C3-7 cycloalkene ring, a 3- to 7-membered heterocycloalkene ring, a C5-12 spirocycloalkane ring, or a 5- to 12-membered spir
• C 1-6 alkyl is unsubstituted or substituted with 1 to 2 groups selected from the group consisting of carboxy, hydroxy and -O-C 1-6 alkyl, and n is an integer of 0 to 3, or a pharma- ceutically acceptable salt thereof.
• a in the above formula (1) is -O-, -S-, or -CR b R c -, preferably -O- or -CR b R c -, more preferably -O- or -CF 2 -, and particularly preferably -O-.
• R a in the above formula (1) is hydrogen or C 1-2 alkyl, preferably hydrogen or methyl, and more preferably hydrogen.
• R b and R c in the above formula (1) are each independently hydrogen or halogen, preferably halogen, and more preferably F.
• n R 1s in the above formula (1) are each independently halogen, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , or 3- to 7-membered heterocycloalkyl (wherein the heterocycloalkyl has 1 or 2 nitrogen atoms as ring member atoms); in another embodiment of the present invention, n R 1s in the above formula (1) are each independently halogen, -O-C 1-6 alkyl optionally substituted with 1 to 3 halogens, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , or 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom, preferably -O-C 1-6 alkyl optionally substituted with 1 to 3 halogens, -N(C 1-3 alkyl) 2 .
• a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring atom, more preferably —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, even more preferably —O—C 1-3 alkyl, and most preferably methoxy.
• R 2 in the above formula (1) is hydrogen or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl or ethyl, and even more preferably methyl.
• R 3 in the above formula (1) is hydrogen or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl or ethyl, and even more preferably methyl.
• ring Q 1 in the above formula (1) is a C 6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle (the aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms), a C 3-7 cycloalkane ring, or a C 3-7 cycloalkene ring; in another embodiment of the present invention, ring Q 1 in the above formula (1) is a benzene ring optionally having 1 or 2 groups selected from the group consisting of halogen and C 1-3 alkyl, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms, a C 4-7 cycloalkane ring, or a C 4-7 cycloalkene ring, preferably a benzene ring optionally having one substituent selected from the group consisting of halogen and C 1-3 alkyl, or a
• L 1 in the above formula (1) is preferably a single bond, —O—, C 1-3 alkylene-, or —C( ⁇ O)—, more preferably a single bond, —O—, —CH 2 —, or —C( ⁇ O)—, even more preferably a single bond, —O—, or —C( ⁇ O)—, and particularly preferably a single bond.
• ring Q2 in the above formula (1) is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a C3-7 cycloalkane ring, a 3- to 7-membered heterocycloalkane ring (the heterocycloalkane ring has 1 or 2 nitrogen atoms as ring member atoms), a C3-7 cycloalkene ring, or a 5- to 12-membered spiroheterocycloalkane ring (the spiroheterocycloalkane ring has 1 or 2 nitrogen atoms as ring member atoms), and in another embodiment of the present invention, ring Q2 in the above formula (1) is a benzene ring optionally substituted with one halogen, a C4-7 cycloalkane ring, a C4-7 cycloalkene ring optionally substituted with one halogen, a piperidine ring, or a 7-azaspiro[
• R 5 in the above formula (1) is preferably carboxy, or C 1-6 alkyl optionally substituted with 1 to 2 groups selected from the group consisting of carboxy, hydroxy, and -O-C 1-6 alkyl, more preferably carboxy, or C 1-6 alkyl optionally substituted with one group selected from the group consisting of carboxy and hydroxy, even more preferably C 1-6 alkyl optionally substituted with one group selected from the group consisting of carboxy and hydroxy.
• A is -O-, R2 is methyl; R3 is methyl; R 4 is C 1-6 alkyl optionally substituted with 1 to 3 halogens, —C( ⁇ O)—C 1-6 alkyl optionally substituted with 1 to 3 halogens, or a 6-membered heteroaryl having 1 or 2 nitrogen atoms as ring members (the heteroaryl is optionally substituted with 1 halogen); Ring Q1 is a benzene ring optionally having one substituent selected from the group consisting of halogen and C1-3 alkyl, or a pyridine ring;
• the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein L1 is a single bond, --O--, or --C(.dbd.O)---, and ring Q2 is a benzene ring, a C4-7 cycloalkane ring, or a C4-7 cycloalkene
• the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (1') or a pharma- ceutically acceptable salt thereof.
• A is —O— or —CF 2 —;
• R 1 is halogen, —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, —N(H)—C 1-3 alkyl, —N(C 1-3 alkyl) 2 , or a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom;
• R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;
• Ring Q1 is a benzene ring optionally having
• A is -O-, R2 is methyl; R3 is methyl; R 4 is C 1-6 alkyl optionally substituted with 1 to 3 halogens, —C( ⁇ O)—C 1-6 alkyl optionally substituted with 1 to 3 halogens, or a 6-membered heteroaryl having 1 or 2 nitrogen atoms as ring members (the heteroaryl is optionally substituted with 1 halogen); Ring Q1 is a benzene ring optionally having one substituent selected from the group consisting of halogen and C1-3 alkyl, or a pyridine ring;
• the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein L1 is a single bond, --O--, or --C(.dbd.O)---, and ring Q2 is a benzene ring, a C4-7 cycloalkane ring, or a C4-7 cycloalken
• the present invention is directed to a compound of the following group: trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid, 2-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)phenyl]propanoic acid, ⁇ trans-4-[(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl
• the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof has SF-1 antagonist activity, and therefore can be used as a partial structure in a larger molecule (e.g., a multifunctional molecule) by combining with other functional moieties.
• the compound represented by formula (1) of the present invention or a pharma- ceutically acceptable salt thereof specifically binds to SF-1, and therefore can be used as a SF-1 binding moiety in a larger molecule (e.g., a multifunctional molecule) by combining with other functional moieties.
• a polyfunctional molecule that contains a moiety corresponding to the compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof.
• the compound represented by formula (1) is a complete structure in itself, so when linking it to other partial structures, it is necessary to remove a specific atom or atomic group from any position in the compound.
• a carboxy group present at the end of the compound represented by formula (1) is linked to an amino group in another partial structure by dehydration condensation, the "part corresponding to the compound represented by formula (1)" in the molecule after linking is structurally different from the compound represented by formula (1) in that the "-OH" part of the carboxy group has been removed.
• the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof from which a specific atom or atomic group has been removed due to the linking reaction is referred to as the "part corresponding to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof.”
• the linking point when linking the compound represented by formula (1) to another partial structure is not particularly limited as long as it maintains the function of the compound represented by formula (1), particularly SF-1 inhibitory activity and SF-1 binding activity, but preferably includes any position in R5 .
• the polyfunctional molecule of the present invention has a portion corresponding to the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof linked directly to another functional portion at any position in R5 or linked via a linker.
• the any position in R5 preferably includes a carboxy portion or an amine portion in R5 .
• a "multifunctional molecule” means a molecule that includes a moiety having two or more specific functions (functionalities).
• the moiety corresponding to the compound represented by formula (1) of the present invention or a pharma- ceutical acceptable salt thereof has SF-1 antagonist activity or SF-1 binding activity, and therefore the multifunctional molecule of the present invention includes at least one other functional moiety having a specific function.
• the multifunctional molecule of the present invention is a "bifunctional molecule”
• the multifunctional molecule of the present invention is a "trifunctional molecule", a "tetrafunctional molecule”, and a "pentafunctional molecule”, respectively.
• the multifunctional molecule of the present invention is a bifunctional molecule, a trifunctional molecule, a tetrafunctional molecule, or a pentafunctional molecule, preferably a bifunctional molecule, a trifunctional molecule, or a tetrafunctional molecule, more preferably a bifunctional molecule or a trifunctional molecule, and particularly preferably a bifunctional molecule.
• the other functional moiety may be a moiety having the same function as the moiety corresponding to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof, or may be a moiety having a different function.
• the polyfunctional molecule is a homopolyfunctional molecule, and in another aspect, the polyfunctional molecule is a heteropolyfunctional molecule.
• the polyfunctional molecule of the present invention is preferably a heterobifunctional molecule or a heterotrifunctional molecule, and more preferably a heterobifunctional molecule.
• the other functional moieties contained in the polyfunctional molecule of the present invention are not particularly limited, but are preferably those which can be reasonably expected to have beneficial effects such as enhancing or complementing the activity of a moiety having SF-1 inhibitory/binding activity when linked to the moiety.
• E3 ligase binding moieties or E3 ligase-recruiting moieties
• autophagy-recruiting moieties include, but are not limited to, E3 ligase binding moieties (or E3 ligase-recruiting moieties), autophagy-recruiting moieties, lysosome-recruiting moieties, kinase-recruiting moieties, phosphatase-recruiting moieties, glycosyltransferase-recruiting moieties, acetyltransferase-recruiting moieties, ADCs, and the like.
• such other functional moieties may include, for example, substances that are useful exclusively for research purposes, such as specific molecular markers and radioactive labels, or functional substituents for making the compound of formula (1) into a prodrug.
• a "binding moiety” refers to a moiety that binds to a target (e.g., an "E3 ligase")
• a "mobilization moiety” refers to a moiety that allows for the recruitment of a target (e.g., an "E3 ligase”). Since a moiety that binds to a target can be used to recruit the target, in one embodiment of the present invention, the terms "binding moiety” and “mobilization moiety” are used interchangeably.
• E3 ligase binding site refers to a protein that recruits an E2 ubiquitin-conjugating enzyme carrying ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 protein to the substrate.
• a multifunctional molecule in which a moiety corresponding to the compound represented by formula (1) of the present invention or a pharma- ceutical acceptable salt thereof is linked to an E3 ligase-binding moiety can induce degradation of SF-1.
• a multifunctional molecule comprising a moiety corresponding to the compound represented by formula ( 1 ) of the present invention or a pharma- ceutical acceptable salt thereof and another functional moiety, wherein the compound or the moiety corresponding to a pharma-ceutical acceptable salt thereof is linked directly or via a linker to the other functional moiety at any position in R5, and the other functional moiety is an E3 ligase-binding moiety.
• TPD Targeted Protein Degradation
• the POI binding portion and the E3 ligase binding portion each play an almost independent and separate role, and therefore, when each block (part) that has been proven to function is combined, the expected effect is highly likely to be obtained. Therefore, as the E3 ligase binding portion (or a combination of a ligase binding portion and a linker portion) in the multifunctional molecule of the present invention, the E3 ligase binding portion (or a combination of a ligase binding portion and a linker portion) of any target protein degradation inducer that has been confirmed to be useful, for example, the E3 ligase binding portion (or a combination of a ligase binding portion and a linker portion) disclosed in Patent Documents 1-9 and Non-Patent Documents 7-9 can be applied.
• E3 ligase binding moieties in heterobifunctional molecules such as ARV-471, ARV-110, CFT8634, CFT7455, CFT1946, ARV-766, AR-LDD, GT20029, NX-2127, HSK29116, BGB-16673, DT-2216, FHD-609, LNK01002, KT-474, KT-413, NX-5948, KT-333, CG001419, and CFT8919, which have been reported to be subjected to clinical trials or preclinical trials.
• the moiety corresponding to the compound of formula (1) of the present invention or a pharma- ceutical acceptable salt thereof may be substituted with an E3 ligase binding moiety (or a combination of a ligase binding moiety and a linker moiety) of any target protein degradation inducer that has been confirmed to be useful thus far, such as the E3 ligase binding moieties (or combinations of a ligase binding moiety and a linker moiety) disclosed in Patent Documents 1-8, Non-Patent Documents 7-9, etc., or ARV-471, ARV-110, CFT8634, CFT7455, CFT1946, ARV-766, AR- When linked to the E3 ligase binding portion (or a combination of the ligase binding portion and the linker portion) of heterobifunctional molecules such as LDD, GT20029, NX-2127, HSK29116, BGB-16673, DT-2216, FHD-609, LNK01002, KT-4
• the E3 ligases targeted by the multifunctional molecules of the present invention include cereblon (CRBN), von Hippel-Lindau (VHL), cellular inhibitor of apoptosis protein (cIAP), DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 15 (DCAF15), DDB1 and CUL4 associated factor 1
• CRBN cereblon
• VHL von Hippel-Lindau
• cIAP cellular inhibitor of apoptosis protein
• DCAF11 DDB1 and CUL4 associated factor 11
• DCAF15 DDB1 and CUL4 associated factor 15
• DDB1 and CUL4 associated factor 1 examples include mouse double minute 2 homolog (MDM2), Kelch-like ECH-associated protein 1 (KEAP1), RING finger protein 4 (RNF4), RING finger protein 114 (RNF114), Aryl hydrocarbon receptor (AhR), or Fem-1 homolog B (FEM1B), and preferably, CRBN, VHL,
• the E3 ligase binding portion is a CRBN binding portion, a VHL binding portion, a cIAP binding portion, a DCAF11 binding portion, a DCAF15 binding portion, a DCAF16 binding portion, an MDM2 binding portion, a KEAP1 binding portion, an RNF4 binding portion, an RNF114 binding portion, an AhR binding portion, or an FEM1B binding portion, preferably a CRBN binding portion, a VHL binding portion, or a cIAP binding portion, more preferably a CRBN binding portion or a VHL binding portion, and even more preferably a CRBN binding portion.
• the "CRBN binding moiety" in the present invention any compound moiety having any structure can be used without limitation as long as it exhibits the desired binding ability to CRBN.
• the CRBN binding moieties disclosed in Patent Documents 1-9 and Non-Patent Documents 7-9 can be exemplified.
• thalidomide and its derivatives lenalidomide and pomalidomide are known to exhibit binding ability to CRBN. Therefore, in one aspect of the present invention, the CRBN binding moiety is selected from thalidomide, lenalidomide, pomalidomide, thalidomide derivatives, lenalidomide derivatives, and pomalidomide derivatives.
• the "derivative" in the context of the E3 ligand binding moiety means one that has a structural difference from the parent molecule, the E3 ligand binding molecule, but maintains the desired binding activity to the target E3 ligase, or has a higher binding activity to the target E3 ligase.
• compounds designated ARV-471, ARV-110, CFT8634, CFT7455, CFT1946, AR-LDD, NX-2127, KT-413, NX-5948, CG001419, and CFT8919 have been subjected to clinical or preclinical testing as target protein degraders or proteolysis targeting chimeras (PROTACs) containing a CRBN-binding moiety.
• the CRBN-binding moiety may be the CRBN-binding moiety in these compounds.
• the E3 ligase binding portion (CRBN binding portion) of the present invention may be that mentioned in Non-Patent Document 9.
• the VHL binding moiety may include VH032 (J. D. Sander and J. K. Joung, Nat. Biotechnol., 2014, 32, 347-355), VH101 (M. Toure and C. M. Crews, Angew. Chem., Int. Ed., 2016, 55, 1966-1973), VH298 (S. L. Schreiber, Cell, 2021, 184, 3-9), or derivatives thereof.
• VH032 J. D. Sander and J. K. Joung, Nat. Biotechnol., 2014, 32, 347-355
• VH101 M. Toure and C. M. Crews, Angew. Chem., Int. Ed., 2016, 55, 1966-1973
• VH298 S. L. Schreiber, Cell, 2021, 184, 3-9, or derivatives thereof.
• the cIAP binding moiety may include MeBS (J. A. Doudna and E. Charpentier, Science, 2014, 346, 1258096), MV1 (Y. Fedorov, et al., RNA, 2006, 12, 1188-1196), LCL161 (A. L. Jackson, et al., J. Burchard, M. Mao, B. Li, G. Cavet and P. S. Linsley, Nat. Biotechnol., 2003, 21, 635-637), or derivatives thereof.
• MeBS J. A. Doudna and E. Charpentier, Science, 2014, 346, 1258096
• MV1 Y. Fedorov, et al., RNA, 2006, 12, 1188-1196
• LCL161 A. L. Jackson, et al., J. Burchard, M. Mao, B. Li, G. Cavet and P. S. Linsley, Nat. Biotechnol., 2003, 21, 635-637
• the DCAF11 binding moiety may include the ligands or derivatives thereof disclosed in S. Khan, X. et al., Nat. Med., 2019, 25, 1938-1947.
• the DCAF15 binding moiety can include E7820 (L. Snyder, American Association for Cancer Research Annual Meeting, April 2021) or a derivative thereof.
• the DCAF16 binding moiety may be KB02 (G. Weng, et al., Nucleic Acids Res., 2021, 49, D1381-D1387) or a derivative thereof.
• the MDM2 binding moiety may include Nutlin-3a (J. S. Lazo and E. R. Sharlow, Annu. Rev. Pharmacol. Toxicol., 2016, 56, 23-40), Idasanutlin (L. Jin, W. Wang and G. Fang, Annu. Rev. Pharmacol. Toxicol., 2014, 54, 435-456), or a derivative thereof.
• the KEAP1 binding moiety may include CDDO (R. G. Guenette, et al., Chem. Soc. Rev., 2022, 51, 5740-5756), a ligand disclosed in L. Snyder, American Association for Cancer Research Annual Meeting, April 2021, or a derivative thereof.
• CDDO R. G. Guenette, et al., Chem. Soc. Rev., 2022, 51, 5740-5756
• a ligand disclosed in L. Snyder, American Association for Cancer Research Annual Meeting, April 2021 or a derivative thereof.
• the RNF4 binding moiety may be CCW-16 (I. Sosic, et al., Chem. Soc. Rev., 2022, 51, 3487-3534) or a derivative thereof.
• the RNF114 binding moiety may include Nimbolide (M. Bekes, et al., Nat. Rev. Drug Discovery, 2022, 21, 181-200), EN219 (M. He, et al., Signal Transduction Targeted Ther., 2022, 7, 181), or a derivative thereof.
• the AhR binding moiety can include beta-NF (K. Li and C. M. Crews, Chem. Soc. Rev., 2022, 51, 5214-5236) or a derivative thereof.
• the FEM1B binding moiety may be EN106 (M. He, et al., Front. Cell Dev. Biol., 2021, 9, 685106) or a derivative thereof.
• linker In the polyfunctional molecule of the present invention, the moiety corresponding to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof may be directly linked to other functional moieties as long as it exhibits the desired function (e.g., SF-1 inhibitory activity or SF-1 decomposition activity), but is preferably linked via a linker.
• a polyfunctional molecule is provided in which the moiety corresponding to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof and the other functional moiety (e.g., E3 ligase binding moiety) are directly linked or linked via a linker, preferably linked via a linker.
• the linker used in the polyfunctional molecule of the present invention is not particularly limited as long as it does not impair the desired function (e.g., SF-1 inhibitory activity or SF-1 decomposition activity), and therefore, any linker of a structure that is reasonably expected not to impair the desired function (e.g., SF-1 inhibitory activity or SF-1 decomposition activity) can be adopted.
• the composition and length of the linker can affect the formation of the ternary complex of POI/heterobifunctional molecule/E3 ligase, the degradation-inducing activity of POI, and the target selectivity.
• Many linker structures used in targeted protein degradation inducers and technical theories for designing and optimizing them have been reported (e.g., Patent Documents 1-8, Non-Patent Documents 7-9).
• the present invention presents a novel POI binding moiety that can be used in such a TPD platform, and therefore there is a high probability that the desired effect will be obtained when a linker whose effectiveness has already been proven is adopted.
• the linker portion in the multifunctional molecule of the present invention may be any linker portion of a target protein degradation inducer that has been confirmed to be useful, such as the linker portions disclosed in Patent Documents 1-8 and Non-Patent Documents 7-9, or the linker portions of ARV-471, ARV-110, CFT8634, ARV-766, AR-LDD, GT20029, NX-2127, HSK29116, BGB-16673, DT-2216, FHD-609, LNK01002, KT-474, KT-413, NX-5948, KT-333, CG001419, CFT7455, CFT1946, or CFT8919 that have been reported to have been subjected to clinical trials or preclinical trials.
• the linker may be a linker structure shown in Table 2 of Non-Patent Document 8, specifically, the following formula:
• n and m each independently represent an integer from 1 to 10.
• n and m each independently represent an integer from 1 to 10.
• n and m in the above formula are each independently an integer from 1 to 5, in another embodiment of the present invention, n and m in the above formula are each independently an integer from 1 to 4, in yet another embodiment of the present invention, n and m in the above formula are each independently an integer from 1 to 3, and in yet another embodiment of the present invention, n and m in the above formula are each independently an integer from 1 to 3, and in yet another embodiment of the present invention, n and m in the above formula are each independently an integer from 1 to 2.
• the binding position of the linker and POI or the linker and E3-ligase can also affect the ternary complex formation of POI/heterobifunctional molecule/E3 ligase, the degradation-inducing activity of POI, and the target selectivity.
• the binding position of the linker it is generally considered essential that the linker is not linked to the main active site of the POI binding portion or the E3 ligase binding portion, and that the linker is linked to a solvent-exposed site of the POI binding portion or the E3 ligase binding portion.
• the portion corresponding to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof is preferably linked to the linker at any position in R5 , and particularly preferably linked to the linker at the carboxy portion or amine portion in R5 .
• the linking position of the linker and the E3 ligase binding portion is appropriately selected from the above viewpoint with reference to known reports.
• the linker of the present invention may be "-L 2 -L 3 -L 4 -" as defined in formula (2) below.
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• a in the above formula (2) is —O—, —S—, or —CR b R c —, preferably —O— or —CR b R c —, more preferably —O— or —CF 2 —, and particularly preferably —O—.
• R a in the above formula (2) is hydrogen or C 1-2 alkyl, preferably hydrogen or methyl, and more preferably hydrogen.
• R b and R c in the above formula (2) are each independently hydrogen or halogen, preferably halogen, and more preferably F.
