US20230151060A1 - Cyclic peptide compound having kras inhibitory action - Google Patents

Cyclic peptide compound having kras inhibitory action Download PDF

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Publication number
US20230151060A1
US20230151060A1 US17/773,733 US202017773733A US2023151060A1 US 20230151060 A1 US20230151060 A1 US 20230151060A1 US 202017773733 A US202017773733 A US 202017773733A US 2023151060 A1 US2023151060 A1 US 2023151060A1
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Prior art keywords
trifluoromethyl
spiro
chloro
ethyl
isobutyl
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US17/773,733
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Inventor
Mikimasa Tanada
Koji Takano
Atsushi Matsuo
Minoru TAMIYA
Aya CHIYODA
Toshiya Ito
Takeo Iida
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Publication of US20230151060A1 publication Critical patent/US20230151060A1/en
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
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    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/21—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton the carbon skeleton being further substituted by doubly-bound oxygen atoms
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    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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Definitions

  • the present invention relates to cyclic peptide compounds having Kras inhibitory action, non-natural amino acids for use in the production of cyclic peptide compounds, and production methods therefor.
  • Ras is a protein belonging to the small GTPase family, and Kras, Nras, and Hras are known. Ras is in an inactive state or an active state according to whether it is bound to GTP or GDP. It is activated by the exchange reaction from GDP to GTP by GEFs (guanine nucleotide exchange factors) and inactivated by the hydrolysis reaction of GTP by GAPs (GTPase-activating proteins) (NPL 1). Activated Ras induces cell proliferation, survival, and differentiation by activating various downstream signals in the MAPK pathway, PI3K/Akt pathway, RAL pathway, and such, and the constitutive activation of Ras plays an important role in the development and progression of cancer.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase-activating proteins
  • Ras-RAF-MEK-ERK pathway is activated by the activation of an upstream signal of Ras, constitutive activation of Ras, and/or activating mutations of Ras (NPL 2).
  • NPL 2 activating mutations of Ras
  • G12, G13, and Q61 are known as hot spots of Ras mutation, and G12 is frequently found mutated in Kras and Q61 in Nras. These mutations are also known to be associated with the prognosis of patients (NPL 3).
  • medium sized molecules When it comes to access to a tough target, as typified by inhibition of a protein-protein interaction, medium sized molecules (having a molecular weight of 500 to 2000) may be superior to low molecular weight compounds. Also, medium sized molecules may be superior to antibodies in that they can migrate into cells.
  • peptide drugs are highly valuable molecular species, with more than 40 peptide drugs being already commercially available (NPL 4). Representative examples of such peptide drugs include cyclosporin A and polymyxin B, which are peptides containing some non-natural amino acids.
  • a non-natural amino acid refers to an amino acid that is not naturally encoded on mRNA. It is highly interesting that non-natural amino acids that are not encoded on mRNA are contained in naturally-occurring cyclosporin A and polymyxin B.
  • NPL 5 Since the discovery of the pharmaceutical utility of naturally-occurring peptides, peptides having pharmacological activity and bioabsorbability have been attracting attention, and those having a molecular weight of about 500 to 2000 have been actively researched (NPL 5).
  • the present invention provides compounds effective for Ras-mutant cancer and non-natural amino acids useful for the production thereof.
  • PTL 1 and PTL 2 describe drug-like peptides, but do not describe a peptide having an antitumor effect on cancers including Ras-mutant cancer.
  • PTL 3 describes the inhibition of binding between Ras and SOS
  • PTL 4 describes a peptide competing with a compound that binds to Ras.
  • none of these documents shows any pharmacological action, especially action on tumor cells. These documents do not describe drug-like peptides, either.
  • NPL 1 shows the relationship between Ras and cancer in detail. This document describes molecules that bind to Ras. Although their efficacy was shown in preclinical studies, no compound was shown to be effective as a drug specifically on Ras-mutant cancer. Also, no drug-like cyclic peptide is disclosed.
  • NPL 2 provides detailed descriptions about Ras and the RAF-MEK-ERK pathway, which is downstream of Ras. Although this document suggests the possibility of treating Ras-mutant cancer with RAF, MEK, and ERK inhibitors, it does not show any compound that directly inhibits Ras.
  • NPL 3 describes a compound that binds to the GTP/GDP binding site of Ras and inhibits the function of Ras, and the mechanism thereof. This document describes the interaction with the GTP/GDP binding site in detail, but does not show pharmacological action, especially action on tumor cells.
  • NPL 4 describes peptides that are used as drugs, but does not describe a drug-like peptide or a peptide useful for Ras-mutant cancer.
  • NPL 5 describes the molecular form and pharmacokinetics of cyclic peptides, but does not describe a compound useful for Ras-mutant cancer.
  • NPLs 6 to 8 describe peptides that bind to Ras, but their action on tumor cells is limited, and, in addition, a drug-like peptide is not described.
  • Ras-mutant cancer has no effective treatment and the unmet need is strong, a drug that directly inhibits Ras and exhibits a clinical therapeutic effect has not been developed yet. Also, a peptide that satisfies drug-likeness has not been found.
  • the peptide compounds of interest in the present invention are breakthrough drugs that directly bind to Ras and inhibit its interaction with SOS, whereby they suppress the activation of Ras and inhibit the proliferation of cancer cells having Ras mutation.
  • the present inventors found cyclic peptide compounds that interact with Ras. The inventors also found that those cyclic peptide compounds inhibit the binding between Ras and SOS. In addition, the inventors found specific non-natural amino acids contained in the cyclic peptide compounds and methods for production thereof. The inventors found that the cyclic peptide compounds have, as a pharmacological effect, a proliferation inhibitory effect on tumor cells having Ras mutation.
  • L 1 is a single bond, or —CHM 1 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, wherein n and m are each independently 1 or 2,
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4-to 8-membered cyclic amino), and C 1 -C 6 alkylsulfonyl, or
  • R 1 and P 1 together with the carbon atom to which R 1 is attached and the nitrogen atom to which P 1 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 1 and Q 1 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 1 and M 1 together with the carbon atom to which R 1 is attached and the carbon atom to which M 1 is attached, form a 3- to 8-membered alicyclic ring,
  • P 1 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 1 and Q 1 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C 1 -C 6 alkylsulfonyl, or
  • R 2 and P 2 together with the carbon atom to which R 2 is attached and the nitrogen atom to which P 2 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 2 and Q 2 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or except when R 2 and P 2 form a 4- to 7-membered saturated heterocyclic ring,
  • P 2 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to
  • R 2 and Q 2 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), or
  • R 3 and P 3 together with the carbon atom to which R 3 is attached and the nitrogen atom to which P 3 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 3 and Q 3 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 3 and P 3 form a 4- to 7-membered saturated heterocyclic ring
  • P 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino
  • R 3 and Q 3 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 3 is hydrogen or C 1 -C 6 alkyl
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 4 and P 4 together with the carbon atom to which R 4 is attached and the nitrogen atom to which P 4 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 4 and Q 4 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 4 and P 4 form a 4- to 7-membered saturated heterocyclic ring
  • P 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 4 and Q 4 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 4 is hydrogen or C 1 -C 6 alkyl
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hal
  • R 5 and P 5 together with the carbon atom to which R 5 is attached and the nitrogen atom to which P 5 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 5 and Q 5 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 5 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 5 and Q 5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 5 is hydrogen or C 1 -C 6 alkyl
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 6 and P 6 together with the carbon atom to which R 6 is attached and the nitrogen atom to which P 6 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 6 and Q 6 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 6 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 6 and Q 6 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 6 is hydrogen or C 1 -C 6 alkyl
  • R 7 is C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 , or
  • R 7 and P 7 together with the carbon atom to which R 7 is attached and the nitrogen atom to which P 7 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 7 and Q 7 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 7 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 7 and Q 7 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 7 is hydrogen or C 1 -C 6 alkyl
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyloxycarbonylC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, 5- to 10-membered heteroarylC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C 1 -C 6
  • R 8 and P 8 together with the carbon atom to which R 8 is attached and the nitrogen atom to which P 8 is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS 8 , and S 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 7 -C 14 aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C
  • R 8 and Q 8 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 8 and P 8 form a 4- to 7-membered saturated heterocyclic ring
  • P 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC 1 -C 6 alkyl, C 6 -C 10 aryl, C 7 -C 14 aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C
  • R 8 and Q 8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 8 is hydrogen or C 1 -C 6 alkyl
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkylsulfony
  • R 9 and P 9 together with the carbon atom to which R 9 is attached and the nitrogen atom to which P 9 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 9 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 9 and Q 9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 9 is hydrogen or C 1 -C 6 alkyl
  • R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C 1 -C 6 alkylsulfonyl, or
  • R 10 and P 10 together with the carbon atom to which R 10 is attached and the nitrogen atom to which P 10 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 10 and Q 10 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 10 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 10 and Q 10 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 10 is hydrogen or C 1 -C 6 alkyl
  • L 11 is a single bond, or —CHM 11 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, wherein n and m are each independently 1 or 2,
  • R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or aminocarbonyl (wherein the amino is —NH 2 , mono C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C 1 -C 6 alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkylsulfonyl
  • R 11 and P 11 together with the carbon atom to which R 11 is attached and the nitrogen atom to which P 11 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 11 and Q 11 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 11 and M 11 together with the carbon atom to which R 11 is attached and the carbon atom to which M 11 is attached, form a 3- to 8-membered alicyclic ring,
  • P 11 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 11 is hydrogen or C 1 -C 6 alkyl
  • L 11 is —CHM 11 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, and when L 1 is —CHM 1 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, L 11 is a single bond, and
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with one or more halogens, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), or hydroxy), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or
  • R 1 and P 1 together with the nitrogen atom to which P 1 is attached and the carbon atom to which R 1 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 1 and P 1 form a 4- to 7-membered saturated heterocyclic ring
  • P 1 is hydrogen or C 1 -C 6 alkyl
  • R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 al
  • R 3 and P 3 together with the nitrogen atom to which P 3 is attached and the carbon atom to which R 3 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 3 and P 3 form a 4- to 7-membered saturated heterocyclic ring
  • P 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), or C 3 -C 8 cycloalkyl,
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 4 and P 4 together with the nitrogen atom to which P 4 is attached and the carbon atom to which R 4 is attached form a 4- to 7-membered saturated heterocyclic ring
  • R 4 and P 4 form a 4- to 7-membered saturated heterocyclic ring
  • P 4 is C 1 -C 6 alkyl or C 1 -C 6 alkoxyC 1 -C 6 alkyl
  • R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6
  • P 5 is hydrogen or C 1 -C 6 alkyl
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 6 and P 6 together with the nitrogen atom to which P 6 is attached and the carbon atom to which R 6 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 6 and P 6 form a 4- to 7-membered saturated heterocyclic ring
  • P 6 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 7 is C 6 -C 10 aryloxyC 1 -C 6 alkyl (wherein the C 6 -C 10 aryloxyC 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and C 1 -C 6 haloalkyl), C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 ), C 7 -C 14 aralkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, or 5- to 10-membered heteroary
  • Q 7 is hydrogen or C 1 -C 6 alkyl
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), optionally protected 4- to 7-membered heterocyclylC 1 -C 6 alkyl, optionally protected 4- to 7-membered heterocycl
  • R 8 and P 8 together with the nitrogen atom to which P 8 is attached and the carbon atom to which R 8 is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a 3- to 8-membered saturated carbon ring or a 6- to 10-membered aromatic ring, and the 4- to 7-membered saturated heterocyclic ring is optionally substituted with one or more halogens, hydroxy, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroarylC 1 -C 6 alkoxy, C 7 -C 14 aralkoxy (wherein the C 7 -C 14 aralkoxy is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C 1 -C 6 alk
  • R 8 and P 8 form a 4- to 7-membered saturated heterocyclic ring
  • P 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with one or more halogens, hydroxy, di-C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxy, or amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino)), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), hydroxy, or 5- to 10-membered heteroaryl optionally substituted with one or more halogens), C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogens, C 1 -C 6 alkyl, C 1 -
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 9 and P 9 together with the nitrogen atom to which P 9 is attached and the carbon atom to which R 9 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 9 and Q 9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 9 is hydrogen or C 1 -C 6 alkyl
  • R 9 and P 9 form a 4- to 7-membered saturated heterocyclic ring
  • P 9 is hydrogen or C 1 -C 6 alkyl
  • R 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, or R 10 and P 10 , together with the nitrogen atom to which P 10 is attached and the carbon atom to which R 10 is attached, form a 4- to 7-
  • R 10 and P 10 form a 4- to 7-membered saturated heterocyclic ring
  • P 10 is hydrogen or C 1 -C 6 alkyl
  • R 11 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with hydroxy or aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino)), C 7 -C 14 aralkyl optionally substituted with one or more halogens, or aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, wherein the cyclic amino is optionally further substituted with
  • R 11 and M 11 together with the carbon atom to which R 11 is attached and the carbon atom to which M 11 is attached, form a 3- to 8-membered alicyclic ring,
  • R 11 and P 1 together with the nitrogen atom to which P 11 is attached and the carbon atom to which R 11 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 11 and P 11 form a 4- to 7-membered saturated heterocyclic ring
  • P 11 is hydrogen or C 1 -C 6 alkyl
  • R 11 is —CONR 11A R 11B , wherein
  • R 11A and R 11B are each independently hydrogen or C 1 -C 6 alkyl, or R 11A and R 11B , together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic ring, wherein the 4- to 8-membered saturated heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, C 1 -C 6 alkyl, and 4- to 7-membered heterocyclyl.
  • R 7 is —(CH 2 ) x —O y —(CH 2 ) z1 —C 6 -C 10 aryl or —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 4 alkoxy, —CN, C 1 -C 3 alkylsulfonyl, hydroxy, and SF 5 , wherein
  • x 1, 2, or 3
  • y is 0 or 1
  • z1 is 0, 1, 2, or 3
  • z2 is 1, 2, or 3
  • R 4 and P 4 together with the nitrogen atom to which P 4 is attached and the carbon atom to which R 4 is attached, form a 4- to 7-membered saturated heterocyclic ring.
  • R 8 and P 8 together with the nitrogen atom to which P 8 is attached and the carbon atom to which R 8 is attached, form a 4- to 7-membered saturated heterocyclic ring.
  • R 8 is —(CH 2 ) x —O y —(CH 2 ) z1 —C 6 -C 10 aryl or —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 4 alkoxy, —CN, C 1 -C 3 alkylsulfonyl, hydroxy, and SF 5 , wherein
  • x 1, 2, or 3
  • y is 0 or 1
  • z1 is 0, 1, 2, or 3
  • z2 is 1, 2, or 3
  • R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl, and Q 9 is C 1 -C 6 alkyl, or
  • R 9 and Q 9 together with the carbon atom to which they are attached form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 1 is hydrogen or C 1 -C 6 alkyl
  • P 1 is hydrogen or C 1 -C 6 alkyl
  • M 1 is hydrogen
  • R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 al
  • R 3 and P 3 together with the nitrogen atom to which P 3 is attached and the carbon atom to which R 3 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 3 and P 3 form a 4- to 7-membered saturated heterocyclic ring
  • P 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), or C 3 -C 8 cycloalkyl,
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 4 and P 4 together with the nitrogen atom to which P 4 is attached and the carbon atom to which R 4 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 4 and P 4 form a 4- to 7-membered saturated heterocyclic ring
  • P 4 is C 1 -C 6 alkyl or C 1 -C 6 alkoxyC 1 -C 6 alkyl
  • R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6
  • P 5 is hydrogen or C 1 -C 6 alkyl
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 6 and P 6 together with the nitrogen atom to which P 6 is attached and the carbon atom to which R 6 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 6 and P 6 form a 4- to 7-membered saturated heterocyclic ring
  • P 6 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 7 is C 6 -C 10 aryloxyC 1 -C 6 alkyl (wherein the C 6 -C 10 aryloxyC 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and C 1 -C 6 haloalkyl), C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 ), C 7 -C 14 aralkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, or 5- to 10-membered heteroary
  • Q 7 is hydrogen or C 1 -C 6 alkyl
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), C 1 -C 6 aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), optionally protected 4- to 7-membered heterocyclylC 1 -C 6 alkyl, optionally protected 4- to 7
  • R 8 and P 8 together with the nitrogen atom to which P 8 is attached and the carbon atom to which R 8 is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a 3- to 8-membered saturated carbon ring or a 6- to 10-membered aromatic ring, and the 4- to 7-membered saturated heterocyclic ring is optionally substituted with one or more halogens, hydroxy, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroarylC 1 -C 6 alkoxy, C 7 -C 14 aralkoxy (wherein the C 7 -C 14 aralkoxy is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C 1 -C 6 alk
  • R 8 and P 8 form a 4- to 7-membered saturated heterocyclic ring
  • P 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with one or more halogens, hydroxy, di-C 1 -C 6 alkylaminocarbonyl, or C 1 -C 6 alkoxy), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino,
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogens, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 9 and P 9 together with the nitrogen atom to which P 9 is attached and the carbon atom to which R 9 is attached, form a 4- to 7-membered saturated heterocyclic ring.
