WO2017031209A1

WO2017031209A1 - Tubulysin analogs and methods

Info

Publication number: WO2017031209A1
Application number: PCT/US2016/047347
Authority: WO
Inventors: Iontcho Radoslavov Vlahov; Fei You; Paul Joseph Kleindl; Marilynn VETZEL; Joseph Anand Reddy; Christopher Paul Leamon
Original assignee: Endocyte Inc
Current assignee: Endocyte Inc
Priority date: 2015-08-18
Filing date: 2016-08-17
Publication date: 2017-02-23
Anticipated expiration: 2018-02-18

Abstract

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.

Description

TUBULYSIN ANALOGS AND METHODS

CROSS REFERENCE TO RELATED APPLICATION

[001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional

Application Serial No. 62/206,689, filed August 18, 2015, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[002] 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.

BACKGROUND

[003] 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. (A.

Domling, et al., Mol. Diversity 2005, 9, 141-147). These compounds show high cytotoxicity tested against a panel of cancer cell lines with IC₅₀ values in the low picomolar range; thus, they are of interest as potential anticancer therapeutics.

[004] Structurally, 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:

Tubulysin R R'

A OH CH₂CH(CH₃)₂

B OH CH₂CH₂CH₃

C OH CH₂CH₃

D H CH₂CH(CH₃)₂

E H CH₂CH₂CH₃

F H CH₂CH₃

G OH CH=C(CH₃)₂

H H CH₃

I OH CH₃

[005] The total synthesis of tubulysin D possessing C-terminal tubuphenylalanine (R = H) has been reported. (H. Peltier, et al., J. Am. Chem. Soc. 2006, 128, 16018-16019). Also, a modified synthetic protocol toward the synthesis of tubulysin B (R = OH) has been reported. (O. Pando, et at., Org. Lett. 2009, 11, 5567-5569).

[006] 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

WO2014/062697. Because there is great interest in tubulysins and their application in drug conjugates, there is a need to overcome challenges related to tubulysins. (See for example, WO2012/019123). For example, difficulties have been reported in the preparation of tubulysins due to the sensitivity of the ester moieties present in the structure to hydrolysis. As a result, prior efforts to synthesize tubulysins have been challenged to find reaction conditions for certain chemical transformations that do not result in degradation of the core structure or unwanted side products. Therefore, there exists a great need for novel chemical syntheses of tubulysins that avoid certain problems that have existed before.

[007] Herein is presented the design and total synthesis of tubulysin analogs less prone to degradation under acidic/basic conditions and enzymatic hydrolysis.

SUMMARY

[008] In one aspect, the present disclosure provides processes for preparing a compound of the formula VII

VII

[009] wherein R¹, R², R³, R⁵, R⁶ and R⁹ are as defined herein.

[010] In another aspect, the present disclosure provides processes for preparing a compound of the formula Vila

Vila

[011] wherein R⁶ and R⁹ are as defined herein.

[012] In another aspect, the present disclosure provides compounds of the formula VII

[013] wherein R¹, R², R³, R⁵, R⁶ and R⁹ are as defined herein.

[014] In another aspect, the present disclosure provides compounds of the formula Vila

Vila [015] wherein R⁶ and R⁹ are as defined herein.

[016] In another as ect, the disclosure provides compounds of the formula XVIX

XVIX

[017] wherein R², R³, R⁵, R⁶ and R⁹ are as defined herein

[018] The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[019] 1. A process for preparing a compound of the formula II

[020] wherein

[021] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[022] 2 3 4

R , R and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl,

[023] comprising contacting a compound of the formula I

[024] wherein [025] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl

[026] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent.

[027] 2. The process of clause 1, wherein the base is sodium hydride.

[028] 3. The process of clause 1 or 2, wherein the alkylating agent is a methylating agent.

[029] 4. The process of clause 1, 2 or 3, wherein the alkylating agent is methyliodide.

[030] 5. The process of any one of the preceding clauses, wherein the organic solvent is DMF.

[031] 6. A process for preparing a compound of the formula III

III

[032] wherein

[033] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[034] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[035] comprising contacting a compound of the formula II

[036] wherein

[037] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[038] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ 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.

[040] 6a. A process for preparing a compound of the formula III

[041] wherein

[042] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl, and

[043] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[044] comprising contacting a compound of the formula II

[045] wherein

[046] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[047] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl

[048] 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.

[049] 7. The process of clause 6 or 6a, wherein the base is KHMDS. [050] 8. The process of clause 6, 6a or 7, wherein the alkylating agent is bromomethyl pentyl ether.

[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.

[052] 9. The process of clause 6, 6a, 7 or 8, wherein the organic solvent is THF or toluene.

[053] 10. A process for preparing a compound of the formula IV

[054] wherein

[055] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[056] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[057] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[058] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[059] comprising contacting a compound of the formula III

III

[060] wherein [061] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[062] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[063] with an activated ester of the formula

6 7 8

[064] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[065] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[066] in the presence of a palladium catalyst and a hydrogen source.

[067] 10a. A process for preparing a compound of the formula IV

[068] wherein

[069] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[070] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; 6 7 8

[071] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[072] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[073] comprising contacting a compound of the formula III

III

[074] wherein

[075] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[076] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[077] with an activated ester of the formula

6 7 8

[078] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[080] in the presence of a palladium catalyst and a hydrogen source.

[081] 11. The process of clause 10 or 10a, wherein the palladium catalyst is 10% Pd/C.

[082] 12. The process of clause 10, 10a or 11, wherein the hydrogen source is hydrogen gas.

[083] 13. A process for preparing a compound of the formula V

[084] wherein

[085] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[086] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[087] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[088] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[089] comprising contacting a compound of the formula IV

[090] wherein [091] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[092] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[093] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[094] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[095] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C.

[096] 13a. A process for preparing a compound of the formula V

[097] wherein

[098] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[099] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0100] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0101] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0102] comprising contacting a compound of the formula IV

[0103] wherein

[0104] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0105] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0106] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0107] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0108] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C.

[0109] 14. The process of clause 13 or 13a, wherein the base is lithium hydroxide.

[0110] 15. The process of clause 13, 13a or 14, wherein the aqueous solvent system is a mixture of methanol and water.

[0111] 16. A process for preparing a compound of the formula VI

VI

[0112] wherein

[0113] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[0114] R 2 3

and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0115] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0116] R 7 R 8

and are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0117] comprising contacting a compound of the formula V

[0118] wherein

[0119] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[0120] R 2 3

6 7 8

[0121] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0122] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0123] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C.

[0124] 16a. A process for preparing a compound of the formula VI

VI

[0125] wherein

[0126] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0127] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0128] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0129] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0130] comprising contacting a compound of the formula V

[0131] wherein

[0132] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0133] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0134] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0135] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0136] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C.

[0137] 17. The process of clause 16 or 16a, wherein the activating agent is DCC-resin.

[0138] 18. A process for preparing a compound of the formula VII

VII

[0139] wherein [0140] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[0141] R 2 3

6 7 8

[0142] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0143] R 7 8

and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0144] R⁹ is H or -OH;

[0145] comprising contacting a compound of the formula VI

VI

[0146] wherein

[0147] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl;

[0148] R 2 3

and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0149] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0150] R 7 8

and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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.

[0152] 18a. A process for preparing a compound of the formula VII

VII

[0153] wherein

[0154] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0155] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0156] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0157] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0158] R⁹ is H or -OH;

[0159] comprising contacting a compound of the formula VI

VI [0160] wherein

[0161] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0162] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0163] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0164] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0165] 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.

[0166] 19. The process of clause 18 or 18a, wherein the amino acid is Tup or Tut, or a salt thereof.

[0167] 20. The process of clause 18, 18a or 19, wherein the base is di-isopropylethylamine.

[0168] 21. The process of clause 18, 18a, 19 or 20, wherein the polar organic solvent is DMF.

[0169] 22. A process for preparing a compound of the formula VII

VII

[0170] wherein

[0171] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0172] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0173] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0174] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0175] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl,

C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0176] R⁹ is H or -OH;

[0177] comprising one or more of

[0178] a. contacting a c

[0179] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0180] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula II

II

[0181] wherein [0182] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0183] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; or

[0184] b. contacting a c

[0185] wherein

[0186] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0187] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0188] 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

[0189] wherein

[0190] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0191] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0192] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; or

[0193] c. contacting a compound of the formula III

[0194] wherein

[0195] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0196] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0197] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0198] with an activated ester of the formula

6 7 8

[0199] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0201] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

[0202] wherein

[0203] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0204] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0205] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0206] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0207] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0208] d. contacting a compound of the formula IV

IV

[0209] wherein

[0210] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0211] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0212] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0213] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0214] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0215] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

V

[0216] wherein

[0217] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or

[0218] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C1-C12 alkyl;

[0219] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0220] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0221] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0222] e. contacting a compound of the formula V

V

[0223] wherein

[0224] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0225] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0226] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0227] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0228] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0229] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

[0230] wherein

[0231] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0232] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0233] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0234] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0235] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0236] f. contacting a compound of the formula VI

VI

[0237] wherein

[0238] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0239] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0240] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0241] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0242] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0243] 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 to provide a compound of the formula VII

VII [0244] wherein

[0245] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0246] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0247] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0248] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0249] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0250] R⁹ is H or -OH.