• n R 1s in the above formula (2) are each independently halogen, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , or 3- to 7-membered heterocycloalkyl (wherein the heterocycloalkyl has 1 or 2 nitrogen atoms as ring member atoms); in another embodiment of the present invention, n R 1s in the above formula (1) are each independently halogen, -O-C 1-6 alkyl optionally substituted with 1 to 3 halogens, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , or 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom, preferably -O-C 1-6 alkyl optionally substituted with 1 to 3 halogens, -N(C 1-3 alkyl) 2 .
• a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring atom, more preferably —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, even more preferably —O—C 1-3 alkyl, and most preferably methoxy.
• R 2 in the above formula (2) is hydrogen or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl or ethyl, and even more preferably methyl.
• R 3 in the above formula (2) is hydrogen or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl or ethyl, and even more preferably methyl.
• ring Q 1 in the above formula (2) is a C 6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle (the aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms), a C 3-7 cycloalkane ring, or a C 3-7 cycloalkene ring; in another embodiment of the present invention, ring Q 1 in the above formula (1) is a benzene ring optionally having 1 or 2 groups selected from the group consisting of halogen and C 1-3 alkyl, a 6- to 12-membered monocyclic or bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms, a C 4-7 cycloalkane ring, or a C 4-7 cycloalkene ring, preferably a benzene ring optionally having one substituent selected from the group consisting of halogen and C 1-3 alkyl, or a
• L 1 in the above formula (2) is preferably a single bond, —O—, C 1-3 alkylene, or —C( ⁇ O)—, more preferably a single bond, —O—, —CH 2 —, or —C( ⁇ O)—, even more preferably a single bond, —O—, or —C( ⁇ O)—, and particularly preferably a single bond.
• ring Q2 in the above formula (2) is a C6-12 monocyclic or bicyclic aromatic hydrocarbon ring, a C3-7 cycloalkane ring, a 3- to 7-membered heterocycloalkane ring (the heterocycloalkane ring has 1 or 2 nitrogen atoms as ring member atoms), a C3-7 cycloalkene ring, or a 5- to 12-membered spiroheterocycloalkane ring (the spiroheterocycloalkane ring has 1 or 2 nitrogen atoms as ring member atoms), and in another embodiment of the present invention, ring Q2 in the above formula (1) is a benzene ring optionally substituted with one halogen, a C4-7 cycloalkane ring, a C4-7 cycloalkene ring optionally substituted with one halogen, a piperidine ring, or a 7-azaspiro[
• L3 in the above formula (2) is preferably piperazinediyl, piperazine-2-onediyl, piperidinediyl, pyrrolidinediyl, azetidinediyl, or 3-oxa-9-azabicyclo[3.3.1]nonanediyl, more preferably piperazinediyl, piperazine-2-onediyl, piperidinediyl, or 3-oxa-9-azabicyclo[3.3.1]nonanediyl, even more preferably piperazinediyl or piperidinediyl, and particularly preferably piperazinediyl.
• A is -O-, R2 is methyl; R3 is methyl; R 4 is C 1-6 alkyl optionally substituted with 1 to 3 halogens, —C( ⁇ O)—C 1-6 alkyl optionally substituted with 1 to 3 halogens, or a 6-membered heteroaryl having 1 or 2 nitrogen atoms as ring members (the heteroaryl is optionally substituted with 1 halogen); Ring Q1 is a benzene ring optionally having one substituent selected from the group consisting of halogen and C1-3 alkyl, or a pyridine ring;
• the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein L1 is a single bond, --O--, or --C(.dbd.O)---, and ring Q2 is a benzene ring, a C4-7 cycloalkane ring, or a C4-7 cycloalkene
• the compound represented by formula (2) or a pharma- ceutically acceptable salt thereof is a compound represented by the following formula (2') or a pharma- ceutically acceptable salt thereof.
• A is —O— or —CF 2 —;
• R 1 is halogen, —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens, —N(H)—C 1-3 alkyl, —N(C 1-3 alkyl) 2 , or a 4- to 6-membered heterocycloalkyl having one nitrogen atom as a ring member atom;
• R 2 and R 3 are each independently hydrogen or C 1-6 alkyl;
• Ring Q1 is a benzene ring optionally having
• formula (2') corresponds to a subordinate concept of formula (2)
• the definitions, explanations, preferred embodiments, etc. of each group in formula (2) above all apply to each group in formula (2').
• this specification when “a compound represented by formula (2)” is mentioned without any particular reservation, this means a concept that includes "a compound represented by formula (2')", in other words, "a compound represented by formula (2) and formula (2')".
• R6 in the above formula (2) and formula (2') is an E3 ligase binding moiety
• R6 in the above formula (2) and formula (2') is a CRBN binding moiety.
• the remarks in ⁇ 3. E3 ligase binding moiety> above can be applied as they are to the E3 ligase binding moiety or CRBN binding moiety that can be used as R6 .
• R 6 in the above formula (2) and formula (2′) is the following formula:
• R 8 is hydrogen or C 1-6 alkyl
• W, X, Y, and Z each independently represent a nitrogen atom or a carbon atom optionally having one group selected from the group consisting of halogen, C 1-6 alkyl, and —O—C 1-6 alkyl
• l, m, and n each independently represent an integer of 0 to 3
• the wavy line represents the bonding position to L4 .
• R 6 in the above formula (2) and formula (2′) is represented by the following formula:
• R 8 is hydrogen or C 1-6 alkyl; V is a halogen, and the wavy line indicates the bonding position to L4 .
• R 1 is —O—C 1-6 alkyl optionally substituted with 1 to 3 halogens
• R 4 is C 1-6 alkyl optionally substituted by 1 to 3 halogens or C 3-6 cycloalkylmethyl optionally substituted by 1 trifluoromethyl
• the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein ring Q1 is a benzene ring optionally having 1 or 2 groups selected from the group consisting of halogen and C1-6 alkyl, a 9- to 10-membered bicyclic aromatic heterocycle having 1 or 2 nitrogen atoms as ring member atoms, a C4-7 cycloalkane ring, or a C4-7 cycloalkene ring, and L1 is a single bond or -O-.
• A is -O-
• Ring Q1 is a benzene ring optionally having one halogen atom;
• the compound or a pharma- ceutically acceptable salt thereof is provided, wherein L1 is a single bond, and Ring Q2 is a cyclohexene ring.
• the compound represented by formula (2) or a pharma- ceutically acceptable salt thereof may be in the form of a crystal.
• a crystal of the compound represented by formula (2) or a pharma-ceutically acceptable salt thereof is provided.
• the crystal can be produced by a method known per se, or a method described in the Examples below, or a method equivalent thereto.
• Powder X-ray diffraction measurement of crystals may be performed by methods generally used in the field, for example, by the method described in the Examples below.
• the diffraction angle (2 ⁇ ) in powder X-ray diffraction may vary within a range of about ⁇ 0.2° 2 ⁇ .
• the lattice constant of hydrates and dehydrates may change due to the attachment and detachment of water of crystallization, which may cause a change in the diffraction angle (2 ⁇ ) in powder X-ray diffraction.
• the intensity of the diffraction peak may also change due to differences in the growth plane of the crystal (crystal habit), etc.
• the scope of the present invention also includes hydrates and dehydrates obtained from them.
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij ]Quinoline-1(2H)-yl]piperidine-2,6-dione benzenesulfonate crystals, which have peaks at diffraction angles (2 ⁇ ) of 2.15 ⁇ 0.2, 8.30 ⁇ 0.2, 10.29 ⁇ 0.2, 14.75 ⁇ 0.2, 17.19 ⁇ 0.2, 20.00 ⁇ 0.2, 21.34 ⁇ 0.2, 22.68 ⁇ 0.2, 23.77
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij ]Quinoline-1(2H)-yl]piperidine-2,6-dione ethanesulfonate crystals, which have peaks at diffraction angles (2 ⁇ ) of 2.21 ⁇ 0.2, 12.04 ⁇ 0.2, 14.87 ⁇ 0.2, 17.69 ⁇ 0.2, 18.93 ⁇ 0.2, 20.41 ⁇ 0.2, 22.42 ⁇ 0.2, 23.19 ⁇ 0.2, 24.
• the crystal is (3RS)-3-[7-( ⁇ 1-[(4R)-2'-fluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-carbonyl]piperidin-4-yl ⁇ amino)-2-oxo-5,6-dihydro-4H-imidazo[4,5,1 -ij]Quinoline-1(2H)-yl]piperidine-2,6-dione 10-camphorsulfonate crystals, which have peaks at diffraction angles (2 ⁇ ) of 3.89 ⁇ 0.2, 6.81 ⁇ 0.2, 7.68 ⁇ 0.2, 8.20 ⁇ 0.2, 10.28 ⁇ 0.2, 13.15 ⁇ 0.2, 15.97 ⁇ 0.2, 16.81 ⁇
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxa
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-d e]Quinoxaline-1(2H)-yl]piperidine-2,6-dione salicylate crystals, which have peaks at diffraction angles (2 ⁇ ) of 2.20 ⁇ 0.2, 4.34 ⁇ 0.2, 9.45 ⁇ 0.2, 10.97 ⁇ 0.2, 13.23 ⁇ 0.2, 16.98 ⁇ 0.2, 18.09 ⁇ 0.2, 20.20 ⁇ 0.2, 21.32 ⁇ 0.2, and 25.
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]
• the crystal is (3RS)-3-[7-(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[1,1'-biphenyl]-4-yl]methyl ⁇ piperazine-1-carbonyl)-2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoline
• the term “pharmaceutical acceptable salt” means a salt that can be used as a medicine.
• the compound or polyfunctional molecule of the present invention can form a basic salt (also called “base addition salt”) by reacting with a base, and when it has a basic group, it can form an acidic salt (also called “acid addition salt”) by reacting with an acid.
• the pharmaceutical acceptable salt of the compound represented by formula (1) or the compound represented by formula (2) is a basic salt
• the pharmaceutical acceptable salt of the compound represented by formula (1) or the compound represented by formula (2) is an acidic salt.
• the "basic salt” in the present invention preferably includes alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidine salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; or amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, and aspartic acid salts.
• alkali metal salts such as sodium salts, potassium salts, and lithium salts
• alkaline earth metal salts such as magnesium salts and calcium salts
• organic base salts such as N-methylmorpholine salts, triethyl
• the “acid salt” in the present invention preferably includes inorganic acid salts such as hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, and hydroiodides, nitrates, perchlorates, sulfates, and phosphates; lower alkane sulfonates, such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; arylsulfonates, such as benzenesulfonates and p-toluenesulfonates; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, and maleates; or amino acid salts, such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts.
• hydrohalides
• the compounds of the present invention or pharma- ceutically acceptable salts thereof may absorb water molecules and become hydrates when left in the air or when recrystallized, and such hydrates are also included in the present invention.
• the compounds of the present invention or pharma-ceutically acceptable salts thereof may absorb a certain type of solvent and become solvates when left in a solvent or when recrystallized, and such solvates are also included in the present invention.
• the compounds of the present invention or pharma-ceutically acceptable salts thereof may exist as amorphous or crystalline.
• the compound of the present invention or its pharmaceutically acceptable salt may also be labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes.
• isotopes that can be incorporated into the compound of the present invention or its pharmaceutically acceptable salt include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, and fluorine isotopes, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, and 18 F, respectively.
• Radioactive or non-radioactive labeled compounds may be useful to help determine or measure the effectiveness of the compound of the present invention, for example, by characterizing the site or mode of action, or the binding affinity to a pharmacologically important site of action.
• Such isotopically labeled compounds can be prepared by conventional techniques generally known to those skilled in the art.
• the compounds of the present invention may exist in various isomers, such as geometric isomers such as cis- and trans-isomers, tautomers, rotational isomers, and optical isomers such as d- and l-isomers (including enantiomers and diastereomers), depending on the types and combinations of substituents.
• geometric isomers such as cis- and trans-isomers, tautomers, rotational isomers, and optical isomers such as d- and l-isomers (including enantiomers and diastereomers), depending on the types and combinations of substituents.
• the compounds of the present invention include all such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known resolution means.
• the present invention also includes prodrugs of the compounds represented by formula (1) or formula (2).
• a prodrug is a compound having a group that can be converted to an amino group, a hydroxy group, a carboxy group, or the like of the compound by hydrolysis or under physiological conditions, and examples of groups that form such prodrugs include groups described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc.
• the prodrugs include: (1) When an amino group is present in the compound, examples of the compound include compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated), and the like.
• examples of the compound include compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl
• the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated), and the like.
• examples of the compound include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated).
• compositions and pharmaceutical uses in one aspect of the present invention, a composition for inhibiting SF-1, a composition for inducing the degradation of SF-1, or a pharmaceutical composition is provided, which contains a compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof, a polyfunctional molecule containing a moiety corresponding to said compound or a pharma- ceutically acceptable salt thereof, or a compound represented by the above formula (2) or a pharma- ceutically acceptable salt thereof, or a crystal thereof.
• a method for treating a disease comprises administering to a subject in need of treatment an effective amount of a compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof, a polyfunctional molecule containing a moiety corresponding to said compound or a pharma- ceutically acceptable salt thereof, or a compound represented by the above formula (2) or a pharma- ceutically acceptable salt thereof, or a crystal thereof.
• a compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof, a polyfunctional molecule containing a moiety corresponding to said compound or a pharma- ceutically acceptable salt thereof, or a compound represented by the above formula (2) or a pharma- ceutically acceptable salt thereof, or a crystal thereof, for use in the treatment of a disease is provided.
• composition for inhibiting SF-1 refers to a composition intended to inhibit SF-1.
• Inhibition of SF-1 typically means inhibiting the physiological activity of SF-1, particularly blocking or attenuating the expression of genes transcriptionally controlled by SF-1.
• Inhibition of SF-1 can be achieved by directly binding to SF-1 to block or attenuate the transcription-inducing activity of downstream genes, but can also be achieved by acting on an upstream protein of SF-1 without directly binding to SF-1, thereby blocking or attenuating the physiological activity of SF-1.
• composition for inhibiting SF-1 includes not only compositions intended solely to inhibit SF-1, but also those that include the inhibition of SF-1 as one of their purposes.
• composition for inhibiting SF-1 typically includes those that list the inhibition of SF-1 as one of their uses in the attached documentation, packaging, promotional materials, etc., but also includes those that substantially include the inhibition of SF-1 as one of their uses, even if there is no such explicit indication.
• composition for inducing the degradation of SF-1 means a composition intended to induce the degradation of SF-1.
• composition for inducing the degradation of SF-1 includes not only compositions intended solely to induce the degradation of SF-1, but also those that include the induction of degradation of SF-1 as one of their purposes.
• Composition for inducing the degradation of SF-1 typically includes those whose intended use is to induce the degradation of SF-1 in the attached documentation, packaging, promotional materials, etc., but also includes those that essentially include the induction of degradation of SF-1 as one of their intended uses, even if there is no such explicit indication.
• the term "pharmaceutical composition” refers to a composition used for the treatment/prevention of any disease.
• the compound or polyfunctional molecule of the present invention has SF-1 antagonist activity, and therefore can be used as a composition for the treatment and/or prevention of diseases in which SF-1 is involved in the development or progression of the disease.
• diseases include, but are not limited to, castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, cancer such as breast cancer, Cushing's syndrome, and primary aldosteronism.
• the pharmaceutical composition of the present invention is for treating castration-resistant prostate cancer, adrenocortical carcinoma, Leydig tumor, hormone-sensitive prostate cancer, cancer such as breast cancer, Cushing's syndrome, or primary aldosteronism, in a further aspect of the present invention, the pharmaceutical composition of the present invention is for treating castration-resistant prostate cancer or adrenocortical carcinoma, in another aspect of the present invention, the pharmaceutical composition of the present invention is for treating castration-resistant prostate cancer, and in yet another aspect of the present invention, the pharmaceutical composition of the present invention is for treating adrenocortical carcinoma.
• the route of administration of such compositions to humans or other animals may be oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.
• parenteral administration using intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.
• oral administration is preferred from the viewpoint of reducing the burden of taking medication.
• Solid compositions for oral administration include tablets, powders, granules, etc.
• Such solid compositions contain at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl picoridone, magnesium aluminometasilicate, etc., in addition to the compound or polyfunctional molecule of the present invention.
• Such solid compositions may contain inactive additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, dissolution aids, etc., according to conventional methods.
• Tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.
• Liquid compositions for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like.
• inert diluents such as purified water or ethanol.
• such liquid compositions may contain auxiliary agents such as solubilizers and wetting agents, sweeteners, flavorings, fragrances, preservatives, and the like.
• Injectables for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions, etc.
• Aqueous solvents include, for example, distilled water for injection and physiological saline.
• Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80, etc.
• Such injection compositions may further contain isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizing agents, etc.
• These injection compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, by blending with a bactericide, or by irradiation.
• these injection compositions can be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injection solvent before use.
• External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, etc. These external preparations may contain commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions, etc.
• ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc.
• Transmucosal agents such as inhalants and nasal agents may be solid, liquid, or semisolid, and may be manufactured according to a conventional method.
• known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. may be appropriately added.
• a suitable device for inhalation or insufflation may be used as a method of administration.
• known devices such as metered dose inhalation devices or nebulizers may be used to administer the compound or polyfunctional molecule alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharma- ceutically acceptable carrier.
• Dry powder inhalers and the like may be for single or multiple administration, and may use dry powders or powder-containing capsules.
• a suitable propellant may be used.
• the agent may be in the form of a pressurized aerosol spray using a suitable gas such as a chlorofluoroalkane, a hydrofluoroalkane, or carbon dioxide.
• composition of the present invention may contain other active ingredients or may be used in combination with another composition containing other active ingredients. Such combinations may be administered simultaneously or separately, successively or at a desired time interval.
• the simultaneous administration preparations may be combined or formulated separately.
• the amount of the compound or polyfunctional molecule of the present invention loaded into a composition or the amount administered to a subject is not particularly limited as long as it is an amount effective for achieving the purpose, and can be appropriately selected depending on the purpose of use, the subject's age, weight, symptoms, health condition, and progression of the disease.
• the daily dosage may be administered once a day, or in multiple divided doses.
• effective amount or “therapeutically effective amount” means an amount effective for treating, preventing the progression of, or alleviating existing symptoms in the subject being treated.
• the effective amount can be appropriately determined in accordance with conventional methods, taking into account the desired therapeutic effect and side effects.
• the compound or a pharma- ceutical acceptable salt thereof, the polyfunctional molecule, the composition for inhibiting SF-1, the composition for inducing the degradation of SF-1, or the pharmaceutical composition of the present invention may be used in combination with other antitumor agents, such as alkylating agents, metabolic antagonists, antitumor antibiotics, microtubule inhibitors, topoisomerase inhibitors, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecular targeted drugs, and other antitumor agents.
• antitumor agents such as alkylating agents, metabolic antagonists, antitumor antibiotics, microtubule inhibitors, topoisomerase inhibitors, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecular targeted drugs, and other antitumor agents.
• alkylating agents include alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide, and chlorambucil; aziridine alkylating agents such as carboquone and thiotepa; epoxide alkylating agents such as dibromomannitol and dibromodalcitol; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin, and ranimustine; busulfan; improsulfan tosylate; and dacarbazine.
• alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide, and chlorambucil
• aziridine alkylating agents such as carboquone and thiotepa
• epoxide alkylating agents such as dibromomannitol and dibromodalcitol
• nitrosourea alkylating agents such as car
• Examples of various metabolic antagonists include purine metabolic antagonists such as 6-mercaptopurine, 6-thioguanine, and thioinosine; pyrimidine metabolic antagonists such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, enocitabine, and capecitabine; folate metabolic antagonists such as methotrexate, trimetrexate, and pemetrexed; and active folate agents such as levofolinate.
• purine metabolic antagonists such as 6-mercaptopurine, 6-thioguanine, and thioinosine
• pyrimidine metabolic antagonists such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, enocitabine, and capecitabine
• folate metabolic antagonists such as methotrexate, trimetrexate
• Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, epirubicin, and amrubicin; mitomycin C; bleomycin; peplomycin; chromomycin A3; and actinomycin D.
• anthracycline antibiotic antitumor agents such as daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, epirubicin, and amrubicin
• mitomycin C bleomycin
• peplomycin chromomycin A3
• actinomycin D actinomycin D.
• Microtubule inhibitors include, for example, vinca alkaloids such as vindesine, vincristine, vinblastine, and vinorelbine; taxanes such as paclitaxel, docetaxel, and cabazitaxel; eribulin, etc.
• Topoisomerase inhibitors include epipodophyllotoxins such as etoposide and teniposide; camptothecin derivatives such as irinotecan; etc.
• BRMs include, for example, tumor necrosis factor and indomethacin.
• Hormonal agents include, for example, hydrocortisone, cortisone acetate, fludrocortisone, fludrocortisone acetate, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfestrol, ethinyl estradiol, chlormadinone, glucocorticoids, medroxyprogesterone, bicalutamide, enzalutamide, apalutamide, glorutamide, flutamide, anastrozole, exemestane, letrozole, abiraterone, goserelin, leuprorelin, toremifene, degarerx, mitotane, and tamoxifen.
• vitamins examples include vitamin C and vitamin A.
• antitumor antibodies and molecular targeted drugs include antitumor antibodies (including modified forms thereof) such as trastuzumab, rituximab, cetuximab, pertuzumab, nimotuzumab, pembrolizumab, camrelizumab, denosumab, bevacizumab, infliximab, and ramucirumab; kinase inhibitors such as imatinib, gefitinib, erlotinib, sunitinib, lapatinib, eganelisib, sorafenib, dasatinib, nilotinib, vemurafenib, osimertinib, apatinib, and cabozantinib; PARP inhibitors such as olaparib, rucaparib, velparib, and niraparib; and molecular targeted drugs such as OR-449.