  • R 9 and Q 9 form a 4- to 7-membered saturated heterocyclic ring
  • Q 9 is hydrogen or C 1 -C 6 alkyl
  • R 9 and P 9 form a 4- to 7-membered saturated heterocyclic ring
  • P 9 is hydrogen or C 1 -C 6 alkyl
  • R 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, or
  • R 10 and P 10 together with the nitrogen atom to which P 10 is attached and the carbon atom to which R 10 is attached, form a 4- to 7-membered saturated heterocyclic ring,
  • R 10 and P 10 form a 4- to 7-membered saturated heterocyclic ring
  • P 10 is hydrogen or C 1 -C 6 alkyl
  • R 11 is hydrogen, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with hydroxy, or C 7 -C 14 aralkyl optionally substituted with one or more halogens, and P 11 is hydrogen or C 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C 1 -C 6 alkylsulfonyl, or
  • R 2 and P 2 together with the carbon atom to which R 2 is attached and the nitrogen atom to which P 2 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 2 and Q 2 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 2 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 2 and Q 2 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), or
  • R 3 and P 3 together with the carbon atom to which R 3 is attached and the nitrogen atom to which P 3 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 3 and Q 3 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 3 and P 3 form a 4- to 7-membered saturated heterocyclic ring
  • P 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, wherein the 4- to 8-membered cyclic amino
  • R 3 and Q 3 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 3 is hydrogen or C 1 -C 6 alkyl
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 4 and P 4 together with the carbon atom to which R 4 is attached and the nitrogen atom to which P 4 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 4 and Q 4 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 4 and P 4 form a 4- to 7-membered saturated heterocyclic ring
  • P 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 4 and Q 4 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 4 is hydrogen or C 1 -C 6 alkyl
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hal
  • R 5 and P 5 together with the carbon atom to which R 5 is attached and the nitrogen atom to which P 5 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 5 and Q 5 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 5 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 5 and Q 5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 5 is hydrogen or C 1 -C 6 alkyl
  • R 6 is hydrogen or C 1 -C 6 alkyl
  • R 6 and P 6 together with the carbon atom to which R 6 is attached and the nitrogen atom to which P 6 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 6 and Q 6 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 6 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 6 and Q 6 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 6 is hydrogen or C 1 -C 6 alkyl
  • R 7 is C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 , or
  • R 7 and P 7 together with the carbon atom to which R 7 is attached and the nitrogen atom to which P 7 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 7 and Q 7 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 7 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 7 and Q 7 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 7 is hydrogen or C 1 -C 6 alkyl
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyloxycarbonylC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, 5- to 10-membered heteroarylC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy, C 1 -C 6
  • R 8 and P 8 together with the carbon atom to which R 8 is attached and the nitrogen atom to which P 8 is attached, form a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring is optionally fused with a saturated carbon ring or an aromatic ring, the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogens), or OS 8 , and S 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 7 -C 14 aralkyl (wherein the aralkyl is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C
  • R 8 and Q 8 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 8 and P 8 form a 4- to 7-membered saturated heterocyclic ring
  • P 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC 1 -C 6 alkyl, C 6 -C 10 aryl, C 7 -C 14 aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C
  • R 8 and Q 8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 8 is hydrogen or C 1 -C 6 alkyl
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkylsulfony
  • R 9 and P 9 together with the carbon atom to which R 9 is attached and the nitrogen atom to which P 9 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 9 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 9 and Q 9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 9 is hydrogen or C 1 -C 6 alkyl
  • R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C 1 -C 6 alkylsulfonyl, or
  • R 10 and P 10 together with the carbon atom to which R 10 is attached and the nitrogen atom to which P 10 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 10 and Q 10 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • P 10 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 10 and Q 10 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 10 is hydrogen or C 1 -C 6 alkyl
  • L 11 is —CHMn 11 —, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, wherein n and m are each independently 1 or 2,
  • R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or aminocarbonyl (wherein the amino is —NH 2 , mono C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C 1 -C 6 alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkylsulfonyl
  • R 11 and P 11 together with the carbon atom to which R 11 is attached and the nitrogen atom to which P 11 is attached, form a 4- to 7-membered saturated heterocyclic ring, or
  • R 11 and Q 11 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring, or
  • R 11 and M 11 together with the carbon atom to which R 11 is attached and the carbon atom to which M 11 is attached, form a 3- to 8-membered alicyclic ring,
  • P 11 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino),
  • R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • Q 11 is hydrogen or C 1 -C 6 alkyl
  • R 11 and M 11 form a 3- to 8-membered alicyclic ring
  • M 11 is hydrogen
  • at least three of P 2 to P 11 are not hydrogen.
  • a pharmaceutical composition for treating or preventing cancer in a subject comprising an effective amount of the cyclic peptide compound or salt thereof, or solvate thereof according to any one of [1] to [13].
  • the pharmaceutical composition according to [17], wherein the cancer is pancreatic cancer.
  • the pharmaceutical composition according to any one of [17] to [18], wherein the subject is a human.
  • the present invention can provide novel cyclic peptide compounds having anti-tumor action, non-natural amino acids for use in the production of the cyclic peptide compounds, and production methods therefor.
  • Alloc group Allyloxycarbonyl group
  • DIAD Diisopropyl azodicarboxylate
  • DIPEA N,N-Diisopropylethylamine
  • Fmoc group 9-Fluorenylmethyloxycarbonyl group
  • PPTS Pyridinium p-toluenesulfonate
  • HATU 0-(7-Aza-1H-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • Trt group Triphenylmethyl group
  • halogen atoms examples include F, Cl, Br, and I.
  • Alkyl herein means a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, and has a subset of hydrocarbyl or hydrocarbon group structures not containing either a heteroatom (which refers to an atom other than carbon and hydrogen atoms) or an unsaturated carbon-carbon bond but containing hydrogen and carbon atoms in its backbone.
  • the alkyl includes linear and branched alkyls.
  • the alkyl has 1 to 20 carbon atoms (C 1 -C 20 , hereinafter “C p -C q ” means that the number of carbon atoms is p to q), and is preferably C 1 -C 10 alkyl, and more preferably C 1 -C 6 alkyl.
  • alkyl examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbut
  • Alkenyl herein means a monovalent group having at least one double bond (two adjacent SP 2 carbon atoms). Depending on the configuration of a double bond and a substituent (if present), the geometrical form of the double bond can be
  • E E
  • Z cis or trans configuration.
  • the alkenyl includes linear and branched alkenyls.
  • the alkenyl is preferably C 2 -C 10 alkenyl, and more preferably C 2 -C 6 alkenyl, and specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans forms), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.
  • Alkynyl herein means a monovalent group having at least one triple bond (two adjacent SP carbon atoms).
  • the alkynyl includes linear and branched alkynyls.
  • the alkynyl is preferably C 2 -C 10 alkynyl, and more preferably C 2 -C 6 alkynyl, and specific examples include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2′-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.
  • Cycloalkyl herein means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes a monocyclic ring, a bicyclo ring, and a spiro ring.
  • the cycloalkyl is preferably C 3 -C 8 cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.
  • Aryl herein means a monovalent aromatic hydrocarbon ring, and is preferably C 6 -C 10 aryl. Specific examples of the aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl).
  • Heterocyclyl herein means a non-aromatic cyclic monovalent group containing 1 to 5 hetero atoms in addition to carbon atoms.
  • the heterocyclyl may have a double and/or triple bond within the ring, a carbon atom within the ring may be oxidized to form carbonyl, and heterocyclyl may be a monocyclic ring or a condensed ring.
  • the number of atoms constituting the ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), and more preferably 4 to 7 (4- to 7-membered heterocyclyl).
  • heterocyclyl examples include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, azetidinyl, oxazolidone, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, t
  • Protected heterocyclyl herein means a group in which one or more functional groups, such as an amino group, contained in the above-defined “heterocyclyl” are protected with a protecting group, and is preferably 4- to 7-membered protected heterocyclyl.
  • protecting group include Boc, Fmoc, Cbz, Troc, and Alloc
  • specific examples of the protected heterocyclyl include Boc-protected azetidine.
  • Heterocycloalkylidene herein means a divalent group obtained by removing two hydrogen atoms from one carbon atom of the above-defined “heterocyclyl”, in which a free valence forms a part of a double bond.
  • the heterocycloalkylidene is preferably 4- to 7-membered heterocycloalkylidene, and specific examples include tetrahydropyran-4-ylidene and azetidin-3-ylidene.
  • “Protected heterocycloalkylidene” herein means a group in which one or more functional groups, such as an amino group, contained in the above-defined “heterocycloalkylidene” are protected with a protecting group, and is preferably 4- to 7-membered protected heterocycloalkylidene.
  • Specific examples of the protecting group include Boc, Fmoc, Cbz, Troc, and Alloc, and specific examples of the protected heterocycloalkylidene include Boc-protected azetidin-3-ylidene.
  • Heteroaryl herein means an aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms.
  • the ring may be a monocyclic ring, may be a condensed ring formed with another ring, or may be partially saturated.
  • the number of atoms constituting the ring is preferably 5 to 10 (5- to 10-membered heteroaryl) and more preferably 5 to 7 (5- to 7-membered heteroaryl).
  • heteroaryl examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyrid
  • Alkoxy herein means an oxy group to which the above-defined “alkyl” is bonded, and is preferably C 1 -C 6 alkoxy. Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.
  • Alkenyloxy herein means an oxy group to which the above-defined “alkenyl” is bonded, and is preferably C 2 -C 6 alkenyloxy. Specific examples of the alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans forms), 3-butenyloxy, pentenyloxy, and hexenyloxy.
  • Cycloalkoxy herein means an oxy group to which the above-defined “cycloalkyl” is bonded, and is preferably C 3 -C 8 cycloalkoxy. Specific examples of the cycloalkoxy include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.
  • Aryloxy herein means an oxy group to which the above-defined “aryl” is bonded, and is preferably C 6 -C 10 aryloxy. Specific examples of the aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.
  • Amino herein means —NH 2 in a narrow sense and —NRR′ in a broad sense, wherein R and R′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R′, together with the nitrogen atom to which they are attached, form a ring.
  • the amino is preferably —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4- to 8-membered cyclic amino, or the like.
  • “Monoalkylamino” herein means a group corresponding to the above-defined “amino” wherein R is hydrogen and R′ is the above-defined “alkyl”, and is preferably mono-C 1 -C 6 alkylamino. Specific examples of the monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.
  • Dialkylamino herein means a group corresponding to the above-defined “amino” wherein R and R′ are independently the above-defined “alkyl”, and is preferably di-C 1 -C 6 alkylamino. Specific examples of the dialkylamino include dimethylamino and diethylamino.
  • Cyclic amino herein means a group corresponding to the above-defined “amino” wherein R and R′, together with the nitrogen atom to which they are attached, form a ring, and is preferably 4- to 8-membered cyclic amino.
  • Specific examples of the cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.
  • Protected amino herein means an amino group protected with any protecting group. Specific examples of the protected amino include amino protected with a protecting group such as Boc, Fmoc, Cbz, Troc, or Alloc.
  • Aminocarbonyl herein means a carbonyl group to which the above-defined “amino” is bonded, and is preferably —CONH 2 , mono-C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.
  • aminocarbonyl examples include —CONH 2 , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl.
  • Alkenyloxycarbonyl herein means a carbonyl group to which the above-defined “alkenyloxy” is bonded, and is preferably C 2 -C 6 alkenyloxycarbonyl.
  • alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans forms), 3-butenyloxycarbonyl, pentenyloxycarbonyl, and hexenyloxycarbonyl.
  • Alkylsulfonyl herein means a sulfonyl group to which the above-defined “alkyl” is bonded, and is preferably C 1 -C 6 alkylsulfonyl. Specific examples of the alkylsulfonyl include methylsulfonyl.
  • “Hydroxyalkyl” herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with hydroxyl groups, and is preferably C 1 -C 6 hydroxyalkyl. Specific examples of the hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.
  • Haloalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with halogen, and is preferably C 1 -C 6 haloalkyl, and more preferably C 1 -C 6 fluoroalkyl.
  • Specific examples of the haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.
  • Cyanoalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with cyano, and is preferably C 1 -C 6 cyanoalkyl. Specific examples of the cyanoalkyl include cyanomethyl and 2-cyanoethyl.
  • aminoalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “amino”, and is preferably C 1 -C 6 aminoalkyl.
  • Specific examples of the aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, and 4-aminobutyl.
  • Carboxyalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with carboxy, and is preferably C 2 -C 6 carboxyalkyl. Specific examples of the carboxyalkyl include carboxymethyl.
  • Alkenyloxycarbonylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkenyloxycarbonyl”, and is preferably C 2 -C 6 alkenyloxycarbonyl C 1 -C 6 alkyl, and more preferably C 2 -C 6 alkenyloxycarbonyl C 1 -C 2 alkyl.
  • Specific examples of the alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.
  • Alkoxyalkyl herein means a group in which one of more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkoxy”, and is preferably C 1 -C 6 alkoxy C 1 -C 6 alkyl, and more preferably C 1 -C 6 alkoxy C 1 -C 2 alkyl.
  • Specific examples of the alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, 1-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.
  • Cycloalkylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “cycloalkyl”, and is preferably C 3 -C 8 cycloalkyl C 1 -C 6 alkyl, and more preferably C 3 -C 6 cycloalkyl C 1 -C 2 alkyl.
  • Specific examples of the cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • Cycloalkoxylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “cycloalkoxy”, and is preferably C 3 -C 8 cycloalkoxy C 1 -C 6 alkyl, and more preferably C 3 -C 6 cycloalkoxy C 1 -C 2 alkyl. Specific examples of the cycloalkoxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.
  • Heterocyclylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heterocyclyl”, and is preferably 4- to 7-membered heterocyclyl C 1 -C 6 alkyl, and more preferably 4- to 7-membered heterocyclyl C 1 -C 2 alkyl.
  • Specific examples of the heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.
  • Alkylsulfonylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “alkylsulfonyl”, and is preferably C 1 -C 6 alkylsulfonyl C 1 -C 6 alkyl, and more preferably C 1 -C 6 alkylsulfonyl C 1 -C 2 alkyl.
  • Specific examples of the alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.
  • Aminocarbonylalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aminocarbonyl”, and is preferably aminocarbonyl C 1 -C 6 alkyl, and more preferably aminocarbonyl C 1 -C 4 alkyl.
  • aminocarbonylalkyl examples include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.
  • Aryloxyalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aryloxy”, and is preferably C 6 -C 10 aryloxy C 1 -C 6 alkyl, and more preferably C 6 -C 10 aryloxy C 1 -C 2 alkyl. Specific examples of the aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.
  • Alkyl (arylalkyl) herein means a group in which one or more hydrogen atoms of the above-defined “alkyl” are replaced with the above-defined “aryl”, and is preferably C 7 -C 14 aralkyl, and more preferably C 7 -C 10 aralkyl. Specific examples of the aralkyl include benzyl, phenethyl, and 3-phenylpropyl.
  • Alkoxy herein means an oxy group to which the above-defined “aralkyl” is bonded, and is preferably C 7 -C 14 aralkoxy, and more preferably C 7 -C 10 aralkoxy. Specific examples of the aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.
  • Alkoxyalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “aralkoxy”, and is preferably C 7 -C 14 aralkoxy C 1 -C 6 alkyl, and more preferably C 7 -C 14 aralkoxy C 1 -C 2 alkyl.
  • Specific examples of the aralkoxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.
  • Heteroarylalkyl herein means a group in which one or more hydrogen atoms of the above-defined “alkyl” are replaced with the above-defined “heteroaryl”, and is preferably 5- to 10-membered heteroaryl C 1 -C 6 alkyl, and more preferably 5- to 10-membered heteroaryl C 1 -C 2 alkyl.
  • heteroarylalkyl examples include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.
  • Heteroarylalkoxy herein means an oxy group to which the above-defined “heteroarylalkyl” is bonded, and is preferably 5- to 10-membered heteroaryl C 1 -C 6 alkoxy, and more preferably 5- to 10-membered heteroarylC 1 -C 2 alkoxy. Specific examples of the heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.
  • Heteroarylalkoxyalkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heteroarylalkoxy”, and is preferably 5- to 10-membered heteroaryl C 1 -C 6 alkoxy C 1 -C 6 alkyl, and more preferably 5- to 10-membered heteroaryl C 1 -C 2 alkoxy C 1 -C 2 alkyl.
  • Specific examples of the heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.