[0251] 23. A process for preparing a compound of the formula VII

VII

[0252] wherein

[0253] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0254] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0255] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0256] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0257] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0258] R⁹ is H or -OH;

[0259] comprising

[0260] a. contacting a compound of the formula I

[0261] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0262] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula II

[0263] wherein [0264] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0265] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; followed by

[0266] b. contacting a compound of the formula II

II

[0267] wherein

[0268] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0269] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0270] 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

III

[0271] wherein

[0272] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0273] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0274] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; followed by

[0275] c. contacting a compound of the formula III

III

[0276] wherein

[0277] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0278] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0279] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0280] with an activated ester of the formula

6 7 8

[0281] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0283] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

[0284] wherein

[0285] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0286] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0287] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0288] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0289] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0290] d. contacting a compound of the formula IV

IV

[0291] wherein

[0292] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0293] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0294] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0295] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0296] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0297] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

v

[0298] wherein

[0299] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0300] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0301] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl,

C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0302] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0303] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0304] e. contacting a compound of the formula V

v

[0305] wherein

[0306] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0307] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0308] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; 6 7 8

[0309] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0310] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0311] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

[0312] wherein

[0313] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0314] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0315] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0316] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0317] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by [0318] f. contactin a compound of the formula VI

VI

[0319] wherein

[0320] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0321] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0322] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0323] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0324] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0325] 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 to provide a compound of the formula VII

VII

[0326] wherein

[0327] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0328] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0329] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0330] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0331] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0332] R⁹ is H or -OH.

[0333] 24. A process for preparing a compound of the formula Vila

Vila

[0334] wherein

6 7 8

[0335] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0336] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl,

[0337] R⁹ is H or -OH;

[0338] comprising one or more of

[0339] a. contacting a compound of the formula la

la

[0340] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula Ila

or

Ila

[0341] b. contacting a compound of the formula Ila

Ila

[0342] 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 Ilia

Ilia

[0343] c. contacting a compound of the formula Ilia

[0344] with an activated ester of the formula

6 7 8

[0345] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0346] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0347] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IVa

IVa

[0348] wherein 6 7 8

[0349] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0350] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0351] d. contacting a compound of the formula IVa

IVa

[0352] wherein

6 7 8

[0353] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0354] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0355] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula Va

Va

[0356] wherein

6 7 8

[0357] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0358] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0359] e. contacting a com ound of the formula Va

Va

[0360] wherein

6 7 8

[0361] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0362] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0363] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula Via

Via

[0364] wherein

6 7 8

[0365] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0367] f. contacting a compound of the formula Via

Via

[0368] wherein

[0369] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0370] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0371] 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 to provide a compound of the formula Vila

Vila

[0372] wherein

[0373] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; [0374] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0375] R⁹ is H or -OH.

[0376] 24a. A process for preparing a compound of the formula Vila

Vila

[0377] wherein

[0378] R⁵ 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;

[0379] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0380] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl,

C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0381] R⁹ is H or -OH;

[0382] comprising one or more of

[0383] a. contacting a compound of the formula la

la [0384] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula lib

lib

[0385] wherein R¹ is Ci-C₆ alkyl; or

[0386] b. contacting a compound of the formula lib

lib

[0387] 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

Illb

[0388] c. contacting a compound of the formula Illb

Illb

[0389] wherein [0390] R¹ is Ci-C₆ alkyl; and

[0391] R⁵ 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;

[0392] with an activated ester of the formula

6 7 8

[0393] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0394] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0395] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IVb

IVb

[0396] wherein

[0397] R¹ is Ci-C₆ alkyl;

[0398] R⁵ 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;

[0399] R 6 is 7 8

-Ci-Ci₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and [0400] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0401] d. contacting a compound of the formula IVb

IVb

[0402] wherein

[0403] R¹ is Ci-C₆ alkyl;

[0404] R⁵ 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;

[0405] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0406] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0407] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula Vb

Vb

[0408] wherein

[0409] R¹ is Ci-C₆ alkyl; [0410] R⁵ 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;

6 7 8

[0411] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0412] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0413] e. contacting a compound of the formula Vb

Vb

[0414] wherein

[0415] R¹ is Ci-C₆ alkyl;

[0416] R⁵ 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;

6 7 8

[0417] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0418] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0419] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VIb

VIb

[0420] wherein

[0421] R¹ is Ci-C₆ alkyl;

[0422] R⁵ 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;

6 7 8

[0423] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0424] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0425] f. contacting a compound of the formula VIb

VIb

[0426] wherein

[0427] R¹ is Ci-C₆ alkyl;

[0428] R⁵ 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;

6 7 8

[0429] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0430] 7 8

R and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0431] 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 to provide a compound of the formula Vllb

Vllb

[0432] wherein

[0433] R¹ is Ci-C₆ alkyl;

[0434] R⁵ 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;

6 7 8

[0435] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0436] 7 and 8

R R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0437] R⁹ is H or -OH.

[0438] 25. A process for preparing a compound of the formula Vllb

Vila

[0439] wherein

6 7 8

[0440] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0441] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0442] R⁹ is H or -OH;

[0443] comprising

[0444] a. contacting a compound of the formula la

la

[0445] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula Ila

Ila

[0446] followed by [0447] b. contacting a compound of the formula Ila

Ila

[0448] 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 Ilia; followed by

Ilia

[0449] followed by

[0450] c. contacting a compound of the formula Ilia

Ilia

[0451] with an activated ester of the formula

6 7 8

[0452] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0454] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IVa

IVa

[0455] wherein

[0456] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0457] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0458] d. contacting a compound of the formula IVa

IVa

[0459] wherein

[0460] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0462] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula Va

Va

[0463] wherein

6 7 8

[0464] 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0465] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0466] e. contacting a com ound of the formula Va

Va

[0467] wherein

[0468] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0470] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula Via

Via

[0471] wherein

[0472] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0473] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0474] f. contacting a compound of the formula Via

Via

[0475] wherein

[0476] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0478] 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 to provide a compound of the formula Vila

Vila

[0479] wherein

6 7 8

[0480] 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0481] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0482] R⁹ is H or -OH.

[0483] 24a. A process for preparing a compound of the formula Vllb

Vllb

[0484] wherein

[0485] R¹ is Ci-C₆ alkyl; [0486] R⁵ 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;

6 7 8

[0487] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0488] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl,

[0489] R⁹ is H or -OH;

[0490] comprising one or more of

[0491] a. contacting a com ound of the formula la

la

[0492] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula lib

lib

[0493] wherein R¹ is Ci-C₆ alkyl; followed by

[0494] b. contacting a compound of the formula lib

lib

[0495] wherein R¹ is Ci-C₆ 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

Illb

[0496] wherein

[0497] R¹ is Ci-C₆ alkyl; and

[0498] R⁵ 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

[0499] c. contacting a compound of the formula Illb

Illb

[0500] wherein

[0501] R¹ is Ci-C₆ alkyl;

[0502] R⁵ 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;

[0503] with an activated ester of the formula

6 7 8

[0504] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0505] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0506] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IVb

IVb

[0507] wherein

[0508] R¹ is Ci-C₆ alkyl;

[0509] R⁵ 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;

[0510] R 6 is 7 8

-Ci-Ci₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0511] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0512] d. contacting a compound of the formula IVb

IVb

[0513] wherein

[0514] R¹ is Ci-C₆ alkyl;

[0515] R⁵ 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;

6 7 8

[0516] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0517] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0518] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula Vb

Vb

[0519] wherein

[0520] R¹ is Ci-C₆ alkyl;

[0521] R⁵ 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;

6 7 8

[0522] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0523] 7 8

R and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0524] e. contacting a compound of the formula Vb

Vb

[0525] wherein

[0526] R¹ is Ci-C₆ alkyl;

[0527] R⁵ 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;

6 7 8

[0528] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0529] 7 8

R and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0530] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a com ound of the formula VIb

VIb

[0531] wherein [0532] R¹ is Ci-C₆ alkyl;

[0533] R⁵ 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;

6 7 8

[0534] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0535] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0536] f. contactin a compound of the formula VIb

VIb

[0537] wherein

[0538] R¹ is Ci-C₆ alkyl;

[0539] R⁵ 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;

6 7 8

[0540] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0541] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0542] 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 to provide a compound of the formula Vllb

Vllb

[0543] wherein

[0544] R¹ is Ci-C₆ alkyl;

[0545] R⁵ 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;

6 7 8

[0546] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0547] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0548] R⁹ is H or -OH.

[0549] 26. The process of any one of clauses 22 to 25a, wherein the base in step (a) is sodium hydride.

[0550] 27. The process of any one of clauses 22 to 26, wherein the alkylating agent in step (a) is a methylating agent.

[0551] 28. The process of any one of clauses 22 to 27, wherein the alkylating agent in step (a) is methyliodide.

[0552] 29. The process of any one of clauses 22 to 28, wherein the organic solvent in step (a) is DMF.

[0553] 30. The process of any one of clauses 22 to 29, wherein base in step (b) is KHMDS.

[0554] 31. The process of any one of clauses 22 to 30, wherein the alkylating agent in step (b) is bromomethyl pentyl ether.

[0555] 32. The process of any one of clauses 22 to 31, wherein the organic solvent in step (b) is THF or toluene. [0556] 33. The process of any one of clauses 22 to 32, wherein the palladium catalyst in step (c) is 10% Pd/C.

[0557] 34. The process of any one of clauses 22 to 33, wherein the hydrogen source in step (c) is hydrogen gas.