• antitumor agents include, for example, platinum compounds such as cisplatin, carboplatin, and oxaliplatin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceglatone, sizofiran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.
• the compound of the present invention or a pharma- ceutical acceptable salt thereof, polyfunctional molecule, composition for inhibiting SF-1, composition for inducing the degradation of SF-1, or pharmaceutical composition may be used in combination with an antibody-drug conjugate (ADC) containing the other antitumor agent as a payload, or a targeted protein degradation inducer having the other antitumor agent as a POI ligand.
• ADC antibody-drug conjugate
• the compound of the present invention or a pharma- ceutical acceptable salt thereof, polyfunctional molecule, composition for inhibiting SF-1, composition for inducing the degradation of SF-1, or pharmaceutical composition may be administered simultaneously with or separately from the above-mentioned concomitant drug, and may be formulated as a combination drug or kit.
• antitumor agents that are suitably used in combination with the compound of the present invention or a pharma- ceutical acceptable salt thereof, polyfunctional molecule, composition for inhibiting SF-1, composition for inducing the degradation of SF-1, or pharmaceutical composition include one or more selected from anthracycline compounds such as doxorubicin; platinum compounds such as cisplatin and carboplatin; antitumor antibodies such as nivolumab, pembrolizumab, and camrelizumab; molecular targeted drugs such as eganelisib, apatinib, cabozantinib, and OR-449; mitotane; and etoposide.
• anthracycline compounds such as doxorubicin
• platinum compounds such as cisplatin and carboplatin
• antitumor antibodies such as nivolumab, pembrolizumab, and camrelizumab
• molecular targeted drugs such as eganelis
• antitumor agents that are suitably used in combination with the compound of the present invention or a pharma- ceutical acceptable salt thereof, the polyfunctional molecule, the composition for inhibiting SF-1, the composition for inducing the degradation of SF-1, or the pharmaceutical composition include one or more selected from hormonal agents such as abiraterone, enzalutamide, grou- tamide, and apalutamide; microtubule inhibitors such as docetaxel and cabazitaxel; PARP inhibitors such as olaparib and rucaparib; androgen receptor degradation inducers such as ARV-110, ARV-766, and CC-94676; CYP11A1 enzyme inhibitors such as ODM-208; and antitumor antibodies such as nivolumab, pembrolizumab, and camrelizumab.
• hormonal agents such as abiraterone, enzalutamide, grou- tamide, and apalutamide
• A is -O-, -S-, -NR a -, or -CR b R c -;
• R a is hydrogen or C 1-3 alkyl;
• R b and R c are each independently hydrogen, halogen, or C 1-3 alkyl, and said alkyl is unsubstituted or substituted with 1 to 3 halogens;
• n R 1 's are each independently halogen, hydroxy, -CN, C 1-6 alkyl, C 2-6 alkenyl, -O-C 1-6 alkyl, -N(H)-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , C 3-7 cycloalkyl, or 3- to 7-membered heterocycloalkyl;
• the alkyl and alkenyl are each independently unsubstituted or substituted with 1 to 3 halogens;
• the cycloalkyl and heterocycloalkyl are each independently unsubstit
• the compound of formula (10) of the present invention can be used as a production intermediate for the compound of formula (2) or formula (2') of the present invention, or is useful as a production intermediate, as described in detail in the following general production method and examples.
• the compound of formula (10) of the present invention is the same as the compound of formula (1) except that the definition of R 10 is different from that of the compound of formula (1). Therefore, the definitions, explanations, preferred embodiments, etc. of each group in the above formula (1) are all applicable to each group in formula (10) except for those related to R 5 .
• R 10 in the above formula (10) is a C 1-6 alkyl substituted with one 3- to 7-membered heterocycloalkyl (the heterocycloalkyl is unsubstituted or substituted with an amino protecting group), preferably a C 1-6 alkyl substituted with one 4- to 6-membered heterocycloalkyl (the heterocycloalkyl is unsubstituted or substituted with an amino protecting group), more preferably a C 1-6 alkyl substituted with one 6-membered heterocycloalkyl (the heterocycloalkyl is unsubstituted or substituted with an amino protecting group), and particularly preferably a C 1-6 alkyl substituted with piperazine (the heterocycloalkyl is unsubstituted or substituted with an amino protecting group).
• protecting group for an amino group refers to a protecting group used as a protecting group for an amino group in the synthesis of an organic compound
• protecting groups include alkoxycarbonyl groups such as tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and 2-trimethylsilylethoxycarbonyl; allyloxycarbonyl; arylmethoxycarbonyl groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and 2-nitrobenzyloxycarbonyl; 9-nitrobenzyloxycarbonyl, 9-nitrobenzyloxycarbonyl, and 9-nitrobenzyloxycarbonyl;
• suitable protecting groups include fluorenylmethyloxycarbonyl groups; arylmethyl groups such as benzyl, 4-methoxybenzyl, 2,3-dimethoxybenz
• the intermediates produced in the manufacturing methods described below may be isolated and purified by column chromatography (including normal and reverse phase) using silica gel, alumina, etc., recrystallization, reprecipitation, distillation, etc., or may be used in the next reaction as is without isolation and purification.
• column chromatography including normal and reverse phase
• silica gel, alumina, etc. recrystallization, reprecipitation, distillation, etc.
• the contents of all patent, non-patent, or literature references expressly cited in this specification are hereby incorporated by reference in their entirety.
• the compounds, their pharma- ceutically acceptable salts, and their intermediates can be produced by applying various known production methods utilizing the characteristics based on the types of their basic skeletons or substituents.
• the protecting group or the group that can be easily converted into the functional group may be appropriately selected depending on the reaction conditions of the production method for producing the compound. According to such a method, after the group is introduced and the reaction is carried out, the protecting group can be removed or converted into a desired group as necessary to obtain the desired compound.
• a prodrug of a compound can be produced by introducing a specific group into a raw material or intermediate, or by carrying out a reaction using the resulting compound, in the same manner as the above-mentioned protecting group.
• reaction for producing a prodrug can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation, etc.
• functional group conversion and use of protective groups in production intermediates used in each step of the following methods can be carried out by known methods or methods equivalent thereto, or methods described in the examples below or methods equivalent thereto.
• symbols used in the formulae without a definition have the same meanings as defined above.
• THF Tetrahydrofuran
• DMF N,N-Dimethylformamide
• DMA N,N-Dimethylacetamide
• HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
• DIPEA N,N-Diisopropylethylamine
• RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS registration number: 1445085-77-7)
• BrettPhos Pd G3 [(2-dicyclohexylphosphin
• compound a12 in which R 4 is a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms or a C 3-6 cycloalkylmethyl group optionally substituted with one trifluoromethyl group compound a11 in which R 4 is a C 1-6 alkylcarbonyl group optionally substituted with 1 to 3 halogen atoms, and compound a14 in which R 4 is a 6-membered heteroaryl group having 1 or 2 nitrogen atoms as ring member atoms (the heteroaryl group may be substituted with one halogen atom)
• a general production method for each reaction site is shown in order, but each step does not necessarily have to be carried out in the order shown below as long as it does not affect the reaction substrate and reaction product.
• Pg 1 is a protecting group for a carboxy group (e.g., a methyl group, an ethyl group, a benzyl group, a tert-butyl group, or the like), M is a metal or metal halide (e.g., magnesium, lithium, or zinc halide, etc.); R a1 is a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C 3-6 cycloalkyl group optionally substituted by 1 trifluoromethyl group; R a2 represents the following formula:
• R X is R 5 or a group convertible to R 5 ;
• R a3 is a 6-membered heteroaryl group having 1 or 2 nitrogen atoms as ring atoms (the heteroaryl group may be substituted with 1 halogen atom).
• the first step is a step of obtaining compound A3 by aldol condensation reaction of compound A1 and compound A2.
• the aldol condensation reaction in this step can be carried out, for example, by reacting compound A1 with compound A2 using acetic acid and piperidine as catalysts.
• the second step is a step of obtaining compound a5 by 1,4-nucleophilic addition of compound a4 to the ⁇ , ⁇ -unsaturated ester of compound a3.
• the 1,4-nucleophilic addition reaction in this step can be carried out, for example, by reacting compound a3 with compound a4 in a solvent such as THF in the presence of a copper reagent such as copper(II) bromide.
• the reaction temperature is preferably from -78°C to room temperature.
• the third step is to obtain compound a6 by hydrolysis of the ester of compound a5 and decarboxylation of the resulting carboxy group.
• the hydrolysis and decarboxylation in this step can be carried out, for example, by reacting compound a5 with a base such as sodium hydroxide under heating in a solvent such as ethylene glycol.
• the fourth step is a step of obtaining compound a7 by reducing the cyano group of compound a6.
• the reduction reaction in this step can be carried out, for example, by reacting compound a6 with a reducing agent such as lithium aluminum hydride under heating in a solvent such as THF.
• the fifth step is a step of obtaining compound a9 from compound a7 and compound a8 by reductive amination.
• the reductive amination in this step can be carried out, for example, by reacting compound a7 and compound a8 with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloromethane or methanol. In this reaction, it may be preferable to add an acid such as acetic acid.
• the reductive amination in this step can also be carried out, for example, by using a Dean-Stark apparatus to react compound a7 with compound a8 in a solvent such as toluene, heat the resulting imine, and then reacting the resulting imine with a reducing agent such as sodium borohydride in a solvent such as methanol.
• a reducing agent such as sodium borohydride in a solvent such as methanol.
• the sixth step is a step of condensing compound a9 and compound a10 to obtain compound a11.
• the condensation reaction in this step can be carried out, for example, by reacting compound a9 and compound a10 with a condensing agent such as HATU in a solvent such as DMF.
• the condensation reaction in this step can also be carried out by reacting an acid chloride obtained by reacting compound a10 with oxalyl chloride or the like in a solvent such as dichloromethane, with compound a9 in the presence of a base such as DIPEA in a solvent such as dichloromethane.
• the seventh step is a step of obtaining compound a12 by reducing the carbonyl group of compound a11.
• the reduction reaction in this step can be carried out, for example, by reacting compound a11 with a reducing agent such as borane-THF complex under heating in a solvent such as THF.
• the eighth step is a step of obtaining compound a14 from compound a9 and compound a13 by Buchwald amination reaction or aromatic nucleophilic substitution reaction.
• the Buchwald amination reaction in this step can be carried out, for example, in a solvent such as 1,4-dioxane, in the presence of a base such as cesium carbonate, or a metal catalyst such as RuPhos Pd G3 or BrettPhos Pd G3, by reacting compound a9 with compound a13 under heating.
• the aromatic nucleophilic substitution reaction in this step can be carried out, for example, in a solvent such as 2-butanol or N,N-dimethylacetamide, in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene or potassium carbonate, by reacting compound a9 with compound a13 under heating.
• a solvent such as 2-butanol or N,N-dimethylacetamide
• a base such as 1,8-diazabicyclo[5.4.0]-7-undecene or potassium carbonate
• R5 is represented by the following formula:
• the R5 moiety can be introduced according to a known method.
• Examples of the known method include, but are not limited to, WO 2013088315 A1 and WO 2020192588 A1.
• R5 is represented by the following formula:
• the R5 moiety can be introduced according to a known method.
• the known method include, but are not limited to, J. Org. Chem., 2000, 65, 1, 169-175 and Tetrahedron Lett., 1998, ,39, 5731-5734.
• R5 is represented by the following formula:
• the R5 moiety can be introduced according to a known method.
• the known method include, but are not limited to, J. Org. Chem., 2015, 80, 6391-6399 and WO 2019148132 A1.
• R b1 is a single bond or a C 1-6 alkylene group which may have a group selected from the group consisting of a hydroxy group, a C 1-6 alkoxy group, a piperazinyl group and a 1-tert-butoxycarbonylpiperazinyl group, and Pg 1 is a protecting group for a carboxy group.
• the first step is a step of obtaining compound b2 from compound b1 by a deprotection reaction of the carboxy protecting group Pg 1.
• the deprotection reaction in this reaction can be carried out by a method usually used for deprotection of a carboxy protecting group.
• Pg 1 is a methyl group or an ethyl group
• the deprotection reaction can be carried out by reacting compound b1 with a base such as an aqueous sodium hydroxide solution in a solvent such as methanol.
• R c1 is a single bond or a C 1-6 alkylene group which may have a substituent selected from the group consisting of a carboxy group, a hydroxy group and a C 1-6 alkoxy group, Pg 1 is a protecting group for a carboxy group, Pg 2 is a protecting group for an amino group, and X c is a leaving group.
• the first step is to obtain compound c2 by reducing the ester of compound c1.
• the reduction reaction in this step can be carried out, for example, by reacting compound c1 with a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a solvent such as THF.
• the second step is a step of converting the hydroxy group of compound c2 into a leaving group to obtain compound c3.
• leaving groups in this step include a methanesulfonyloxy group and a paratoluenesulfonyloxy group, and the conversion can be performed by a commonly used method (reagents, solvents, reaction conditions, etc.).
• the third step is a step of obtaining compound c5 from compound c3 and compound c4 by a nucleophilic substitution reaction.
• the nucleophilic substitution reaction in this step can be carried out by reacting compound c3 with compound c4 under heating in a solvent such as DMF or acetonitrile, and/or can also be carried out in the presence of a base such as N,N-diisopropylethylamine.
• the fourth step is a step of obtaining compound c6 by deprotecting the protecting group Pg2 of the amino group of compound c5.
• the deprotection reaction in this step can be carried out by a method usually used for deprotecting a protecting group of an amino group.
• Pg2 is a tert-butoxycarbonyl group
• it can be carried out by reacting compound c5 with an acid such as hydrogen chloride or trifluoroacetic acid in a solvent such as dichloromethane.
• Pg 3 is a protecting group for a hydroxy group (e.g., a methyl group, a benzyl group, a methoxymethyl group, etc.)
• Lg is a leaving group
• R d1 is represented by the following formula:
• R d2 is a C 1-3 alkylamino group, a di-C 1-3 alkylamino group, or a 4- to 6-membered saturated heterocyclic group having one nitrogen atom as a ring atom
• R d3 is a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms.
• the first step is a step of obtaining compound d2 from compound d1 by a deprotection reaction of the hydroxyl protecting group Pg 3.
• the deprotection reaction in this step can be carried out by a method usually used for deprotection of a hydroxyl protecting group.
• Pg 3 is a methyl group
• the deprotection reaction can be carried out by reacting compound d1 with sodium thiomethoxide under heating in a solvent such as DMF. This reaction can also be carried out under microwave irradiation.
• the reaction temperature is preferably 80°C to 160°C.
• the second step is a step of obtaining compound d3 from compound d2 by triflation of the hydroxy group.
• the triflation reaction in this step can be carried out, for example, by reacting compound d2 with a triflation agent such as trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as pyridine.
• the third step is a step of obtaining compound d5 from compound d3 and amine d4 by Buchwald amination.
• the Buchwald amination in this step can be carried out by reacting compound d3 with amine d4 under heating in a solvent such as 1,4-dioxane in the presence of a ligand such as 2-(di-tert-butylphosphino)biphenyl and a metal catalyst such as tris(dibenzylideneacetone)dipalladium(0).
• the fourth step is a step of obtaining compound d7 by an alkylation reaction between compound d2 and alkylating agent d6.
• the alkylation reaction in this step can be carried out, for example, by reacting alkylating agent d6 with compound d2 under heating in a solvent such as DMF in the presence of a base such as potassium carbonate.
• the reaction temperature is preferably from room temperature to 150°C.
• R is the following formula:
• M is a dihydroxyboryl group, a pinacolatoboryl group, or the like;
• R X is R5 or a group that can be converted to R5 .
• the first step is to convert carboxylic acid e1 to acid chloride e2.
• the chlorination reaction in this step can be carried out, for example, by reacting compound e1 with a chlorinating agent such as oxalyl chloride or thionyl chloride in a solvent such as dichloromethane in the presence of a catalytic amount of DMF.
• the second step is a step of obtaining compound e4 by a coupling reaction between compound e2 and compound e3.
• the coupling reaction in this step can be carried out, for example, by reacting compound e2 with compound e3 under heating in a solvent such as toluene in the presence of a base such as cesium carbonate and a metal catalyst such as tetrakis(triphenylphosphine)palladium(0).
• Literature examples for the coupling reaction in this step include, for example, Catalysts, 2019, 9(1), 53.
• R X is R 5 or a group that can be converted to R 5 ]
• R f1a , R f1b , R f1c , and R f1d each independently represent a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
• R f2 is OH or a leaving group, where, when R f2 is OH, R f3 is OH or a leaving group, or, when R f2 is a leaving group, R f3 is OH;
• Y 1 is a halogen atom, a trifluoromethanesulfonyloxy group, a pinacolatoboryl group, or a dihydroxyboryl group, and when Y 1 is a halogen atom or a trifluoromethanesulfonyloxy group,
• Y 2 is a pinacolatoboryl group or a dihydroxyboryl group, or when Y 1 is a pinacolatoboryl group or a dihydroxyboryl group, Y 2 is
• the first step is a step of obtaining compound f3 from compound f1 and compound f2.
• this reaction can be carried out by Mitsunobu reaction.
• the Mitsunobu reaction in this step can be carried out, for example, by reacting compound f1 and compound f2 with a phosphine such as triphenylphosphine and an azodicarboxylate such as diisopropyl azodicarboxylate in a solvent such as THF.
• a phosphine such as triphenylphosphine
• an azodicarboxylate such as diisopropyl azodicarboxylate
• this reaction can be carried out by nucleophilic substitution reaction.
• the nucleophilic substitution reaction in this step can be carried out, for example, by reacting compound f1 and compound f2 with a base such as potassium carbonate or cesium carbonate under heating in a solvent such as DMF or N,N-dimethylacetamide.
• a base such as potassium carbonate or cesium carbonate under heating in a solvent such as DMF or N,N-dimethylacetamide.
• the second step is to obtain compound f6 by a coupling reaction between compound f4 and compound f5.
• the coupling reaction in this step can be carried out by heating compound f4 and compound f5 in a solvent such as aqueous 1,4-dioxane in the presence of a base such as potassium carbonate and a metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct.
• the third step is a step of obtaining compounds f9 and f10 by the Mitsunobu reaction of compounds f7 and f8.
• the Mitsunobu reaction in this step can be carried out, for example, by reacting compounds f7 and f8 with a phosphorane reagent such as cyanomethylenetributylphosphorane under heating in a solvent such as toluene.
• the fourth step is a step of obtaining compound f11 by a reduction reaction of compound f9.
• the reduction reaction in this step can be carried out under the same conditions as in the first step of Method C.
• the fifth step is a step of obtaining compound f12 from compound f11 by an oxidation reaction.
• the oxidation reaction in this step can be carried out, for example, by reacting compound f11 with an oxidizing agent such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one or manganese(IV) oxide in a solvent such as dichloromethane.
• compound f13 can be obtained by subjecting compound f10 to the same steps as the fourth and fifth steps of this method.
• R 6′ is the following formula:
• R 6′′ is an imide protecting group (e.g., a (2-trimethylsilylethoxy)methyl group, a tert-butoxycarbonyl group, a benzyloxymethyl group, etc.);
• Q3 is represented by the following formula:
• Pg1 is any group selected from Pg1 is a protecting group for a carboxy group (e.g., a methyl group, an ethyl group, a tert-butyl group, etc.).
• R 6′ is a group represented by the following formula:
• this step can be carried out by deprotecting the protecting group of compound (4).
• the deprotection reaction in this step can be carried out by a method commonly used for deprotecting the protecting group of the nitrogen atom of an imide.
• the deprotection reaction in this step can be carried out by reacting compound (4) with an acid such as trifluoroacetic acid in a dichloromethane solvent to remove the trimethylsilylethyl group, and then reacting with a base such as N,N'-dimethylethylenediamine in a solvent such as ethyl acetate.
• R 6′ is a group represented by the following formula:
• this step can be carried out by a cyclization reaction.
• the cyclization reaction in this step can be carried out, for example, by reacting compound (4) with an acid such as benzenesulfonic acid under heating in a solvent such as acetonitrile.
• the cyclization reaction in this step can be carried out, for example, by reacting compound (4) with a base such as potassium tert-butoxide in a solvent such as THF.
• R 6′ is a group represented by the following formula:
• this step can be carried out by catalytic hydrogen reduction reaction.
• the catalytic hydrogen reduction reaction in this step can be carried out, for example, by reacting compound (4) with a metal catalyst such as palladium on carbon under a hydrogen atmosphere in a solvent such as ethyl acetate or ethanol.
• compound h4 in which L 4 is —C( ⁇ O)— can be produced according to the following method.
• L 3 is a piperazinediyl group, a piperazine-2-onediyl group, a piperidinediyl group, a pyrrolidinediyl group, an azetidinediyl group, or a 3-oxa-9-azabicyclo[3.3.1]nonanediyl group, and Xh is a halogen atom.
• the first step is a step of converting compound h1 to compound h2 by a carbonylation reaction.
• the carbonylation reaction in this step can be carried out, for example, by reacting compound h1 with 2,4,6-trichlorophenyl formate (CAS registration number: 4525-65-9) under heating in a solvent such as toluene in the presence of a base such as triethylamine, a ligand such as XantPhos, and a metal catalyst such as palladium(II) acetate in a carbon monoxide atmosphere.
• the second step is a step of obtaining compound h4 from compound h2 and compound h3 by an amidation reaction.
• the amidation reaction in this step can be carried out, for example, by reacting compound h2 with compound h3 under heating in a solvent such as acetonitrile in the presence of a base such as DIPEA and a catalyst such as 4-dimethylaminopyridine.