  • Heterocycloalkylidenealkyl herein means a group in which one or more hydrogens of the above-defined “alkyl” are replaced with the above-defined “heterocycloalkylidene”, and is preferably 4- to 7-membered heterocycloalkylidene C 1 -C 6 alkyl, and more preferably 4- to 7-membered heterocycloalkylidene C 1 -C 2 alkyl.
  • Specific examples of the heterocycloalkylidenealkyl include tetrahydro-4H-pyran-4-ylidenemethyl and azetidin-3-ylidenemethyl.
  • Alkoxyalkenyl herein means a group in which one or more hydrogens of the above-defined “alkenyl” are replaced with the above-defined “alkoxy”, and is preferably C 1 -C 6 alkoxy C 2 -C 6 alkenyl. Specific examples of the alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.
  • aminocarbonylalkenyl herein means a group in which one or more hydrogens of the above-defined “alkenyl” are replaced with the above-defined “aminocarbonyl”, and is preferably aminocarbonyl C 2 -C 6 alkenyl.
  • Specific examples of the aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonylcarbonyl)-prop-2-en-1-yl.
  • Haloalkoxy herein means a group in which one or more hydrogens of the above-defined “alkoxy” are replaced with halogen, and is preferably C 1 -C 6 haloalkoxy. Specific examples of the haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.
  • Alkylene herein means a divalent group derived by further removing any one hydrogen atom from the above “alkyl”, and is preferably C 4 -C 8 alkylene.
  • Specific examples of the alkylene include —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH(CH 3 )CH 2 —, —C(CH 3 ) 2 —, —(CH 2 ) 4 —, —CH(CH 3 )CH 2 CH 2 —, —C(CH 3 ) 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH(CH 3 )—, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, and —(CH 2 ) 8 —.
  • Alicyclic ring herein means a non-aromatic hydrocarbon ring.
  • the alicyclic ring may have an unsaturated bond within the ring, and may be a polycyclic ring having two or more rings.
  • a carbon atom constituting the ring may be oxidized to form carbonyl.
  • the alicyclic ring is preferably a 3- to 8-membered alicyclic ring, and specific examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.
  • “Saturated heterocyclic ring” herein means a non-aromatic heterocyclic ring containing 1 to 5 hetero atoms in addition to carbon atoms and not containing a double bond and/or a triple bond within the ring.
  • the saturated heterocyclic ring may be a monocyclic ring, or may form a condensed ring with another ring, e.g., an aromatic ring such as a benzene ring.
  • the saturated heterocyclic ring is preferably a 4- to 7-membered saturated heterocyclic ring, and specific examples include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidone ring, a dioxolane ring, a diox
  • “Peptide chain” herein refers to a peptide chain in which 1, 2, 3, 4, or more natural amino acids and/or non-natural amino acids are connected by an amide bond and/or an ester bond.
  • the peptide chain is preferably a peptide chain comprising 1 to 4 amino acid residues, and more preferably a peptide chain consisting of 1 to 4 amino acid residues.
  • optical protected herein means that a group may be protected with any protecting group.
  • “One or more” herein means one or two or more. When “one or more” is used in a context relating to the substituent of a group, the phrase means a number encompassing one to the maximum number of substituents permitted by that group. Specific examples of “one or more” include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and/or a greater number.
  • the compound of the present invention can be a salt thereof, and preferably a chemically or pharmaceutically acceptable salt thereof.
  • the compound of the present invention or a salt thereof can be a solvate thereof, and preferably a chemically or pharmaceutically acceptable solvate thereof.
  • salts of the compound of the present invention include hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as a sodium salt and a potassium salt; alkaline earth metal salts such as a magnesium salt and a calcium salt; and ammonium salts such as an ammonium salt, an alkylammonium salt, a dialkylammonium salt, a trialkylammonium salt, and a tetraalkylammonium salt.
  • a solvate of a compound refers to a phenomenon in which solute molecules strongly attract solvent molecules in a solution and form one molecular group, and is called a hydrate when the solvent is water.
  • the solvate of the compound of the present invention is preferably a hydrate, and specific examples of such hydrates include mono- to deca-hydrates, preferably mono- to penta-hydrates, and more preferably mono- to tri-hydrates.
  • the solvate of the compound of the present invention includes not only a solvate formed of a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), or dimethylformamide, but also a solvate formed of a plurality of solvents.
  • a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, or 2-propanol), or dimethylformamide, but also a solvate formed of a plurality of solvents.
  • amino acid as used herein includes natural and unnatural amino acids.
  • natural amino acid refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, or Pro.
  • unnatural amino acid include, but are not particularly limited to, ⁇ -amino acids, ⁇ -amino acids, D-amino acids, N-substituted amino acids, ⁇ , ⁇ -disubstituted amino acids, amino acids having side chains that are different from those of natural amino acids, and hydroxycarboxylic acids.
  • Amino acids herein may have any conformation.
  • amino acid side chain there is no particular limitation on the selection of amino acid side chain, but in addition to a hydrogen atom, it can be freely selected from, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group.
  • One or two non-adjacent methylene groups in such a group are optionally substituted with an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO 2 —).
  • Each group may have a substituent, and there are no limitations on the substituent.
  • one or more substituents may be freely and independently selected from any substituents including a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom.
  • substituents include an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, and cycloalkyl group.
  • amino acids herein may be compounds having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included in amino acids).
  • the main chain amino group of an amino acid may be unsubstituted (an NH 2 group) or substituted (i.e., an —NHR group, where R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl which may have a substituent, one or two non-adjacent methylene groups in such a group may be substituted with an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO 2 —), and the carbon chain bonded to the N atom and the carbon atom at the position a may form a ring, as in proline).
  • —NHR group where R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl which may have a substituent, one or two non-adjacent methylene groups in such a group may be substituted with
  • the R substituent is selected as the substituent in the aforementioned amino acid side chain is selected.
  • the R is included in the “amino acid side chain” as used herein.
  • Such amino acids in which the main chain amino group is substituted are herein called “N-substituted amino acids.”
  • Preferred examples of the “N-substituted amino acids” as used herein include, but are not limited to, N-alkylamino acids, N—C 1 -C 6 alkylamino acids, N—C 1 -C 4 alkylamino acids, and N-methylamino acids.
  • amino acids as used herein which constitute a peptide compound include all isotopes corresponding to each amino acid.
  • the isotope of the “amino acid” refers to one having at least one atom replaced with an atom of the same atomic number (number of protons) and different mass number (total number of protons and neutrons).
  • Examples of isotopes contained in the “amino acid” constituting the peptide compounds of the present invention include a hydrogen atom, a carbon atom, a nitrogen atom, an oxygen atom, a phosphorus atom, a sulfur atom, a fluorine atom, and a chlorine atom, which respectively include 2 H and 3 H; 13 C and 14 C; 15 N; 17 O and 18 O; 31 P and 32 P; 35 S; 18 F; and 36 Cl.
  • Substituents containing a halogen atom as used herein include include a halogen-substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, or aralkyl group. More specific examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl.
  • Substituents containing an O atom include groups such as hydroxy (—OH), oxy (—OR), carbonyl (—C ⁇ O—R), carboxy (—CO 2 H), oxycarbonyl (—C ⁇ O—OR), carbonyloxy (—O—C ⁇ O—R), thiocarbonyl (—C ⁇ O—SR), carbonylthio (—S—C ⁇ O—R), aminocarbonyl (—C ⁇ O—NHR), carbonylamino (—NH—C ⁇ O—R), oxycarbonylamino (—NH—C ⁇ O—OR), sulfonylamino (—NH—SO 2 —R), aminosulfonyl (—SO 2 —NHR), sulfamoylamino (—NH—SO 2 —NHR), thiocarboxyl (—C ⁇ O—SH), and carboxylcarbonyl (—C ⁇ O—CO 2 H).
  • groups such as hydroxy (—OH), oxy (—OR), carbon
  • Examples of oxy include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy.
  • the alkoxy is preferably C1-C4 alkoxy and C1-C2 alkoxy, and particularly preferably methoxy or ethoxy.
  • carbonyl examples include formyl (—C ⁇ O—H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.
  • oxycarbonyl examples include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.
  • carbonyloxy examples include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.
  • thiocarbonyl examples include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.
  • carbonylthio examples include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.
  • aminocarbonyl examples include alkylaminocarbonyl (examples of which include C1-C6 or C1-C4 alkylaminocarbonyl, in particular, ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, and aralkylaminocarbonyl.
  • alkylaminocarbonyl examples of which include C1-C6 or C1-C4 alkylaminocarbonyl, in particular, ethylaminocarbonyl and methylaminocarbonyl
  • cycloalkylaminocarbonyl alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, and aralkylaminocarbonyl.
  • Additional examples include compounds in which the H atom bonded to the N atom in —C ⁇ O—NHR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
  • Examples of carbonylamino include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Additional examples include compounds in which the H atom bonded to the N atom in —NH—C ⁇ O—R is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
  • Examples of oxycarbonylamino include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. Additional examples include compounds in which the H atom bonded to the N atom in —NH—C ⁇ O—OR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
  • Examples of sulfonylamino include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Additional examples include compounds in which the H atom attached to the N atom in —NH—SO 2 —R is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
  • aminosulfonyl examples include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Additional examples include compounds in which the H atom attached to the N atom in —SO 2 —NHR is further replaced with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
  • sulfamoylamino examples include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino.
  • the two H atoms bonded to the N atoms in —NH—SO 2 —NHR may be further replaced with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.
  • Substituents containing an S atom include groups such as thiol (—SH), thio (—S—R), sulfinyl (—S ⁇ O—R), sulfonyl (—SO 2 —R), and sulfo (—SO 3 H).
  • thio examples include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio.
  • sulfonyl examples include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.
  • Substituents containing an N atom include groups such as azido (—N 3 , also called “azido group”), cyano (—CN), primary amino (—NH 2 ), secondary amino (—NH—R; also called monosubstituted amino), tertiary amino (—NR(R′); also called disubstituted amino), amidino (—C( ⁇ NH)—NH 2 ), substituted amidino (—C( ⁇ NR)—NR′ R′′), guanidino (—NH—C( ⁇ NH)—NH 2 ), substituted guanidino (—NR—C( ⁇ NR′′′)—NR′R′′), aminocarbonylamino (—NR—CO—NR′R′′), pyridyl, piperidino, morpholino, and azetidinyl.
  • secondary amino examples include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.
  • tertiary amino examples include amino groups having any two substituents each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)amino, where any two such substituents may form a ring.
  • Specific examples include dialkylamino, in particular, C1-C6 dialkylamino, C1-C4 dialkylamino, dimethylamino, and diethylamino.
  • C p -C q dialkylamino group refers to an amino group substituted with two C p -C q alkyl groups, where the two C p -C q alkyl groups may be the same or different.
  • substituted amidino examples include groups in which three substituents R, R′, and R′′′ on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.
  • substituted guanidino examples include groups in which R, R′, R′′, and R′′′ are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these substituents form a ring.
  • aminocarbonylamino examples include groups in which R, R′, and R′′ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these substituents form a ring.
  • amino acid residue constituting the peptide compound may be simply referred to as an “amino acid”.
  • the present invention relates to a cyclic peptide compound represented by formula (1) below or a salt thereof, or a solvate thereof.
  • the ring is composed of 11 amino acid residues.
  • the amino acid residue having P 1 , Q 1 , R 1 , and L 1 in the formula may be referred to as core 1, the amino acid residue having P 2 , Q 2 , and R 2 as core 2, the amino acid residue having P 3 , Q 3 , and R 3 as core 3, the amino acid residue having P 4 , Q 4 , and R 4 as core 4, the amino acid residue having P 5 , Q 5 , and R 5 as core 5, the amino acid residue having P 6 , Q 6 , and R 6 as core 6, the amino acid residue having P 7 , Q 7 , and R 7 as core 7, the amino acid residue having P 8 , Q 8 , and R 8 as core 8, the amino acid residue having P 9 , Q 9 , and R 9 as core 9, the amino acid residue having P 10 , Q 10 , and R 10 as core 10, and the amino acid residue having P 1 , Q 11 , R 11 , and L 11 as core 11.
  • L 1 is a single bond or is —CHM 1 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • L 11 is a single bond or is —CHM 11 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —, wherein one of L 1 and L 11 is a single bond.
  • L 11 is —CHM 11 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • L 1 is —CHM 1 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —.
  • M 1 is hydrogen except when R 1 and M 1 form a 3- to 8-membered alicyclic ring
  • M 11 is hydrogen except when R 11 and M 11 form a 3- to 8-membered alicyclic ring.
  • L 1 or L 11 is —(CH 2 ) n S(CH 2 ) m —
  • specific examples of —(CH 2 ) n S(CH 2 ) m — include —CH 2 SCH 2 —, —CH 2 CH 2 SCH 2 —, —CH 2 SCH 2 CH 2 —, and —CH 2 CH 2 SCH 2 CH 2 —.
  • L 1 or L 11 is —(CH 2 ) n S(O)(CH 2 ) m —
  • specific examples of —(CH 2 ) n S(O)(CH 2 ) m include —CH 2 S(O)CH 2 —, —CH 2 CH 2 S(O)CH 2 —, —CH 2 S(O)CH 2 CH 2 —, and —CH 2 CH 2 S(O)CH 2 CH 2 —.
  • L 1 or L 11 is —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • specific examples of —(CH 2 ) n S(O) 2 (CH 2 ) m include —CH 2 S(O) 2 CH 2 —, —CH 2 CH 2 S(O) 2 CH 2 —, —CH 2 S(O) 2 CH 2 CH 2 —, and —CH 2 CH 2 S(O) 2 CH 2 CH 2 —.
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkylsulfonyl.
  • R 1 is preferably C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with one or more halogens, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), or hydroxy), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3
  • R 1 is more preferably C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, methylsulfonylC 1 -C 2 alkyl, C 2 -C 3 alkynyl; C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with one or more fluorines, mono-C 1 -C 4 alkylaminocarbonyl, or hydroxy; C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 2 alkyl, or C 3 -C 6 cycloalkoxyC 1 -C 2 alkyl.
  • R 1 examples include methyl, ethyl, i-propyl, n-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, n-hexyl, 3-methylbutyl, 2-methylbutyl, n-pentyl, but-3-yn-1-yl, propargyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(t-butylamino)-2-oxoethoxy)methyl, 3,3-difluorobutyl, n-propoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, cyclohexyl,
  • R 1 is preferably hydrogen.
  • R 1 and P 1 together with the carbon atom to which R 1 is attached and the nitrogen atom to which P 1 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 1 and Q 1 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 1 and Q 1 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • R 1 and M 1 when core 1 is ⁇ -amino acid, R 1 and M 1 , together with the carbon atom to which R 1 is attached and the carbon atom to which M 1 is attached, can form a 3- to 8-membered alicyclic ring.
  • the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.
  • M 1 when core 1 is ⁇ -amino acid, M 1 is hydrogen except when R 1 and M 1 form a 3- to 8-membered alicyclic ring.
  • P 1 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 1 is preferably hydrogen or C 1 -C 6 alkyl. Specific examples of such P 1 include hydrogen, methyl, ethyl, and n-propyl.
  • Q 1 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 1 is ⁇ -amino acid
  • specific examples of core 1 include MeAla, Ala, Pic(2), MeLeu, MeCha, MeVal, EtAla, nPrAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeAOC(2), MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeSer, MeAbu(4-F3), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeSer(iPen), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), Me
  • core 1 is ⁇ -amino acid
  • specific examples of core 1 include bAla and bMeAla.
  • R 2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, and C 1 -C 6 alkylsulfonyl.
  • R 2 is preferably C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl.
  • R 2 is more preferably C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, methylsulfonylC 1 -C 2 alkyl, C 2 -C 6 alkenyl, C 2 -C 3 alkynyl, C 1 -C 6 alkoxyC 1 -C 2 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 2 alkyl, or C 3 -C 6 cycloalkoxyC 1 -C 2 alkyl.
  • R 2 examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, pentan-3-yl, n-propoxymethyl, cyclopropoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, 3-methyl-butoxy-methyl, 2-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, cyanomethyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, allyl, 3-methylbut-2-en-1-yl, propargyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexylmethyl, cyclopen
  • R 2 and P 2 together with the carbon atom to which R 2 is attached and the nitrogen atom to which P 2 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 2 and Q 2 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 2 and Q 2 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 2 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 2 is preferably hydrogen.
  • Q 2 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 2 examples include Ala, Val, Leu, Ile, Nle, PRA, Chg, Cha, Ala(cPent), Ala(cBu), Ala(cPr), Gly(cPent), Gly(cBu), Gly(cPr), Hle, Ser(nPr), Ser(cPr), Ser, Abu(4-F3), Ahp(2), Abu, Nva, Hnl(7-F2), Ser(Me), Ser(iPen), Thr, Algly, Pregly, Ser(cBu), Ser(Tfe), Ala(CN), Thr(Me), Hse(Me), Met(O2), and Nva(3-Et).