[0558] 35. The process of any one of clauses 22 to 34, wherein the base in step (d) is lithium hydroxide.

[0559] 36. The process of any one of clauses 22 to 35, wherein the aqueous solvent system in step (d) is a mixture of methanol and water.

[0560] 37. The process of any one of clauses 22 to 36, wherein the activating agent in step (e) is DCC-resin.

[0561] 38. 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.

[0562] 39. The process of any one of clauses 22 to 38, wherein the base in step (f) is di- isopropylethylamine.

[0563] 40. The process of any one of clauses 22 to 39, wherein the polar organic solvent in step (f) is DMF.

[0564] 41. A process comprising

[0565] a. contacting a c

[0566] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0567] with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula II

[0568] wherein [0569] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0570] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; followed by

[0571] b. contacting a compound of the formula II

[0572] wherein

[0573] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0574] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0575] 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

III

[0576] wherein

[0577] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0578] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0579] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl.

[0580] 42. The process of 41, wherein the base in step (a) is sodium hydride.

[0581] 43. The process of clause 41 or 42, wherein the alkylating agent in step (a) is a methylating agent.

[0582] 44. The process of any one of clauses 41 to 43, wherein the alkylating agent in step (a) is methyliodide.

[0583] 45. The process of any one of clauses 41 to 44, wherein the organic solvent in step (a) is DMF.

[0584] 46. The process of any one of clauses 41 to 45, wherein base in step (b) is KHMDS.

[0585] 47. The process of any one of clauses 41 to 46, wherein the alkylating agent in step (b) is bromomethyl pentyl ether.

[0586] 47a. 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.

[0587] 48. The process of any one of clauses 41 to 47a, wherein the organic solvent in step (b) is THF or toluene.

[0588] 49. A process comprising

[0589] a. contacting a compound of the formula II

[0590] wherein

[0591] R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

[0592] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ 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

[0594] wherein

[0595] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0596] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0597] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; followed by

[0598] b. contacting a compound of the formula III

[0599] wherein

[0600] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0601] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0602] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0603] with an activated ester of the formula

6 7 8

[0604] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0605] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0606] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

[0607] wherein

[0608] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0609] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; [0610] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0611] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0612] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl.

[0613] 50. The process of clause 49, wherein base in step (a) is KHMDS.

[0614] 51. The process of clause 49 or 50, wherein the alkylating agent in step (a) is

bromomethyl pentyl ether or l-bromo-2-hexene.

[0615] 52. The process of any one of clauses 49 to 51, wherein the organic solvent in step (a) is THF or toluene.

[0616] 53. The process of any one of clauses 49 to 52, wherein the palladium catalyst in step (b) is 10% Pd/C.

[0617] 54. The process of any one of clauses 49 to 53, wherein the hydrogen source in step (b) is hydrogen gas.

[0618] 55. A process comprising

[0619] a. contacting a compound of the formula III

III

[0620] wherein

[0621] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0622] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0623] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0624] with an activated ester of the formula

6 7 8

[0625] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0626] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0627] in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

[0628] wherein

[0629] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0630] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; [0631] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0632] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0633] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0634] b. contacting a compound of the formula IV

[0635] wherein

[0636] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0637] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0638] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0639] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0641] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

V

[0642] wherein

[0643] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0644] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0645] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0646] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0647] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl.

[0648] 56. The process of clause 55, wherein the palladium catalyst in step (a) is 10% Pd/C.

[0649] 57. The process of clause 55 or 56, wherein the hydrogen source in step (a) is hydrogen gas.

[0650] 58. The process of any one of clauses 55 to 57, wherein the base in step (b) is lithium hydroxide. [0651] 59. The process of any one of clauses 55 to 58, wherein the aqueous solvent system in step (b) is a mixture of methanol and water.

[0652] 60. A process comprising

[0653] a. contacting a compound of the formula IV

[0654] wherein

[0655] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0656] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0657] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0658] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0659] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0660] with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

V

[0661] wherein

[0662] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0663] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0664] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0665] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0666] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0667] b. contacting a compound of the formula V

[0668] wherein

[0669] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0670] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0671] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0672] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0673] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0674] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

[0675] wherein

[0676] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0677] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0678] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0679] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0680] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl.

[0681] 61. The process of clause 60, wherein the base in step (a) is lithium hydroxide.

[0682] 62. The process of clause 60 or 61, wherein the aqueous solvent system in step (a) is a mixture of methanol and water.

[0683] 63. The process of any one of clauses 60 to 62, wherein the activating agent in step (b) is DCC-resin.

[0684] 64. A process comprising

[0685] a. contacting a compound of the formula V

[0686] wherein

[0687] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0688] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0689] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0690] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0692] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

[0693] wherein

[0694] R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0695] R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0696] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0697] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0698] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; followed by

[0699] b. contacting a compound of the formula VI

VI

[0700] wherein

[0701] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0702] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0703] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0704] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0705] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0706] 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 to provide a compound of the formula VII

VII

[0707] wherein [0708] R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or [0709] R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

[0710] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

[0711] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0712] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0713] R⁹ is H or -OH.

[0714] 65. The process of clause 64, wherein the activating agent in step (e) is DCC-resin.

[0715] 66. The process of clause 64 or 65, wherein the amino acid in step (f) is Tup or Tut, or a salt thereof.

[0716] 67. The process of any one of clauses 64 to 66, wherein the base in step (f) is di- isopropylethylamine.

[0717] 68. The process of any one of clauses 64 to 68, wherein the polar organic solvent in step (f) is DMF.

[0718] 69. The process of any one of clauses 18 to 40 or 64 to 68, wherein R⁹ is -H.

[0719] 70. The process of any one of clauses 18 to 40 or 64 to 68, wherein R⁹ is -OH.

[0720] 71. The process of any one of clauses 10 to 40 or 49 to 70, wherein R⁶ is -C₁-C₁₂ alkyl- NR⁷R⁸.

[0721] 72. The process of any one of clauses 10 to 40 or 49 to 71, wherein R⁶ is -C₁-C₁₂ alkyl- NR⁷R⁸, and R⁷ and R⁸ are Ci-C₆ alkyl. [0722] 73. The process of any one of clauses 10 to 40 or 49 to 72, wherein R⁶ is -C₁-C₁₂ alkyl- NR⁷R⁸, and R⁷ and R⁸ are methyl.

[0723] 74. The process of any one of clauses 10 to 40 or 49 to 72, wherein R⁶ is -CH₂NR⁷R⁸, and R⁷ and R⁸ are Ci-C₆ alkyl.

[0724] 75. The process of any one of clauses 10 to 40 or 49 to 73, wherein R⁶ is -CH₂N(CH₃)₂.

[0725] 76. The process of any one of clauses 10 to 40 or 49 to 70, wherein R⁶ is 3- to 7- membered heterocycloalkyl.

[0726] 77. The process of any one of clauses 10 to 40, 49 to 70 or 76, wherein R⁶ is 3- to 7- membered heterocycloalkyl substituted with a Ci-C₆ alkyl.

[0727] 78. The process of any one of clauses 10 to 40, 49 to 70, 76 or 77, wherein R⁶ is N- methylpiperidin-2- yl .

[0728] 79. The process of any one of clauses 1 to 15 or 22 to 63, wherein R⁴ is Ci-C₆ alkyl.

[0729] 80. The process of any one of clauses 1 to 15, 22 to 63 or 79, wherein R⁴ is methyl.

[0730] 81. The process of any one of clauses 6 to 80, wherein R⁵ is C₁-C₁₂ alkyl substituted with CrC₆ alkoxy.

[0731] 82. The process of any one of clauses 6 to 81, wherein R⁵ is -CH₂-Ci-C6 alkoxy.

[0732] 83. The process of any one of clauses 6 to 82, wherein R⁵ is -CH₂- OCH₂CH₂CH₂CH₂CH₃.

[0733] 84. The process of any one of the preceding clauses, wherein R¹ is methyl.

[0734] 85. The process of any one of the preceding clauses, wherein R is Ci-C₆ alkyl.

[0735] 86. The process of any one of the preceding clauses, wherein R is sec -butyl.

[0736] 87. The process of any one of the preceding clauses, wherein R is Ci-C₆ alkyl.

[0737] 88. The process of any one of the preceding clauses, wherein R is iso-propyl.