• L 3 is a piperazinediyl group, a piperazine-2-onediyl group, a piperidinediyl group, a pyrrolidinediyl group, an azetidinediyl group, or a 3-oxa-9-azabicyclo[3.3.1]nonanediyl group, and Xi is a halogen atom.
• the first step is a step of converting compound i1 to compound i2 by a formylation reaction.
• the formylation reaction in this step can be carried out, for example, by reacting compound i1 with a reducing agent such as triethylsilane under heating in a solvent such as toluene in the presence of a base such as triethylamine, a ligand such as XantPhos, and a metal catalyst such as palladium(II) acetate in a carbon monoxide atmosphere. In this reaction, it may be preferable to add saccharin.
• a reducing agent such as triethylsilane under heating in a solvent such as toluene
• a base such as triethylamine
• a ligand such as XantPhos
• a metal catalyst such as palladium(II) acetate in a carbon monoxide atmosphere.
• the second step is a step of obtaining compound i4 from compound i2 and compound i3 by reductive amination.
• the reductive amination in this step can be carried out, for example, by reacting compound i2 and compound i3 with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloromethane or methanol. In this reaction, it may be preferable to add an acid such as acetic acid.
• the reductive amination in this step can also be carried out, for example, by using a Dean-Stark apparatus to react compound i3 with compound i2 under heating in a solvent such as toluene to obtain an imine, and then reacting the imine with a reducing agent such as sodium borohydride in a solvent such as methanol.
• a reducing agent such as sodium borohydride in a solvent such as methanol.
• R 1 , R 2 , R 3 , R 4 , R 6′ , ring Q 1 , ring Q 2 , ring Q 3 , L 1 , and L 4 are the same as defined above, and L 3 is a piperazinediyl group, a piperazine-2-onediyl group, a piperidinediyl group, a pyrrolidinediyl group, an azetidinediyl group, or a 3-oxa-9-azabicyclo[3.3.1]nonanediyl group.
• the first step is a step of condensing compound j1 and compound j2 to obtain compound j3.
• the condensation reaction in this step can be carried out, for example, by reacting compound j1 and compound j2 with a condensing agent such as HATU in a solvent such as DMF.
• the condensation reaction in this step can also be carried out by reacting compound j1 with a chlorinating agent such as oxalyl chloride in a solvent such as dichloromethane in the presence of a catalytic amount of DMF to obtain an acid chloride, which can be reacted with compound j2 in a solvent such as dichloromethane in the presence of a base such as DIPEA.
• compound k3 in which L 2 is —CH 2 — can be prepared according to the following method.
• R 1 , R 2 , R 3 , R 4 , R 6′ , ring Q 1 , ring Q 2 , ring Q 3 , L 1 , and L 4 are the same as defined above, and L 3 is a piperazinediyl group, a piperazine-2-onediyl group, a piperidinediyl group, a pyrrolidinediyl group, an azetidinediyl group, or a 3-oxa-9-azabicyclo[3.3.1]nonanediyl group.
• the first step is a step of obtaining compound k3 from compound k1 and compound k2 by a reductive amination reaction.
• the reductive amination reaction in this step can be carried out under the same conditions as in the second step of Method I.
• a compound in which L 2 is a C 2-6 alkylene group can also be obtained under similar conditions by changing compound k1 to the corresponding aldehyde.
• compound 16 in which Q2 is a benzene ring optionally substituted with one halogen atom and L2 is --NHCO-- can be produced according to the following method.
• X 1 is a halogen atom
• Pg2 is a protecting group for an amino group
• R l1 is represented by the following formula:
• R l2a , R l2b , R l2c , and R l2d are each independently a hydrogen atom or a halogen atom
• R l3 is a group represented by the following formula:
• the first step is to obtain compound l3 from compound l1 and compound l2 by Buchwald amination.
• the amination reaction in this step can be carried out by reacting compound l1 with compound l2 under heating in a solvent such as tert-butyl alcohol or DMSO in the presence of a ligand such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene or tBuXPhos; a metal catalyst such as tris(dibenzylideneacetone)dipalladium(0); and a base such as cesium carbonate or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene.
• a solvent such as tert-butyl alcohol or DMSO
• a metal catalyst such as tris(dibenzylideneacetone)dipalladium(0)
• a base such as cesium carbonate or 7-methyl-1,5,7-triazabicy
• the second step is a step of converting compound l3 to compound l4 by a deprotection reaction of the amino-protecting group Pg 2.
• the deprotection reaction in this step can be carried out by a method commonly used for deprotection of an amino-protecting group.
• Pg 2 is a tert-butoxycarbonyl group
• it can be carried out by reacting compound l3 with an acid such as hydrochloric acid in a solvent such as dichloromethane.
• the third step is a step in which compound l6 is obtained by a condensation reaction between compound l4 and compound l5.
• the condensation reaction in this step can be carried out under the same conditions as in the first step of Method J.
• the fourth step is a step of obtaining compound l6 from compound l4 and compound l7 by a urea reaction.
• the urea reaction in this step can be carried out by reacting compound l4 with triphosgene in a solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine to obtain a carbamoyl chloride, which is then reacted with compound l7 in a solvent such as dichloromethane in the presence of a base such as triethylamine.
• R X is represented by the following formula:
• compound m5 in which L 2 is a C 1-6 alkylene group can be produced according to the following method.
• L3 is a piperazinediyl group, a piperazine-2-onediyl group, a piperidinediyl group, a pyrrolidinediyl group, an azetidinediyl group, or a 3-oxa-9-azabicyclo[3.3.1]nonanediyl group
• Lg is a leaving group (e.g., a bromine atom, an iodine atom, a chlorine atom, a methanesulfonyloxy group, a paratoluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc.)
• R m1 is represented by the following formula:
• R X is represented by the following formula:
• the first step is to obtain compound m2 by reducing the ester group of compound m1.
• the reduction reaction in this step can be carried out, for example, by reacting compound m1 with a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a solvent such as tetrahydrofuran.
• the second step is a step of converting the hydroxy group of compound m2 into a leaving group to obtain compound m3.
• leaving groups in this step include bromine atoms, iodine atoms, chlorine atoms, methanesulfonyloxy groups, paratoluenesulfonyloxy groups, and trifluoromethanesulfonyloxy groups, and the conversion into a leaving group can be carried out by commonly used methods (reagents, solvents, reaction conditions, etc.).
• the third step is a step of obtaining compound m5 by a nucleophilic substitution reaction between compound m3 and compound m4.
• the nucleophilic substitution reaction in this step can be carried out by reacting compound m3 with compound m4 under heating in a solvent such as DMF or acetonitrile. In this reaction, it may be preferable to add a base such as N,N-diisopropylethylamine.
• R y is represented by the following formula:
• the starting compound (6) is known or is prepared according to a known method or a similar method using a known compound as a starting material.
• the known compound can be purchased from a commercial supplier or can be readily synthesized by a method described in the literature or a similar method. Examples of known literature include, but are not limited to, WO2022081928 A1, WO2022081927 A1, WO2019060693 A1, WO2019038717 A1, ACS Med. Chem. Lett., 2021, 12, 1733, WO2021170109 A1, etc.
• Compound n8 which is any group selected from the above, can be produced according to the following method.
• Y 1 is a halogen atom
• Y2 is a halogen atom, a dihydroxyboryl group, a pinacolatoboryl group, or the like
• R n1a and R n1b each independently represent a hydrogen atom or a halogen atom
• Pg2 is a protecting group for an amino group
• n is an integer of 1 or 2.
• the first step is a reaction in which compound n1 is converted to compound n2 by a halogenation reaction.
• the halogenation reaction in this step can be carried out, for example, by reacting compound n1 with a halogenating agent such as N-bromosuccinimide, benzyltrimethylammonium tribromide, or N-iodosuccinimide in a solvent such as DMF.
• the second step is a step of obtaining compound n4 by urea conversion of compound n2 using compound n3.
• the urea conversion reaction in this step can be carried out, for example, by reacting compound n2 with compound n3 in a solvent such as dichloromethane in the presence of a base such as DIPEA.
• the third step is a step of obtaining compound n5 by a cyclization reaction of compound n4.
• the cyclization reaction in this step can be carried out, for example, by reacting compound n4 with a copper catalyst such as copper(I) iodide under heating in a solvent such as DMSO in the presence of a copper ligand such as trans-4-hydroxy-L-proline and a base such as tripotassium phosphate.
• the reaction temperature is preferably 80°C to 160°C.
• the fourth step is a step of obtaining compound n7 from compound n5 and compound n6.
• this step can be carried out by an alkylation reaction.
• the alkylation reaction in this step can be carried out, for example, by reacting compound n5 with compound n6 in a solvent such as DMF in the presence of a base such as potassium carbonate or cesium carbonate.
• Y2 is a pinacolatoboryl group or the like, this step can be carried out by a Chan-Lam-Evans coupling reaction.
• the Chan-Lam-Evans coupling reaction in this step can be carried out, for example, by reacting compound n5 with compound n6 under heating in an organic solvent such as acetonitrile in the presence of a base such as triethylamine and a metal catalyst such as copper(II) acetate.
• the fifth step is a step of converting compound n7 to compound n8 by a deprotection reaction of the amino-protecting group Pg 2.
• the deprotection reaction in this step can be carried out by a method usually used for deprotection of an amino-protecting group.
• Compound o4 which is any group selected from the above, can be produced according to the following method.
• a 1 , A 2 , and A 3 each independently represent a carbon atom or a nitrogen atom;
• Xo is a halogen atom, a pinacolatoboryl group, or the like;
• Y 1 is a nitro group or a halogen atom;
• R o1 is R 8 or R 6′ ;
• R o4 is R 8 or R 6′ ;
• a 1 is a nitrogen atom, R o2 is absent;
• a 1 is a carbon atom, R o2 is a hydrogen atom or a halogen atom;
• R o1 and R o2 are bonded to each other to form a group represented by the following formula:
• Compound o1 and compound o2 are publicly known, or can be produced by appropriately combining publicly known methods or methods similar thereto using publicly known compounds as starting materials.
• Examples of the above-mentioned publicly known methods include, but are not limited to, Bioorg. Med. Chem., 2013, 21, 125, J. Med. Chem., 1995, 38, 5, 771-793, WO2011163355 A1, WO2005044793 A2, WO2007015877 A2, WO2021213929 A1, WO2018039384 A1, and WO2016097749 A1.
• the first step is a step of obtaining compound o2 by nitrating or halogenating compound o1.
• the nitration reaction in this step can be carried out, for example, by reacting compound o1 with a nitrating agent such as potassium nitrite in an acid solvent such as trifluoroacetic acid.
• the halogenation reaction in this step can be carried out under the same conditions as in the first step of Method N.
• the second step is a step of obtaining compound o4 from compound o2 and compound o3 by alkylation reaction or Chan-Lam-Evans coupling reaction.
• the alkylation or Chan-Lam-Evans coupling reaction in this step can be carried out under the same conditions as in the fourth step of Method N.
• Compound p5 which is any group selected from the above, can be produced according to the following method.
• a 1 is CH or a nitrogen atom
• A2 is CH2 or NH
• Xp is a halogen atom
• R p1 , R p2 , and R p3 each independently represent a hydrogen atom or a halogen atom.
• the first step is to obtain compound p2 by nuclear reduction of compound p1.
• the nuclear reduction reaction in this step can be carried out, for example, by reacting compound p1 with a reducing agent such as diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate under heating in a solvent such as dichloroethane in the presence of an acid such as boronic acid or paratoluenesulfonic acid.
• a reducing agent such as diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate under heating in a solvent such as dichloroethane in the presence of an acid such as boronic acid or paratoluenesulfonic acid.
• the second step is a step of obtaining compound p4 by urea conversion from compound p2 and compound p3.
• the urea conversion reaction in this step can be carried out under the same conditions as in the fourth step of Method L.
• the third step is a step of obtaining compound p5 by a cyclization reaction of compound p4.
• the cyclization reaction in this step can be carried out under the same conditions as in the third step of Method N.
• the reaction temperature is preferably from room temperature to 100°C.
• R x′ is the following formula:
• the method for producing the raw material compound represented by the formula: is a group that can be converted to a group represented by the formula:
• compound q12 in which R 4 is a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms or a C 3-6 cycloalkylmethyl group optionally substituted with 1 trifluoromethyl group compound q11 in which R 4 is a C 1-6 alkylcarbonyl group optionally substituted with 1 to 3 halogen atoms, and compound q14 in which R 4 is a 6 - membered heteroaryl group having 1 or 2 nitrogen atoms as ring member atoms (the heteroaryl group may be substituted with 1 halogen atom)
• General production methods for each reaction site are shown in order, but each step does not necessarily have to be carried out in the order shown below as long as it does not affect the reaction substrate and the reaction product.
• Pg 1 is a protecting group for a carboxy group
• M is a metal or metal halide (e.g., magnesium halide, lithium halide, zinc halide, etc.);
• R q1 is a hydrogen atom, a C 1-5 alkyl group optionally substituted by 1 to 3 halogen atoms, or a C 3-6 cycloalkyl group optionally substituted by 1 trifluoromethyl group;
• R q2 represents the following formula:
• R q3 is a 6-membered heteroaryl group having 1 or 2 nitrogen atoms as ring atoms (the heteroaryl group may be substituted with 1 halogen atom).
• the first step is to obtain compound q3 by aldol condensation reaction of compound q1 and compound q2.
• the aldol condensation reaction in this step can be carried out by reacting compound q1 with compound q2 using, for example, acetic acid and piperidine as catalysts.
• the second step is a step of obtaining compound q5 by 1,4-nucleophilic addition of compound q4 to the ⁇ , ⁇ -unsaturated ester of compound q3.
• the 1,4-nucleophilic addition reaction in this step can be carried out, for example, by reacting compound q3 with compound q4 in a solvent such as THF in the presence of a copper reagent such as copper(II) bromide.
• the reaction temperature is preferably from -78°C to room temperature.
• the third step is to obtain compound q6 by hydrolysis of the ester group of compound q5 and decarboxylation of the resulting carboxy group.
• the hydrolysis and decarboxylation in this step can be carried out, for example, by reacting compound q5 with a base such as sodium hydroxide under heating in a solvent such as ethylene glycol.
• the fourth step is a step of obtaining compound q7 by reducing the cyano group of compound q6.
• the reduction reaction in this step can be carried out, for example, by reacting compound q7 with a reducing agent such as lithium aluminum hydride under heating in a solvent such as THF.
• the fifth step is a step of obtaining compound q9 from compound q7 and compound q8 by reductive amination.
• the reductive amination in this step can be carried out under the same conditions as in the second step of Method I.
• the sixth step is a step in which compound q9 and compound q10 are condensed to obtain compound q11.
• the condensation reaction in this step can be carried out under the same conditions as in the first step of Method J.
• the seventh step is a step of obtaining compound q12 by reducing the carbonyl group of compound q11.
• the reduction reaction in this step can be carried out, for example, by reacting compound q11 with a reducing agent such as borane-THF complex under heating in a solvent such as THF.
• the eighth step is a step of obtaining compound q14 from compound q9 and compound q13 by Buchwald amination reaction or aromatic nucleophilic substitution reaction.
• the Buchwald amination reaction in this step can be carried out, for example, in a solvent such as 1,4-dioxane, in the presence of a base such as cesium carbonate, or a metal catalyst such as RuPhos Pd G3 or BrettPhos Pd G3, by reacting compound q9 with compound q13 under heating.
• the aromatic nucleophilic substitution reaction in this step can be carried out, for example, in a solvent such as 2-butanol or N,N-dimethylacetamide, in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene or potassium carbonate, by reacting compound q9 with compound q13 under heating.
• a solvent such as 2-butanol or N,N-dimethylacetamide
• a base such as 1,8-diazabicyclo[5.4.0]-7-undecene or potassium carbonate
• compound r4 in which L 1 is —C( ⁇ O)— can be prepared according to the following method.
• R is the following formula:
• M is a group represented by M is a dihydroxyboryl group, a pinacolatoboryl group, or the like.
• the first step is to convert carboxylic acid r1 to acid chloride r2.
• the chlorination reaction in this step can be carried out, for example, by reacting compound r1 with a chlorinating agent such as oxalyl chloride or thionyl chloride in a solvent such as dichloromethane in the presence of DMF.
• the second step is a step of obtaining compound r4 by a coupling reaction between compound r2 and compound r3.
• the coupling reaction in this step can be carried out, for example, by reacting compound r2 with compound r3 under heating in a solvent such as toluene in the presence of a base such as cesium carbonate and a metal catalyst such as tetrakis(triphenylphosphine)palladium(0).
• a solvent such as toluene
• a base such as cesium carbonate
• a metal catalyst such as tetrakis(triphenylphosphine)palladium(0).
• Pg 3 is a protecting group for a hydroxy group (e.g., a methyl group, a benzyl group, a methoxymethyl group, etc.)
• Lg is a leaving group
• R a is represented by the following formula:
• R b is a C 1-3 alkylamino group, a di-C 1-3 alkylamino group, or a 4- to 6-membered saturated heterocyclic group having one nitrogen atom as a ring atom;
• R c is a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms.
• the first step is a step of obtaining compound s2 from compound s1 by deprotection of the hydroxyl protecting group Pg 3.
• the deprotection reaction in this step can be carried out by a method commonly used for deprotection of a hydroxyl protecting group.
• Pg 3 is a methyl group
• the deprotection reaction can be carried out by reacting compound s1 with sodium thiomethoxide under heating in a solvent such as DMF. This reaction can also be carried out under microwave irradiation.
• the reaction temperature is preferably 80°C to 160°C.
• the second step is a step of obtaining compound s3 by triflation of the hydroxy group of compound s2.
• the triflation reaction in this step can be carried out, for example, by reacting compound s2 with a triflation agent such as trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as pyridine.
• the third step is a step of obtaining compound s5 from compound s3 and amine s4 by a Buchwald amination reaction.
• the Buchwald amination reaction in this step can be carried out by reacting compound s3 with amine s4 under heating in a solvent such as 1,4-dioxane in the presence of a ligand such as 2-(di-tert-butylphosphino)biphenyl and a metal catalyst such as tris(dibenzylideneacetone)dipalladium(0).
• the fourth step is a step of obtaining compound s7 from compound s2 by an alkylation reaction using alkylating agent s6.
• the alkylation reaction in this step can be carried out, for example, by reacting compound s2 with alkylating agent s6 such as an alkyl halide in a solvent such as DMF in the presence of a base such as potassium carbonate under heating.
• the reaction temperature is preferably from room temperature to 150°C.
• R y′ is represented by the following formula:
• the raw material compound (8) has the following formula:
• a compound in which L 4 is —C( ⁇ O)— as represented by the following formula (I) can be produced by a method similar to that of Method H.
• the raw material compound (8) has the following formula:
• the compound represented by the formula (I) in which L 4 is CH 2 can be produced by a method similar to that of Method I.
• compound t6 in which L 4 is NH and compound t8 in which L 4 is N—R 9 (R 9 represents a C 1-6 alkyl group) can be produced according to the following method.
• Xt is a halogen atom
• Pg2 is a protecting group for an amino group.
• the first step is to obtain compound t2 from compound t1 by reduction of the nitro group.
• the reduction reaction in this step can be carried out by reacting compound t1 with a metal catalyst such as palladium on carbon in a solvent such as ethanol or THF under a hydrogen atmosphere.
• the second step is a step of obtaining compound t4 from compound t3 by Buchwald amination.
• the amination reaction in this step can be carried out under the same conditions as in the first step of Method L.
• the third step is a step of obtaining compound t2 by a deprotection reaction of the protecting group Pg 2 of the amino group of compound t4.
• the deprotection reaction in this step can be carried out by a method usually used for deprotection of a protecting group of an amino group.
• Pg 2 is a tert-butoxycarbonyl group
• it can be carried out by reacting compound t4 with an acid such as hydrochloric acid in a solvent such as dichloromethane.
• the fourth step is a step of obtaining compound t6 from compound t2 and compound t5 by a reductive amination reaction.
• the reductive amination reaction in this step can be carried out under the same conditions as in the second step of Method I.
• the reductive amination reaction in this step can also be carried out by reacting compound t2 and compound t5 with a reducing agent such as borane-THF complex in a solvent such as THF.
• the fifth step is a step of obtaining compound t8 from compound t6 and compound t7 by reductive amination.
• the reductive amination in this step can be carried out under the same conditions as in the fourth step of this method.
• R u1a , R u1b , R u1c , and R u1d each independently represent a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
• R u2 is a hydroxy group or a leaving group (wherein, when R u2 is a hydroxy group, R u3 is a hydroxy group or a leaving group, or, when R u2 is a leaving group, R u3 is a hydroxy group);
• Y 1 is a halogen atom, a trifluoromethanesulfonyloxy group, a pinacolatoboryl group, or a dihydroxyboryl group (wherein, when Y 1 is a halogen atom or a trifluoromethanesulfonyloxy group, Y 2 is a pinacolatoboryl group or a dihydroxyboryl group, or, when Y 1 is a pinacolatoboryl group
• Pg 1 is a protecting group for a carboxy group.
• the first step is a step of obtaining compound u3 from compound u1 and compound u2.
• this reaction can be carried out by Mitsunobu reaction.
• the Mitsunobu reaction in this step can be carried out, for example, by reacting compound u1 and compound u2 with a phosphine such as triphenylphosphine and an azodicarboxylate such as diisopropyl azodicarboxylate in a solvent such as tetrahydrofuran.
• a phosphine such as triphenylphosphine
• an azodicarboxylate such as diisopropyl azodicarboxylate
• this reaction can be carried out by nucleophilic substitution reaction.