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • R 3 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino) or hydroxy), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C
  • R 3 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with mono-C 1 -C 4 alkylaminocarbonyl or hydroxy, mono-C 1 -C 4 alkylaminocarbonylC 1 -C 2 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 2 alkyl, benzyl, or phenethyl.
  • R 3 include hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 3-methylbutyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, n-propoxymethyl, cyclopropoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, 3-methylamino-3-oxo-propyl, cyclohexyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, and phenethyl.
  • R 3 and P 3 together with the carbon atom to which R 3 is attached and the nitrogen atom to which P 3 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 3 and Q 3 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 3 and Q 3 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 3 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogens), or C 3 -C 8 cycloalkyl.
  • P 3 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxyC 1 -C 2 alkyl, 4- to 8-membered cyclic aminoC 1 -C 2 alkyl optionally substituted with one or more halogens, or C 3 -C 6 cycloalkyl.
  • Specific examples of such P 3 include hydrogen, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, i-butyl, 2-ethoxyethyl, and 2-(4,4-difluoro-1-piperidyl)ethyl.
  • Q 3 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 3 examples include MeAla, Ala, Pic(2), MeLeu, MeCha, MeVal, EtAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, MeHle, MeSer(nPr), MeSer(cPr), MeSer(iPen), MeThr, Abu, MeGly, EtGly, Gly, nBuGly, iPrGly, cPrGly, nPrGly, iBuGly, (EtOEt)NGly, 2-(pip-4-F2)-EtGly, Pro, Aze(2), MeGln(Me), MePhe, and MeHph.
  • R 4 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen or C 1 -C 4 alkyl. Specific examples of R 4 include hydrogen and methyl.
  • R 4 and P 4 together with the carbon atom to which R 4 is attached and the nitrogen atom to which P 4 is attached, can form a 4- to 7-membered saturated heterocyclic ring (preferably, 4- or 5-membered saturated heterocyclic ring).
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 4 and Q 4 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 4 and Q 4 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 4 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 4 is preferably C 1 -C 6 alkyl or C 1 -C 6 alkoxyC 1 -C 6 alkyl.
  • P 4 is more preferably hydrogen, C 1 -C 6 alkyl, or C 1 -C 4 alkoxyC 1 -C 2 alkyl. Specific examples of P 4 include methyl, ethyl, n-propyl, n-butyl, i-propyl, i-pentyl, and 2-ethoxyethyl.
  • Q 4 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 4 examples include MeAla, Pic(2), MeGly, EtGly, nBuGly, nPrGly, (EtOEt)NGly, Pro, Aze(2), and iPenGly.
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C
  • R 5 is preferably C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C
  • R 5 is more preferably C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, methylalkylsulfonylC 1 -C 2 alkyl, C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with one or more fluorines, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 2 alkyl, C 3 -C 6 cycloalkoxyC 1 -C 2 alkyl, benzyl or phenethyl optionally substituted with one or more halogens, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyano, phenoxyC 1 -C 2 alkyl optionally substituted with one or more halogens, benzyloxyC 1
  • R 5 examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, propargyl, 3,3-difluorobutyl, n-propoxymethyl, cyclopropoxymethyl, hydroxymethyl, 2,2,2-trifluoroethyl, 5,5-difluorobutyl, methoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 1-methoxyethyl, 2-methoxyethyl, 2-methylsulfonylethyl, (2-chlorophenoxy)methyl, allyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopentylmethyl, cyclohexylmethyl,
  • R 5 together with R 8 can form C 4 -C 8 alkylene.
  • C 4 -C 8 alkylene is preferably —(CH 2 ) 8 —.
  • R 5 and P 5 together with the carbon atom to which R 5 is attached and the nitrogen atom to which P 5 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 5 and Q 5 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 5 and Q 5 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 5 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 5 is preferably hydrogen or C 1 -C 2 alkyl, and specific examples include hydrogen, methyl, and ethyl.
  • Q 5 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 5 examples include MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeSer, MeAbu(4-F3), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeSer(iPen), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(02), MePhe, MeHph, MePhe(4-Cl), MeThr(Bn), EtPhe(4-Cl), MePhe(2-CN), MePhe(3-CN), MePhe(4-CN),
  • R 6 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen or C 1 -C 3 alkyl. Specific examples of R 6 include hydrogen and methyl.
  • R 6 and P 6 together with the carbon atom to which R 6 is attached and the nitrogen atom to which P 6 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 6 and Q 6 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 6 and Q 6 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 6 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxyamino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 6 is preferably C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl, and more preferably C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl. Specific examples of such P 6 include methyl, ethyl, and cyclopropyl.
  • Q 6 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 6 examples include MeAla, MeGly, EtGly, cPrGly, D-Pro, D-MeAla, and D-Pic(2).
  • R 7 is C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 .
  • R 7 is preferably C 6 -C 10 aryloxyC 1 -C 6 alkyl (wherein the C 6 -C 10 aryloxyC 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen and C 1 -C 6 haloalkyl), C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, cyano, C 1 -C 6 alkylsulfonyl, and SF 5 ), C 7 -C 14 aralkoxyC 1 -C 6 alkyl optionally substituted with one or more halogens, or 5- to 10-membered
  • R 7 is preferably —(CH 2 ) x —O y —(CH 2 ) z1 —C 6 -C 10 aryl or —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1 -C 4 alkyl (preferably methyl), C 2 -C 4 alkynyl (preferably ethynyl), C 1 -C 3 haloalkyl (preferably difluoromethyl, trifluoromethyl), C 1 -C 3 haloalkoxy (preferably difluoromethoxy, trifluoromethoxy), C 1 -C 4 alkoxy (preferably methoxy, ethoxy, isopropoxy, n-butoxy, t-butoxy), —CN, C 1 -C 3 alkylsulfonyl (preferably methylsulfonyl), and
  • Such —(CH 2 ) x —O y —(CH 2 ) z1 —C 6 -C 10 aryl or —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl is preferably —CH 2 —C 6 -C 10 aryl or —(CH 2 ) 2 —C 6 -C 10 aryl, which is optionally substituted with the above-mentioned group(s).
  • the substituent is preferably on C 6 -C 10 aryl in the group, and when —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl has a substituent, the substituent is preferably on 5- to 10-membered heteroaryl in the group.
  • R 7 examples include ((4-chlorobenzyl)oxy)methyl, 2-(4-chlorophenoxy)ethyl, 2-(3,4-dichlorophenoxy)ethyl, 2-(4-(trifluoromethylphenoxy))ethyl, (4-chlorophenoxy)methyl, ((3-chlorobenzyl)oxy)methyl, ((2-chlorobenzyl)oxy)methyl, 3-iodobenzyl, 3-chlorobenzyl, 3-methylbenzyl, 3-fluorobenzyl, 3,5-difluorobenzyl, 4-methylphenethyl, 4-(trifluoromethyl)phenethyl, 3-chloro-5-fluorobenzyl, 3-cyanobenzyl, 3-(trifluoromethoxy)benzyl, benzyl, 4-fluorophenethyl, 2-fluoro-4-(trifluoromethyl)phenethyl, 3-chlorophenethyl, 4-chloroph
  • R 7 and P 7 together with the carbon atom to which R 7 is attached and the nitrogen atom to which P 7 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 7 and Q 7 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 7 and Q 7 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 7 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 7 is preferably hydrogen.
  • Q 7 is hydrogen, C 1 -C 6 alkyl, or C 7 -C 14 aralkyl, and is preferably hydrogen.
  • core 7 examples include Phe(3-Cl), Phe(3-Me), Phe(3-F), Phe(35-F2), Hph(4-Me), Hph(4-CF3), Phe(3-Cl-5-F), Phe(3-I), Phe(3-CN), Phe(3-OCF3), Phe, Hph(4-F), Hph(4-CF3-2-F), Hph(3-Cl), Hph(4-Cl), Hph(4-CF3-3-F), Hph(F5), Hph(245-F3), Hph(2-F-5-Cl), Hph(2-F-4-Cl), Hph(24-F2), Hph(2-F-6-Cl), Hph(246-F3), Hph(4-CF3-3-Cl), Hph(3-CF3), Hph(4-SF5), Hph(4-CF3-35-F2),
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyloxycarbonylC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 6 -C 10 aryloxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, C 7 -C 14 aralkoxyC 1 -C 6 alkyl, 5 to 10-membered heteroarylC 1 -C 6 alkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, carboxy
  • R 8 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 aminoalkyl (wherein the amino is —NH 2 , protected amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen atoms), optionally protected 4- to 7-membered heterocyclylC 1 -C 6 alkyl, optionally protected 4- to 7
  • R 8 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 carboxyalkyl, protected aminoC 1 -C 4 alkyl, mono-C 1 -C 4 alkylaminocarbonylC 1 -C 2 alkyl, di-C 1 -C 4 alkylaminocarbonylC 1 -C 2 alkyl, 4- to 8-membered cyclic aminocarbonylC 1 -C 2 alkyl optionally substituted with one or more fluorine atoms, 4- to 8-membered cyclic aminoC 1 -C 2 alkyl optionally substituted with one or more fluorine atoms, optionally protected 4- to 7-membered heterocyclylC 1 -C 2 alkyl, optionally protected 4- to 7-membered heterocycloalkylideneC 1 -C 2 alkyl, mono-C 1 -C 4 alky
  • R 8 is preferably —(CH 2 ) x —O y —(CH 2 ) z1 —C 6 -C 10 aryl or —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl optionally substituted with one to five groups independently selected from the group consisting of halogen, C 1 -C 4 alkyl (preferably methyl), C 2 -C 4 alkynyl (preferably ethynyl), C 1 -C 3 haloalkyl (preferably difluoromethyl, trifluoromethyl), C 1 -C 3 haloalkoxy (preferably trifluoromethoxy), C 1 -C 4 alkoxy (preferably methoxy), —CN, C 1 -C 3 alkylsulfonyl (preferably methylsulfonyl), hydroxy, and SF 5 , wherein provided that the sum of x, y, and z1 or
  • the substituent is preferably on C 6 -C 10 aryl in the group, and when —(CH 2 ) x —O y —(CH 2 ) z2 -5- to 10-membered heteroaryl has a substituent, the substituent is preferably on 5- to 10-membered heteroaryl in the group.
  • R 8 include hydrogen, methyl, ethyl, i-propyl, n-propyl, n-butyl, 2-methylpropyl, 1-methylpropyl, neopentyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, 3,3-difluorobutyl, n-propoxymethyl, 3-methylbutoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, 2-methylbutyl, 5,5-difluoropentyl, 3-methylamino-3-oxo-propyl, ((5-fluoripyridin-3-yl)methoxy)methyl, 4-(((allyloxy)carbonyl)amino)butyl, 2-hydroxy-2-oxoethyl, (5-fluoripyridin-3-yl)methyl, 2-(3,3-difluoropiperidinyl)ethyl,
  • R 8 together with R 5 , can form C 4 -C 8 alkylene.
  • C 4 -C 8 alkylene is preferably —(CH 2 ) 8 —.
  • R 8 and P 8 together with the carbon atom to which R 8 is attached and the nitrogen atom to which P 8 is attached, can form a 4- to 7-membered saturated heterocyclic ring (preferably 4- or 5-membered saturated heterocyclic ring).
  • the 4- to 7-membered saturated heterocyclic ring may be condensed with a saturated carbocyclic ring or an aromatic ring.
  • the 4- to 7-membered saturated heterocyclic ring is optionally substituted with halogen, oxo, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, 4- to 8-membered cyclic amino (wherein the cyclic amino is optionally substituted with one or more halogen atoms), or OS 8 .
  • S 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 7 -C 14 aralkyl (wherein the aralkyl is optionally substituted with one or more halogen atoms, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy), or 5- to 10-membered heteroarylC 1 -C 6 alkyl.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • These saturated heterocyclic rings may be condensed with a 3- to 8-membered saturated carbocyclic ring (preferably a cyclohexane ring) or a 6- to 10-membered aromatic ring (preferably a benzene ring).
  • the 4- to 7-membered saturated heterocyclic ring is preferably substituted one or more halogen atoms, hydroxy, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkoxy, C 6 -C 10 aryl, 5- to 10-membered heteroarylC 1 -C 6 alkoxy, C 7 -C 14 aralkoxy (wherein the C 7 -C 14 aralkoxy is optionally substituted with one or more halogen atoms, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy), 4- to 8-membered cyclic amino optionally substituted with one or more halogen atoms, or 5- to 10-membered heteroaryl.
  • substituent of the 4- to 7-membered saturated heterocyclic ring include halogen, hydroxy, oxo, ethoxy, 2-hydroxyethyl, phenyl, difluoroethoxy; benzyloxy optionally substituted with one or more substituents independently selected from the group consisting of one or more halogen atoms, methyl, trifluoromethyl, methoxy, and difluoromethoxy; 5- to 6-membered heteroarylmethoxy, 4- to 8-membered cyclic amino optionally substituted with one or more fluorine atoms, phenyl, and 5- to 6-membered heteroaryl.
  • R 8 and Q 8 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 8 and Q 8 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclylC 1 -C 6 alkyl, C 6 -C 10 aryl, C 7 -C 14 aralkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroarylC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkoxy, amino (where
  • P 8 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with one or more halogen atoms, hydroxy, di-C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxy, or amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino)), aminocarbonylC 1 -C 6 alkyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with one or more halogen
  • P 8 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl; C 1 -C 4 alkoxyC 1 -C 2 alkyl optionally substituted with one or more fluorine atoms, hydroxy, dimethylaminocarbonyl, methoxy, amino, methylamino, or dimethylamino; dimethylaminocarbonylC 1 -C 4 alkyl, aminoC 1 -C 4 alkyl (wherein the amino is —NH 2 ), 4- to 8-membered cyclic aminoC 1 -C 4 alkyl optionally substituted with one or more fluorines or methyl, C 2 -C 3 alkenyl, C 2 -C 6 hydroxyalkenyl, dimethylaminocarbonylC 2 -C 3 alkenyl, methoxyC 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl optionally substituted with one or more fluorine atoms, 4-
  • P 8 include hydrogen, methyl, ethyl, n-butyl, allyl, 2-hydroxyethyl, 2-ethoxyethyl, 2-(dimethylaminocarbonylmethoxy)ethyl, 2-(2-hydroxy-2-methylpropoxy)ethyl, 4-aminobutyl, 2-piperazin-1-ylethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl, 2-(2-methoxyethoxy)ethyl, 2-(2,2-difluoroethoxy)ethyl, 2-(2-aminoethoxy)ethyl, 2-[2-(methylamino)ethoxy]ethyl, 2-[2-(dimethylamino)ethoxy]ethyl, 5-hydroxypentyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, benzyl, (
  • Q 8 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 8 examples include MeAla, Ala, Pic(2), MeLeu, EtAla, MeSer(tBuOH), MeSer(NtBu-Aca), MeAla(cPent), MeAla(cPr), MeNva, MeNle, Val, Leu, MeNva(5-F2), MeSer(nPr), MeHnl(7-F2), MeSer(iPen), MeThr, MeHse(Me), Ile, Nle, PRA, Chg, Abu, Hnl(7-F2), Ser(iPen), Algly, Pregly, EtGly, nBuGly, (EtOEt)NGly, Pro, Aze(2), MeGln(Me), MePhe, MePhe(4-Cl), MePhe(3-CN), MePhe(4-CN), MePhe(2-F), MePhe(3-F), MePhe(4-F), MePhe(2-Cl), MePhe(3-Cl
  • R 9 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or 5- to 10-membered heteroarylC 1 -C 6 alkoxyC 1 -C 6 alkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alkyl
  • R 9 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), hydroxy, or 5- to 10-membered heteroaryl optionally substituted with one or more halogen atoms), C 3 -C 8 cycloalkylC 1 -C 6 alkyl, or C 7 -C 14 aralkyl (wherein the C 7 -C 14 aralkyl is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms, C 1 -C
  • R 9 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 3 alkenyl; C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with mono-C 1 -C 4 alkylaminocarbonyl, hydroxy, or 5- to 6-membered heteroaryl optionally substituted with one or more fluorine atoms; and benzyl or phenethyl optionally substituted with one or more groups independently selected from the group consisting of C 3 -C 6 cycloalkylC 1 -C 2 alkyl, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and cyano.