[0738] 89. A process for reparing a compound of the formula XVIX

XVIX

[0739] wherein

₂ Q

[0740] R and R are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C6 alkenyl, C₂-C6 alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; [0741] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

-OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)R^u, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NR^uR^{i r}, -S(0)₂NRⁿR^{i r}, -OS(0)NR^uR^ir, -OS(0)₂NR^uR^ir, -NRⁿR^{i r}, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NRⁿS(0)R¹², -NRⁿS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NR^uS(0)₂NR¹²R^12', -P(0)(OR^u)₂, -C(0)Rⁿ, -C(0)ORⁿ or -C(0)NRⁿR^ir; or

[0742] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

6 7 8

[0743] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0744] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0745] R⁹ is H or -OH; and

[0746] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0747] comprising

[0748] a. contacting a compound of the formula I

I

[0749] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0750] with an oxidizing a ent to provide a compound of the formula VIII

VIII

[0751] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0752] b. contacting a com ound of the formula VIII

VIII

[0753] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0754] with a reducing agent to rovide a compound of the formula IX

[0755] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0756] c. contacting a compound of the formula IX

[0757] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0758] with a base and a sil l chloride reagent to provide a compound of the formula X

[0759] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0760] d. contacting a compound of the formula X

[0761] wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0762] with a base in the presence of an alkylating agent to provide a compound of the formula XI

XI

[0763] wherein [0764] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0765] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0766] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

[0767] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0768] e. contacting a compound of the formula XI

XI

[0769] wherein

[0770] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; [0771] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0772] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

[0773] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl

[0774] with an activated ester of the formula

6 7 8

[0775] wherein R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

[0776] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0777] to provide a compound of the formula XII

XII

[0778] wherein

[0779] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0780] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0781] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0782] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0783] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and [0784] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0785] f. contacting a compound of the formula XII

XII

[0786] wherein

[0787] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0788] R⁵ is C1-C12 alkyl, wherein each hydrogen atom in C1-C12 alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0789] R⁵ is C1-C12 alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C1-C12 alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)2NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)2NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C1-C12 alkyl;

6 7 8

[0790] R is -C1-C12 alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; [0791] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0792] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0793] with a non-nucleo hilic fluoride reagent to provide a compound of the formula XIII

XIII

[0794] wherein

[0795] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0796] R⁵ is Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0797] R⁵ is Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0798] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0799] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0800] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0801] g. contacting a compound of the formula XIII

XIII

[0802] wherein

[0803] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0804] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a CrC₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0805] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; 6 7 8

[0806] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0807] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0808] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0809] with a sulfonyl chloride reagent in the presence of an amine base to provide a compound of the formula XIV

XIV

[0810] wherein

[0811] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0812] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0813] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹², -NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

6 7 8

[0814] 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0815] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0816] R¹⁰ is selected from the group consisting of H, -CF_3i Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, C₆-Cio aryl-CH₃ and 5- to 7-membered heteroaryl; and

[0817] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0818] h. contacting a com ound of the formula XIV

XIV

[0819] wherein

[0820] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0821] R⁵ is Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

-OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)R^u, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NR^uR^{i r}, -S(0)₂NRⁿR^{i r}, -OS(0)NR^uR^ir, -OS(0)₂NR^uR^ir, -NRⁿR^{i r}, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NRⁿS(0)R¹², -NRⁿS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NR^uS(0)₂NR¹²R^12', -P(0)(OR^u)₂, -C(0)Rⁿ, -C(0)ORⁿ or -C(0)NRⁿR^ir; or [0822] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0823] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0824] R¹⁰ is selected from the group consisting of H, -CF_3i Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, C₆-Cio aryl-CH₃ and 5- to 7-membered heteroaryl; and

[0825] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0826] with tetrabutylammonium azide to provide a compound of the formula XV

XV

[0827] wherein

[0828] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

[0829] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0830] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0831] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0832] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0833] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0834] h. contacting a com ound of the formula XV

XV

[0835] wherein

[0836] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; [0837] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0838] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0839] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0840] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0841] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0842] with a hydrogen source in the presence of a palladium catalyst, followed by acetic anhydride to provide a compound of the formula XVI

XVI [0843] wherein

[0844] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0845] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0846] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0847] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0848] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0849] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0850] i. contacting a compound of the formula XVI

XVI

[0851] wherein

[0852] R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- Cio aryl, and 5- to 7-membered heteroaryl;

[0853] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0854] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0855] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0856] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and [0857] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0858] with a tributyltin reagent to provide a compound of the formula XVII

XVII

[0859] wherein

[0860] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0861] R⁵ is Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0862] R⁵ is Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

[0863] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; [0864] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0865] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0866] j. contacting a compound of the formula XVII

XVII

[0867] wherein

[0868] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0869] R⁵ is Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0870] R⁵ is Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

[0871] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0872] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0873] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0874] with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a com ound of the formula XVIII

XVIII

[0875] wherein

[0876] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0877] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a CrC₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0878] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹,

-OC(0)Rⁿ, -OC(0)NR^uR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)R^u, -S(0)R^u, -S(0)₂Rⁿ, -S(0)₂OR^u, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NRⁿR^ir, -NR^uR^ir, -N RⁿC(0)R¹², -NRⁿC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NRⁿS(0)R¹², -NRⁿS(0)₂R¹², -NR^uS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(OR^u)₂, -C(0)Rⁿ, -C(0)ORⁿ or -C(0)NRⁿR^ir; or

[0879] R⁵ is Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

[0880] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0881] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0882] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

[0883] k. contacting a compound of the formula XVIII

XVIII

[0884] wherein

[0885] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; [0886] R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

[0887] R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir, -NR^uR^ir, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

6 7 8

[0888] R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0889] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

[0890] R 11 , R 11' , R 12 and R 12' are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0891] 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 to provide a compound of the formula XVIX

XVIX

[0892] wherein

[0893] R 2 and R 3 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

[0894] R⁵ is Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ,

-OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)R^u, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NR^uR^{i r}, -S(0)₂NRⁿR^{i r}, -OS(0)NR^uR^ir, -OS(0)₂NR^uR^ir, -NRⁿR^{i r}, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NRⁿS(0)R¹², -NRⁿS(0)₂R¹², -NRⁿS(0)NR¹²R^12',

-NR^uS(0)₂NR¹²R -P(0)(OR^u)₂, -C(0)Rⁿ, -C(0)ORⁿ or -C(0)NRⁿR^ir; or

[0895] R is Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)Rⁿ, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NR^uR^ir, -OS(0)NRⁿR^ir, -OS(0)₂NR^uR^ir,

-NR^uR^ir -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NR^uS(0)R¹²,

-NR^uS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿRⁿ ; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

[0896] R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

[0897] R 7 and R 8 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; [0898] R⁹ is H or OH; and

[0899] R¹¹, R¹¹ , R¹² and R¹² are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl.

[0900] 90. The process of claim 89, wherein the oxidizing agent in step (a) is 1,2-benziodoxol- 3(lH)-one.

[0901] 91. The process of claim 89 or 90, wherein the reducing agent in step (b) is borane dimethyl sulfide (BH₃ DMS) in the presence of a catalytic amount of (3aK)-l-Methyl-3,3- diphenyltetrahydro-3H-pyrrolo[ 1 ,2-c] [ 1 ,3,2]oxazaborole.

[0902] 92. The process of any one of claims 89 to 91, wherein the base in step (c) is imidazole.

[0903] 93. The process of any one of claims 89 to 92, wherein the silyl chloride reagent in step (c) is TES-C1.

[0904] 94. The process of any one of claims 89 to 93, wherein the base in step (d) is KHMDS.

[0905] 95. The process of any one of claims 89 to 94, wherein the alkylating agent in step (d) is bromomethyl pentyl ether.

[0906] 96. The process of any one of claims 89 to 95, wherein the non-nucleophilic fluoride reagent of step (f) is HF TEA.

[0907] 97. The process of any one of claims 89 to 96, wherein the sulfonyl chloride reagent in step (g) is methylsulfonyl chloride.

[0908] 98. The process of any one of claims 89 to 97, wherein the amine base in step (g) is triethylamine.

[0909] 99. The process of any one of claims 89 to 98, wherein the hydrogen source in step (h) is hydrogen gas.

[0910] 100. The process of any one of claims 89 to 99, wherein the palladium catalyst in step

(h) is 10% Pd/C.

[0911] 101. The process of any one of claims 89 to 100, wherein the tributyltin reagent of step

(i) is tributyltin hydroxide.

[0912] 102. The process of any one of claims 89 to 101, wherein the activating agent of step (j) is DCC-resin.

[0913] 103. The process of any one of claims 89 to 102, wherein the amino acid of step (k) is Tup or Tut, or a salt thereof.

[0914] 104. The process of any one of claims 89 to 103, wherein the base of step (k) is DIPEA.

[0915] 105. The process of any one of claims 89 to 104, wherein the polar organic solvent of step (k) is DMF. DEFINITIONS

[0916] As used herein, the term "alkyl" includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C₁-C₁₂, C₁-C₁₀, C₁-C9, Ci-Cg, C₁-C₇, Ci-C₆, and Ci-C₄, Illustratively, such particularly limited length alkyl groups, including Ci-C₈, Ci-C₇, Ci-C₆, and Ci-C₄, and the like may be referred to as "lower alkyl." Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (=0), thiocarbonyl, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in the various embodiments provided herein. It will be understood that "alkyl" may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an "alkyl" group, as described herein, with a "carboxy" group may be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.

[0917] As used herein, the term "alkenyl" includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e. C=C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C₂-C₁₂, C₂-C9, C₂-Q, C₂-C₇, C₂-C₆, and C₂-C₄. Illustratively, such particularly limited length alkenyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referred to as lower alkenyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3- butenyl, and the like.

[0918] As used herein, the term "alkynyl" includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e. C≡C). It will be understood that in certain embodiments alkynyl may each be advantageously of limited length, including C₂-C₁₂, C₂-C9, C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄. Illustratively, such particularly limited length alkynyl groups, including C₂-C₈, C₂-C₇, C₂-C₆, and C₂-C₄ may be referred to as lower alkynyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3- butynyl, and the like.

[0919] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C₆-Cio aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthalenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.

[0920] As used herein, the term "cycloalkyl" refers to a 3 to 15 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C₃-C₁₃, C₃-C₆, C₃-C₆ and C₄-C₆. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like.

[0921] As used herein, the term "heterocycloalkyl" refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.

Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms. Heterocycloalkyl may also have one of more double bonds, including double bonds to nitrogen (e.g. C=N or N=N) but does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7- membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H- pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like.