• the nucleophilic substitution reaction in this step can be carried out, for example, by reacting compound u1 and compound u2 with a base such as potassium carbonate or cesium carbonate under heating in a solvent such as DMF or DMA.
• the second step is a step of obtaining compound u6 by a coupling reaction between compound u4 and compound u5.
• the coupling reaction in this step can be carried out by heating compound u4 and compound u5 in a solvent such as aqueous 1,4-dioxane in the presence of a base such as potassium carbonate and a metal catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct.
• the third step is a step of obtaining compounds u9 and u10 from compounds u7 and u8 by Mitsunobu reaction.
• the Mitsunobu reaction in this step can be carried out, for example, by reacting compounds u7 and u8 with a phosphorane reagent such as cyanomethylenetributylphosphorane under heating in a solvent such as toluene.
• the fourth step is a step of obtaining compound u11 by a reduction reaction of compound u9.
• the reduction reaction in this step can be carried out under the same conditions as in the first step of Method M.
• the fifth step is a step of obtaining compound u12 by oxidation of compound u11.
• the oxidation reaction in this step can be carried out, for example, by reacting compound u11 with an oxidizing agent such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one or manganese(IV) oxide in a solvent such as dichloromethane.
• compound u13 can be obtained by subjecting compound u10 to the same processes as the fourth and fifth steps of this method.
• the compound or multifunctional molecule of the present invention specifically binds to SF-1.
• the binding activity to SF-1 can be measured using any known method, for example, by reacting a test substance with a molecule (e.g., DAX1 peptide) known to specifically bind to SF-1 (particularly, SF-1 ligand binding domain (LBD)), and SF-1 (particularly, SF-1-LBD), and quantifying the reduction in the binding rate to SF-1 by the molecule known to specifically bind to SF-1 (e.g., by calculating an IC 50 value).
• a test substance having an IC 50 value of 100 ⁇ M or less is considered to specifically bind to SF-1.
• the compound or multifunctional molecule of the present invention has an IC 50 value of 100 ⁇ M or less, preferably an IC 50 value of 10 ⁇ M or less, and particularly preferably an IC 50 value of 1 ⁇ M or less, with respect to the reduction in the binding rate to SF-1 by a molecule (e.g., DAX1 peptide) known to specifically bind to SF- 1 .
• a molecule e.g., DAX1 peptide
• the compound or polyfunctional molecule of the present invention has an IC50 value of 100 ⁇ M or less, preferably an IC50 value of 10 ⁇ M or less, and particularly preferably an IC50 value of 1 ⁇ M or less, with respect to reducing the binding rate of the DAX1 peptide to SF-1-LBD in the test system and test conditions disclosed in Test Example 1 of the present specification.
• the compound or polyfunctional molecule according to the present invention has SF-1 antagonist activity.
• SF-1 antagonist activity can be measured using any known method, for example, by adding a test substance to cells expressing SF-1, culturing the cells for a certain period of time, and then quantifying the decrease in the expression level of SF-1 target genes (e.g., CYP11A1, CYP17A1, CYP21A2, STAR, etc.) (e.g., calculating IC 50 value).
• SF-1 target genes e.g., CYP11A1, CYP17A1, CYP21A2, STAR, etc.
• IC 50 value e.g., calculating IC 50 value
• the compound or polyfunctional molecule according to the present invention has an IC 50 value of 100 ⁇ M or less, preferably an IC 50 value of 10 ⁇ M or less, and particularly preferably an IC 50 value of 1 ⁇ M or less, against a target gene of SF- 1 (e.g., CYP11A1, CYP17A1, CYP21A2 and/or STAR).
• a target gene of SF- 1 e.g., CYP11A1, CYP17A1, CYP21A2 and/or STAR.
• the compound or polyfunctional molecule according to the present invention has an IC 50 value of 100 ⁇ M or less, preferably an IC 50 value of 10 ⁇ M or less, and particularly preferably an IC 50 value of 1 ⁇ M or less, against CYP11A1, CYP17A1, CYP21A2 and/or STAR in the test system and test conditions disclosed in Test Example 2 of the present specification.
• the compound or polyfunctional molecule according to the present invention has SF-1 degradation-inducing activity.
• the SF-1 degradation-inducing activity can be measured using any known method, for example, by adding a test substance to cells expressing SF-1, culturing the cells for a certain period of time, and then quantifying the expression level of SF-1.
• the SF-1 degradation-inducing activity can also be measured, for example, by knocking in an easily detectable peptide tag (e.g., HiBiT tag) at the endogenous SF-1 gene locus in cells expressing SF-1, adding a test substance to the cells, culturing the cells for a certain period of time, and then observing the expression level of the peptide tag.
• an easily detectable peptide tag e.g., HiBiT tag
• the compound or polyfunctional molecule according to the present invention has a DC 50 value of 100 ⁇ M or less against SF-1, preferably a DC 50 value of 10 ⁇ M or less, and particularly preferably a DC 50 value of 1 ⁇ M or less.
• the compound or polyfunctional molecule according to the present invention has a DC 50 value of 100 ⁇ M or less against SF-1 in the test system and under the test conditions disclosed in Test Example 3 of the present specification, preferably has a DC 50 value of 10 ⁇ M or less, and particularly preferably has a DC 50 value of 1 ⁇ M or less.
• the compound or multifunctional molecule according to the present invention has a growth inhibitory activity against tumors in which SF-1 is involved in the development or progression of the tumor.
• the compound or multifunctional molecule according to the present invention has a growth inhibitory activity against adrenocortical carcinoma.
• the compound or multifunctional molecule according to the present invention has a growth inhibitory activity against NCI-H295R cells, which are adrenocortical carcinoma cell lines.
• the growth inhibitory activity against tumor cells can be measured using any known method, and typically, the growth inhibitory activity can be measured by adding a test substance to a model cell of a target tumor, culturing the cell for a certain period of time, and then quantifying the growth rate of the tumor cells.
• a test substance with a concentration (GI 50 value) of 100 ⁇ M or less that inhibits 50% of tumor cell growth is considered to have growth inhibitory activity.
• the compound or polyfunctional molecule according to the present invention has a GI 50 value of 100 ⁇ M or less against tumor cells (e.g., NCI-H295R cells), preferably has a GI 50 value of 10 ⁇ M or less, and particularly preferably has a GI 50 value of 1 ⁇ M or less.
• tumor cells e.g., NCI-H295R cells
• the compound or polyfunctional molecule according to the present invention has a GI 50 value of 100 ⁇ M or less against tumor cells (e.g., NCI-H295R cells) in the test system and test conditions disclosed in Test Example 4 of the present specification, preferably has a GI 50 value of 100 ⁇ M or less, and particularly preferably has a GI 50 value of 10 ⁇ M or less.
• tumor cells e.g., NCI-H295R cells
• the compound or multifunctional molecule according to the present invention has antitumor activity against tumor cells in which SF-1 is involved in the development or progression, such as NCI-H295R cells, an adrenocortical carcinoma cell line, VCaP cells, a prostate cancer cell line, or an animal model (e.g., mouse) in which a tumor derived from a prostate cancer patient is subcutaneously transplanted.
• the antitumor activity in the transplant model can be measured using any known method, for example, using the protocols described in Test Examples 5 and 6 of the present specification.
• the therapeutic effect of the compound or multifunctional molecule according to the present invention against breast cancer can be measured, for example, using the protocol described in Test Example 7 of the present specification.
• the structure shown here indicates that the asymmetric carbon in the structure is a mixture of ⁇ - and ⁇ -configuration.
• the reagents, solvents, equipment, etc. used in the following examples are commercially available unless otherwise specified.
• the raw material compounds used are publicly known compounds and are either commercially available or synthesized and identified according to publicly known methods or methods equivalent thereto, unless otherwise specified.
• Example A1 Ethyl cyano(2,2-dimethyltetrahydro-4H-pyran-4-ylidene)acetate
• Ethyl cyanoacetate (175 mL, 1.65 mol) was added dropwise to 2,2-dimethyltetrahydro-4H-pyran-4-one (CAS registration number: 1194-16-7) (200 g, 1.56 mol) over 10 minutes under ice cooling, acetic acid (18 mL, 0.32 mol) was added dropwise over 5 minutes, and piperidine (31 mL, 0.31 mol) was added dropwise over 10 minutes. The reaction solution was warmed to room temperature and stirred for 41 hours.
• reaction solution was diluted with ethyl acetate (2 L) and washed with 1 mol/L aqueous sodium hydroxide solution (1.5 L), water (1.5 L), and saturated saline in that order.
• the organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and further dried under reduced pressure to obtain the title compound (324 g, 1.45 mol, yield 93%).
• Example A2> [4-(4-chlorophenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl](cyano)ethyl acetate
• the title compound was obtained in the same manner as in ⁇ Example C3> using the compound obtained in ⁇ Example A1> and 4-chlorophenylmagnesium bromide (CAS registration number: 873-77-8).
• Example A3> 2-[4-(4-chlorophenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine
• the title compound was obtained by using the compound obtained in ⁇ Example A2> and carrying out the same operations as in ⁇ Example C4> and ⁇ Example C5> in order.
• Example A4 Ethyl trans-4-(4-formylphenoxy)cyclohexanecarboxylate 4-Hydroxybenzaldehyde (CAS registration number: 123-08-0) (10.0 g, 81.9 mmol), ethyl cis-4-hydroxycyclohexanecarboxylate (WO 2011143645 A1) (14.8 g, 86.0 mmol), and tri-n-butylphosphine (24.5 mL, 98.3 mmol) in toluene (400 mL) were added little by little at room temperature, and the mixture was stirred at room temperature for 1 hour and at 95° C. for 3 hours.
• the reaction solution was cooled to room temperature, diluted with ethyl acetate (600 mL), and washed successively with water and saturated saline.
• the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the precipitated solid was filtered off and washed with a mixed solvent of hexane/ethyl acetate (1/1).
• the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.94 g, 21.5 mmol, yield 26%).
• Example A5> Ethyl trans-4- ⁇ 4-[( ⁇ 2-[4-(4-chlorophenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexanecarboxylate
• the title compound was obtained in the same manner as in ⁇ Example D1> using the compounds obtained in ⁇ Example A4> and ⁇ Example A3>.
• Example A6> trans-4-(4- ⁇ [ ⁇ 2-[4-(4-chlorophenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (2,2-dimethylpropanoyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid
• the title compound was obtained by carrying out the same operations as in ⁇ Example D2> and ⁇ Example S4> in order.
• Example B1> Ethyl cyano ⁇ 2,2-dimethyl-4-[4-(trifluoromethoxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ acetate Using the compound obtained in ⁇ Example A1> and 4-(trifluoromethoxy)phenylmagnesium bromide (CAS registration number: 169222-42-8, 0.50 mol/L THF solution), the title compound was obtained in the same manner as in ⁇ Example C3>.
• Example B2> 2- ⁇ 2,2-dimethyl-4-[4-(trifluoromethoxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethanamine Using the compound obtained in ⁇ Example B1>, the title compound was obtained by carrying out the same operations as in ⁇ Example C4> and ⁇ Example C5> in order.
• Example B3> Ethyl trans-4-(4- ⁇ [(2- ⁇ 2,2-dimethyl-4-[4-(trifluoromethoxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• the title compound was obtained in the same manner as in ⁇ Example D1> using the compounds obtained in ⁇ Example A4> and ⁇ Example B2>.
• Example B4> Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(trifluoromethoxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate Using the compound obtained in ⁇ Example B3>, the title compound was obtained in the same manner as in ⁇ Example D2>.
• Example B5> trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(trifluoromethoxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid
• the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example C1 Ethyl (cis-4-hydroxycyclohexyl)acetate To a solution of cis-2-(4-hydroxycyclohexyl)acetic acid (CAS registration number: 68592-22-3) (2.53 g, 16.0 mmol) in ethanol (46 mL), sulfuric acid (0.086 mL, 1.60 mmol) was added and heated under reflux for 7 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.66 g, 14.3 mmol, yield 89%).
• Example C2> Ethyl [trans-4-(2-chloro-4-formylphenoxy)cyclohexyl]acetate
• the title compound was obtained in the same manner as in ⁇ Example A4> using the compound obtained in ⁇ Example C1> and 3-chloro-4-hydroxybenzaldehyde (CAS registration number: 2420-16-8).
• Example C3 Ethyl cyano[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetate
• Ethyl cyano(2,2-dimethyltetrahydro-4H-pyran-4-ylidene)acetate (8.92 g, 40.0 mmol) in THF (131 mL) was added with copper(I) bromide dimethylsulfide complex (0.805 g, 3.92 mmol) at -78°C and stirred at the same temperature for 2 hours, then 4-methoxyphenylmagnesium bromide (CAS registration number: 13139-86-1) (0.50 mol/L THF solution, 100 mL, 50 mmol) was added dropwise at the same temperature over 20 minutes.
• the reaction solution was stirred for 1.5 hours while warming to room temperature, and left at room temperature overnight.
• Copper(I) bromide dimethylsulfide complex (0.805 g, 3.92 mmol) was added to the reaction solution at -78°C and stirred at the same temperature for 5 minutes, then 4-methoxyphenylmagnesium bromide (0.50 mol/L THF solution, 47 mL, 23.5 mmol) was added dropwise over 5 minutes at the same temperature, and the mixture was stirred for 6 hours while warming to room temperature.
• 1 mol/L hydrochloric acid 80 mL was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate.
• Example C4 [4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetonitrile
• Ethyl cyano[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetate (10.8 g, 32.6 mmol) in ethylene glycol (109 mL) was added with sodium hydroxide (3.26 g, 81.5 mmol) at room temperature, stirred at 150° C. for 7 hours, and left at room temperature overnight. Ice, water, and 1 mol/L hydrochloric acid were added to the reaction solution under ice cooling, and the pH was adjusted to 1-2, and then extracted with DCM.
• the obtained organic layer was washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.91 g, 22.8 mmol, yield 70%).
• Example C5 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine [4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]acetonitrile (8.72 g, 33.6 mmol) in THF (224 mL) was added with lithium aluminum hydride (3.19 g, 84.1 mmol) over 10 minutes under ice cooling, and the mixture was stirred for 1.5 hours while warming to room temperature, 4 hours at 35° C., and 2 hours at 50° C.
• Example C6> Ethyl (trans-4- ⁇ 2-chloro-4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexyl)acetate Using the compounds obtained in ⁇ Example C2> and ⁇ Example C5>, the title compound was obtained in the same manner as in ⁇ Example D1>.
• Example C7 Ethyl [trans-4-(2-chloro-4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexyl]acetate Using the compound obtained in ⁇ Example C6>, the title compound was obtained in the same manner as in ⁇ Example D2>.
• Example D1 Ethyl trans-4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexanecarboxylate
• Ethyl trans-4-(4-formylphenoxy)cyclohexanecarboxylate (4.00 g, 14.5 mmol) was added to a solution of 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine (3.89 g, 14.8 mmol) in toluene (72.4 mL) at room temperature, and the mixture was heated to reflux under a Dean-Stark apparatus.
• the mixture was stirred for 7 hours while gradually removing the solvent, and then left at room temperature overnight.
• the reaction solution was heated to reflux under a Dean-Stark apparatus.
• the mixture was stirred for 1 hour while gradually removing the solvent, and then allowed to cool, after which the organic solvent was distilled off under reduced pressure.
• the resulting residue was dissolved in methanol (145 mL), and sodium borohydride (0.714 g, 17.4 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes and then for 1.5 hours while warming to room temperature.
• a saturated aqueous solution of ammonium chloride and water were added to the reaction solution under ice cooling, and the mixture was left overnight.
• reaction mixture was extracted with DCM, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the resulting residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (5.13 g, 9.79 mmol, yield 68%).
• Example D2 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Ethyl trans-4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexanecarboxylate (1.11 g, 2.12 mmol) in DCM (21 mL) solution was added with triethylamine (0.588 mL, 4.24 mmol) and pivaloyl chloride (421 mg, 3.49 mmol) under ice cooling, and stirred at room temperature for 2.5 hours.
• Example D3 trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate (1.18 g, 1.94 mmol) in methanol (19.4 mL) was added at room temperature with 1 mol/L aqueous sodium hydroxide solution (9.71 mL, 9.71 mmol), stirred at the same temperature for 30 minutes, and allowed to stand overnight.
• reaction solution was neutralized by adding 1 mol/L hydrochloric acid (9.71 mL, 9.71 mmol) under ice cooling, and the organic solvent was then distilled off under reduced pressure.
• the organic layer was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the residue purified by silica gel column chromatography (DCM/methanol) to give the title compound (943 mg, 1.63 mmol, yield 84%).
• Example E1 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Example E2> trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid Using the compound obtained in ⁇ Example E1>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example F1 trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-hydroxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid
• Sodium thiomethoxide (0.484 g, 6.90 mmol) was added to a solution of trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid (200 mg, 0.345 mmol) in DMF (3.45 mL) at room temperature, and the mixture was stirred at 100° C.
• Example F2 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-hydroxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-hydroxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid (1.33 g, 2.35 mmol) in DMF (23.5 mL) were added DIPEA (2.05 mL, 11.8 mmol) and iodoethane (0.940 mL, 11.8 mmol) at room temperature, the mixture was stirred at room temperature for 1 hour, and the mixture was allowed to stand at
• Example F3 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(propan-2-yloxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-hydroxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate 80.0 mg, 0.135 mmol) in DMF (1.32 mL) were added potassium carbonate (146 mg, 1.06 mmol) and 2-bromopropane (0.0991 mL, 1.06 mmol) at room temperature, followed by stirring at 130° C.
• Example F4> trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(propan-2-yloxy)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid Using the compound obtained in ⁇ Example F3>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example G1 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[2,2-dimethyl-4-(4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Example G2 Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(pyrrolidin-1-yl)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Ethyl trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[2,2-dimethyl-4-(4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate 50.0 mg, 0.0689 mmol) in 1,4-dioxane (1.38 mL) was added at room temperature to a solution of tris(dibenzylideneacetone)dipalladium(0) (6.3 mg,
• Example G3> trans-4-(4- ⁇ [(2,2-dimethylpropanoyl)(2- ⁇ 2,2-dimethyl-4-[4-(pyrrolidin-1-yl)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid
• the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example H1 trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)-N-(dimethylsulfamoyl)cyclohexanecarboxamide Trans-4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid (85 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS registration number: 25952-53-8) (56 mg, 0.29 mmol), and 4-dimethylaminopyridine (54 mg, 0.44
• reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed successively with 1 mol/L hydrochloric acid, water, and saturated saline.
• the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (64 mg, 0.093 mmol, yield 62%).
• Example I1 Ethyl trans-4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (pyridin-2-yl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• reaction mixture was stirred at 100°C for 2 hours.
• tripotassium phosphate 100 mg, 0.471 mmol
• 2-bromopyridine 0.030 mL, 0.31 mmol
• RuPhos Pd G3 4 mg, 0.005 mmol
• RuPhos Pd G3 4 mg, 0.005 mmol
• BrettPhos Pd G3 4 mg, 0.004 mmol
• cesium carbonate 120 mg, 0.368 mmol
• Example I2> trans-4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (pyridin-2-yl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid Using the compound obtained in ⁇ Example I1>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example J1 Methyl 3-[4-(4-formylphenoxy)phenyl]-2,2-dimethylpropanoate Using methyl 3-(4-hydroxyphenyl)-2,2-dimethylpropanoate (WO2008130514 A1) and 4-fluorobenzaldehyde (CAS registration number: 459-57-4), the title compound was obtained in the same manner as in Example P1.
• Example J2 Methyl 3-(4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ phenyl)-2,2-dimethylpropanoate 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethanamine (309 mg, 1.17 mmol) and methyl 3-[4-(4-formylphenoxy)phenyl]-2,2-dimethylpropanoate (367 mg, 1.17 mmol) were dissolved in 1,2-dichloroethane (6.0 mL), acetic acid (0.60 mL) was added, and the mixture was stirred at room temperature for 1 hour.
• Example J3 Methyl 3-[4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)phenyl]-2,2-dimethylpropanoate Methyl 3-(4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ phenyl)-2,2-dimethylpropanoate (241 mg, 0.431 mmol) and pivalic acid (52.8 mg, 0.517 mmol) were dissolved in DMF (6.0 mL), HATU (205 mg, 0.538 mmol) and DIPEA (0.187 mL, 1.08 mmol) were added, and the mixture was stirred at room temperature for 3 days
• Example J4> 3-[4-(4- ⁇ [(2,2-dimethylpropanoyl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)phenyl]-2,2-dimethylpropanoic acid Using the compound obtained in ⁇ Example J3>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example K1 Benzyl (cis-4-hydroxycyclohexyl)acetate Rhodium-alumina (10.0 g) was added to a solution of 4-hydroxyphenylacetic acid (CAS registration number: 156-38-7) (10.0 g, 65.7 mmol) in ethanol (200 mL), and the mixture was stirred at 50° C. under a hydrogen atmosphere for 8 hours. Insoluble matter was filtered off with Celite and washed with ethanol. The resulting solution was concentrated to about 200 mL, and rhodium-alumina (10.0 g) was added thereto, and the mixture was stirred at 50° C. under a hydrogen atmosphere for 4 hours. Insoluble matter was filtered off with Celite and washed with ethanol.
• the filtrate was concentrated under reduced pressure.
• the residue was dissolved in DMF (130 mL), and potassium carbonate (18.2 g, 131 mmol) was added thereto at room temperature.
• Benzyl bromide (11.7 mL, 98.6 mmol) was added dropwise under water cooling, and the mixture was stirred at room temperature overnight.
• the reaction mixture was diluted with diethyl ether, washed with water, 1 mol/L hydrochloric acid, and saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.65 g, 30.8 mmol, yield 47%).