  • R 9 More specific examples of R 9 include hydrogen, methyl, ethyl, i-propyl, 2-methylpropyl, 2,2,2-trifluoroethyl, 5,5-difluoropentyl, methoxymethyl, n-propoxymethyl, 3-methylbutoxymethyl, 3-(dimethylamino)3-oxopropyl, (2-hydroxy-2-methyl-propyloxy)methyl, (2-(tert-butylamino)-2-oxoethoxy)methyl, (5-fluoropyridin-3-yl)methyl, allyl, cyclohexylmethyl, benzyl, phenethyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 4-methoxybenzyl, 2-(trifluoromethyl)
  • R 9 and P 9 together with the carbon atom to which R 9 is attached and the nitrogen atom to which P 9 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 9 and Q 9 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 9 and Q 9 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 9 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 9 is preferably hydrogen or C 1 -C 6 alkyl, and more preferably hydrogen, methyl, n-propyl, or n
  • Q 9 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen or methyl.
  • R 9 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 7 -C 14 aralkyl
  • Q 9 is C 1 -C 6 alkyl
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • core 9 examples include MeAla, Ala, MeLeu, MeCha, MeVal, MeSer(tBuOH), MeSer(NtBu-Aca), Val, Leu, MeSer(nPr), MeHnl(7-F2), MeSer(iPen), Ser(nPr), Abu(4-F3), Abu, Ser(Me), Gly, nBuGly, nPrGly, MePhe, MeHph, MePhe(4-Cl), MePhe(2-F), MePhe(3-F), MePhe(4-F), MePhe(2-Cl), MePhe(3-Cl), MePhe(2-Me), MePhe(4-Me), MePhe(2-CF3), MePhe(3-CF3), MePhe(4-CF3), MeTyr(Me), MePhe(2-OCF3), MePhe(3-OCF3), MePhe(4-OCF3), D-Pro, Phe,
  • R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl, each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, and C 1 -C 6 alkylsulfonyl.
  • R 10 is preferably C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylsulfonylC 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with one or more halogen atoms, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylC 1 -C 6 alkyl, C 3 -C 8 cycloalkoxyC 1 -C 6 alkyl, or C 7 -C 14 aralkyl.
  • R 10 is more preferably C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 4 hydroxyalkyl, methylsulfonylC 1 -C 2 alkyl, C 2 -C 3 alkynyl, C 1 -C 4 alkoxyC 1 -C 2 alkyl optionally substituted with one or more fluorine atoms, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylC 1 -C 2 alkyl, C 3 -C 6 cycloalkoxyC 1 -C 2 alkyl, benzyl, or phenethyl.
  • R 10 More specific examples of R 10 include methyl, ethyl, n-propyl, i-propyl, 2-methylpropyl, 1-methylpropyl, n-butyl, 2-methylbutyl, 3-methylbutyl, n-pentyl, propargyl, 3,3-difluorobutyl, 5,5-difluoropentyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, n-propoxymethyl, 1-hydroxyethyl, cyclopropoxymethyl, cyclobutoxymethyl, (2,2,2-trifluoroethoxy)methyl, 2-methylsulfonylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, and phenethyl.
  • R 10 and P 10 together with the carbon atom to which R 10 is attached and the nitrogen atom to which P 10 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 10 and Q 10 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 10 and Q 10 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • P 10 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 10 is preferably hydrogen or C 1 -C 2 alkyl, and specific examples include hydrogen and methyl.
  • Q 10 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • core 10 examples include MeAla, MeLeu, MeCha, MeVal, MeAla(cPent), MeAla(cBu), MeAla(cPr), MeChg, MeGly(cPent), MeGly(cBu), MeGly(cPr), MeAbu, MeNva, MeNle, Val, Leu, MeNva(5-F2), MeHle, MeIle, MeSer(nPr), MeSer(cPr), MeHnl, MeHnl(7-F2), MePRA, MeSer(Me), MeThr, MeSer(cBu), MeSer(Tfe), MeThr(Me), MeHse(Me), MeMet(O2), Ile, Nle, Chg, Ala(cBu), Gly(cPent), Hle, Nva, Phe, and Hph.
  • R 11 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 7 -C 14 aralkyl, or aminocarbonyl (wherein the amino is —NH 2 , mono C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), each of which is optionally substituted with one or more groups independently selected from the group consisting of halogen, oxo, hydroxy, C 1 -C 6 alkyl, 4- to 7-membered heterocyclyl, aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino), and C 1 -C 6 alky
  • R 11 is preferably hydrogen, C 1 -C 6 alkoxyC 1 -C 6 alkyl optionally substituted with hydroxy, or C 7 -C 14 aralkyl optionally substituted with one or more halogen atoms.
  • R 11 is more preferably hydrogen, C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with hydroxy, or benzyl optionally substituted with fluorine, and specific examples include hydrogen, (2-hydroxy-2-methyl-propyloxy)methyl, benzyl, 3-fluorobenzyl, and 4-fluorobenzyl.
  • R 11 is preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl (wherein the C 1 -C 6 alkoxyC 1 -C 6 alkyl is optionally substituted with hydroxy or aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino)), C 7 -C 14 aralkyl optionally substituted with one or more halogen atoms, or aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl
  • R 11 is more preferably hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 6 alkoxyC 1 -C 2 alkyl optionally substituted with mono-C 1 -C 4 alkylaminocarbonyl, dimethylaminocarbonyl; 4- to 8-membered cyclic aminocarbonyl optionally substituted with one or more fluorine atoms, C 1 -C 4 alkyl, or 4- to 7-membered heterocyclyl; benzyl or phenethyl.
  • R 11 When core 11 is ⁇ -amino acid, specific examples of R 11 include hydrogen, methyl, isobutyl, trifluoromethyl, allyl, prop-2-yn-1-yl, (isopentyloxy)methyl, ⁇ 2-(t-butylamino)-2-oxoethoxy ⁇ methyl, dimethylaminocarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, 3,3-dimethylpyrrolidinylcarbonyl, 3,3,4,4-tetrafluoropyrrolidinylcarbonyl, 4-methylpiperidinylcarbonyl, 4-(t-butyl)-piperidinylcarbonyl, 3,3,4,4,5,5-hexafluoropiperidinylcarbonyl, 3,3-difluoropiperidinylcarbonyl, 4,4-difluoropiperidinylcarbonyl, piperidinylcarbonyl, morpholinocarbonyl, o
  • R 11 is preferably aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • R 11 and P 11 together with the carbon atom to which R 11 is attached and the nitrogen atom to which P 11 is attached, can form a 4- to 7-membered saturated heterocyclic ring.
  • the 4- to 7-membered saturated heterocyclic ring is preferably an azetidine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, or a morpholine ring.
  • R 11 and Q 11 together with the carbon atom to which they are attached, can form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring.
  • R 11 and Q 11 form a 3- to 8-membered alicyclic ring or a 4- to 7-membered saturated heterocyclic ring
  • the 3- to 8-membered alicyclic ring is preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring
  • the 4- to 7-membered saturated heterocyclic ring is preferably a tetrahydrofuran ring or a tetrahydropyran ring.
  • R 11 and M 11 when core 11 is ⁇ -amino acid, R 11 and M 11 , together with the carbon atom to which R 11 is attached and the carbon atom to which M 11 is attached, can form a 3- to 8-membered alicyclic ring.
  • the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.
  • M 11 when core 11 is ⁇ -amino acid, M 11 is hydrogen except when R 11 and M 11 form a 3- to 8-membered alicyclic ring.
  • P 11 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy, amino (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino, each of which is optionally substituted with halogen), and aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • P 11 is preferably hydrogen or C 1 -C 6 alkyl. Specific examples of such P 11 include hydrogen, methyl, ethyl, and n-propyl.
  • Q 11 is hydrogen or C 1 -C 6 alkyl, and preferably hydrogen.
  • R 11 is preferably —CONR 11A R 11B , wherein R 11A and R 11B are each independently hydrogen or C 1 -C 6 alkyl (preferably methyl), or R 11A and R 11B , together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic ring.
  • the 4- to 8-membered saturated heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms (preferably fluorine), one or more oxo groups, one or more C 1 -C 6 alkyl groups (preferably C 1 -C 4 alkyl), and 4- to 7-membered heterocyclyl (preferably oxetan-3-yl).
  • one or more halogen atoms preferably fluorine
  • one or more oxo groups preferably C 1 -C 6 alkyl groups (preferably C 1 -C 4 alkyl)
  • 4- to 7-membered heterocyclyl preferably oxetan-3-yl
  • core 11 is ⁇ -amino acid
  • specific examples of core 11 include MeSer(tBuOH), MeGly, MePhe, MePhe(3-F), MePhe(4-F), and D-MePhe.
  • core 11 When core 11 is ⁇ -amino acid, specific examples of core 11 include bAla, bMeAla, 2-ACHxC, 2-ACPnC, 3-CF3-bAla, Asp-mor, Asp-mor(26-bicyc), Asp-mor(SO2), Asp-NMe2, Asp-oxz, Asp-pip, Asp-pip(345-F6), Asp-pip(4-Me), Asp-pip-tBu, Asp-piz(oxe), Asp-pyrro, Asp-pyrro(34-F4), Asp-pyrro(3-Me2), D-(Propargyl)Gly-(C#CH2), D-3-Abu, D-3-MeAbu, D-Gly(Allyl)-(C#CH2), D-Hph-(C#CH2), D-Leu-(C#CH2), D-MeAsp-pyrr
  • L 11 is —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m , or —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • specific examples of core 11 include MeCys(AcOH)—NMe2.
  • At least three of P 1 to P 11 are not hydrogen.
  • At least three, at least four, at least five, or at least six of P 1 to P 11 are preferably C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is preferably methyl or ethyl.
  • the present invention can be a compound having formula (1) wherein one of —CO-L 1 - and —CO-L 11 -is replaced with —(CH 2 ) n C ⁇ CCH 2 S(CH 2 ) m —, —(CH 2 ) n CH ⁇ CHCH 2 S(CH 2 ) m —, or —(CH 2 ) n+3 S(CH 2 ) m —, wherein n is 1, 2, or 3, and m is 1 or 2.
  • —S— may be oxidized to be —S(O)— or —S(O) 2 —.
  • L 11 is a single bond
  • L 1 is a single bond
  • Groups other than L 1 and L 11 in formula (1) are as described above.
  • the present invention relates to a cyclic peptide compound represented by formula (1′) below or a salt thereof, or a solvate thereof.
  • L 11 is —CHM 1 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —,
  • n and m are each independently 1 or 2
  • R 2 to R 11 , P 2 to P 11 , Q 2 to Q 11 , and M 1 are the same as the definitions of R 2 to R 11 , P 2 to P 11 , Q 2 to Q 11 , and M 11 in formula (1), respectively.
  • the ring is composed of 10 amino acid residues.
  • the amino acid residue having P 2 , Q 2 , and R 2 in the formula may be referred to as core 2, the amino acid residue having P 3 , Q 3 , and R 3 as core 3, the amino acid residue having P 4 , Q 4 , and R 4 as core 4, the amino acid residue having P 5 , Q 5 , and R 5 as core 5, the amino acid residue having P 6 , Q 6 , and R 6 as core 6, the amino acid residue having P 7 , Q 7 , and R 7 as core 7, the amino acid residue having P 8 , Q 8 , and R 8 as core 8, the amino acid residue having P 9 , Q 9 , and R 9 as core 9, the amino acid residue having P 10 , Q 10 , and R 10 as core 10, and the amino acid residue having P 1 , Q 11 , R 11 , and L 11 as core 11.
  • L 11 is —CHM 11 -, —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m —, or —(CH 2 ) n S(O) 2 (CH 2 ) m —.
  • M 11 is the same as M 11 in formula (1).
  • M 11 can be hydrogen, or M 11 can, together with R 11 , the carbon atom to which R 11 is attached, and the carbon atom to which M 11 is attached, form a 3- to 8-membered alicyclic ring.
  • the 3- to 8-membered alicyclic ring is preferably a cyclopentane ring or a cyclohexane ring.
  • —(CH 2 ) n S(CH 2 ) m — specific examples include —CH 2 SCH 2 —, —CH 2 CH 2 SCH 2 —, —CH 2 SCH 2 CH 2 —, and —CH 2 CH 2 SCH 2 CH 2 —.
  • L 11 is —(CH 2 ) n S(O)(CH 2 ) m —
  • specific examples of —(CH 2 ) n S(O)(CH 2 ) m — include —CH 2 S(O)CH 2 —, —CH 2 CH 2 S(O)CH 2 —, —CH 2 S(O)CH 2 CH 2 —, and —CH 2 CH 2 S(O)CH 2 CH 2 —.
  • L 11 is —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • specific examples of —(CH 2 ) n S(O) 2 (CH 2 ) m — include —CH 2 S(O) 2 CH 2 —, —CH 2 CH 2 S(O) 2 CH 2 —, —CH 2 S(O) 2 CH 2 CH 2 —, and —CH 2 CH 2 S(O) 2 CH 2 CH 2 —.
  • R 11 is preferably aminocarbonyl (wherein the amino is —NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or 4- to 8-membered cyclic amino).
  • R 11 is more preferably —CONR 11A R 11B , wherein R 11A and R 11B are each independently hydrogen or C 1 -C 6 alkyl (preferably methyl), or R 11A and R 11B , together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic ring.
  • the 4- to 8-membered saturated heterocyclic ring is optionally substituted with one or more groups independently selected from the group consisting of one or more halogen atoms (preferably fluorine atom(s)), one or more oxo groups, one or more C 1 -C 6 alkyl groups (preferably C 1 -C 4 alkyl group(s)), and 4- to 7-membered heterocyclyl (preferably oxetan-3-yl).
  • R 11 include dimethylaminocarbonyl.
  • Q 11 is preferably hydrogen or C 1 -C 6 alkyl, and more preferably hydrogen.
  • P 11 is preferably hydrogen or C 1 -C 6 alkyl. Specific examples of such P 11 include hydrogen, methyl, ethyl, and n-propyl.
  • L 11 is —(CH 2 ) n S(CH 2 ) m —, —(CH 2 ) n S(O)(CH 2 ) m , or —(CH 2 ) n S(O) 2 (CH 2 ) m —
  • specific examples of core 11 include MeCys(AcOH)—NMe2.
  • Preferable groups in each of cores 2 to 11 in formula (1′) may be the same as the preferable groups in each corresponding core in formula (1). Further, the specific amino acids listed above as cores 2 to 11 of formula (1) can be used as amino acids of each corresponding core of formula (1′).
  • cyclic peptide compound represented by formula (1′) include the following:
  • the present invention can be a cyclic peptide compound represented by formula (2) below that further specifies formula (1) above.
  • each group in formula (2) is the same as the definition of each group in formula (1).
  • the cyclic peptide compound represented by formula (2) preferably has each of the following groups.
  • R 1 is C 1 -C 6 alkyl (preferably C 1 -C 4 alkyl, and more preferably methyl or 2-methylpropyl), and P 1 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 2 is C 1 -C 6 alkyl (preferably C 3 -C 6 alkyl, and more preferably 1-methylpropyl), and P 2 is hydrogen or C 1 -C 6 alkyl (preferably hydrogen or C 1 -C 3 alkyl, and more preferably hydrogen or methyl), and/or
  • R 3 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and P 3 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 4 is hydrogen, and P 4 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), or R 4 and P 4 , together with the carbon atom to which R 4 is attached and the nitrogen atom to which P 4 is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably, an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably an azetidine ring or a pyrrolidine ring), and/or
  • R 5 is C 1 -C 6 alkoxyC 1 -C 6 alkyl (preferably C 2 -C 6 alkoxy C 1 -C 2 alkyl, and more preferably C 3 -C 5 alkoxymethyl); C 7 -C 14 aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with a group independently selected from the group consisting of halogen (preferably fluorine or chlorine), C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), C 1 -C 6 haloalkyl (preferably C 1 -C 3 fluoroalkyl, and more preferably trifluoromethyl), and C 1 -C 6 alkoxy (preferably C 1 -C 3 alkoxy, and more preferably methoxy); C 3 -C 8 cycloalkyl (preferably C 3 -C 6 cycloalkyl, and more preferably C 5 -C 6 cycloal
  • R 6 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and P 6 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl or ethyl), or R 6 and P 6 , together with the carbon atom to which R 6 is attached and the nitrogen atom to which P 6 is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably, an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably a pyrrolidine ring), and/or
  • R 7 is C 7 -C 14 aralkyl (preferably benzyl or phenethyl) optionally substituted with 1 to 5 (preferably 1 to 3) groups independently selected from the group consisting of halogen (preferably fluorine, chlorine, or iodine) and C 1 -C 6 haloalkyl (preferably C 1 -C 3 fluoroalkyl, and more preferably trifluoromethyl), P 7 is hydrogen, and Q 7 is hydrogen, and/or
  • R 8 is C 1 -C 6 alkyl (preferably C 1 -C 4 alkyl, and more preferably 2-methylpropyl, isopropyl, or n-butyl), C 2 -C 6 alkynyl (preferably C 2 -C 3 alkynyl, and more preferably propargyl), 4- to 8-membered cyclic aminocarbonylC 1 -C 6 alkyl (preferably 4- to 8-membered cyclic aminocarbonylC 1 -C 2 alkyl, and more preferably 4- to 8-membered cyclic aminocarbonylmethyl) optionally substituted with 1 to 5 (preferably 1 to 3) fluorine atoms, 5- to 10-membered heteroarylC 1 -C 6 alkyl (preferably 5- to 10-membered heteroarylC 1 -C 2 alkyl, and more preferably 5- to 10-membered heteroarylmethyl), or C 7 -C 14 aralkyl (preferably benzyl or phenethyl) optionally
  • R 9 is benzyl, and Q 9 is hydrogen; or R 9 and Q 9 are each independently C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), or R 9 and Q 9 , together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring (preferably a 3- to 6-membered alicyclic ring, more preferably a cyclobutane ring or a cyclopentane ring), and P 9 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 10 is C 1 -C 6 alkyl (preferably C 1 -C 4 alkyl, and more preferably isopropyl, 1-methylpropyl, or 2-methylpropyl) or C 3 -C 8 cycloalkyl (preferably C 3 -C 6 cycloalkyl, and more preferably cyclopentyl or cyclohexyl), and P 10 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 11 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), di-C 1 -C 6 alkylaminocarbonyl (preferably di-C 1 -C 3 alkylaminocarbonyl, and more preferably dimethylaminocarbonyl), or 4- to 8-membered cyclic aminocarbonyl (preferably azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, 4-morpholinylcarbonyl, or 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl), P 11 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and M 11 is hydrogen.