[0922] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like.

[0923] As used herein, "hydroxy" or ""hydroxyl" refers to an -OH group.

[0924] As used herein, "alkoxy" refers to both an -O-(alkyl) or an -0-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0925] As used herein, "aryloxy" refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.

[0926] As used herein, "mercapto" refers to an -SH group.

[0927] As used herein, "alkylthio" refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0928] As used herein, "arylthio" refers to an -S-aryl or an -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.

[0929] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0930] As used herein, "trihalomethyl" refers to a methyl group having three halo substituents, such as a trifluoromethyl group.

[0931] As used herein, "cyano" refers to a -CN group.

[0932] As used herein, "sulfinyl" refers to a -S(0)R^a group, where R^a is any variable group as described in the various embodiments provided herein, or R^a may be a hydroxyl group.

[0933] As used herein, "sulfonyl" refers to a -S(0)₂R^a group, where R^a is any variable group as described in the various embodiments provided herein, or R^a may be a hydroxyl group. [0934] As used herein, "S-sulfonamido" refers to a -S(0)₂NR^aR^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0935] As used herein, "N-sulfonamido" refers to a -NR^aS(0)₂R^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0936] As used herein, "O-carbamyl" refers to a -OC(0)NR^aR^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0937] As used herein, "N-carbamyl" refers to an R^aOC(0)NR^b- group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0938] As used herein, "O-thiocarbamyl" refers to a -OC(S)NR^aR^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0939] As used herein, "N-thiocarbamyl" refers to a R^aOC(S)NR^b- group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0940] As used herein, "amino" refers to an -NR^aR^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0941] As used herein, "C-amido" refers to a -C(0)NR^aR^b group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0942] As used herein, "N-amido" refers to a R^aC(0)NR^b- group, where R^a and R^b are any variable group as described in the various embodiments provided herein.

[0943] As used herein, "nitro" refers to a -N0₂ group.

[0944] As used herein, "bond" refers to a covalent bond.

[0945] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycle group optionally substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.

[0946] As used herein, "independently" means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of "independently optionally" means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of "independently" means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.

[0947] As used herein, "amino acid" (a.k.a. "AA") means any molecule that includes an alpha- carbon atom covalently bonded to an amino group and an acid group. The acid group may include a carboxyl grou . "Amino acid" may include molecules having one of the formulas:

[0948] wherein R^s is a side group and Φ includes at least 3 carbon atoms. "Amino acid" includes stereoisomers such as the D-amino acid and L- amino acid forms. Illustrative amino acid groups include, but are not limited to, the twenty endogenous human amino acids and their derivatives, such as lysine (Lys), asparagine (Asn), threonine (Thr), serine (Ser), isoleucine (lie), methionine (Met), proline (Pro), histidine (His), glutamine (Gin), arginine (Arg), glycine (Gly), aspartic acid (Asp), glutamic acid (Glu), alanine (Ala), valine (Val), phenylalanine (Phe), leucine (Leu), tyrosine (Tyr), cysteine (Cys), tryptophan (Trp), tubuphenylalanine (Tup), tubutyrosine (Tut), phosphoserine (PSER), sulfo-cysteine, argino succinic acid (ASA), hydroxyproline, phosphoethanolamine (PEA), sarcosine (SARC), taurine (TAU), carnosine (CARN), citrulline (CIT), anserine (ANS), 1,3-methyl-histidine (ME-HIS), alpha-amino-adipic acid (AAA), beta-alanine (BALA), ethanolamine (ETN), gamma-amino-butyric acid (GABA), beta-amino-isobutyric acid (BAIA), alpha-amino-butyric acid (BABA), L-allo-cystathionine (cystathionine- A; CYSTA-A), L-cystathionine (cystathionine-B; CYSTA-B), cystine, allo- isoleucine (ALLO-ILE), DL-hydroxylysine (hydroxylysine (I)), DL-allo-hydroxylysine

(hydroxylysine (2)), ornithine (ORN), homocystine (HCY), 3-amino-L-alanine (L-2,3- diaminopropionic acid or Dap) and derivatives thereof. It will be appreciated that each of these examples are also contemplated in connection with the present disclosure in the D- configuration as noted above. Specifically, for example, D-lysine (D-Lys), D-asparagine (D- Asn), D-threonine (D-Thr), D-serine (D-Ser), D-isoleucine (D-Ile), D-methionine (D-Met), D- proline (D-Pro), D-histidine (D-His), D-glutamine (D-Gln), D-arginine (D-Arg), D-glycine (D- Gly), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-alanine (D-Ala), D-valine (D-Val), D-phenylalanine (D-Phe), D-leucine (D-Leu), D-tyrosine (D-Tyr), D-cysteine (D-Cys), D- tryptophan (D-Trp), D-tubuphenylalanine (D-Tup), D-tubutyrosine (D-Tut), D-citrulline (D- CIT), D-carnosine (D-CARN), and the like. DETAILED DESCRIPTION

[0949] In each of the foregoing and each of the following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds described, but also include any and all hydrates and/or solvates of the compounds described. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and/or coordination conjugates with water and/or various solvents, in the various physical forms of the conjugates. Accordingly, the above formulae are to be understood to include and represent those various hydrates and/or solvates. It is also to be understood that the non-hydrates and/or non-solvates of the conjugate formulae are described by such formula, as well as the hydrates and/or solvates of the compounds described.

[0950] The present disclosure provides processes for preparing a compound of the formula VII

[0951] wherein R¹, R², R³, R⁵, R⁶ and R⁹ are as defined herein.

[0952] In an exemplary first step, the disclosure provides processes comprising contacting a compound of the formula I

[0953] wherein R 2", R 3^J and R 4" are as defined herein with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula II

1 2 3 4

[0954] wherein R , FT, R^J and R" are as defined herein. In some embodiments, the base can be a base capable of removing a proton from a hydroxyl group in the compound of the formula I, such as an inorganic base or an organic base. In some embodiments, the base can be an inorganic base. In some embodiments, the base can be a hydride reagent, such as NaH or KH. In some embodiments, the organic solvent can be any inert organic solvent. In some

embodiments, the organic solvent can be a polar organic solvent. In some embodiments, the organic solvent can be a polar aprotic organic solvent. Exemplary organic solvents include, but are not limited to, diethyl ether, DCM, DMF, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the alkylating agent can be any alkylating agent having the formula R^a-X, where X is a leaving group and R^a is an electrophile. In some embodiments, the alkylating agent can be any methylating agent known in the art, such as Mel, methytriflate, methyl fluorosulfonate, trimethylsulfonium hydroxide, tetramethylammonium boromide, and the like. In some embodiments, the first step can be carried out at a temperature of about 0 °C to about 25 °C.

[0955] In an exemplary second step, the disclosure provides processes comprising contacting a compound of the formula II

II

1 2 3 4

[0956] wherein R , R", R^J and R" are as defined herein 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

III

[0957] wherein R¹, R², R³, R⁴ and R⁵ are as defined herein.

[0958] In some embodiments, the base can be any non-nucleophilic base known in the art, such as potassium bis(trimethylsilyl)amide (KHMDS), sodium bis(trimethylsilyl)amide (NaHMDS),

N,N-diisopropylethyl amine (DIPEA), l,8-diazabicycloundec-7-ene (DBU), 2,6-di-tert- butylpyridine, phosphazene bases, lithium diisopropylamide (LDA), lithium

tetramethylpiperidine (LiTMP, Harpoon base), and the like. In some embodiments, the base can be KHMDS or NaHMDS . In some embodiments, the organic solvent can be any inert organic solvent. In some embodiments, the solvent can be a non-polar solvent. Exemplary non-polar solvents include, but are not limited to, toluene, hexane, heptane, benzene, and the like. In some embodiments, the organic solvent can be a polar organic solvent. In some embodiments, the organic solvent can be a polar aprotic organic solvent. Exemplary organic solvents include, but are not limited to, diethyl ether, DCM, DMF, NMP, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the alkylating agent can be any alkylating agent having the formula R⁵-X, where X is a leaving group and R⁵ is an electrophile. In some embodiments, the alkylating agent is of the formula R⁵-X, wherein X is a leaving group and R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to

7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)Rⁿ, -OC(0)NRⁿR^ir, -OS(0)Rⁿ, -OS(0)₂Rⁿ, -SR¹¹, -SC(0)R^u, -S(0)Rⁿ, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NR^uR^{i r}, -S(0)₂NRⁿR^{i r}, -OS(0)NR^uR^ir, -OS(0)₂NR^uR^ir, -NRⁿR^{i r}, -NRⁿC(0)R¹², -NR^uC(0)OR¹², -NRⁿC(0)NR¹²R^12', -NRⁿS(0)R¹², -NRⁿS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NR^uS(0)₂NR¹²R^12', -P(0)(OR^u)₂, -C(0)Rⁿ, -C(0)ORⁿ or -C(0)NRⁿR^ir.

[0959] In some embodiments, the alkylating agent is of the formula R⁵-X, wherein X is a leaving group and R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, 5- to 7-membered heteroaryl, -OR¹¹, -OC(0)R^u, -OC(0)NRⁿR^{i r}, -OS(0)Rⁿ, -OS(0)₂R^U, -SR¹¹, -SC(0)R^u, -S(0)R^u, -S(0)₂Rⁿ, -S(0)₂ORⁿ, -S(0)NRⁿR^ir, -S(0)₂NRⁿR^ir, -OS(0)NR^uR^ir,

-OS(0)₂NR^uR^ir, -NRⁿR^ir, -NRⁿC(0)R¹², -NRⁿC(0)OR¹², -NRⁿC(0)NR¹²R^12',

-NR^uS(0)R¹², -NRⁿS(0)₂R¹², -NRⁿS(0)NR¹²R^12', -NRⁿS(0)₂NR¹²R^12', -P(0)(ORⁿ)₂, -C(0)Rⁿ, -C(0)OR^u or -C(0)NRⁿR^ir; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl.

