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WO2017031209A1 - Analogues de tubulysine et procédés associés - Google Patents

Analogues de tubulysine et procédés associés Download PDF

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WO2017031209A1
WO2017031209A1 PCT/US2016/047347 US2016047347W WO2017031209A1 WO 2017031209 A1 WO2017031209 A1 WO 2017031209A1 US 2016047347 W US2016047347 W US 2016047347W WO 2017031209 A1 WO2017031209 A1 WO 2017031209A1
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alkyl
alkenyl
membered heterocycloalkyl
cycloalkyl
alkynyl
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Iontcho Radoslavov Vlahov
Fei You
Paul Joseph Kleindl
Marilynn VETZEL
Joseph Anand Reddy
Christopher Paul Leamon
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Endocyte Inc
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Endocyte Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure relates to tubulysin derivatives and methods for making the same.
  • the disclosure also relates to the use of such tubulysin derivatives in the preparation of drug conjugates of tubulysins.
  • Tubulysins are natural products isolated from mycobacterial species. (F. Sasse, et al., J. Antibiot. 2000, 53, 879-885). They are potent mitotic poisons that inhibit the polymerization of tubulin into microtubules. (H. Steinmetz, et al., Chem. Int. Ed. 2004, 43, 4888-4892; M. Khalil, et al., ChemBioChem. 2006, 7, 678-683;G. Kaur, et al., Biochem. J. 2006, 396, 235-242).
  • Tubulysins are extremely potent cytotoxic molecules, exceeding the cell growth inhibition of any clinically relevant traditional chemo therapeutic, including epothilones, paclitaxel, and vinblastine. Furthermore, tubulysins are potent against multidrug resistant cell lines.
  • Domling, et al., Mol. Diversity 2005, 9, 141-147 These compounds show high cytotoxicity tested against a panel of cancer cell lines with IC 50 values in the low picomolar range; thus, they are of interest as potential anticancer therapeutics.
  • tubulysins are linear tetrapeptides comprised of N-methyl pipecolic acid (Mep), isoleucine (He), tubuvaline (Tuv) and tubutyrosine (Tut). All natural isolated tubulysins possess an acid, base, and enzyme-sensitive N-acyloxymethyl substituent, as well as an enzyme-labile acetate group. Both functional groups are essential for the potent cytotoxicity of tubulysins. Examples of seven natural tubul sins are as follows:
  • tubulysins have recently found application in the development of binding ligand-drug conjugates where tubulysin serves as the agent being delivered to the patient to provide a therapeutic benefit. Examples of such applications include the conjugates described in
  • the present disclosure provides processes for preparing a compound of the formula VII
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 9 are as defined herein.
  • the present disclosure provides processes for preparing a compound of the formula Vila
  • R 1 , R 2 , R 3 , R 5 , R 6 and R 9 are as defined herein.
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R , R and R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl,
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - Cio aryl, and 5- to 7-membered heteroaryl
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl [039] with a base in an organic solvent at a temperature of from about -78 °C to about 25 °C in the presence of an alkylating agent.
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl, and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl
  • [051] 8a The process of clause 6, 6a or 7, wherein the alkylating agent is bromomethyl pentyl ether, (2E)-l-bromo-2-hexene, (2Z)-l-bromo-2-hexene, (E)-l-bromo-5-methylhex-2-ene, (Z)- l-bromo-5-methylhex-2-ene, (E)-l-bromo-3-phenyl-prop-2-ene, (Z)-l-bromo-3-phenyl-prop-2- ene, benzyl bromide or p-trifluoromethylbenzyl bromide.
  • the alkylating agent is bromomethyl pentyl ether, (2E)-l-bromo-2-hexene, (2Z)-l-bromo-2-hexene, (E)-l-bromo-5-methylhex-2-ene, (Z)- l-bromo-5
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3_C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; 6 7 8
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [079] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • Ci-C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl;
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; [0151] with an amino acid, or a salt thereof, in the presence of a base in a polar organic solvent at a temperature of from about -20 °C to about 50 °C.
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0172] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl,
  • R 9 is H or -OH
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; or
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0191] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; or
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0196] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0200] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0204] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0211] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or
  • R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C1-C12 alkyl;
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0225] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0232] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0239] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0246] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0254] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0273] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0278] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0282] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0286] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0293] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0300] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl,
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0307] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; 6 7 8
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0314] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by [0318] f. contactin a compound of the formula VI
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0321] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0328] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl,
  • R 9 is H or -OH
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0366] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl,
  • R 9 is H or -OH
  • R 1 is Ci-C 6 alkyl
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R 6 is 7 8
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; or
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R and R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0453] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0461] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C ⁇ -C ⁇ 2 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0469] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0477] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C ⁇ -C ⁇ 2 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl,
  • R 9 is H or -OH
  • R 1 is Ci-C 6 alkyl
  • R 1 is Ci-C 6 alkyl; with a base in an organic solvent at a temperature of from about -78 °C to about 25 °C in the presence of an alkylating agent to provide a compound of the formula Illb
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en- l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl; followed by
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en- l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R 6 is 7 8
  • each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R and R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen- l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en- l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R and R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 is Ci-C 6 alkyl
  • R 5 is selected from the group consisting of methyl pentyl ether, (2E)-2-hexen-l-yl, (2Z)-2-hexen-l-yl, (E)-5-methylhex-2-en-l-yl, (Z)-5-methylhex-2-en-l-yl, (E)-3-phenyl-prop- 2-en-l-yl, (Z)-3-phenyl-prop-2-en-l-yl, benzyl and p-trifluoromethylbenzyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • step (d) is a mixture of methanol and water.
  • step (e) is DCC-resin.
  • step (f) The process of any one of clauses 22 to 37, wherein the amino acid in step (f) is Tup or Tut, or a salt thereof.
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0578] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl.
  • step (a) The process of 41, wherein the base in step (a) is sodium hydride.
  • step (b) The process of any one of clauses 41 to 46, wherein the alkylating agent in step (b) is bromomethyl pentyl ether, (2E)-l-bromo-2-hexene, (2Z)-l-bromo-2-hexene, (E)-l-bromo-5- methylhex-2-ene, (Z)-l-bromo-5-methylhex-2-ene, (E)-l-bromo-3-phenyl-prop-2-ene, (Z)-l- bromo-3-phenyl-prop-2-ene, benzyl bromide or p-trifluoromethylbenzyl bromide.
  • the alkylating agent in step (b) is bromomethyl pentyl ether, (2E)-l-bromo-2-hexene, (2Z)-l-bromo-2-hexene, (E)-l-bromo-5- methylhex-2-ene,
  • R 1 is a C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7- membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; and
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; [0593] with a base in an organic solvent at a temperature of from about -78 °C to about 25 °C in the presence of an alkylating agent to provide a compound of the formula III
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0596] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0601] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0609] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl.
  • step (a) The process of any one of clauses 49 to 51, wherein the organic solvent in step (a) is THF or toluene.
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0622] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0630] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0637] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0640] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0644] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl.
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0656] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - C 10 aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0663] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0670] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0677] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl.
  • step (a) The process of clause 60 or 61, wherein the aqueous solvent system in step (a) is a mixture of methanol and water.
  • step (b) The process of any one of clauses 60 to 62, wherein the activating agent in step (b) is DCC-resin.
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0688] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and [0691] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently Ci-Ci 2 alkyl, wherein each hydrogen atom in Ci-Ci 2 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0695] R 1 and R 5 are each independently Ci-Ci 2 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in Ci-Ci 2 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Ci
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 6 is -Ci-Ci 2 alkyl-NR 7 R 8 or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; followed by
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0702] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl; and
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 1 and R 5 are each independently C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl; or [0709] R 1 and R 5 are each independently C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocyclo
  • R 2 and R 3 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl; and
  • R 9 is H or -OH.
  • step (e) is DCC-resin.
  • R and R are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C6 alkenyl, C 2 -C6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 5 is C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, 5- to 7-membered heteroaryl, -OR 11 , -OC(0)R n ,
  • R 5 is C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, 5- to 7-membered heteroaryl, -OR 11 , -OC(0)R n , -OC(0)NR n R ir , -OS(0)R n , -OS(0) 2 R n , -SR 11 , -SC(0)R n , -S(0)R n , -S(0) 2 R n , -S(0) 2 OR n , -S(0)NR n R ir , -S(0) 2 NR
  • each hydrogen atom in 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF 3 , or C 1 -C 12 alkyl;
  • R is -C 1 -C 12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl;
  • R 7 and R 8 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, and 5- to 7-membered heteroaryl;
  • R 9 is H or -OH
  • R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 - Cio aryl, and 5- to 7-membered heteroaryl;
  • R 5 is C 1 -C 12 alkyl, wherein each hydrogen atom in C 1 -C 12 alkyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, 5- to 7-membered heteroaryl, -OR 11 , -OC(0)R n ,
  • R 5 is C 1 -C 12 alkyl or C 2 -C 6 alkenyl, wherein each hydrogen atom in C 1 -C 12 alkyl or C 2 -C 6 alkenyl is optionally substituted with a Ci-C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, 5- to 7-membered heteroaryl, -OR 11 , -OC(0)R n , -OC(0)NR n R ir , -OS(0)R n , -OS(0) 2 R n , -SR 11 , -SC(0)R n , -S(0)R n , -S(0) 2 R n , -S(0) 2 OR n , -S(0)NR n R ir , -S(0) 2 NR
  • R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 _C 6 cycloalkyl, 3- to 7-membered
  • heterocycloalkyl C 6 -Cio aryl, and 5- to 7-membered heteroaryl