  • the present invention can be a cyclic peptide compound represented by formula (3) below that further specifies formula (1) above.
  • each group in formula (3) is the same as the definition of each group in formula (1).
  • the cyclic peptide compound represented by formula (3) preferably has each of the following groups.
  • R 1 is hydrogen
  • P 1 is hydrogen or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl)
  • M 1 is hydrogen
  • R 2 is hydrogen or C 1 -C 6 alkyl (preferably C 3 -C 6 alkyl, and more preferably 1-methylpropyl), and P 2 is hydrogen or C 1 -C 6 alkyl (preferably hydrogen or C 1 -C 3 alkyl, and more preferably hydrogen or methyl), and/or
  • R 3 is hydrogen, P 3 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 4 is hydrogen
  • P 4 is C 1 -C 6 alkyl (preferably hydrogen or C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 5 is C 3 -C 8 cycloalkylC 1 -C 6 alkyl (preferably C 3 -C 6 cycloalkylC 1 -C 2 alkyl, and more preferably C 5 -C 6 cycloalkylmethyl), and P 5 is C 1 -C 2 alkyl (preferably methyl), and/or
  • R 6 is hydrogen, and P 6 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 7 is C 7 -C 14 aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with 1 to 5 (preferably 1 to 3) groups independently selected from the group consisting of halogen and C 1 -C 6 haloalkyl (preferably C 1 -C 3 fluoroalkyl, and more preferably trifluoromethyl), and P 7 is hydrogen, and Q 7 is hydrogen, and/or
  • R 8 and P 8 together with the carbon atom to which R 8 is attached and the nitrogen atom to which P 8 is attached, form a 4- to 7-membered saturated heterocyclic ring (preferably an azetidine ring, a pyrrolidine ring, or a piperidine ring, and more preferably a pyrrolidine ring), and/or
  • R 9 and Q 9 together with the carbon atom to which they are attached, form a 3- to 8-membered alicyclic ring (preferably a 3- to 6-membered alicyclic ring, and more preferably a cyclobutane ring or a cyclopentane ring), and P 9 is hydrogen, and/or
  • R 10 is C 3 -C 8 cycloalkyl (preferably C 3 -C 6 cycloalkyl, and more preferably cyclopentyl or cyclohexyl), and P 10 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl), and/or
  • R 11 is hydrogen, C 7 -C 14 aralkyl (preferably benzyl or phenethyl, and more preferably benzyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms (preferably fluorine), or C 1 -C 6 alkoxyC 1 -C 6 alkyl (preferably C 2 -C 6 alkoxyC 1 -C 2 alkyl, and more preferably C 3 -C 5 alkoxymethyl) optionally substituted with one hydroxy group, and P 11 is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl, and more preferably methyl).
  • the present invention can be a cyclic peptide compound represented by formula (4) below that further specifies formula (1) above.
  • R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (4) are the same as R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (2) above, respectively, and n and m are each independently 1 or 2.
  • —S— in formula (4) may be oxidized to be —S(O)— or —S(O) 2 —.
  • the present invention can be a cyclic peptide compound represented by formula (5) below that further specifies formula (1) above.
  • R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (5) are the same as R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (2) above, respectively, and n and m are each independently 1 or 2.
  • —S— in formula (5) may be oxidized to be —S(O)— or —S(O) 2 —.
  • the present invention can be formula (6) below wherein —CO-L 1 -in formula (1) above is replaced with —(CH 2 ) n C ⁇ CCH 2 S(CH 2 ) m —, —(CH 2 ) n CH ⁇ CHCH 2 S(CH 2 ) m —, or —(CH 2 ) n+3 S(CH 2 ) m —, and L 11 is a single bond.
  • R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (6) are the same as R 1 to R 11 , P 1 to P 1 , Q 7 , and Q 9 in formula (2) above, respectively,
  • —S— in formula (6) may be oxidized to be —S(O)— or —S(O) 2 —.
  • the present invention can be formula (7) below wherein —CO-L 11 -in formula (1) is replaced with —(CH 2 ) n C ⁇ CCH 2 S(CH 2 ) m —, —(CH 2 ) n CH ⁇ CHCH 2 S(CH 2 ) m —, or —(CH 2 ) n+3 S(CH 2 ) m —, and L 1 is a single bond.
  • R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (7) are the same as R 1 to R 11 , P 1 to P 11 , Q 7 , and Q 9 in formula (2), respectively,
  • —S— in formula (7) may be oxidized to be —S(O)— or —S(O) 2 —.
  • the present invention can be a cyclic peptide compound represented by formula (8) below.
  • R 2 to R 11 , P 2 to P 11 , Q 7 , and Q 9 in formula (8) are the same as R 2 to R 11 , P 2 to P 11 , Q 7 , and Q 9 in the above-mentioned formula (1), respectively, and n and m are each independently 1 or 2. Further, —S— in formula (8) may be oxidized to be —S(O)— or —S(O) 2 —.
  • cyclic peptide compound of the present invention is as follows.
  • the structural formulae of the following compounds (1) to (762), (764) to (845), (847) to (1027), (1029) to (1146), and (1148) to (2186) are shown in Table 24. That is, the numbers given to the following compounds correspond to the numbers given to the compounds shown in Table 24, respectively.
  • the present invention also relates to a non-natural amino acid for use in the production of the cyclic peptide compound of the present invention.
  • the non-natural amino acid of the present invention is an N-protected non-natural amino acid for use in the production of the peptide compound using a solid-phase synthesis method
  • the non-natural amino acid of the present invention is a non-natural amino acid having a free amino group obtained by removing the protecting group from the N-protected non-natural amino acid.
  • Examples of the protecting group of the N-protected non-natural amino acid include an Fmoc group, a Boc group, a Cbz group, an Alloc group, a nosyl group, a dinitronosyl group, a t-Bu group, a trityl group, and a cumyl group.
  • an Fmoc group, a Boc group, a Cbz group, and an Alloc group are preferable, and an Fmoc group is more preferable.
  • N-protected non-natural amino acid having an Fmoc group as a protecting group include the following amino acids.
  • Examples of chemical synthesis methods for the peptide compounds or the cyclic peptide compounds herein include a liquid-phase synthesis method, a solid-phase synthesis method using Fmoc synthesis, Boc synthesis, or the like, and a combination thereof.
  • Fmoc synthesis a basic unit is an amino acid in which a main-chain amino group is protected with an Fmoc group, and a side-chain functional group is protected as necessary with piperidine or a protecting group that is not cleaved by a base, such as a t-Bu group, a THP group, or a Trt group, and a main-chain carboxylic acid is not protected.
  • the basic unit is not particularly limited as long as it is a combination having an Fmoc-protected amino group and a carboxyl group.
  • dipeptide may be a basic unit.
  • the basic unit disposed at the N terminus may be a unit other than the Fmoc amino acid.
  • it may be a Boc amino acid or a carboxylic acid analog which does not have an amino group.
  • the main-chain carboxyl group, or a side-chain carboxyl group of an amino acid that has a carboxyl group in a side chain and in which the main-chain carboxyl group is protected with a suitable protecting group, is supported on a solid phase by a chemical reaction with the functional group of a solid-phase carrier.
  • the Fmoc group is deprotected by a base such as piperidine or DBU, and a newly produced amino group and a subsequently added, basic-unit protected amino acid having a carboxyl group are subjected to a condensation reaction to produce a peptide bond.
  • a base such as piperidine or DBU
  • various combinations such as a combination of DIC and HOBt, a combination of DIC and HOAt, and a combination of HATU and DIPEA are possible as activating agents for the carboxyl group.
  • the desired peptide sequence can be produced by repeating the Fmoc group deprotection and the subsequent peptide bond forming reaction.
  • cleavage from the solid phase and deprotection of the optionally introduced protecting group of the side-chain functional group are conducted. Further, conformational conversion and cyclization of the peptide can be performed before cleaving from the solid phase. Cleaving from the solid phase and deprotection may be performed under the same conditions, e.g., in 90:10 TFA/H 2 O, or deprotection may be performed under different conditions as necessary. Cleaving from the solid phase may be achieved using a weak acid such as 1% TFA in some cases, and Pd or the like may be used as a protecting group to utilize the orthogonality of both chemical reactions. During or at the end of these steps, a step such as cyclization can also be performed.
  • a side-chain carboxylic acid and an N-terminal main-chain amino group can be condensed, and a side-chain amino group and a C-terminal main-chain carboxylic acid can be condensed.
  • reaction orthogonality is required between the carboxylic acid on the C-terminal side and the side-chain carboxylic acid to be cyclized, or between the main-chain amino group or hydroxy group on the N-terminal side and the side-chain amino group to be cyclized.
  • the protecting group is selected in consideration of the orthogonality of the protecting group.
  • the reaction product thus obtained can be purified by a reverse-phase column, a molecular sieve column, or the like. Details of these procedures are described in, for example, the Solid-Phase Synthesis Handbook published by Merck on May 1, 2002. Commercially available resins for solid phase synthesis are usable, and examples include CTC resin, Wang resin, and SASRIN resin.
  • An Fmoc amino acid can be supported on a resin by the method described in WO2013/100132 or WO2018/225864. Specifically, for example, 2-chlorotrityl chloride resin and a solvent (e.g., dehydrated dichloromethane) are introduced into a filter-equipped reaction vessel to swell the resin.
  • a solvent e.g., dehydrated dichloromethane
  • the solvent and the resin are separated, and then a mixture of the resin, a C-terminal free Fmoc amino acid dissolved in a solvent (e.g., dehydrated dichloromethane), a solvent (e.g., dehydrated methanol), and a base (e.g., diisopropylethylamine) is added to the reaction vessel and mixed to support the Fmoc amino acid on the resin.
  • a solvent e.g., dehydrated dichloromethane
  • a base e.g., diisopropylethylamine
  • n represents an integer of 1 to 11; P 1 to P 11 , Q 1 to Q 11 , and R 1 to R 11 mean P 1 to P 11 , Q 1 to Q 11 , and R 1 to R 11 as defined herein, respectively; L 1 and L 11 mean L 1 and L 11 as described herein, respectively; L 2 to L 10 are single bonds; and ⁇ (circle) means a resin portion.
  • the above structure shows that in the Fmoc-amino acid, the 2-chlorotrityl group on the resin is bonded to the carboxylic acid of the Fmoc amino acid via an ester bond.
  • the compound described herein when the defined group undergoes undesired chemical conversion under the conditions of the performed method, the compound can be produced by means of, for example, protection and deprotection of a functional group.
  • Selection and introduction/removal procedures of a protecting group can be performed according to, for example, the methods described in Greene's “Protective Groups in Organic Synthesis” (5th Ed., John Wiley & Sons, 2014), which may be suitably used depending on the reaction conditions. Further, the order of reaction steps such as introduction of a substituent can be changed as necessary.
  • the protecting group for an amino group is an Fmoc, Boc, Cbz, or Alloc group.
  • carbamate groups can be introduced by reacting an amino group with a carbamating agent in the presence of a basic catalyst.
  • a carbamating agent include Boc 2 O, BocOPh, FmocOSu, FmocCl, CbzCl, and AllocCl.
  • the basic catalyst include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, and N,N-dimethylaminopyridine.
  • a carbamate group which is a protecting group for an amino group can be removed under basic conditions, acidic conditions, hydrogenolysis reaction conditions, or the like.
  • a method for transforming a linear peptide compound into a cyclic peptide compound can be performed by carrying out a bond forming reaction within the molecule according to, for example, the method described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition by R. C. Larock, or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition by M. B. March. After the bond forming reaction, further, a functional group transforming reaction can also be performed.
  • Examples of the bond forming reaction include a C(O)—N bond formed from carboxylic acid and amine; a C—O—C bond, a C(O)—O bond, and a C(S)—O bond using an oxygen atom; a C(O)—S bond, a C(S)—S bond, a C—S—S—C bond, a C—S—C bond, a C—S(O)—C bond, and a C—S(O 2 )—C bond using a sulfur atom; and a C—N—C bond, a C ⁇ N—C bond, an N—C(O)—N bond, an N—C(S)N bond, and a C(S)—N bond using a nitrogen atom.
  • examples include C—C bond forming reactions catalyzed by a transition metal, such as Suzuki reaction, Heck reaction, and Sonogashira reaction.
  • Examples of the functional group transforming reaction further performed after the bond forming reaction include an oxidation reaction and a reduction reaction.
  • a specific example is a reaction for oxidizing a sulfur atom to transform it into a sulfoxide group or a sulfone group.
  • Another example is a reduction reaction for reducing a triple bond or a double bond of carbon-carbon bonds to a double bond or a single bond.
  • a covalent bond between two amino acids may be formed by bonding between side chains of two amino acids, bonding between a side chain and a main chain, or the like.
  • a black circle or a black square below indicates an amino acid residue, and connected black circles or black squares represent a peptide chain connected by an amide bond.
  • the number of amino acid residues constituting a peptide chain are not particularly limited, and the number of black circles or black squares below does not represent the number of amino acid residues.
  • a peptide compound having a cyclic moiety may be referred to as a “cyclic peptide compound”.
  • the “cyclic moiety” of a peptide compound means a cyclic portion formed of two or more connected amino acid residues.
  • L —CH 2 — in the case of aspartic acid or its derivative
  • L —CH 2 CH 2 — in the case of glutamic acid or its derivative
  • L —CH 2 — in the case of aspartic acid or its derivative
  • L —CH 2 CH 2 — in the case of glutamic acid or its derivative
  • Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the haloalkyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the haloalkyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • a C—S(O)—C or C—S(O) 2 —C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone.
  • Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the vinyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the vinyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • a C—S(O)—C or C—S(O) 2 —C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone.
  • Cyclic Moieties of Cyclic Peptide Compounds Having Linear Moieties can be Cyclized by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the ethynyl group of an amino acid residue with the thiol group of an amino acid residue in the molecule to form a C—S—C bond.
  • a C—S(O)—C or C—S(O) 2 —C bond can also be formed by oxidizing and converting a sulfur atom to a sulfoxide or sulfone.
  • the double bond site can also be reduced and converted to a single bond.
  • Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting different vinyl groups of amino acid residues with each other in the molecule to form a C—C bond.
  • Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting different vinyl groups of amino acid residues with each other in the molecule to form a C—C bond.
  • Cyclic moieties of cyclic peptide compounds having linear moieties can be cyclized by reacting the azido group of an amino acid residue with the ethynyl group of an amino acid residue in the molecule to form a triazole ring.
  • Cyclic peptide compounds described in “General preparation method 1 for cyclic peptide compounds” in which the linear moiety is C-Term can also be similarly cyclized by reacting the azido group of an amino acid residue with the ethynyl group of an amino acid residue in the molecule to form a triazole ring.
  • P n represents a substituent for a nitrogen atom
  • R n and Q n each represent an amino acid side chain
  • a black circle represents an amino acid residue
  • linked black circles represent a peptide chain linked by amide bonds
  • m represents the number of amino acid residues and may be any integer of 1 or more.
  • Peptides containing N-alkylamino acids can be synthesized according to the general peptide synthesis method described in the present Examples using an Fmoc-protected N-alkylamino acid as a raw material, or alternatively can be prepared by alkylating the N-terminal nitrogen on a resin as illustrated below.