[0960] In some embodiments, the alkylating agent is of the formula R⁵-X, wherein X is a leaving group and R⁵ is C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl.

[0961] In some embodiments, the alkylating agent is of the formula R⁵-X, wherein X is a leaving group and R⁵ is C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C6-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Cn alkyl.

[0962] In some embodiments, the alkylating agent can be an alkyl-halide, such as chloromethyl methyl ether, benzyloxymethyl chloride, 2-methoxyethoxymethyl chloride, 2- (Trimethylsilyl)ethoxymethyl chloride, (dimethyl-i-butylsilyloxy)methyl chloride, p- methoxybenzyloxymethyl chloride, guaiacolmethyl chloride, /?-anisyloxymethyl chloride, (phenyldimethylsilyl)methoxymethyl chloride, i-butoxymethyl chloride, ethoxyethyl chloride, chloromethyl pentyl ether, 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, and the like. In some embodiments, the alkylating agent can be bromomethyl pentyl ether.

[0963] In an exemplary third step, the disclosure provides processes comprising contacting a compound of the formula III

III

[0964] wherein R 1 R 2", R 3^J, R 4" and R 5^J are as defined herein with an activated ester of the formula

[0965] wherein R⁶ is as defined herein in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

IV

[0966] wherein R¹ R², R³, R⁴, R⁵ and R⁶ are as defined herein.

[0967] In some embodiments, the hydrogen source can be hydrogen gas. In some embodiments, the palladium catalyst can be any palladium catalyst known in the art, such as heterogeneous palladium catalysts, homogeneous palladium catalysts, supported palladium catalysts, and the like. Exemplary palladium catalysts, include but are limited to, 5% Pd/C, 10% Pd/C, 10% Pd/alumina, 5% Pd/barium sulfate, 10% Pd/barium sulfate, 5% Pd/barium carbonate, 5% Pd/calcium carbonate, 10% Pd/calcium carbonate, and the like. In some embodiments, the palladium catalyst can be 10% Pd/C. In some embodiments, the palladium catalyst is used in about 0.01 to about 0.5 equivalents compared to the compound of the formula III. In some embodiments, the reaction can be carried out in an inert organic solvent. In some embodiments, the inert organic solvent can be a polar organic solvent. In some embodiments, the inert organic solvent can be a polar aprotic organic solvent. Exemplary inert organic solvents include, but are not limited to, diethyl ether, DCM, DMF, NMP, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the inert organic solvent can be NMP.

[0968] In some embodiments, the compound of the formula

[0969] wherein R⁶ is as defined herein can be prepared by contacting a carboxylic acid of the formula R⁶-C0₂H with pentafluorophenol in an organic solvent in the presence of a condensing agent, such as 3-(ethyliminomethylideneamino)-N,N-dimethylpropan-l-amine hydrochloride (EDC^'HCl). In some embodiments, the com ound of the formula

[0970] is prepared and contacted with the compound of the formula III in about 1.0 to about 2.0 equivalents compared to the compound of the formula III. In some embodiments, the reaction can be carried out in an inert organic solvent. In some embodiments, the inert organic solvent can be a polar organic solvent. In some embodiments, the inert organic solvent can be a polar aprotic organic solvent. Exemplary inert organic solvents include, but are not limited to, diethyl ether, DCM, DMF, NMP, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the inert organic solvent can be NMP.

[0971] In an exemplary fourth step, the disclosure provides processes comprising contacting a compound of the formula IV

IV

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined herein with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

V

[0972] wherein R¹, R², R³, R⁵ and R⁶ are as defined herein.

[0973] In some embodiments, the base can be an inorganic base. In some embodiments, the base can be a weak inorganic base, such as lithium hydroxide. In some embodiments, it is convenient to use an excess of weak inorganic base. In some embodiments, the weak inorganic base is used in an amount of about 1.1 equivalents to about 10 equivalents. In some embodiments, the aqueous solvent system can be a mixture of an alcohol and water, such as methanol/water or ethanol/water.

[0974] In an exemplary fifth step, the disclosure provides processes comprising contacting a compound of the formula V

V

[0975] wherein R¹, R², R³, R⁵ and R⁶ are as defined herein with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

[0976] wherein R¹, R², R³, R⁵ and R⁶ are as defined herein. [0977] In some embodiments, the activating agent can be N-cyclohexyl carbodiimide (DCC), or DCC-resin. In some embodiments, the reaction can be carried out in an inert organic solvent. In some embodiments, the inert organic solvent can be a polar organic solvent. In some embodiments, the inert organic solvent can be a polar aprotic organic solvent. Exemplary inert organic solvents include, but are not limited to, diethyl ether, DCM, DMF, NMP, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the inert organic solvent can be DCM.

[0978] In an exemplary sixth step, the disclosure provides processes comprising contacting a compound of the formula VI

VI

[0979] wherein R¹, R², R³, R⁵ and R⁶ are as defined herein 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 to provide a compound of the formula VII

[0980] wherein R¹, R², R³, R⁵, R⁶ and R⁹ are as defined herein.

[0981] In some embodiments, the amino acid is tubuphenylalanine (Tup) or tubutyrosine (Tut), or a salt thereof. In some embodiments, the amino acid is tubuphenylalanine (Tup) HC1. In some embodiments, the amino acid is tubutyrosine (Tut) HC1. In some embodiments, the base can be any non-nucleophilic base known in the art, such as potassium bis(trimethylsilyl)amide (KHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), N,N-diisopropylethyl amine (DIPEA), l,8-diazabicycloundec-7-ene (DBU), 2,6-di-tert-butylpyridine, phosphazene bases, lithium diisopropylamide (LDA), lithium tetramethylpiperidine (LiTMP, Harpoon base), and the like. In some embodiments, the base can be DIPEA. Exemplary polar organic solvents include, but are not limited to, diethyl ether, DCM, DMF, NMP, THF, EtOAc, acetone, acetonitrile, DMSO, nitromethane, propylene carbonate and the like. In some embodiments, the inert organic solvent can be EtOAc.

[0982] It will be appreciated that the methods and compounds described herein are useful in the preparation of drug delivery conjugates, where the tubulysin analogs described herein act as a therapeutic agent to be delivered to the site of action in a patient by a binding ligand or targeting ligand. Examples of such drug delivery conjugates include those described in

WO2014/062697. Furthermore, it will be appreciated that the methods described in

WO2014/062697 for the preparation of drug delivery conjugates can be modified accordingly to incorporate the tubulysin derivatives described herein in such conjugates.

EXAMPLES

[0983] CHEMISTRY EXAMPLES

[0984] Materials

[0985] l-bromo-2-pentene (predominantly trans), benzyl bromide, 4-trifluoromethylbenzyl bromide, were purchased from Sigma Aldrich (St. Louis, MO); (2E)-l-bromo-2-hexene was purchased from Aldlab Chemicals (Woburn, MA); (E)-l-Bromo-5-methylhex-2-ene was synthesized according to the procedure reported on Organic Letters, 2013, 15(17), 4616-4619.

[0986] Example 1: Synthesis of EC1820 (7)

EC1820 (7)

[0987] Step 1: 1.2 g of dipeptide 1 (3 mmol) was dissolved in 3 mL of DMF and cooled to 0°C. To the solution was added 120 mg of NaH (60% in mineral oil, 3 mmol). The reaction was stirred for 30 min. under argon, and 200 μΐ_^ of Mel (1.08 eq.) was added. The reaction was stirred for an additional 2 hr., at which time LC/MS showed that the majority of the starting material was consumed. The reaction was quenched and diluted with H₂0, and the aqueous mixture was extracted with EtOAc. The organic layer was washed with H₂0 followed by brine, and dried over Na₂S0₄. The solvent was then removed under reduced pressure to give an oily residue. The product was purified by automated flash chromatography using EtOAc/Petroleum ether as the eluent to give 0.8 g (65%) of the desired methyl ether product 2.

[0988] Step 2: 0.8 g of dipeptide methyl ether 2 (1.95 mmol) was dissolved in 8 mL of anhydrous THF (inhibitor- free). The solution was cooled to -45°C in a dry ice/acetonitrile bath. After 15 min, 4.1 mL of KHMDS (0.5 M in toluene, 2.05 mmol, 1.05 eq.) was added dropwise. The resulting reaction mixture was stirred at -45°C for 15 min. at which time 420 μΐ_^ of bromomethyl pentyl ether was added. The reaction was stirred for an additional 30 min., at which time LC/MS showed no remaining dipeptide methyl ether starting material. The reaction was quenched with 10% NaCl/1% NaHC0₃ aqueous solution, and the aqueous mixture was extracted with EtOAc. The organic layer was washed twice with 10% NaCl/1% NaHC0₃ aqueous solution followed by brine, and dried over Na₂S0₄. The solvent was removed under reduced pressure. The product was purified by automated flash chromatography using MeOH/DCM as the eluent to give 210 mg (21%) of the desired product, EC1794 (3). LCMS

(ESI) [M+H]⁺ 512.39. 1H NMR (CD₃OD): δ 7.95 (s, 1H), 4.75 (d, J = 10.3 Hz, 1H), 4.55 (d, J = 10.3 Hz, 1H), 4.51 (dd, J = 10.3, 2.4 Hz, 1H), 3.90 (s, 3H), 3.76 (d, J = 9.3 Hz, 1H), 3.51-3.48 (m, 1H), 3.44-3.40 (m, 1H), 3.35 (s, 3H), 2.20-2.18 (m, 2H), 2.01 (m, br, 1H), 1.83-1.70 (m, 2H), 1.68-1.52 (m, 2H), 1.38-1.24 (m, 5H), 1.01-0.96 (m, 9 H), 0.88 (d , J = 6.8 Hz, 3H), 0.85 (t, br, J = 6.8 Hz, 3H).