• Example K2> Benzyl [trans-4-(4-formylphenoxy)cyclohexyl]acetate
• the title compound was obtained in the same manner as in ⁇ Example A4> using the compound obtained in ⁇ Example K1> and 4-hydroxybenzaldehyde (CAS registration number: 123-08-0).
• Example K3> Benzyl (trans-4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexyl)acetate Using the compounds obtained in ⁇ Example K2> and ⁇ Example C5>, the title compound was obtained in the same manner as in ⁇ Example D1>.
• Example K4> Benzyl [trans-4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoropropyl)amino]methyl ⁇ phenoxy)cyclohexyl]acetate Using the compound obtained in ⁇ Example K3> and 3,3,3-trifluoropropionaldehyde (CAS registration number: 460-40-2), the title compound was obtained in the same manner as in ⁇ Example T1>.
• Example K5> [trans-4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoropropyl)amino]methyl ⁇ phenoxy)cyclohexyl]acetic acid Using the compound obtained in ⁇ Example K4>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example L1> Ethyl trans-4-(4- ⁇ [(2- ⁇ 2,2-dimethyl-4-[4-(methylamino)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)(2,2-dimethylpropanoyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• the title compound was obtained in the same manner as in ⁇ Example G2> using the compound obtained in ⁇ Example G1> and methylamine (2.0 mol/L THF solution).
• Example L2> trans-4-(4- ⁇ [(2- ⁇ 2,2-dimethyl-4-[4-(methylamino)phenyl]tetrahydro-2H-pyran-4-yl ⁇ ethyl)(2,2-dimethylpropanoyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid Using the compound obtained in ⁇ Example L1>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• CHIRALCEL OZ-H registered trademark, Daicel Corporation
• Example M2 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide HATU (43.8 g, 115 mmol) was added to a solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (CAS registration number: 889940-13-0) (18.0 g, 115 mmol) in DMF (150 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0°C and stirred for 5 minutes.
• Example M3 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide (24.7 g, 61.5 mmol) in THF (60 mL) was added with borane-THF complex (0.89 mol/L THF solution, 240 mL, 210 mmol) and stirred under heating and reflux for 9 hours.
• Example M4> Ethyl trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• the title compound was obtained in the same manner as in ⁇ Example T1> using the compounds obtained in ⁇ Example M3> and ⁇ Example A4>.
• Example M5 trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid
• the title compound was obtained by the same method as in Example S4 using the compound obtained in Example M4.
• Example N1> N-[4-(4-bromophenoxy)benzyl]-N- ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide
• the title compound was obtained by using the compound obtained in ⁇ Example C5> and 4-(4-bromophenoxy)benzaldehyde (Bioorg. Med. Chem. Lett., 2004, 14, 4179-4183.) and carrying out the same operations as in ⁇ Example D1> and ⁇ Example D2> in that order.
• Example N2 N- ⁇ 4-[(4- ⁇ [dimethyl(oxide)- ⁇ 6 -sulfanylidene]amino ⁇ cyclohexyl)oxy]benzyl ⁇ -N- ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide N-[4-(4-bromophenoxy)benzyl]-N- ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide (150 mg, 0.246 mmol) in toluene (5 mL) was added with dimethylsulfoximine (CAS registration number: 1520-31-6) (35 mg, 0.38 mmol), (S)-(-)-Tol-BINAP (26 mg, 0.038 mmol), cesium
• Example O1 Ethyl trans-4-(4- ⁇ [(5-fluoropyrimidin-2-yl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylate
• Ethyl trans-4- ⁇ 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]phenoxy ⁇ cyclohexanecarboxylate (65.5 mg, 0.125 mmol) and 2-butanol (1.5 mL, 16 mmol) were added to a mixture of 2-chloro-5-fluoropyrimidine (CAS registration number: 62802-42-0) (0.030 mL, 0.24 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (0.0
• the reaction mixture was added with 1.5 hours of stirring at 150°C under microwave irradiation. Water and saturated saline were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers obtained were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (47.4 mg, 0.0765 mmol, yield 61%).
• Example O2> trans-4-(4- ⁇ [(5-fluoropyrimidin-2-yl) ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino]methyl ⁇ phenoxy)cyclohexanecarboxylic acid Using the compound obtained in ⁇ Example O1>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example P1 Methyl 2-[4-(4-formylphenoxy)phenyl]propanoate 4-Fluorobenzaldehyde (CAS Registry Number: 459-57-4) (0.637 mL, 5.94 mmol) and methyl 2-(4-hydroxyphenyl)propanoate (J. Med. Chem., 2007, 50, 3984-4002.) (1.07g, 5.94 mmol) were dissolved in N,N-dimethylacetamide (10 mL), potassium carbonate (2.46 g, 17.8 mmol) was added, and the mixture was stirred at 130°C for 8 hours, then returned to room temperature and left overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• Example P3> 2-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)phenyl]propanoic acid Using the compound obtained in ⁇ Example P2>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example Q1 Methyl 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]-2-methylbenzoate Using the compound obtained in ⁇ Example C5> and methyl 4-formyl-2-methylbenzoate (CAS registration number: 74733-23-6), the title compound was obtained in the same manner as in ⁇ Example J2>.
• Example Q2 Methyl 4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropanoyl)amino]methyl ⁇ -2-methylbenzoate 3,3,3-trifluoro-2,2-dimethylpropanoic acid (CAS registration number: 889940-13-0) (1.25 g, 8.04 mmol) was dissolved in DCM (10 mL), DMF (0.05 mL) was added, and the mixture was stirred at room temperature.
• DCM 10 mL
• DMF 0.05 mL
• Oxalyl chloride (0.748 mL, 8.84 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of methyl 4-[( ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ amino)methyl]-2-methylbenzoate (1.14 g, 2.68 mmol) and triethylamine (2.23 mL, 16.1 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 24 hours. Water and saturated aqueous sodium bicarbonate were added to the reaction solution, and the mixture was extracted with DCM.
• ⁇ Example Q3> 4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropanoyl)amino]methyl ⁇ -2-methylbenzoic acid Using the compound obtained in ⁇ Example Q2>, the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example Q4 3-[4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropanoyl)amino]methyl ⁇ -2-methylbenzoyl)phenyl]propanoic acid 4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropanoyl)amino]methyl ⁇ -2-methylbenzoic acid (1.06 g, 1.93 mmol) was dissolved in DCM (10 mL), DMF (0.05 mL) was added, and the mixture was stirred at room temperature.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate).
• the obtained crude product was dissolved in ethanol (4.0 mL), and 1 mol/L aqueous sodium hydroxide solution (0.754 mL, 0.754 mmol) was added and stirred at room temperature for 16 hours.
• the reaction solution was concentrated under reduced pressure, and the residue was neutralized with water and 2 mol/L hydrochloric acid, and then extracted with ethyl acetate.
• the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (15.0 mg, 0.0220 mmol, 15% yield).
• Example R1 Ethyl (2S)-2-ethoxy-3-[4-(4-formylphenoxy)phenyl]propanoate Using 4-fluorobenzaldehyde (CAS Registry Number: 459-57-4) and ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate (CAS Registry Number: 222555-06-8), the title compound was obtained in the same manner as in Example P1.
• Example R2> Ethyl (2S)-2-ethoxy-3-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)phenyl]propanoate
• the title compound was obtained in the same manner as in ⁇ Example T1>.
• Example S1 Ethyl (cis-4-hydroxycyclohexyl)acetate Under a nitrogen atmosphere, lithium tri(sec-butyl)borohydride (1.07 mol/L THF solution, 39.3 mL, 42.1 mmol) was added dropwise over 30 minutes to a solution of ethyl 2-(4-oxocyclohexyl)acetate (CAS registration number: 58012-34-3) (7.75 g, 42.1 mmol) in THF (170 mL) at -78°C, and the mixture was stirred at -78°C for 2 hours.
• lithium tri(sec-butyl)borohydride (1.07 mol/L THF solution, 39.3 mL, 42.1 mmol
• THF ethyl 2-(4-oxocyclohexyl)acetate
• Example S2> Ethyl ⁇ trans-4-[(5-formylpyridin-2-yl)oxy]cyclohexyl ⁇ acetate
• the title compound was obtained in the same manner as in ⁇ Example A4> using the compound obtained in ⁇ Example S1> and 6-hydroxynicotinaldehyde (CAS registration number: 106984-91-2).
• Example S3> Ethyl ⁇ trans-4-[(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ pyridin-2-yl)oxy]cyclohexyl ⁇ acetate
• the title compound was obtained in the same manner as in ⁇ Example T1>.
• Example T1 Benzyl [trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexyl]acetate 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (450 mg, 1.16 mmol) in methanol (11.6 mL) was added with benzyl [trans-4-(4-formylphenoxy)cyclohexyl]acetate (450 mg, 1.28 mmol) and acetic acid (0.199 mL, 3.48 mmol) at room temperature, and the mixture was stirred at 50
• Example T2> [trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)cyclohexyl]acetic acid
• the title compound was obtained in the same manner as in ⁇ Example S4>.
• Example U2> N-[4-(benzyloxy)benzyl]-3,3-difluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropanamide
• the title compound was obtained in the same manner as in ⁇ Example Q2>.
• reaction solution was diluted with ethyl acetate, and insoluble matter was filtered off with Celite.
• the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (714 mg, 1.46 mmol, yield 92%).
• Example U4 (cis-4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ cyclohexyl)methyl 4-methylbenzenesulfonate (cis-4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ cyclohexyl)methanol (WO2007126041 A1) (8.20 g, 22.2 mmol) was added to a DCM (200 mL) solution of triethylamine (4.63 mL, 33.4 mmol) and paratoluenesulfonyl chloride (4.67 g, 24.5 mmol), and the mixture was stirred under heating and reflux for 7 hours.
• the reaction solution was cooled to room temperature, and then ethanol (2 mL) was added and the mixture was stirred at room temperature for 10 hours.
• Water and saturated saline were added, and the mixture was extracted with ethyl acetate.
• the organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.89 g, 17.0 mmol, yield 76%).
• Example U6 tert-Butyl( ⁇ cis-4-[(methylsulfinyl)methyl]cyclohexyl ⁇ oxy)diphenylsilane Sodium periodate (4.04 g, 18.9 mmol) was added to a solution of tert-butyl( ⁇ cis-4-[(methylsulfanyl)methyl]cyclohexyl ⁇ oxy)diphenylsilane (6.28 g, 15.8 mmol) in methanol (100 mL) and water (25 mL), and the mixture was stirred at room temperature for 15 hours. Saturated saline and water were added to the reaction solution, and the mixture was extracted with ethyl acetate.
• Example U8 Benzyl ⁇ [(cis-4-hydroxycyclohexyl)methyl](methyl)oxide- ⁇ 6 -sulfanylidene ⁇ carbamate
• Tetrabutylammonium fluoride (1.0 mol/L THF solution, 30 mL, 30 mmol) was added to a solution of benzyl ⁇ [(cis-4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ cyclohexyl)methyl](methyl)oxide- ⁇ 6 -sulfanylidene ⁇ carbamate (3.97 g, 7.04 mmol) in THF (30 mL), and the mixture was stirred at 65° C. for 2 hours.
• the reaction solution was cooled to room temperature, water and saturated saline were added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (1.70 g, 5.22 mmol, 74% yield).
• CHIRALPAK IC registered trademark, Daicel Corporation
• Example V1 tert-butyl 2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate 4-bromo-3-fluorobenzaldehyde (CAS Registry Number: 133059-43-5) (4.00 g, 19.7 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS Registry Number: 1562375-30-7) (6.38 g, 20.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM adduct (0.804 g, 0.985 mmol), and sodium carbonate (6.27 g, 59.2 mmol) were dissolved in 1,4-dioxane (45 The residue was dissolved in a mixed solvent of 100 mL of he
• Example V2 (4R)-2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate tert-butyl
• Example V3 (4S)-tert-butyl 2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Racemic tert-butyl 2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate was purified by chiral HPLC [column: CHIRALPAK IG (registered trademark, Daicel Corporation), mobile phase: acetonitrile] to give the R-form (Example V2) as the component eluted first, and the S-form (Example V3) as the component eluted later.
• CHIRALPAK IG registered trademark, Daicel Corporation
• Example V4 (4R)-2'-fluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-carboxylate tert-butyl (4R)-2'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate tert-butyl (0.115 g, 0.378 mmol) and 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (0.147 g, 0.379 m
• Example W1 tert-Butyl 4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS Registry Number: 1562375-30-7) (WO2017051355) (1.14 g, 3.70 mmol), 4-bromobenzaldehyde (CAS Registry Number: 1122-91-4) (694 mg, 3.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) DCM adduct (306 mg, 0.375 mmol), and potassium carbonate (2.0 mol/L aqueous solution, 3.5 mL, 7.0 A suspension of 1,4-dioxane (7.5 mL) of 1,4-dioxane (8.5 mmol) was
• CHIRALPAK IG registered trademark, Daicel Corporation
• Example X2 tert-Butyl 4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazine-1-carboxylate [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl methanesulfonate (0.878 g, 1.32 1.37 g, 7.37 m
• Example Y1 tert-Butyl (2- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]amino ⁇ ethyl)carbamate 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (WO2021170109 A1) (391 mg, 1.43 mmol), and N-Boc-2-aminoacetaldehyde (CAS registration number: 89711-08-0) (364 mg, 2.29 mmol) in methanol (7 mL), and N,N-dimethylacetamide (7 mL) suspension.
• Example Y2> 3- ⁇ 5-[(2-aminoethyl)amino]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ piperidine-2,6-dione dihydrochloride Using the compound obtained in ⁇ Example Y1>, the title compound was obtained in the same manner as in ⁇ Example AO5>.
• Example Y4 Methyl (4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)acetate Methyl (4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-yl)acetate (283 mg, 1.0956 mmol) and 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (300 mg, 0.774 mmol) in methanol (4 mL) were added to a solution of acetic acid (0.133
• reaction mixture was added with 1 mol/L hydrochloric acid (1 mL, 1 mmol) and extracted with DCM.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain the title compound (219 mg, 0.357 mmol, yield 96%).
• the title compound was obtained in the same manner as in ⁇ Example BM9> using the compounds obtained in ⁇ Example Y5> and ⁇ Example Y2>.
• ⁇ Example Z2> tert-Butyl [4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetate
• the title compound was obtained in the same manner as in ⁇ Example Y4>.
• Example Z3> [4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetic acid dihydrochloride Using the compound obtained in ⁇ Example Z2>, the title compound was obtained in the same manner as in ⁇ Example V5>.
• Example Z4 3-Bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 3-Bromopiperidine-2,6-dione (CAS registration number: 62595-74-8) (25.5 g, 133 mmol) was suspended in DCM (250 mL) and, under ice cooling, DIPEA (45 mL, 258 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (29 mL, 170 mmol) were added in sequence and stirred at the same temperature for 40 minutes. The reaction solution was warmed to room temperature and stirred for 16 hours.
• DIPEA 45 mL, 258 mmol
• [2-(chloromethoxy)ethyl]trimethylsilane 29 mL, 170 mmol
• Example Z5 3-(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 1-Methyl-7-nitro-1,3-dihydro-2H-benzimidazol-2-one (WO2020200291 A1) (3.29 g, 17.0 mmol), 3-bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione (11.38 g, 35.31 mmol), and cesium carbonate (16.7 g, 51.3 mmol) in DMF (80 mL) suspension were stirred at room temperature for 26 hours under a nitrogen atmosphere.
• reaction solution was diluted with ethyl acetate and washed with water and saturated saline in sequence.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.76 g, 15.6 mmol, yield 91%).
• Example Z6> 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example Z5>, the title compound was obtained in the same manner as in ⁇ Example BK5>.
• Example Z7> N-[1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]-2-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetamide Using the compounds obtained in ⁇ Example Z6> and ⁇ Example Z3>, the title compound was obtained in the same manner as in ⁇ Example BM9>.
• Example Z8> N-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]-2-[4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetamide Using the compound obtained in ⁇ Example Z7>, the title compound was obtained in the same manner as in ⁇ Example BK9>.
• Example AA1 Ethyl (4'-formyl[biphenyl]-3-yl)acetate Using 4-bromobenzaldehyde (CAS registration number: 1122-91-4) and [3-(2-ethoxy-2-oxoethyl)phenyl]boronic acid (CAS registration number: 1256345-69-3), the title compound was obtained in the same manner as in Example W1.
• Example AA2> Ethyl (4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ [biphenyl]-3-yl)acetate Using the compound obtained in ⁇ Example AA1> and ⁇ Example M3>, the title compound was obtained in the same manner as in ⁇ Example Y4>.
• the title compound was obtained in the same manner as in ⁇ Example Y5>.
• the title compound was obtained in the same manner as in ⁇ Example BM9> using the compound obtained in ⁇ Example AA3> and ⁇ Example Y2>.
• Example AB1 Ethyl cyano(4,4-difluorocyclohexylidene)acetate The title compound was obtained in the same manner as in Example A1 using 4,4-difluorocyclohexanone (CAS registration number: 22515-18-0).
• ⁇ Example AB2> N- ⁇ 2-[4,4-difluoro-1-(4-methoxyphenyl)cyclohexyl]ethyl ⁇ -3,3,3-trifluoro-2,2-dimethylpropan-1-amine Using the compound obtained in ⁇ Example AB1>, the same operations as in ⁇ Example C3>, ⁇ Example C4>, ⁇ Example C5>, ⁇ Example M2>, and ⁇ Example M3> were carried out in order to obtain the title compound.
• Example AB3 Methyl [4-(4-formylphenoxy)piperidin-1-yl]acetate Using tert-butyl 4-(4-formylphenoxy)piperidine-1-carboxylate (WO2015069110 A1) and methyl bromoacetate (CAS registration number: 96-32-2), the title compound was obtained in the same manner as in ⁇ Example AK7>.
• Example AB4> Methyl [4-(4- ⁇ [ ⁇ 2-[4,4-difluoro-1-(4-methoxyphenyl)cyclohexyl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetate Using the compounds obtained in ⁇ Example AB3> and ⁇ Example AB2>, the title compound was obtained in the same manner as in ⁇ Example Y4>.
• Example AB5> [4-(4- ⁇ [ ⁇ 2-[4,4-difluoro-1-(4-methoxyphenyl)cyclohexyl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetic acid Using the compound obtained in ⁇ Example AB4>, the title compound was obtained in the same manner as in ⁇ Example Y5>.
• ⁇ Example AB6> 2-[4-(4- ⁇ [ ⁇ 2-[4,4-difluoro-1-(4-methoxyphenyl)cyclohexyl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]-N-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]acetamide
• the title compound was obtained in the same manner as in ⁇ Example BM9> using the compound obtained in ⁇ Example AB5> and 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (WO2021170109 A1).
• Example AC1 Ethyl cyano(tetrahydro-4H-pyran-4-ylidene)acetate The title compound was obtained in the same manner as in Example A1 using tetrahydro-4H-pyran-4-one (CAS registration number: 29943-42-8).
• ⁇ Example AC2> 3,3,3-trifluoro-N- ⁇ 2-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine Using the compound obtained in ⁇ Example AC1>, the same operations as in ⁇ Example C3>, ⁇ Example C4>, ⁇ Example C5>, ⁇ Example M2>, and ⁇ Example M3> were carried out in order to obtain the title compound.
• Example AC3> methyl [4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetate
• the title compound was obtained in the same manner as in ⁇ Example Y4>.
• Example AC4> [4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetic acid Using the compound obtained in ⁇ Example AC3>, the title compound was obtained in the same manner as in ⁇ Example Y5>.
• Example AC5> N-[1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]-2-[4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetamide
• the title compound was obtained in the same manner as in ⁇ Example BM9>.
• Example AC6> N-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]-2-[4-(4- ⁇ [ ⁇ 2-[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)piperidin-1-yl]acetamide Using the compound obtained in ⁇ Example AC5>, the title compound was obtained in the same manner as in ⁇ Example BK9>.
• Example AF1> N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-[2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetamide
• the title compound was obtained in the same manner as in ⁇ Example BM9> using the compound obtained in ⁇ Example AK9> and 3-(5-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (ACS Med. Chem. Lett., 2021, 12, 1733.
• Example AG1 Ethyl 4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using 4-bromobenzaldehyde (CAS registration number: 1122-91-4) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1), the title compound was obtained in the same manner as in Example W1.
• 4-bromobenzaldehyde CAS registration number: 1122-91-4
• ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate CAS registration number: 1049004-32-1
• Example AG3 (4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)methanol
• Example AH1 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (CAS registration number: 913297-44-6), the title compound was obtained in the same manner as in Example Z5.
• Example AH2> 2,4,6-trichlorophenyl 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate Using the compound obtained in ⁇ Example AH1>, the title compound was obtained in the same manner as in ⁇ Example BY5>.
• Example AI1 Ethyl cis-4-(4-formylphenyl)cyclohexanecarboxylate
• Example AI2 Ethyl trans-4-(4-formylphenyl)cyclohexanecarboxylate
• a suspension of ethyl 4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate (1.1 g, 4.30 mmol) and 7.5% palladium carbon (350 mg) in ethanol (30 mL) was stirred for 1.5 hours.
• the catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure.
• Example AI3> Ethyl cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexanecarboxylate
• the title compound was obtained in the same manner as in ⁇ Example W4>.
• Example AI4> [cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexyl]methanol
• the title compound was obtained in the same manner as in ⁇ Example W5>.