  • the target peptides having an N-alkylamino acid at the N-terminus can be prepared by reacting the nitrogen of the N-terminal Tfa amide (trifluoroacetamide) of a resin-loaded peptide with an alkyl halide under basic conditions, and then treating the peptide with a reducing agent by referring to Organic Letters, 2008, 10, 4815-4818 or the like.
  • cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.
  • the method described in Nature Protocols, 2012, 7, 432-444 which is shown below can also be used as another method of introducing P n onto the N-terminal nitrogen.
  • the target peptides having P n at the N-terminus can be obtained by converting the N-terminal amine of a resin-loaded peptide to an Ns-substituted form, introducing P n by Mitsunobu reaction, and then deprotecting the Ns group.
  • cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.
  • Peptides containing glycine with P n introduced onto the nitrogen atom can be synthesized according to the general peptide synthesis method described in the present Examples using glycine with P n introduced onto the Fmoc-protected nitrogen atom as a raw material, or alternatively can be prepared by substitution reaction between the N-terminal halogenated carbon and an amine as illustrated below.
  • the target peptides having N-terminal glycine with P n introduced onto the nitrogen atom can be obtained by reacting the N-terminal amine with iodoacetic acid and then reacting it with any primary amine by referring to Organic Letters, 2010, 12, 4928-4931 or the like.
  • cyclic peptide compounds can be prepared by elongating, cleaving from the resin, cyclizing, deprotecting, and purifying the peptide according to the general peptide synthesis method described in the present Examples.
  • Peptides containing an aryloxy or heteroaryloxy group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target aryloxy or heteroaryloxy group on the side chain as a raw material, or alternatively can be prepared using a peptide having an alcohol on the side chain as a precursor by referring to Organic Letters, 2014, 16, 4944-4947, Tetrahedron Letters, 2003, 44, 3863-3865, or the like, as illustrated below.
  • peptides having an aryloxy or heteroaryloxy group on the side chain can be prepared by reacting a peptide having an alcohol on the side chain with triarylboroxane-pyridine complex in the presence of copper(II) acetate.
  • n represents the number of methylene groups and may be any integer of 1 or more.
  • Peptides having an ether group excluding an aryloxy or heteroaryloxy group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target ether group on the side chain as a raw material, or alternatively can be prepared using a peptide having an alcohol on the side chain as a precursor by referring to the method described in Journal of Medicinal Chemistry, 2011, 54, 4815-4830 or Journal of Medicinal Chemistry, 2014, 57, 159-170, as illustrated below.
  • the peptides having the target ether group on the side chain can be prepared by reacting a peptide having an alcohol with an etherification agent (such as an alkyl halide) in the presence of silver(I) oxide, or by reacting a peptide having an alcohol with an etherification agent (such as an alkyl halide) using an aqueous sodium hydroxide solution as a base in the presence of a phase transfer catalyst such as a tetraalkylammonium salt.
  • an etherification agent such as an alkyl halide
  • an etherification agent such as an alkyl halide
  • Peptides having an aryl or heteroaryl group on the side chain can be prepared according to the general peptide synthesis method described in the present Examples using an Fmoc amino acid having the target aryl or heteroaryl group on the side chain as a raw material, or alternatively can be prepared using a peptide having a carboxylic acid on the side chain as a precursor by referring to the method described in J. Am. Chem. Soc., 2016, 138, 5016-5019 or the like, as illustrated below.
  • the peptides having the target aryl or heteroaryl group on the side chain can be prepared by activating a peptide having a carboxylic acid on the side chain with N-hydroxyphthalimide, and reacting it with any aryl halide or heteroaryl halide.
  • n represents the number of methylene groups and may be any integer of 1 or more.
  • peptides having an aryl or heteroaryl group on the side chain can also be synthesized by Suzuki coupling using a peptide having a boronic acid on the side chain as a precursor, as illustrated below.
  • the target peptides having an aromatic ring on the side chain can be prepared by synthesizing a precursor peptide using an Fmoc amino acid having a boronic acid on the side chain as a raw material, and reacting it with any aryl halide in the presence of a palladium catalyst.
  • Peptides having an amido group on the side chain can be synthesized using an Fmoc amino acid having the target amido group on the side chain as a raw material, or alternatively can be synthesized by amidation of a peptide having a carboxylic acid on the side chain as a precursor, as illustrated below.
  • the target peptides having an amido group on the side chain can be obtained by deprotecting a peptide having a protected carboxylic acid on the side chain to synthesize a precursor peptide having a carboxylic acid on the side chain, and condensing it with any amine using a condensing agent such as HATU.
  • n below represents the number of methylene groups and may be any integer of 1 or more.
  • Peptides having a double bond on the side chain can be synthesized using an Fmoc amino acid having the target double bond on the side chain as a raw material, or alternatively can be prepared by functionalization of a terminal olefin.
  • a peptide having a terminal olefin on the side chain can be synthesized according to the general peptide synthesis method described in the present Examples, and the side chain can be further converted to a side chain having a highly substituted olefin by coupling with a substrate having any terminal olefin by olefin metathesis reaction. Further, the side chain can be converted to a corresponding side chain by reducing the olefin by hydrogenation reaction.
  • n below represents the number of methylene groups and may be any integer of 1 or more.
  • Peptide compounds with a peptide backbone crosslinked can also be prepared using a peptide having multiple double bonds on the side chain.
  • crosslinked compounds can be prepared by synthesizing a peptide having terminal olefins at two sites on the side chain according to the general peptide synthesis method described in the present Examples, and further crosslinking the two olefins by olefin metathesis reaction by referring to Nature Protocols, 2011, 6, 761-771.
  • compounds crosslinked with saturated alkylenes can be prepared by reducing the olefins by hydrogenation reaction.
  • m and n below represent the number of methylene groups and may be independently any integer of 1 or more.
  • Peptides having a triazole on the side chain can be prepared by click reaction with an azido group.
  • peptide compounds having an azido group on the side chain can be prepared by synthesizing a peptide having an azido group on the side chain according to the general peptide synthesis method described in the present Examples, and coupling the peptide with any acetylene in the presence of copper(I) iodide by referring to Bioorganic & Medicinal Chemistry Letters, 2009, 19, 4130-4133 or the like.
  • n below represents the number of methylene groups and may be any integer of 1 or more.
  • Peptides containing an aryl group substituted with an alkynyl group on the side chain can be synthesized by Sonogashira coupling reaction with an aryl halide group.
  • the conversion to peptide compounds having an aryl group substituted with an alkynyl group on the side chain can be conducted by synthesizing a peptide having an aryl iodide group on the side chain according to the general peptide synthesis method described in the present Examples, and coupling the peptide with any acetylene in the presence of copper(I) iodide.
  • n below represents the number of methylene groups and may be any integer of 1 or more.
  • PG 1 and PG 1 ′ each represent a protecting group for a nitrogen atom
  • PG 2 and PG 2 ′ each represent a protecting group for an oxygen atom
  • PG 3 and PG 4 each represent a protecting group for an amino acid side chain
  • R n and Q n each represent an amino acid side chain
  • P n represents a substituent for a nitrogen atom
  • P′ represents C 1 -C 5 alkyl
  • R, R′, R′′, and R′′′ each represent a substituent for a hydrogen or amino group.
  • a functional group other than the target functional group may cause chemical reaction.
  • only the desired reaction can be allowed to proceed by introducing a protecting group onto a non-target functional group.
  • protecting group introduction and removal reactions include methods described in Greene's “Protective Groups in Organic Synthesis” (5th ed., John Wiley & Sons 2014).
  • For conversion reactions of compound functional groups one can refer to Larock's “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” (5th ed.) or Smith's “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (8th ed.).
  • Non-natural amino acids having a protecting group (PG 1 ) introduced onto the amino acid nitrogen atom can be prepared using the following method.
  • the target C-terminal-free non-natural amino acids can be prepared by introducing a protecting group onto an N-terminal-free amino acid available from a commercial supplier and deprotecting it as necessary according to conventional methods.
  • Non-natural amino acids having a protecting group (PG 1 ′) introduced onto the amino acid nitrogen atom can be prepared using the following method.
  • the target C-terminal-free non-natural amino acids can be prepared by deprotecting an amino acid that has a protecting group (PG 1 ) introduced onto the N-terminus which is available from a commercial supplier, and introducing a protecting group, according to conventional methods.
  • Non-natural amino acids having an aminoalkyl group introduced onto the substituent (Pa) of the amino acid nitrogen atom can be prepared using the following method.
  • a bromoacetic acid ester derivative available from a commercial supplier is reacted with an amino alcohol according to the method of King et al. (Tetrahedron Letters, 2002, 43(11), 1987-1990), and then a protecting group (PG 1 ) is introduced onto the nitrogen atom.
  • the hydroxyl group is oxidized according to the method of Dess et al. (J. Org. Chem., 1983, 48(22), 4155-4156), and the aldehyde group is reductively aminated according to the method of Borch et al. (J. Org. Chem. 1972, 37(10), 1673-1674) to introduce an amino group.
  • the target C-terminal-free non-natural amino acid can be prepared by deprotecting the protecting group for the oxygen atom.
  • N-substituted amino acids can also be prepared by the following scheme of introducing a substituent (P n ) onto the amino acid nitrogen atom.
  • P n a substituent
  • a bromoacetic acid ester derivative available from a commercial supplier is reacted with an amine (P n NH 2 ) in the presence of a base, and then a protecting group (PG 1 ) is introduced onto the nitrogen atom.
  • PG 1 protecting group
  • the target C-terminal-free non-natural amino acid can be prepared by deprotecting the protecting group for the oxygen atom.
  • Non-natural amino acids having a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • An oxazolidinone compound having an introduced cyclic protecting group can be obtained by allowing an aldehyde to act on a C-terminal-free amino acid available from a commercial supplier according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81).
  • the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.
  • Non-natural amino acids having a P n group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • the P n group can be introduced onto a commercially available C-terminal-free amino acid by allowing an alkylating agent (P n —X) to act on it in the presence of a base.
  • P n —X alkylating agent
  • a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.
  • Non-natural amino acids having an amido group introduced onto the amino acid side chain can be prepared according to the following scheme.
  • a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.
  • Non-natural amino acids having an amido group introduced onto the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • an amide compound can be obtained by deprotecting the side-chain protecting group and then allowing an amine (R′′R′′′NH) to act on it.
  • the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.
  • Non-natural amino acids having an amino group introduced onto the amino acid side chain can be prepared according to the following scheme.
  • a C-terminal-free non-natural amino acid can be prepared by conducting reduction reaction according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52) and then deprotecting the C-terminal protecting group.
  • Non-natural amino acids having an amino group introduced onto the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • the target C-terminal-free non-natural amino acid can be prepared by conducting reduction reaction according to the method of Reeves et al. (Advanced Synthesis & Catalysis, 2013, 355(1), 47-52) and then performing ring-opening reaction.
  • Non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain can be prepared according to the following scheme.
  • a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.
  • Non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • a C-terminal-free non-natural amino acid can be prepared by ring-opening of the C-terminal cyclic protecting group.
  • C-terminal-free non-natural amino acids having a fluoroalkyl group introduced onto the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can also be prepared by the method shown below.
  • Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain can be prepared according to the following scheme.
  • a non-natural amino acid having an aryl or heteroaryl group introduced and possessing an aralkyl or heteroaralkyl group on the side chain can be prepared by allowing an aryl halide or heteroaryl halide to react according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019).
  • a C-terminal-free non-natural amino acid can be prepared by deprotecting the C-terminal protecting group.
  • Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain and having a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • a non-natural amino acid which has an aryl or heteroaryl group introduced, and has an aralkyl or heteroarylalkyl group on the side chain, and is protected by a cyclic protecting group can be prepared by allowing an aryl halide or heteroaryl halide to react according to the method of Huihui et al. (J. Am. Chem. Soc., 2016, 138(15), 5016-5019).
  • the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.
  • Non-natural amino acids having an aryl or heteroaryl group (such groups are referred to as “Ar” in the scheme) introduced onto the amino acid side chain can be prepared according to the following scheme.
  • the target C-terminal-free non-natural amino acid can be prepared by deprotection reaction and protecting group introduction reaction.
  • Non-natural amino acids having a halogen atom introduced onto the aralkyl group on the amino acid side chain can be prepared according to the following scheme.
  • a halogen atom can be introduced onto the introduced boryl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235).
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.
  • Non-natural amino acids having a halogen atom introduced onto the aralkyl group of the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • a halogen atom can be introduced onto the introduced boryl group using N-halosuccinimide according to the method of Lindner et al. (Chem. Eur. J., 2016, 22, 13218-13235).
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.
  • Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (R b O) group on the amino acid side chain can be prepared according to the following scheme.
  • a cyclized compound can be obtained according to the method of Mitsunobu et al. (Synthesis, 1981, 1,1-28) after introducing a nosyl (Ns) group onto a commercially available serine derivative according to a conventional method.
  • a serine ether compound can be obtained by ring-opening of the cyclized compound with a suitable alcohol (R b OH) in the presence of a Lewis acid such as BF 3 .OEt 2 .
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.
  • Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (R b O) group on the amino acid side chain can be prepared according to the following scheme.
  • a serine ether compound can be obtained by ring-opening of a commercially available cyclic compound with a suitable alcohol (R b OH) in the presence of a Lewis acid such as BF 3 .OEt 2 according to a conventional method.
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from the obtained non-natural amino acid as necessary.
  • Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (—OR b ) group on the amino acid side chain can be prepared according to the following scheme.
  • R b has a further convertible functional group
  • R b can be converted to a target functional group by additional functional group conversion. Examples of such additional functional group conversion include multiple bond reduction reaction.
  • the target C-terminal-free non-natural amino acid can be prepared by deprotecting the obtained non-natural amino acid.
  • Non-natural amino acids having an optionally substituted alkoxy or aralkoxy (—OR b ) group on the amino acid side chain and having a group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction.
  • Non-natural amino acids having a protected hydroxy group on the amino acid side chain can be prepared according to the following scheme.
  • Non-natural amino acids having a protected hydroxy group on the amino acid side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • the target C-terminal-free non-natural amino acid can be prepared by ring-opening reaction and protecting group introduction reaction.
  • Cyclic non-natural amino acids having a substituent (R c ) introduced onto the hydroxyl group of the cyclic amino acid can be prepared according to the following scheme.
  • the hydroxy group of a commercially available cyclic amino acid can be converted to the target —OR c group by appropriately introducing a functional group.
  • an ether bond can be produced by allowing an alkylating agent (R c —X) to react in the presence of a suitable base according to the method of Williamson et al. (Liebigs Ann. Chem. 1851, 77, 37-49).
  • R c has a further convertible functional group
  • R c can be converted to a target functional group by additional functional group conversion.
  • the target C-terminal-free non-natural amino acid can be prepared by deprotection reaction.
  • Cyclic non-natural amino acids having a protecting group (PG 3 ) introduced onto the hydroxyl group of the cyclic amino acid can be prepared according to the following scheme.
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing/removing a protecting group onto/from a commercially available cyclic amino acid.
  • Non-natural amino acids having a boronic acid introduced onto the amino acid side chain can be prepared according to the following scheme.
  • a non-natural amino acid having a boronic acid ester introduced can be obtained by allowing an aldehyde to act on a commercially available glycine derivative according to the method of Lee et al. (Bioorg. Med. Chem. Lett., 2009, 19(17), 4887-5274).
  • the target C-terminal-free non-natural amino acid can be prepared by appropriately introducing or removing a protecting group.
  • Fmoc non-natural amino acids having a carboxyl group on the side chain can be prepared according to the following scheme.
  • the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG 3 .
  • Fmoc non-natural amino acids having a carboxyl group on the side chain and a —CH 2 —P′ group introduced onto the amino acid nitrogen atom can be prepared according to the following scheme.
  • the target Fmoc non-natural amino acid having a carboxyl group on the side chain can be prepared by deprotecting PG 3 .
  • An amino acid having a protected side chain thiol group was subjected to carboxylic acid amidation, and following deprotection of the thiol group, halogenated acetic acid having a protected carboxylic acid was allowed to react to form a thioether bond.
  • the amino acid having a thioether group on the side chain can be produced by deprotecting the side chain carboxylic acid.
  • Peptides containing a thioether group on the peptide main chain can be produced by using as a raw material the aforementioned amino acid having a thioether group on the side chain, but alternatively, they can also be produced by the method of Roberts et al. in which an N-terminal bromoacetamide is reacted with a cysteine side chain (Tetrahedron Letters, 1998, 39, 8357-8360), or the method of Robey et al. in which an N-terminal chloroacetamide is reacted with a cysteine side chain (Journal of Peptide Research, 2000, 56, 115-120).
  • the compounds of the present invention and salts thereof, and solvates thereof include all stereoisomers (such as enantiomers and diastereomers (including cis and trans geometric isomers)) of the target compounds obtained through the above-described reaction steps, and racemates and other mixtures of such isomers.