[0989] Step 3: 60 mg of MEP (0.42 mmol, 1.4 equiv compared to EC1794) was suspended in 1.0 mL NMP. 83 mg of pentafluorophenol (0.45 mmol, 1.5 eq.) and 86 mg of EDC-HC1 (0.45 mmol, 1.5 equiv) were added to the suspension. The reaction mixture was stirred overnight at room temperature, at which time the reaction mixture was transferred into a hydrogenation vessel containing 151 mg of EC1794 (3) in 1.0 mL NMP. 25 mg of 10% Pd/C (dry, 0.05 equiv) was added to the resulting mixture. The hydrogenation vessel was pumped/filled with H₂ three times. Hydrogenation was carried out at 35 PS I H₂ for 3 hours at which time LC/MS showed no remaining EC 1794 starting material. The reaction mixture was passed through a celite pad and washed with EtOAc. The solution diluted with 10% NaCl/1% NaHC0₃ aqueous solution and extracted with EtOAc. The organic layer was washed with brine, and dried over Na₂S0₄. The solvent was removed under reduced pressure after filtering off Na₂S0₄. The product was purified by automated flash chromatography system using MeOH/DCM as the eluent to give 68 mg (38%) of EC1795 (4). LCMS (ESI) [M+H]⁺ 611.39. 1H NMR (500 MHz, CD₃OD): δ 8.39 (s, 1H), 5.35 (d, J = 9.8 Hz, 1H), 4.70 (d, J = 9.3 Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 4.42 (d, J = 9.8 Hz, 1H), 3.90 (s, 3H), 3.51 (m, 2H), 3.33 (s, 3H), 2.96 (dd, br, J = 12.7 Hz, 1H), 2.67 (dd, br, J = 10.8 Hz, 1H), 2.22 (s, 3H), 2.18-1.98 (m, 5H), 1.79 (m, 3H), 1.70-1.50 (m, 7H), 1.40- 1.20 (m, 6H), 1.01 (d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.92 (t , J = 6.8 Hz, 3H), 0.84 (t , J = 6.8 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H).

[0990] ¹³C NMR (125 MHz, CD₃OD): δ 175.07, 174.24, 173.43, 161.73, 146.32, 128.20, 77.48, 68.89, 67.27, 56.76, 55.16, 53.66, 51.24, 43.15, 37.15, 36.37, 31.07, 30.04, 28.90, 28.28, 24.58, 24.33, 22.73, 22.06, 19.26, 18.89, 15.16, 12.96, 9.37.

[0991] Step 4: 24 mg of EC1795 (4) (0.039 mmol) was dissolved in 0.8 mL of MeOH and cooled to 0 °C. 7.3 mg (0.17 mmol, 4.4 eq) of LiOH monohydrate was dissolved in 0.2 mL H₂0 and added to the solution. The reaction mixture was then warmed to room temperature. After 1 hour, LC/MS showed the reaction to be complete. The solvent was removed under reduced pressure. The EC1819 (5) residue was dried under high vacuum and used without further purification. LCMS (ESI) [M-H]^~ 595.68. 1H NMR (500 MHz, CD₃OD): δ 7.95 (s, 1H), 5.28 (d, J = 10.3 Hz, 1H), 4.68 (d, J = 8.8 Hz, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 10.3 Hz, 1H), 3.50 (t, J = 6.8 Hz, 2H), 3.30 (s, 3H), 3.02 (br, 1H), 2.27 (s, br, 3H), 2.23-2.10 (m, 2H), 2.07- 1.94 (m, 2H), 1.88-1.74 (m, 3H), 1.70-1.46 (m, 6H), 1.40-1.27 (m, 6H), 1.21 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.92 (t , J = 7.4 Hz, 3H), 0.87 (t , J = 7.4 Hz, 3H), 0.80 (br, 3H). [0992] Step 5: 8.0 mg of EC1819 (5) (0.013 mmol) was mixed with 24 mg of DCC-resin (0.055 mmol, 4 equiv) and 4 mg of PFP (0.022 mmol, 1.7 equiv) in 0.3 mL anhydrous DCM. The reaction mixture was stirred at room temperature overnight. The resin was filtered off and washed with DCM. The resulting solution of EC1819-PFP ester (6) was concentrated under reduced pressure and used without further purification.

[0993] Step 6: The EC1819-PFP ester (6) was dissolved in 0.2 mL anhydrous DMF. 32 μΐ. of DIPEA (14 eq.) and 2.9 mg of Tut-HCl salt (0.011 mmol, 0.9 eq.) were added to the solution. The reaction mixture was stirred at room temperature for 10 minutes, at which time LC/MS showed complete conversion of the starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂S0_4. The solvent was removed under reduced pressure after filtering off Na₂S0₄ to give 10 mg of crude oily residue. The product was purified on Prep-HPLC with 50 mM NH₄HC0₃ (pH

7.4)/acetonitrile as the eluent to give 4.0 mg (38%) of EC1820 (7). LCMS (ESI) [M+H]⁺ 802.81; ¹H NMR (500 MHz, CD₃OD): δ 8.10 (s, 1H), 7.02 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H), 5.40 (d, J = 9.8 Hz, 1H), 4.68 (d, J = 9.3 Hz, 1H), 4.57 (m, J = 11.2 Hz, 1H), 4.41 (d, J = 10.3 Hz, 1H), 4.32 (m, 2H), 3.50-3.43 (m, 1H), 3.42-3.38 (m, 1H), 3.36 (s, 3H), 3.03 (m, br, 1H), 2.86-2.80 (m, 3H), 2.54-2.46 (m, 1H), 2.32-2.25 (s+m, 3H+1H), 2.15-1.96 (m, 4H), 1.88- 1.76 (m, 3H), 1.74-1.46 (m, 9H), 1.40-1.20 (m, 9H), 1.16 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz, 6H), 0.92 (t , J = 7.3 Hz, 3H), 0.83 (t , J = 6.8 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H). ¹³C NMR (125 MHz, CD₃OD): δ 179.52, 174.97, 173.78, 172.59, 161.34, 155.68, 149.58, 130.30, 128.22, 123.39, 114.77, 77.59, 68.53, 67.05, 56.99, 55.10, 53.84, 49.10, 48.20, 42.89, 39.44, 37.85, 37.36, 37.22, 36.31, 31.07, 29.85, 29.32, 29.03, 28.36, 24.33, 24.29, 22.45, 22.05, 19.30, 18.97, 17.32, 15.11, 12.99, 9.40.

[0994] Example 2: Synthesis of EC1973 (11)

EC1973 (11 )

[0995] Step 1: N,N-dimethylglycine (15 mg, 0.15 mmol), PFP-OH (28mg, 0.15 mmol, 1 eq.) and DCC-resin (200 mg, 0.46 mmol, 3 eq.) were mixed in 1.0 mL anhydrous EtOAc. The reaction mixture was stirred at room temperature overnight. LC/MS showed all N,N- dimethylglycine was converted to the corresponding PFP-ester. The resin was filtered off and mixed with EC1794 (3) (prepared as described above) (51 mg, 0.1 mmol, 0.67 eq.) in 0.3 mL EtOAc. 8.5 mg of 10% dry Pd/C (0.05 equiv) was added to the mixture and the hydrogenation reaction carried out under a H₂ atmosphere (using a balloon filled with H₂). The reaction was monitored by LC/MS. Excess Pd/C was filtered off and washed with MeOH after the reaction had reached completion. The filtrate was then extracted with EtOAc and 1% Na₂CO₃/10%NaCl aqueous solution, and the organic extract washed with brine and dried over Na₂S0₄. Na₂S0₄ was filtered off and the solvent evaporated to give 40 mg of the crude product EC1971 (8) (70%) which was used directly in the next step without further purification.

[0996] Step 2: 40 mg (0.07 mmol) of crude EC1971 (8) was dissolved in 0.5 mL of MeOH. To the solution was added a LiOH aqueous solution (12 mg of LiOH monohydrate in 0.15 mL H₂0, 0.28 mmol, 4 eq.). After 3hrs, LC/MS showed all the starting material had been consumed. The solvent was removed under vacuum. The residue of EC1972 (9) was dried under high vacuum and used without further purification.