• Example AI5 cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexanecarbaldehyde Under ice cooling, a solution of [cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexyl]methanol (520 mg, 0.88 mmol) in DCM (10 mL) was added to 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)
• ⁇ Example AI6> tert-Butyl 4- ⁇ [cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexyl]methyl ⁇ piperazine-1-carboxylate
• the title compound was obtained in the same manner as in ⁇ Example W4>.
• Example AI7 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethyl-N- ⁇ 4-[cis-4-(piperazin-1-ylmethyl)cyclohexyl]benzyl ⁇ propan-1-amine
• Example AI8 tert-Butyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate Using tert-butyl 4-amino-3-(methylamino)benzoate (Bioorg. Med. Chem. Lett., 2002, 12, 3129.), the title compound was obtained in the same manner as in Example AN2.
• Example AI9 tert-Butyl 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate Under ice cooling, sodium hydride (55% oil, 50 mg, 1.15 mmol) was added to a solution of tert-butyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (260 mg, 0.46 mmol) in THF (5 mL) and stirred for 30 minutes.
• 3-bromopiperidine-2,6-dione (CAS registration number: 62595-74-8) (200 mg, 1.04 mmol) was added and stirred at 60°C for 1.5 hours. After cooling, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (165 mg, 0.46 mmol, yield 44%).
• Example AI10 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid
• tert-butyl 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 165 mg, 0.46 mmol
• the reaction solution was concentrated under reduced pressure to obtain crude crystals, which were washed with a small amount of chloroform/ethyl acetate to obtain the title compound (74 mg, 0.24 mmol, yield 53%).
• Example AI11 3- ⁇ 5-[(4- ⁇ [cis-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexyl]methyl ⁇ piperazin-1-yl)carbonyl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ piperidine-2,6-dione 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethyl-N- ⁇ 4-[cis-4-(piperazin-1-ylmethyl)cyclohexyl]benzyl ⁇ propan-1-
• reaction solution was diluted with chloroform and washed with water and saturated saline in that order.
• the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (55 mg, 0.058 mmol, yield 88%).
• Example AJ3> trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexanecarbaldehyde
• the title compound was obtained in the same manner as in ⁇ Example AI5>.
• ⁇ Example AJ5> 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethyl-N- ⁇ 4-[trans-4-(piperazin-1-ylmethyl)cyclohexyl]benzyl ⁇ propan-1-amine
• the title compound was obtained in the same manner as in ⁇ Example AI7>.
• ⁇ Example AJ6> 3- ⁇ 5-[(4- ⁇ [trans-4-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenyl)cyclohexyl]methyl ⁇ piperazin-1-yl)carbonyl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example AJ5> and ⁇ Example AI10>, the title compound was obtained in the same manner as in ⁇ Example AI11>.
• Example AK1 tert-Butyl 7-amino-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate
• a solution of tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (CAS registration number: 171049-41-5) (1.13 g, 4.55 mmol) in acetonitrile (50 mL) was cooled to 0°C, N-bromosuccinimide (0.83 g, 4.66 mmol) was added, and the mixture was stirred at room temperature for 15 hours.
• the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.43 g, 4.37 mmol, yield 96%).
• Example AK2 tert-Butyl 8-bromo-7-[(methylcarbamoyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate
• tert-Butyl 7-amino-8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.8 g, 5.5 mmol) in DCM (28 mL) was added to DIPEA (3.8 mL, 22 mmol), and N-methylcarbamoyl chloride (CAS reg. no.: 6452-47-7) (1.5 g, 17 mmol) was added at 0° C., and the mixture was stirred at room temperature for 17 hours.
• N-methylcarbamoyl chloride 1.0 g, 11 mmol
• DIPEA 1.9 mL, 11 mmol
• the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (1.86 g, 4.84 mmol, yield 88%).
• reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
• organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (540 mg, 1.78 mmol, yield 44%).
• Example AK4 tert-Butyl 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate tert-Butyl 1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate (540 mg, 1.78 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (WO2021262812 A1) (1.11 g, 2.66 mmol), and copper(II) acetate (644 mg, 3.56 mmol) in acetonitrile To the suspension (3.6 mL), triethylamine (0.74 mL, 5.34 mmol) was added and stirred at 80
• Example AK5 tert-Butyl 3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate tert-Butyl 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate (1.0 g, 1.7 mmol) in ethyl acetate (16 mL)-ethanol (16 mL) was added to ASCA-2 (manufactured by N.E.
• Example AK6 tert-Butyl 2-(4-formylphenoxy)-7-azaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-[(methylsulfonyl)oxy]-7-azaspiro[3.5]nonane-7-carboxylate (J. Med. Chem., 2014, 57, 3, 733.) (7.02 g, 22.0 mmol), 4-hydroxybenzaldehyde (CAS: 123-08-0) (2.66 g, 21.8 mmol), and a suspension of cesium carbonate (13.8 g, 42.4 mmol) in DMF (45 mL) were stirred at 100° C. for 4 hours.
• the reaction solution was cooled to room temperature and diluted with ethyl acetate (150 mL). The mixture was washed with water (150 mL) and saturated saline (100 mL) in that order, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.63 g, 19.2 mmol, yield 87%).
• the reaction solution was concentrated under reduced pressure, dried, and then tert-butyl bromoacetate (3.22 mL, 22.0 mmol) was added to the residue and potassium carbonate (12.4 g, 89.7 mmol) in DMF (40 mL) suspension and stirred at room temperature for 4 hours.
• the reaction mixture was diluted with ethyl acetate (100 mL) and washed successively with water (100 mL) and saturated saline (100 mL).
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.57 g, 18.3 mmol, yield 92%).
• ⁇ Example AK8> tert-Butyl [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetate Using the compounds obtained in ⁇ Example M3> and ⁇ Example AK7>, the title compound was obtained in the same manner as in ⁇ Example W4>.
• ⁇ Example AK9> [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetic acid dihydrochloride Using the compound obtained in ⁇ Example AK8>, the title compound was obtained in the same manner as in ⁇ Example V5>.
• Example AK10 3-(8- ⁇ [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetyl ⁇ -1-methyl-2-oxo-1,2,6,7,8,9-hexahydro-3H-imidazo[4,5-h]isoquinolin-3-yl)piperidine-2,6-dione tert-butyl 3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-1,2,3,6,7,9-hexahydro-8H-imidazo[4,5-h]isoquinoline-8-carboxylate (21.4 To a solution of 1 mg, 0.0516 mmol) in DCM (1 m
• Example AL1 tert-Butyl 5-amino-4,6-dibromo-1,3-dihydro-2H-isoindole-2-carboxylate tert-Butyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (CAS registration number: 264916-06-5) (200 mg, 0.85 mmol) was dissolved in a mixed solvent of DCM (12 mL) and methanol (6 mL), and calcium carbonate (230 mg, 2.30 mmol) and benzyltrimethylammonium tribromide (700 mg, 1.80 mmol) were added at room temperature and stirred for 30 minutes.
• Example AL2 tert-Butyl 5-amino-4-bromo-1,3-dihydro-2H-isoindole-2-carboxylate tert-Butyl 5-amino-4,6-dibromo-1,3-dihydro-2H-isoindole-2-carboxylate (33 mg, 0.084 mmol), palladium(II) acetate (2.1 mg, 0.0094 mmol), and (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (5.1 mg, 0.084 mmol) were added with THF (1 mL) and stirred at room temperature for 10 minutes.
• N,N'-dimethylethylenediamine (0.020 mL, 0.019 mmol) was added to the reaction solution and stirred for 10 minutes, then sodium borohydride (4.0 mg, 0.11 mmol) was added and stirred at room temperature for 17 hours.
• a small amount of methanol was added to the reaction mixture, and the mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.022 g, 0.070 mmol, yield 83%).
• Example AL3> tert-Butyl 3-(2,6-dioxopiperidin-3-yl)-1-methyl-2-oxo-2,3,6,8-tetrahydroimidazo[4,5-e]isoindole-7(1H)-carboxylate
• the title compound was obtained by carrying out the same operations as in ⁇ Example AK2>, ⁇ Example AK3>, ⁇ Example AK4>, and ⁇ Example AK5> in order.
• ⁇ Example AL4> 3-[7- ⁇ [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetyl ⁇ -1-methyl-2-oxo-1,6,7,8-tetrahydroimidazo[4,5-e]isoindol-3(2H)-yl]piperidine-2,6-dione Using the compound obtained in ⁇ Example AL3>, the title compound was obtained in the same manner as in ⁇ Example AK10>.
• Example AM1 4-[(4R)-2,2-dimethyl-4- ⁇ 2-[(3,3,3-trifluoro-2,2-dimethylpropyl)amino]ethyl ⁇ tetrahydro-2H-pyran-4-yl]phenol 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (2.00 g, 5.16 mmol) and a suspension of sodium thiomethoxide (1.16 g, 16.6 mmol) in DMF (10 mL) were stirred at 150° C.
• Example AM2 tert-Butyl ⁇ 2-[(4R)-4-(4-hydroxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)carbamate 4-[(4R)-2,2-dimethyl-4- ⁇ 2-[(3,3,3-trifluoro-2,2-dimethylpropyl)amino]ethyl ⁇ tetrahydro-2H-pyran-4-yl]phenol (1.97 g, 5.27 mmol), and triethylamine (2 mL, 14 mmol) in THF (25 mL) solution were added with di-tert-butyl dicarbonate (1.79 g, 8.20 mmol) and stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the
• Example AM3 tert-Butyl (2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamate.
• the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (356 mg, 0.680 mmol, yield 73%).
• Example AM4 N-(2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)-3,3,3-trifluoro-2,2-dimethylpropan-1-amine.
• Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)carbamate (426 mg, 0.812 mmol) in DCM (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (297 mg, 0.701 mmol, yield 86%).
• Example AM5> Ethyl 4'- ⁇ [(2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using the compound obtained in ⁇ Example AG1> and ⁇ Example AM4>, the title compound was obtained in the same manner as in ⁇ Example W4>.
• ⁇ Example AM6> tert-Butyl 4-[(4'- ⁇ [(2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)methyl]piperazine-1-carboxylate
• the title compound was obtained by carrying out the same operations as in ⁇ Example AG3>, ⁇ Example X1>, and ⁇ Example X2> in order.
• Example AM7 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 6-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (CAS registration number: 305790-48-1) (23.8 g, 105 mmol), 3-bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione (68.3 g, 212 mmol), and cesium carbonate (102 g, 313 mmol) in DMF (300 mL) were stirred at room temperature for 45 hours.
• the reaction solution was diluted with ethyl acetate (600 mL) and washed with water (600 mL).
• the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed successively with water and saturated saline.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the resulting solid was washed with hexane to obtain the title compound (32.7 g, 69.8 mmol, yield 67%).
• Example AM8 2,4,6-trichlorophenyl 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione (1.13 g, 2.41 mmol) and 2,4,6-trichlorophenyl formate (CAS Registry Number: 4525-65-9) (816 mg, 3.62 mmol), palladium(II) acetate (27.1 mg, 0.121 mmol), and XantPhos (140 mg, Toluene (24.0 mL) and triethylamine (0.592 mL, 4.27 mmol) were added
• Example AM9 3-[5-( ⁇ 4-[(4'- ⁇ [(2- ⁇ (4R)-4-[4-(difluoromethoxy)phenyl]-2,2-dimethyltetrahydro-2H-pyran-4-yl ⁇ ethyl)(3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)methyl]piperazin-1-yl ⁇ carbonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione tert-butyl
• a 4 mol/L hydrogen chloride/1,4-dioxane solution (0.5 mL, 2 mmol) was added to a solution of 4-[(4'- ⁇ [(2- ⁇ (4R)-4-[4-
• reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (68.0 mg, 0.0614 mmol, yield 95%).
• Example AN1 1,2,3,4-tetrahydroquinoxalin-5-amine 5-aminoquinoxaline (CAS registration number: 16566-20-4) (450 mg, 3.10 mmol) in THF (15 mL) was added with borane-THF complex (1 mol/L THF solution, 7.5 mL, 7.5 mmol) at room temperature and stirred for 15 minutes. Methanol (15 mL) was added to the reaction solution, which was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (414 mg, 2.77 mmol, yield 90%).
• Example AN3> 6- ⁇ [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetyl ⁇ -5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-2(1H)-one Using the compound obtained in ⁇ Example AK9> and ⁇ Example AN2>, the title compound was obtained in the same manner as in ⁇ Example BM9>.
• ⁇ Example AN4> 3-[6- ⁇ [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetyl ⁇ -2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxaline-1(2H)-yl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example AN3>, the title compound was obtained in the same manner as in ⁇ Example Z5>.
• ⁇ Example AN5> 3-[6- ⁇ [2-(4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ phenoxy)-7-azaspiro[3.5]nonan-7-yl]acetyl ⁇ -2-oxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxaline-1(2H)-yl]piperidine-2,6-dione Using the compound obtained in ⁇ Example AN4>, the title compound was obtained in the same manner as in ⁇ Example BK9>.
• Example AO1> 4- ⁇ [(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]amino ⁇ -3-nitrobenzoate benzyl tert-butyl D- ⁇ -glutamate monohydrochloride (CAS registration number: 66575-26-6) (460 mg, 1.93 mmol), 4-fluoro-3-nitrobenzoate benzyl (Org. Lett., 2016, 18, 3706.) (633 mg, 2.30 mmol), and potassium carbonate (814 mg, 5.89 mmol) were suspended in DMF (4 mL) and stirred at room temperature for 5 hours.
• reaction solution was diluted with ethyl acetate and washed with water and saturated saline in that order.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (368 mg, 0.804 mmol, yield 42%).
• Example AO2 Benzyl 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 4- ⁇ [(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]amino ⁇ -3-nitrobenzoate benzyl (317 mg, 0.693 mmol) was added to an acetone (5 mL)-water (1 mL) solution of ammonium chloride (369 mg, 6.90 mmol) and zinc powder (426 mg, 6.52 mmol), and stirred at room temperature for 10 minutes.
• the reaction solution was diluted with ethyl acetate, and the insoluble matter was filtered off with Celite, washed with saturated saline, dried over sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure.
• the residue was dissolved in THF (7 mL), and 1,1'-carbonyldiimidazole (186 mg, 1.15 mmol) was added and stirred at room temperature for 5 hours. 1,1'-carbonyldiimidazole (117 mg, 0.722 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. 1,1'-carbonyldiimidazole (66.5 mg, 0.410 mmol) was added to the reaction solution and stirred at room temperature for 1.5 hours.
• the reaction solution was diluted with methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (226 mg, 0.498 mmol, 72% yield).
• Example AO3 Benzyl 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate Benzyl 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (226 mg, 0.498 mmol) and potassium carbonate (205 mg, 1.48 mmol) were added to a suspension in DMF (1 mL) of iodomethane (0.062 mL, 1.0 mmol) and stirred at room temperature for 4 hours.
• reaction solution was diluted with ethyl acetate and washed with water and saturated saline in that order.
• the organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure and further dried under reduced pressure to obtain the title compound (207 mg, 0.443 mmol, yield 89%).
• Example AO4 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate benzyl 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (195 mg, 0.417 mmol) and 10% palladium carbon (223 mg) in ethyl acetate (2 mL)-ethanol (2 mL) suspension were stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction solution was diluted with chloroform, insoluble matter was filtered off with Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (150 mg, 0.397 mmol, yield 95%).
• Example AO5 3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethyl-N- ⁇ [(4'R)-4'-(piperazin-1-ylmethyl)-2',3',4',5'-tetrahydro[biphenyl]-4-yl]methyl ⁇ propan-1-amine dihydrochloride tert-butyl 4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazine-1-carboxylate (13.8
• Example AP1> 4- ⁇ [(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]amino ⁇ -3-nitrobenzoic acid benzyl tert-butyl L- ⁇ -glutamate monohydrochloride (CAS registration number: 108607-02-9) (280 mg, 1.17 mmol), 4-fluoro-3-nitrobenzoic acid benzyl (Org. Lett., 2016, 18, 3706.) (433 mg, 1.57 mmol), and potassium carbonate (482 mg, 3.49 mmol) were suspended in DMF (2 mL) and stirred at room temperature for 4.5 hours.
• reaction solution was diluted with ethyl acetate and washed with water and saturated saline in that order.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (299 mg, 0.654 mmol, yield 56%).
• Example AP2> Benzyl 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate 4- ⁇ [(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]amino ⁇ -3-nitrobenzoate benzyl (1.09 g, 2.38 mmol) was added to a solution of acetone (15 mL)-water (3 mL) with ammonium chloride (1.10 g, 20.6 mmol) and zinc powder (1.36 g, 20.8 mmol) and stirred at room temperature for 5 minutes.
• the reaction solution was diluted with ethyl acetate, and the insoluble matter was filtered off with Celite, and the filtrate was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was dissolved in THF (24 mL), and 1,1'-carbonyldiimidazole (580 mg, 3.58 mmol) was added and stirred at room temperature for 5 hours. 1,1'-carbonyldiimidazole (366 mg, 2.26 mmol) was added to the reaction solution and stirred for 1.5 hours. 1,1'-carbonyldiimidazole (222 mg, 1.37 mmol) was added to the reaction solution and stirred for 1.5 hours. The reaction solution was diluted with methanol and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/methanol) to obtain the title compound (839 mg, 1.85 mmol, yield 78%).
• Example AP3 Benzyl 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate Benzyl 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (839 mg, 1.85 mmol) and potassium carbonate (757 mg, 5.48 mmol) were added to a suspension in DMF (4 mL) to give iodomethane (0.230 mL, 3.69 mmol), and the mixture was stirred at room temperature for 4 hours.
• reaction solution was diluted with ethyl acetate and washed with water and saturated saline in that order.
• the organic layer was dried over sodium sulfate and then filtered.
• the filtrate was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (783 mg, 1.67 mmol, yield 91%).
• Example AP4> 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate benzyl 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylate (780 mg, 1.67 mmol) in ethyl acetate (8 mL)-ethanol (8 mL) was added to 10% palladium carbon (859 mg) and stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction solution was diluted with chloroform, and insoluble matter was filtered off with Celite. The filtrate was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (647 mg, 1.71 mmol, yield: quantitative).
• Example AR1> N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -1-(trifluoromethyl)cyclobutanecarboxamide Using the compound obtained in ⁇ Example M1> and 1-(trifluoromethyl)cyclobutanecarboxylic acid (CAS registration number: 277756-45-3), the title compound was obtained in the same manner as in ⁇ Example M2>.
• Example AR2> 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-N- ⁇ [1-(trifluoromethyl)cyclobutyl]methyl ⁇ ethanamine Using the compound obtained in ⁇ Example AR1>, the title compound was obtained in the same manner as in ⁇ Example M3>.
• ⁇ Example AR4> tert-Butyl 4-( ⁇ 4'-[( ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ [1-(trifluoromethyl)cyclobutyl]methyl ⁇ amino)methyl]-2,3,4,5-tetrahydro[biphenyl]-4-yl ⁇ methyl)piperazine-1-carboxylate Using the compound obtained in ⁇ Example AR3>, the title compound was obtained by carrying out the same operations as in ⁇ Example AG3>, ⁇ Example X1>, and ⁇ Example X2> in this order.
• Example AS1 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione (5.71 g, 12.2 mmol), triethylsilane (4.0 mL, 25 mmol), triethylamine (5.0 mL, 36 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.37 g, 1.87 mmol) in DMF (60 The suspension (2.1 mL) was stirred under a carbon monoxide atmosphere at 95
• reaction solution was diluted with ethyl acetate and washed successively with water and saturated saline.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.12 g, 5.08 mmol, yield 42%).
• Example AS2 Benzyl 4- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl ⁇ piperazine-1-carboxylate 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-carbaldehyde (1.36 g, 3.26 mmol), 1-carbobenzoxypiperazine (CAS Registry Number: 31166-44-6) (0.811 mL, 4.23 mmol), and acetic acid (0.559 mL, 9.76 mmol) were dissolved in DCM (15 mL, 2.2 mmol).
• Example AS3> Benzyl 4- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl ⁇ piperazine-1-carboxylate Using the compound obtained in ⁇ Example AS2>, the title compound was obtained in the same manner as in ⁇ Example BK9>.
• Example AS4 3-[3-methyl-2-oxo-5-(piperazin-1-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione benzyl 4- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl ⁇ piperazine-1-carboxylate (917 mg, 1.87 mmol) in ethyl acetate (20 mL) was added to 10% palladium carbon (2.33 g) and stirred under hydrogen atmosphere at room temperature for 1.5 hours.
• reaction solution was replaced with nitrogen, diluted with 10% IPA/chloroform (30 mL) and IPA (4 mL), and insoluble matter was filtered off with Celite and washed with 33% IPA/chloroform.
• the filtrate and the washings were combined and concentrated under reduced pressure, and the precipitated solid was washed with ethyl acetate to obtain the title compound (317 mg, 0.887 mmol, yield 48%).
• Example AS5 Ethyl 4'-formyl-2'-methyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1) and 4-bromo-3-methylbenzaldehyde (CAS registration number: 78775-11-8), the title compound was obtained in the same manner as in Example W1.
• Example AT1 Ethyl 3'-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1) and 4-bromo-2-fluorobenzaldehyde (CAS registration number: 57848-46-1), the title compound was obtained in the same manner as in Example W1.
• Example AU1 Ethyl 2',6'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using 4-bromo-3,5-difluorobenzaldehyde (CAS registration number: 135564-22-6) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1), the same operations as in Example W1 and Example W4 were carried out in order to obtain the title compound.