  • the compounds of the present invention may have one or more asymmetric points, and the present invention encompasses racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.
  • the compounds according to the present invention When the compounds according to the present invention are obtained as free forms, they can be converted to salts that may be formed by such compounds, or hydrates or solvates thereof, according to conventional methods.
  • the present invention provides pharmaceutical compositions containing the cyclic peptide compounds of the present invention.
  • compositions of the present invention can be formulated by introducing a pharmaceutically acceptable carrier, in addition to the cyclic peptide compound of the present invention, a salt of the cyclic peptide compound, or a solvate thereof by conventional methods.
  • a pharmaceutically acceptable carrier in addition to the cyclic peptide compound of the present invention, a salt of the cyclic peptide compound, or a solvate thereof.
  • Commonly used excipients, binders, lubricants, colorants, correctives, and as necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, and the like can be used for formulation, and they are blended with ingredients generally used as raw materials of pharmaceutical formulations, and formulated by conventional methods.
  • oral formulations are prepared by adding the cyclic peptide compound of the present invention or a salt thereof, and an excipient, and as necessary, a binder, a disintegrant, a lubricant, a colorant, a corrective, and the like, and then formulating them into powder, fine granules, granules, tablets, coated tablets, capsules, and the like by a conventional method.
  • these ingredients include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resin; silicone oil; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene
  • excipients examples include lactose, corn starch, white soft sugar, glucose, mannitol, sorbitol, microcrystalline cellulose, and silicon dioxide.
  • binders examples include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and meglumine.
  • disintegrants examples include starch, agar, gelatin powder, microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium.
  • lubricants examples include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.
  • colorants those approved as additives to pharmaceuticals are used.
  • cocoa powder, peppermint camphor, empasm, mentha oil, borneol, powdered cinnamon bark, and the like are used.
  • these tablets and granules may be sugar-coated or otherwise coated appropriately as necessary.
  • liquid formulations such as syrups and injectable formulations are prepared, they are formulated by adding pH adjusters, solubilizers, tonicity adjusting agents, and the like, and as necessary, solubilizing agents, stabilizers, and the like to the compounds according to the present invention or pharmacologically acceptable salts thereof using conventional methods.
  • the pharmaceutical compositions can be parenterally used in the form of injectable sterile solutions or suspensions with water or other pharmaceutically acceptable liquids.
  • they would be formulated by appropriately combining with pharmacologically acceptable carriers or media, specifically, sterile water, saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, or binders, and blending in unit dosage forms required in generally approved formulation.
  • carriers may include light anhydrous silicic acid, lactose, microcrystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 60, white soft sugar, carboxymethylcellulose, corn starch, and inorganic salts.
  • the amount of the active ingredient in such a formulation is designed to provide a suitable dose within an indicated range.
  • Sterile compositions for injection can be formulated in a conventional formulation manner using a vehicle such as distilled water for injection.
  • Aqueous solutions for injection include, for example, isotonic solutions containing saline, glucose, and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with appropriate solubilizers, for example, alcohols, specifically, ethanol, polyalcohols, e.g., propylene glycol or polyethylene glycol, and nonionic surfactants, e.g., polysorbate 80 (registered trademark) or HCO-50.
  • solubilizers for example, alcohols, specifically, ethanol, polyalcohols, e.g., propylene glycol or polyethylene glycol
  • nonionic surfactants e.g., polysorbate 80 (registered trademark) or HCO-50.
  • Oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate and benzyl alcohol as solubilizers. They may also be blended with buffering agents such as phosphate buffer and sodium acetate buffer; analgesics such as procaine hydrochloride; stabilizers such as benzyl alcohol and phenol; and antioxidants. Prepared injections are usually packed in suitable ampoules.
  • the administration method is preferably oral administration, but is not limited thereto.
  • parenteral administration include dosage forms of injection, nasal administration, pulmonary administration, and transdermal administration.
  • injection dosage forms include systemic or local administration by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc.
  • the administration method can also be selected according to the age and symptom of the patient.
  • the dosage of the pharmaceutical composition containing the peptide compound prepared by the method of the present invention can be selected, for example, in the range of 0.0001 mg to 1000 mg per kg body weight per dose. Alternatively, the dosage can be selected, for example, in the range of 0.001 to 100000 mg/body per patient; however, it is not necessarily limited to such values.
  • the dosage and the administration method vary according to the body weight, the age, the symptom, and the like of the patient, but can be appropriately selected by those skilled in the art.
  • the compounds of the present invention can be used for inhibiting binding between Kras and SOS.
  • the pharmaceutical compositions of the present invention can be used for treating or preventing cancer in a subject.
  • Specific examples of the cancer include pancreatic cancer.
  • subject herein includes mammals, and mammals are preferably humans.
  • Peptides were elongated by the following basic route (also called the basic peptide synthesis method) according to the peptide synthesis method by Fmoc methods described in WO 2013/100132 or WO 2018/225864, specifically, by the following five steps:
  • Fmoc amino acids described in Tables 2 to 5 were used in peptide syntheses described herein using a peptide synthesizer.
  • Fmoc amino acids described in Table 2 were synthesized according to the methods described in WO 2013/100132 or WO 2018/225864.
  • Fmoc amino acids described in Table 3 were purchased from commercial suppliers or synthesized according to the methods described in WO 2018/225864.
  • Fmoc amino acids described in Table 4 were purchased from commercial suppliers.
  • 3-Amino-1-propanol (3.85 g, 51.3 mmol) was dissolved in anhydrous tetrahydrofuran (51.2 ml) under a nitrogen atmosphere and cooled to 0° C., after which a solution of Compound aa001-a (tert-butyl bromoacetate) (5.0 g, 25.6 mmol) in anhydrous tetrahydrofuran (33.3 ml) was added dropwise. The mixture was stirred at 0° C. for 10 min and then stirred at room temperature for one hour.
  • Compound aa002-a (8.59 g, 84%) was obtained by the same method as in the synthesis of Compound aa001-b using Compound aa001-a (tert-butyl bromoacetate) (5.00 g, 25.6 mmol) as a starting material and using 2-aminoethanol instead of 3-amino-1-propanol.
  • Cyclopropylamine (1.756 g, 30.8 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) under a nitrogen atmosphere and cooled to 0° C., after which a solution of Compound aa001-a (tert-butyl bromoacetate) (3.0 g, 15.38 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) was added dropwise. The mixture was then stirred at room temperature overnight.
  • THF tetrahydrofuran
  • Compound aa004 (2-[9H-fluoren-9-ylmethoxycarbonyl(propan-2-yl)amino]acetic acid, Fmoc-iPrGly-OH) (7.0 g, 48% through three steps) was obtained by the same method as in the synthesis of Compound aa003 using Compound aa001-a (tert-butyl bromoacetate) (6.6 g, 33.8 mmol) as a starting material and using sodium carbonate instead of DIPEA as a base for Fmoc addition in the second step.
  • Fmoc-Asp(OAl)—OH ((2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-prop-2-enoxybutanoic acid, CAS No. 146982-24-3) (200 g, 506 mmol), p-toluenesulfonic acid (5.7 g, 0.05 equivalents), and paraformaldehyde (45.6 g, 3 equivalents) were mixed with toluene and the mixture was stirred at 110° C. for 16 hours. The solvent was evaporated from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution twice.
  • phenylsilane (2.01 g, 18.6 mmol) was added dropwise to a mixture of Compound aa033-c (12 g, 26.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.797 mmol) in DCM (110 mL) at room temperature and the mixture was stirred for 40 minutes.
  • NiBr 2 .3H 2 O nickel bromide trihydrate
  • 4,4′-di-tert-butyl-2,2′-bipyridyl 0.282 g, 1.052 mmol
  • Compound aa034-a (0.72 g, 42%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2 g, 3.51 mmol) and 3-bromo-5-methoxypyridine as raw materials.
  • Compound aa035-a (0.49 g, 29.6%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2.0 g, 3.51 mmol) and 3-bromo-5-methylpyridine as raw materials.
  • Compound aa036-a (752 mg, 43.9%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa033-e (1-O-tert-butyl 4-O-(1,3-dioxoisoindol-2-yl) (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]butanedioate) (2 g, 3.51 mmol) and 5-bromo-2-methoxypyridine as raw materials.
  • Compound aa038-b (722 mg, 30%) was obtained by the same method as in the synthesis of Compound aa033-f using Compound aa038-a (2.6 g, 4.67 mmol) and 3,5-dibromopyridine as raw materials.
  • a concentrate of Compound aa038 was obtained by the same method as in the synthesis of Compound aa033 using Compound aa038-b (722 mg, 1.379 mmol).
  • the resulting concentrate was purified by reverse phase chromatography (acetonitrile/distilled water) to give Compound aa038 ((2S)-3-(5-bromopyridin-3-yl)-2-[9H-fluoren-9-ylmethoxycarbonylamino]propanoic acid, Fmoc-Ala(3-Pyr-5-Br)—OH) (300 mg, 40%).
  • Fmoc-Glu-OtBu ((4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid, CAS No. 84793-07-7) (175 g, 411 mmol), N-hydroxyphthalimide (67.1 g, 411 mmol), WSCI—HCl (78.85 g, 411 mmol), and DMAP (2.51 g, 20.6 mmol) were added to DMF (2 L), and the mixture was stirred at room temperature for 16 hours. 1 mol/L aqueous hydrochloric acid was added to the reaction solution, followed by extraction with TBME.
  • NiBr 2 .3H 2 O nickel bromide
  • 4,4′-di-tert-butyl-2,2′-bipyridyl 0.706 g, 2.63 mmol
  • NiBr 2 .3H 2 O nickel bromide
  • 4,4′-di-tert-butyl-2,2′-bipyridyl 0.605 g, 2.26 mmol
  • 4-Bromopyridine hydrochloride (4.39 g, 22.6 mmol) was desalted by dissolving it in toluene (10 mL), a 5N aqueous sodium hydroxide solution (5 mL), and water (5 mL) and an organic layer was prepared as a 4-bromopyridine solution.
  • reaction solution was then diluted with TBME (150 mL), after which the resulting TBME/DMA solution was washed with an aqueous EDTA ⁇ 2Na solution (16 g dissolved in 250 mL of water) and then washed with saturated aqueous sodium carbonate/water (1/1, 80 mL).
  • aqueous EDTA ⁇ 2Na solution (16 g dissolved in 250 mL of water) and then washed with saturated aqueous sodium carbonate/water (1/1, 80 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the fractions were concentrated under reduced pressure to give Compound aa040-a (2.7 g, 78%).
  • Compound aa040-b (2.7 g, quant.) was obtained by the same method as in the synthesis of Compound aa039-c using Compound aa040-a (2.7 g, 5.89 mmol) as a raw material.
  • Compound aa040-c (1.8 g,75%) was obtained by the same method as in the synthesis of Compound aa039-d using Compound aa040-b (2.55 g, 5.81 mmol) as a raw material.
  • Methyl (S)—N-tritylaziridine-2-carboxylate (CAS No. 75154-68-6) (50 g, 146 mmol) was added to a mixed solution of chloroform (145 mL) and methanol (145 mL), trifluoroacetic acid (TFA) (33 mL, 3 equivalents) was added dropwise at 0° C. under a nitrogen atmosphere, and the mixture was stirred for seven hours.
  • TFA trifluoroacetic acid
  • Compound aa042-a was obtained as a crude product by the same method as in the synthesis of Compound aa069-b using Compound aa043 ((2S)-3-cyclobutyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid) (10.61 g, 27.8 mmol) as a starting material.
  • Compound aa043-a (4.54 g, 74.2%) was obtained by the same method as in the synthesis of Compound aa041-b using Compound aa041-a (1-O-(9H-fluoren-9-ylmethyl) 2-O-methyl (2S)-aziridine-1,2-dicarboxylate) (5 g, 15.46 mmol) and cyclobutanol as raw materials.

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WO2019217307A1 (en) 2018-05-07 2019-11-14 Mirati Therapeutics, Inc. Kras g12c inhibitors
EP3908283A4 (en) 2019-01-10 2022-10-12 Mirati Therapeutics, Inc. KRAS G12C INHIBITORS
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MX2022007515A (es) 2019-12-20 2022-09-19 Mirati Therapeutics Inc Inhibidores de sos1.
JPWO2022097540A1 (es) * 2020-11-05 2022-05-12
US20220411462A1 (en) 2021-05-07 2022-12-29 Chugai Seiyaku Kabushiki Kaisha Methods for producing cyclic compounds comprising n-substituted amino acid residues
TW202308679A (zh) * 2021-05-07 2023-03-01 日商中外製藥股份有限公司 包含環狀胜肽化合物的製劑及其製造方法
WO2022234639A1 (ja) 2021-05-07 2022-11-10 中外製薬株式会社 変異型ｒａｓ（ｇ１２ｄ）に対する選択的結合性を示す結合分子
BR112023022875A2 (pt) * 2021-05-07 2024-01-23 Chugai Pharmaceutical Co Ltd Uso farmacêutico de composto peptídico cíclico
CN117279933A (zh) * 2021-05-07 2023-12-22 中外制药株式会社 相对于hras和nras具有选择性kras抑制作用的环状化合物
WO2023005945A1 (zh) * 2021-07-27 2023-02-02 杭州彗搏科技有限公司 一种环肽及其制备方法和应用
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TW202342495A (zh) 2021-12-28 2023-11-01 日商中外製藥股份有限公司 N-烷基胺基酸及含有n-烷基胺基酸之胜肽的製造方法
WO2023140329A1 (ja) * 2022-01-21 2023-07-27 中外製薬株式会社 がんの治療または予防用医薬
WO2023190283A1 (ja) * 2022-03-28 2023-10-05 中外製薬株式会社 ポリオキシエチレン構造を含む油性成分を含有する化合物製剤
TW202406566A (zh) 2022-05-02 2024-02-16 日商中外製藥股份有限公司 包含用於與界面活性劑結合使用之胜肽化合物的組合物
WO2023214576A1 (ja) * 2022-05-06 2023-11-09 中外製薬株式会社 Ｈｒａｓおよびｎｒａｓに対して選択的なｋｒａｓ阻害作用を有する環状化合物
WO2024024965A1 (ja) * 2022-07-29 2024-02-01 中外製薬株式会社 Ｏ－置換セリン誘導体の製造方法
WO2024080308A1 (ja) * 2022-10-12 2024-04-18 中外製薬株式会社 ペプチド、界面活性剤及びポリマーを含む組成物
WO2024080333A1 (ja) * 2022-10-13 2024-04-18 中外製薬株式会社 Ｎ－置換アミノ酸残基を含む環状ペプチド化合物の製造方法
WO2024085235A1 (ja) * 2022-10-20 2024-04-25 中外製薬株式会社 環状ペプチドの結晶の製造方法
WO2024101402A1 (ja) * 2022-11-09 2024-05-16 中外製薬株式会社 Ｈｒａｓおよびｎｒａｓに対して選択的なｋｒａｓ阻害作用を有する環状化合物を含む医薬組成物

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995004541A1 (en) * 1993-08-06 1995-02-16 Abbott Laboratories N-terminus modified analogs of lhrh
JP6239979B2 (ja) 2011-03-04 2017-11-29 ニューヨーク・ユニバーシティ Ｒａｓの調節因子としての水素結合代替大環状分子
WO2013100132A1 (ja) * 2011-12-28 2013-07-04 中外製薬株式会社 ペプチド化合物の環化方法
GB201217560D0 (en) * 2012-10-02 2012-11-14 Mitopharm Ltd Novel cyclic depsipeptide compounds and their uses
WO2015179434A1 (en) * 2014-05-20 2015-11-26 Ohio State Innovation Foundation Small molecule ras inhibitors
US9944678B2 (en) * 2014-12-19 2018-04-17 Bristol-Myers Squibb Company Immunomodulators
US10017540B2 (en) * 2015-03-11 2018-07-10 California Institute Of Technology Cyclic peptide binder against oncogenic K-Ras
US20190338050A1 (en) * 2016-03-03 2019-11-07 Chugai Seiyaku Kabushiki8 Kaisha Production method for noncyclic peptide-nucleic acid complex having, at n-terminal, amino acid with thiol group near amino group, library thereof, and cyclic peptide-nucleic acid complex library derived from same
EP3442991A4 (en) 2016-04-15 2019-11-20 RA Pharmaceuticals, Inc. RAS-BINDING PEPTIDES AND METHODS OF USE
KR20230169447A (ko) * 2017-06-09 2023-12-15 추가이 세이야쿠 가부시키가이샤 N-치환 아미노산을 포함하는 펩타이드의 합성 방법
CN110869544B (zh) * 2017-06-09 2024-03-08 中外制药株式会社 膜透过性高的环状肽化合物及包含其的文库

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