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Abstract

La présente invention porte sur des dérivés de tubulysine et sur leurs procédés de fabrication. L'invention concerne également l'utilisation de tels dérivés de tubulysine dans la préparation de conjugués médicamenteux de tubulysines.
PCT/US2016/047347 2015-08-18 2016-08-17 Analogues de tubulysine et procédés associés Ceased WO2017031209A1 (fr)

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US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11274124B2 (en) 2017-11-29 2022-03-15 William Marsh Rice University Tubulysin analogues as anticancer agents and payloads for antibody-drug conjugates and methods of treatment therewith
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
US12144864B2 (en) 2018-12-21 2024-11-19 Regeneron Pharmaceuticals, Inc. Tubulysins and protein-tubulysin conjugates

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US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds
US11274124B2 (en) 2017-11-29 2022-03-15 William Marsh Rice University Tubulysin analogues as anticancer agents and payloads for antibody-drug conjugates and methods of treatment therewith
US12144864B2 (en) 2018-12-21 2024-11-19 Regeneron Pharmaceuticals, Inc. Tubulysins and protein-tubulysin conjugates
WO2021232791A1 (fr) * 2020-05-22 2021-11-25 深圳市老年医学研究所 Procédé de préparation de polypeptide actif antitumoral de type tubulysine m efficace

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