• Example AU2 tert-Butyl 4-[(2',6'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)carbonyl]piperazine-1-carboxylate Ethyl 2',6'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-carboxylate (0.124 g,
• Example AU3 3-[5-( ⁇ 4-[(2',6'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)carbonyl]piperazin-1-yl ⁇ methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione tert-butyl 4-[(2',6'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran
• Example AV1 Ethyl 2',3'-difluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-carboxylate
• Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1) and 4-bromo-2,3-difluorobenzaldehyde (CAS registration number: 644985-24-0) were used, and the same operations as in Example W1 and Example W4 were carried out in order to obtain the title compound.
• Example AW2> 3-(7-iodo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione
• cesium carbonate 11 g, 34 mmol
• 7-iodo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one 5.0 g, 17 mmol
• 3-bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 11 g, 34 mmol
• DMF 80 mL
• Example AW3 2,4,6-trichlorophenyl 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinoline-7-carboxylate
• 2,4,6-trichlorophenyl formate (CAS registration number: 4525-65-9) (1.4 g, 6.1 mmol) and XantPhos were added to a solution of 3-(7-iodo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-1(2H)-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione (2.2 g, 4.1 mmol) in toluene (30 mL).
• Example AW4 3- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-1(2H)-yl ⁇ -1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione At room temperature, 2,4,6-trichlorophenyl To a suspension of 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-2-o
• Example AW5 3- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl ⁇ piperidine-2,6-dione Trifluoroacetic acid (0.5 mL) was added to a solution of 3- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-
• the reaction solution was concentrated under reduced pressure, and the residue was neutralized by adding sodium bicarbonate water and extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL), and N,N'-dimethylethylenediamine (0.13 mL, 1.2 mmol) was added and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated saline, the organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (547 mg, 0.566 mmol, yield 95%).
• Example AX1 N- ⁇ [4'-(bromomethyl)-2',3',4',5'-tetrahydro[biphenyl]-4-yl]methyl ⁇ -3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)methyl methanesulfonate (53.0 mg, 0.0796 mmol) in acetone (1 mL) was added to a solution of lithium bromid
• the reaction mixture was added with acetone (1 mL), stirred at 70° C. for 4 hours, and cooled to room temperature.
• the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
• the organic layer was dried over sodium sulfate and then filtered.
• the filtrate was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (42.1 mg, 0.0647 mmol, yield 81%).
• Example AX2 tert-Butyl 4-[(4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl)methyl]-3-oxopiperazine-1-carboxylate N- ⁇ [4'-(bromomethyl)-2',3',4',5'-tetrahydro[biphenyl]-4-yl]methyl ⁇ -3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (42.1 mg, 0.0647 Sodium hydride (55% oil
• Example AY1> 3-(3-methyl-5-nitro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using 1-methyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one (WO2019060693 A1), the title compound was obtained in the same manner as in ⁇ Example Z5>.
• Example AY2> 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example AY1>, the title compound was obtained in the same manner as in ⁇ Example BK5>.
• ⁇ Example AY3> N-[1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2-nitrobenzenesulfonamide Using the compound obtained in ⁇ Example AY2>, the title compound was obtained in the same manner as in ⁇ Example CC1>.
• Example AY4 (trans-3- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl][(2-nitrophenyl)sulfonyl]amino ⁇ cyclobutyl)carbamic acid tert-butyl N-[1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2-nitrobenzenesulfonamide (0.367 g, 0.622 mmol), cis-tert-butyl 3-hydroxycyclobutylcarbamate (CAS registration number: 389890-43-1) (0.175 g, 0.934 3-Hydroxycyclo
• Example AY5 (trans-3- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]amino ⁇ cyclobutyl)carbamate tert-butyl (trans-3- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl][(2-nitrophenyl)sulfonyl]amino ⁇ cyclobutyl)carbamate tert-butyl (0.366 g, 0.482 mmol) was dissolved in DMF (2 mL), and 4-bromobenzenethiol (0.182 g, 9.65 mmol) was added.
• ⁇ Example AY6> 3- ⁇ 5-[(trans-3-aminocyclobutyl)amino]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ -1-(hydroxymethyl)piperidine-2,6-dione dihydrochloride Using the compound obtained in ⁇ Example AY5>, the title compound was obtained in the same manner as in ⁇ Example AO5>.
• Example AZ1 Methyl 1-[7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonan-2-yl]-1H-indazole-5-carboxylate
• Example AZ2 Methyl 2-[7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-yl]-2H-indazole-5-carboxylate
• Methyl indazole-5-carboxylate (CAS Registry Number: 473416-12-5) (327 mg, 1.86 mmol) and tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (CAS Registry Number: 240401-28-9) (470 mg, 1.95 mmol) were added to a suspension of toluene (9 mL) and cyanomethylenetributylphosphorane (CAS Registry Number: 157141-27-0) (1.0 mL, 3.8 mmol) was added and stir
• Example AZ1 500 mg, 1.25 mmol, yield 67%) and Example AZ2 (235 mg, 0.588 mmol, yield 32%).
• Example AZ3> tert-Butyl 2-[5-(hydroxymethyl)-2H-indazol-2-yl]-7-azaspiro[3.5]nonane-7-carboxylate Using the compound obtained in ⁇ Example AZ2>, the title compound was obtained in the same manner as in ⁇ Example W5>.
• Example AZ4 tert-Butyl 2-(5-formyl-2H-indazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate
• Manganese(IV) oxide (291 mg) was added to a solution of tert-butyl 2-[5-(hydroxymethyl)-2H-indazol-2-yl]-7-azaspiro[3.5]nonane-7-carboxylate (233 mg, 0.627 mmol) in chloroform (6 mL), and the mixture was stirred at room temperature for 22 hours.
• Manganese(IV) oxide (345 mg) was added to the reaction mixture, and the mixture was stirred for 5.5 hours.
• the reaction mixture was diluted with ethyl acetate, and the insoluble matter was filtered off with Celite, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (120 mg, 0.325 mmol, 52% yield).
• ⁇ Example AZ5> tert-Butyl 2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2H-indazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate Using the compound obtained in ⁇ Example M3> and ⁇ Example AZ4>, the title compound was obtained in the same manner as in ⁇ Example W4>.
• Example AZ6 tert-Butyl [2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2H-indazol-2-yl)-7-azaspiro[3.5]nonane-7-yl]acetate tert-Butyl 2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2H-indazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (115 mg, 0.155 mmol) in DCM (1 mL) was added
• Example AZ7> [2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2H-indazol-2-yl)-7-azaspiro[3.5]nonan-7-yl]acetic acid dihydrochloride Using the compound obtained in ⁇ Example AZ6>, the title compound was obtained in the same manner as in ⁇ Example V5>.
• Example AZ8> N-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2-[2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2H-indazol-2-yl)-7-azaspiro[3.5]nonan-7-yl]acetamide
• the compound obtained in ⁇ Example AZ7> and 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (WO2021170109 A1) was used in the same manner as in Example BM9 to obtain the title compound
• Example BA1> tert-Butyl 2-[5-(hydroxymethyl)-1H-indazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate Using the compound obtained in ⁇ Example AZ1>, the title compound was obtained in the same manner as in ⁇ Example W5>.
• Example BA2> tert-Butyl 2-(5-formyl-1H-indazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate Using the compound obtained in ⁇ Example BA1>, the title compound was obtained in the same manner as in ⁇ Example AZ4>.
• Example BA3> tert-Butyl 2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -1H-indazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate Using the compound obtained in ⁇ Example M3> and ⁇ Example BA2>, the title compound was obtained in the same manner as in ⁇ Example W4>.
• ⁇ Example BA4> tert-Butyl [2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -1H-indazol-1-yl)-7-azaspiro[3.5]nonan-7-yl]acetate Using the compound obtained in ⁇ Example BA3>, the title compound was obtained in the same manner as in ⁇ Example AZ6>.
• Example BA5> [2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -1H-indazol-1-yl)-7-azaspiro[3.5]nonan-7-yl]acetic acid dihydrochloride Using the compound obtained in ⁇ Example BA4>, the title compound was obtained in the same manner as in ⁇ Example V5>.
• Example BA6> N-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-2-[2-(5- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -1H-indazol-1-yl)-7-azaspiro[3.5]nonan-7-yl]acetamide
• the compound obtained in ⁇ Example BA5> and 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (WO2021170109 A1) was used in the same manner as in Example BM9 to obtain the title compound.
• Example BB1 tert-Butyl 3-fluoro-4-oxocyclohexanecarboxylate
• Tert-butyl 4-oxocyclohexanecarboxylate (CAS registration number: 38446-95-6) (1.01 g, 5.09 mmol) and triethylamine (1.4 mL, 10 mmol) were dissolved in DCM (17 mL), trimethylsilyl trifluoromethanesulfonate (1.1 mL, 6.1 mmol) was added at 0° C., and the mixture was stirred for 20 minutes. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with DCM.
• Example BB2 6-fluoro-4'-formyl-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate tert-butyl 3-fluoro-4-oxocyclohexanecarboxylate tert-butyl (0.436 g, 2.02 mmol) was dissolved in THF (4 mL), and lithium bis(trimethylsilyl)amide (1.12 mol/L THF solution, 2.0 mL, 2.2 mmol) was added at -78°C under nitrogen atmosphere and stirred for 30 minutes.
• N-phenylbis(trifluoromethanesulfonimide) (0.792 g, 2.22 mmol) in THF (4 mL) was added to the reaction solution at -78°C, and then stirred at room temperature for 1 hour.
• the reaction solution was diluted with ethyl acetate, and then washed with 1 mol/L aqueous sodium hydroxide solution, saturated aqueous ammonium chloride solution, and saturated saline solution in that order.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue and (4-formylphenyl)boronic acid (CAS reg.
• Example M3> and the compound obtained in ⁇ Example BB2> the title compound was obtained in the same manner as in ⁇ Example W4>.
• ⁇ Example BB5> tert-butyl 4- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl]methyl ⁇ piperazine-1-carboxylate.
• the title compound was obtained in the same manner as in ⁇ Example BQ1>.
• Example BB6> 1-(hydroxymethyl)-3-[2-oxo-7-(piperazin-1-ylmethyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl]piperidine-2,6-dione dihydrochloride Using the compound obtained in ⁇ Example BB5>, the title compound was obtained in the same manner as in ⁇ Example AO5>.
• Example BC1 6-Bromo-N 2 -methylpyridine-2,3-diamine 6-Bromo-N-methyl-3-nitropyridin-2-amine (CAS registration number: 924293-34-5) (300 mg, 1.29 mmol) in THF (9 mL) was added to a solution of ammonium chloride (280 mg, 5.17 mmol) in water (4.5 mL), cooled with ice, and zinc powder (850 mg, 12.9 mmol) was gradually added. After stirring for 30 minutes, the insoluble matter was filtered off with Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (225 mg, 1.11 mmol, 86% yield).
• Example BC2> 5-Bromo-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one
• the title compound was obtained in the same manner as in ⁇ Example AN2> using the compound obtained in ⁇ Example BC1>.
• Example BC3> 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example BC2>, the title compound was obtained in the same manner as in ⁇ Example Z5>.
• Example BC4> 2,4,6-trichlorophenyl 1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate Using the compound obtained in ⁇ Example BC3>, the title compound was obtained in the same manner as in ⁇ Example BY5>.
• Example BD1> N- ⁇ [trans-4-(4-chlorophenyl)cyclohexyl]methyl ⁇ -3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine
• the title compound was obtained in the same manner as in ⁇ Example W4>.
• Example BD2 tert-Butyl [4-(trans-4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ cyclohexyl)phenyl]carbamate N- ⁇ [trans-4-(4-chlorophenyl)cyclohexyl]methyl ⁇ -3,3,3-trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethylpropan-1-amine (300 mg, 0.505 mmol), tert-butyl carbamate (CAS registration number: 4248-19-5) (95 mg, 0.81 To the mixture (80 mg, 0.112 mmol), 1,2,3,4,5-
• reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure.
• residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (200 mg, 0.30 mmol, yield 59%).
• Example BD3> 4-(trans-4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ cyclohexyl)aniline dihydrochloride Using the compound obtained in ⁇ Example BD2>, the title compound was obtained in the same manner as in ⁇ Example AO5>.
• Example BD5> 3- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]amino ⁇ cyclobutane carboxylic acid
• trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]amino ⁇ cyclobutane carboxylate (245 mg, 0.57 mmol) in DCM (2 mL).
• the reaction solution was concentrated under reduced pressure.
• the residue was subjected to azeotropic distillation with chloroform, and the obtained solid was dried under reduced pressure to obtain the title compound (210 mg, 0.56 mmol, yield 98%).
• ⁇ Example BD6> 3- ⁇ [1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]amino ⁇ -N-[4-(trans-4- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ cyclohexyl)phenyl]cyclobutanecarboxamide
• the title compound was obtained in the same manner as in ⁇ Example BM9> using the compounds obtained in ⁇ Example BD5> and ⁇ Example BD3>.
• Example BE1 Ethyl 4'-[(tert-butoxycarbonyl)amino]-3'-fluoro-2,3,4,5-tetrahydro[biphenyl]-4-carboxylate Using tert-butyl (4-bromo-2-fluorophenyl)carbamate (CAS registration number: 209958-42-9) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexene-1-carboxylate (CAS registration number: 1049004-32-1), the title compound was obtained in the same manner as in Example W1.
• Example BE2> tert-Butyl [3-fluoro-4'-(hydroxymethyl)-2',3',4',5'-tetrahydro[biphenyl]-4-yl]carbamate Using the compound obtained in ⁇ Example BE1>, the title compound was obtained in the same manner as in ⁇ Example AG3>.
• ⁇ Example BE3> tert-butyl (3-fluoro-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2',3',4',5'-tetrahydro[biphenyl]-4-yl)carbamate Using the compound obtained in ⁇ Example BE2>, the title compound was obtained by carrying out the same operations as in ⁇ Example AI5> and ⁇ Example W4> in this order.
• Example BF1 5,8-Dibromo-1,2,3,4-tetrahydroquinoline 5,8-Dibromoquinoline (CAS Registry Number: 81045-39-8) (3.49 g, 12.2 mmol), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (CAS Registry Number: 1149-23-1) (7.69 g, 30.4 mmol), and boric acid (121 mg, 1.96 mmol) in 1,2-dichloroethane (50 mL) were stirred at 60° C. for 5 hours.
• the reaction solution was cooled to room temperature, and ethanol (40 mL) and a 10 mol/L aqueous sodium hydroxide solution (10 mL, 100 mmol) were added, followed by stirring at room temperature for 2 hours.
• Water was added to the reaction solution, and the mixture was extracted with DCM.
• the obtained organic layer was washed with saturated sodium bicarbonate water, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/DCM) to obtain the title compound (2.28 g, 7.84 mmol, yield 64%).
• reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate and water were added, followed by extraction with ethyl acetate.
• organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.25 g, 4.33 mmol, 55% yield).
• Example BF3 (4S)-tert-butyl 5-amino-4-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-5-oxopentanoate.
• Example BF4 2,4,6-trichlorophenyl 1-[(2S)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinoline-7-carboxylate (4S)-5-amino-4-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-5-oxopentanoic acid tert-butyl (387 mg, 0.883 mmol), 2,4,6-trichlorophenyl formate (CAS registration number: 4525-65-9) (304 mg, 1.35 mmol), palladium(II) acetate (23.8 mg, 0.106 To a suspension of XantPhos (101 mg, 0.175 mmol) and XantPhos (101 mg, 0.175
• reaction solution was cooled to room temperature and purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (480 mg, 0.824 mmol, yield 93%).
• the reaction solution was heated to 60°C and stirred for 4.5 hours.
• the reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
• the organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (58.4 mg, 0.0561 mmol, yield 58%).
• Example BG2 (4R)-5-amino-4-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-5-oxopentanoic acid tert-butyl tert-butyl N 2 -[(5,8-dibromo-3,4-dihydroquinolin-1(2H)-yl)carbonyl]-D- ⁇ -glutamate (2.45 g, 4.72 mmol), trans-4-hydroxy-L-proline (244 mg, 1.86 mmol), tripotassium phosphate (3.12 g, 14.7 mmol), and copper(I) iodide (171 mg, 0.898 mmol) in DMSO (15 mL) were stirred at 60° C.
• Example BG3 2,4,6-trichlorophenyl 1-[(2R)-1-amino-5-tert-butoxy-1,5-dioxopentan-2-yl]-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinoline-7-carboxylate (4R)-5-amino-4-(7-bromo-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-5-oxopentanoic acid tert-butyl (312 mg, 0.712 mmol), 2,4,6-trichlorophenyl formate (CAS registration number: 4525-65-9) (199 mg, 0.883 mmol), palladium(II) acetate (16.2 mg, 0.0722 mmol), To a solution of XantPhos (73.3 mg, 0.127 mmol) and XantPhos (73.3
• BG4 >(4R)-5-amino-4- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl ⁇ -5-oxopentanoate tert-butyl 3,3,3-Trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇
• reaction mixture was then heated to 60°C and stirred for 4.5 hours.
• the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (84.7 mg, 0.0813 mmol, yield 66%).
• Example BG5 (3R)-3- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl ⁇ piperidine-2,6-dione (4R)-5-amino-4- ⁇ 7-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl
• Example M3> and the compound obtained in ⁇ Example V1> the title compound was obtained in the same manner as in ⁇ Example W4>.
• Example BH3 3- ⁇ 7-[methyl(piperidin-4-yl)amino]-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl ⁇ -1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione tert-Butyl 4- ⁇ [1-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-7-yl]amino ⁇ piperidine-1-carboxylate (0.160 g, 0.261 mmol) was dissolved in DCM (4 mL), and paraformaldehyde (0.078 g), acetic acid (0.045 mL, 0.79 mmol) and sodium triacetoxyborohydride (0.2
• Example BI1 3- ⁇ 5-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ -1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 3,3,3-Trifluoro-N- ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ -2,2-dimethyl-N- ⁇ [(
• reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
• the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (197 mg, 0.184 mmol, yield 64%).
• Example BI2 3- ⁇ 5-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,3,3-trifluoro-2,2-dimethylpropyl)amino]methyl ⁇ -2,3,4,5-tetrahydro[biphenyl]-4-yl]methyl ⁇ piperazin-1-yl)carbonyl]-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl ⁇ piperidine-2,6-dione Trifluoroacetic acid (0.5 mL) was added to a solution of 3- ⁇ 5-[(4- ⁇ [(4R)-4'- ⁇ [ ⁇ 2-[(4R)-4-(4-methoxyphenyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl]ethyl ⁇ (3,
• the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL), and then N,N'-dimethylethylenediamine (0.0217 mL, 0.202 mmol) was added and stirred at room temperature for 40 minutes. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate water. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
• iron powder 290 mg, 5.17 mmol
• 2-bromo-N-methyl-5-nitropyridin-4-amine CAS registration number: 1234014-33-5
• acetic acid 10 mL
• the reaction solution was diluted with ethyl acetate, insoluble matter was filtered off with Celite, the filtrate was concentrated under reduced pressure, and the residue was neutralized with sodium bicarbonate water.
• Example BJ2> 6-Bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one
• the title compound was obtained in the same manner as in ⁇ Example AN2> using the compound obtained in ⁇ Example BJ1>.
• Example BJ3> 3-(6-bromo-1-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione Using the compound obtained in ⁇ Example BJ2>, the title compound was obtained in the same manner as in ⁇ Example Z5>.
• Example BJ4> 2,4,6-trichlorophenyl 3-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylate Using the compound obtained in ⁇ Example BJ3>, the title compound was obtained in the same manner as in ⁇ Example BY5>.
• Example BK1 8-bromo-5-nitro-1,2,3,4-tetrahydroquinoline 8-bromo-5-nitroquinoline (CAS Registry Number: 139366-35-1) (5.02 g, 19.8 mmol), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (CAS Registry Number: 1149-23-1) (11.1 g, 43.8 mmol), and paratoluenesulfonic acid monohydrate (701 mg, 3.69 mmol) in 1,2-dichloroethane (80 mL) was stirred for 80 minutes at 60° C.
• the reaction solution was cooled to room temperature, and ethanol (40 mL) and a 5 mol/L aqueous sodium hydroxide solution (20 mL, 100 mmol) were added. The mixture was stirred at room temperature for 3 hours, and then ethanol (40 mL) was added and stirred for 3 hours. Water and saturated sodium bicarbonate water were added to the reaction solution, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/DCM) to obtain the title compound (2.83 g, 11.0 mmol, yield 56%).
• a DCM (20 mL) solution of 8-bromo-5-nitro-1,2,3,4-tetrahydroquinoline (2.64 g, 10.3 mmol) and pyridine (2.0 mL, 25 mmol) were added dropwise to a DCM (20 mL) solution of triphosgene (1.90 g, 6.40 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 minutes, warmed to room temperature, and stirred for 2 hours.
• Example BK3 8-bromo-N-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-5-nitro-3,4-dihydroquinoline-1(2H)-carboxamide
• 8-bromo-N-(2,6-dioxopiperidin-3-yl)-5-nitro-3,4-dihydroquinoline-1(2H)-carboxamide 311 mg, 0.756 mmol
• DIPEA 0.254 mL, 1.46 mmol
• 2-(trimethylsilyl)ethoxymethyl chloride (0.142 mL, 0.802 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 15 minutes, then warmed to room temperature and stirred for 1.5 hours.
• Example BK4 3-(7-nitro-2-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidine-2,6-dione 8-Bromo-N-(2,6-dioxo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ piperidin-3-yl)-5-nitro-3,4-dihydroquinoline-1(2H)-carboxamide (4.22 g, 7.79 mmol), trans-4-hydroxy-L-proline (370 mg, 2.82 mmol), copper(I) iodide (269 mg, 1.41 mmol), and tripotassium phosphate (5.00 g, 23.6 mmol) in DMSO (25 The suspension was stirred at 60°C for 1 hour.

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