[0997] Step 3: 6 mg of EC1972 (9) (0.011 mmol), 6 mg of PFP-OH (0.033 mmol, 3 eq.) and 35 mg of DCC-resin (0.082 mmol, 7.5 eq.) were mixed in 0.5 mL of EtOAc and stirred overnight at room temperature. The resin was filtered off and the filtrate containing the activated ester 10 was mixed with 5.3 mg of Tup HC1 salt (0.022 mmol, 2 eq.) in 0.3 mL DMF. 30 of Et₃N (0.22 mmol, 20 equiv) was then added to the reaction mixture. The reaction was monitored with LC/MS. After reaching completion, the reaction mixture was purified by prep-HPLC with actonitrile/H₂0 (10% to 100% ACN). After lyophilization, 1.5 mg (18%) of the desired product EC1973 (11) was obtained. LCMS (ESI) [M+H]⁺ 746.43; 1H NMR (500 MHz, CD₃OD): 8.08 (s, 1H), 7.21 (m, 4H), 7.15 (m, 1H), 5.30 (d, J = 9.8 Hz, 1H), 4.76 (d, J = 9.9 Hz, 1H), 4.56 (dd, J = 10.8, 2.0 Hz, 1H), 4.48 (br, 1H), 4.42 (d, J = 10.3 Hz, 1H), 4.35 (m, 1H), 3.51-3.42 (m, 2H), 3.35 (s, 3H), 3.07 (d, J = 15.6 Hz, 1H), 2.98 (d, J = 15.6 Hz, 1H), 2.95 (dd, J = 13.7, 5.9 Hz, 1H), 2.88 (dd, J = 13.7, 5.9 Hz, 1H), 2.51-2.43 (m, 1H), 2.30 (s, 3H), 2.17-2.10 (m, 1H), 2.07- 1.80 (m, 3H), 1.77 (br, IH), 1.68-1.47 (m, 4H), 1.35-1.25(m, 4H), 1.25-1.16(m, IH), 1.16 (d, J = 7.4 Hz, 3H), 1.00 (t, J = 6.4 Hz, 6H), 0.93 (t , J = 7.3 Hz, 3H), 0.83 (t , J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). ¹³C NMR (125 MHz, CD₃OD): 181.52, 174.98, 173.40, 170.88, 161.31, 149.71, 138.11, 129.25, 127.85, 125.90, 123.29, 77.45, 67.14, 61.80, 56.83, 53.65, 49.68, 44.52, 40.39, 38.71, 38.46, 37.23, 36.61, 31.11, 28.99, 28.32, 24.15, 22.04, 19.26, 18.79, 17.76, 15.16, 12.99, 9.62.

[0998] Example 3: Synthesis of EC1948 (12)

EC1948 (12)

EC1948 (12) was prepared over 3 steps from EC1795 (4) following the same procedures as described in Example 1 for the synthesis of EC1820 (7), except that Tup HCl was used in the last step in place of Tut HCl, with an overall yield of 6.5%. LCMS (ESI) [M+H]⁺ 786.55; 1H NMR (500 MHz, CD₃OD): 8.09 (s, IH), 7.21 (m, 4H), 7.15 (m, IH), 5.40 (d, J = 9.8 Hz, IH), 4.69 (d, J = 9.3 Hz, IH), 4.58 (dd, J = 10.6, 1.7Hz, IH), 4.41 (d, J = 9.8.3 Hz, IH + m, IH), 3.52-3.42 (m, 2H), 3.35 (s, 3H), 2.96-2.90 (m, 2H),3.03 (m, br, IH), 2.86 (dd, J = 13.7, 7.3 Hz, IH), 2.60 (dd, IH), 2.46-2.38 (m, IH), 2.18 (s, 3H), 2.17-1.97 (m, 5H), 1.80-1.72 (m, 3H), 1.68-1.48 (m, 7H), 1.36-1.20 (m, 6H), 1.13 (d, J = 7.3 Hz, 3H), 1.03-0.98 (d+d, 6H), 0.92 (t , J = 7.8 Hz, 3H), 0.83 (t , J = 7.3 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H).

[0999] Example 4: Synthesis of EC2796 (18)

1 ) 0.5 M KHMDS

EC2796 (18)

[01000] Step 1: 2.22 g of dipeptide 1 (5.59 mmol) was dissolved in 9.4 niL of DMF and cooled to 0 °C. The solution was purged with Argon. To the solution, 227 mg of NaH (60% in mineral oil, 5.68 mmol, 1.02 eq) was added. Then 469 μΐ_^ of Etl (5.86 mmole, 1.05 eq.) was added to the reaction mixture. UPLC/MS (10-100% acetonitrile/20 mM NH₄HC0₃, pH 7.4 buffer) was used to monitor the progress of the reaction. After 1.5 hours, the reaction mixture was worked up by extraction between dichloromethane and brine (twice). The organic extract was dried over Na₂S0₄. The salt was filtered off and the solvent was then removed under reduced pressure to give an oily residue. Purification on an automated flash chromatography system using EtOAc/P. Ether gave 1.69 g (71%) of the desired product EC2775 (13) as clear oil. LCMS (ESI) [M+H]⁺, calculated for Ci₉H₃₂N₅0₄S: 426.22; found 426.11. 1H NMR (CD₃OD): 8.35 (s, 1H), 4.55 (m, 1H), 4.15 (m, 1H), 3.91 (s, 3H), 3.66 (d, J = 8 Hz, 1H), 3.60- 3.50 (m, 2H), 2.05-1.96 (m, 1H), 1.92-1.85 (m, 2H), 1.82-1.75 (m, 1H), 1.68-1.59 (m, 1H), 1.33-1.24 (m, 1H), 1.22 (t, J = 7 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3 H), 0.96-.090 (m , 9H).

[01001] Step 2: 0.45 g of dipeptide ethyl ether EC2775 (13) (1.06 mmol) was dissolved in 4 mL of anhydrous THF (inhibitor- free). The solution was cooled to -45°C in a dry ice/acetonitrile bath. After 15 min, 2.2 mL of KHMDS (0.5 M in toluene, 1.1 mmol, 1.05 eq.) was added dropwise. The resulting reaction mixture was stirred at -45°C to -60°C for 30 min. 280 μΐ_^ of l-bromo-2-pentene (2 eq, predominantly trans) was then added at -60°C. The reaction mixture was warmed up to -20°C in 2 hours. Then the reaction mixture was kept at - 20°C overnight (in freezer). LC/MS showed majority of the starting material converted. The reaction was diluted with H₂0 and EtOAc. The layers were separated and the aqueous layer was washed with additional EtOAc. The combined organic layer was washed with brine and dried over Na₂S0₄. The solvent was removed under reduced pressure. Purification on an automated flash chromatography system with EtOAc/P. Ether gave 318 mg (61%) of the desired product, EC2776 (14). LCMS (ESI) [M+H]⁺ calculated for C₂₄H₄₀N₅O₄S: 494.28; found: 494.24. 1H NMR (CD₃OD): 8.35 (s, 1H), 5.81-5.65 (m, 2H), 4.65-4.55 (br, 1H), 4.44 (dd, J 1H), 3.99 (dd, 1H), 3.90 (s, 3H), 3.76 (d, J = 10 Hz, 1H), 3.54 (q, J = 6.5 Hz, 2H), 2.20-2.10 (m, 3H), 2.10- 2.00 (m, 2H), 1.90-1.70 (m, 2H), 1.38-1.28 (m, 1H), 1.23 (t, J = 7 Hz, 3H), 1.15-0.87 (m, 15 H).

[01002] Step 3: 3.7 mg of MEP (0.026 mmol, 2.0 equiv compared to EC2776 (14)) was suspended in 1.0 mL EtOAc. To the suspension, 4.8 mg of pentafluorophenol (0.026 mmol, 2.0 eq.) and 5.0 mg of EDC-HC1 (0.026 mmol, 2.0 equiv) were added. 1 mL of DMF was added to dissolve EDC-HC1. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then transferred into a vial with 6.4 mg of EC2776 (14) (0.013 mmole) in 0.5 mL DMF. To the resulting mixture, 1.5 mg of 10% Pd/C (dry, 0.1 equiv) was added. The reaction vessel was evacuated/filled with H₂ three times. Hydro genation was carried out under H₂ atmosphere with a H₂ balloon. The reaction progress was monitored by UPLC/MS. After the reaction was completed, it was worked up by partition between EtOAc and H₂0. The organic layer was washed with brine and dried over Na₂S0₄. The solvent was removed under reduced pressure after filtering off Na₂S0₄ to give 10 mg of the crude product of EC2794 (15). EC2794

(15) was used without further purification. LCMS (ESI) [M+H]⁺ , calculated for C₃iH₅₃N₄0₅S: 593.37; found: 593.38.

[01003] Step 4: 10 mg of EC2794 (15) (crude, 0.017 mmol) was dissolved in 1.0 mL of

MeOH. 2.8 mg (0.068 mmol, 4 eq) of LiOH monohydrate was dissolved in 0.2 mL H₂0 and added to the solution. The reaction mixture was stirred at room temperature for 4 hours. LC/MS showed complete conversion. The solvent was removed under reduced pressure. The EC2795

(16) residue was dried under high vacuum and used without further purification. LCMS (ESI) [M+H]⁺, calculated for C₂9H₅₀N₅O₅S: 580.35; found: 580.57.

[01004] Step 5: The crude product EC2795 (16) ( 0.013 mmol based on the starting material EC2776 (14)) was mixed with 28 mg of DCC-resin (0.065 mmol, 5 equiv) and 5 mg of PFP (0.028 mmol, 2 equiv) in 2 mL anhydrous EtOAc. After overnight stirring, LC/MS showed no reaction. Resin was filtered off and EtOAc was removed under reduced pressure. Dissolved the residue in 1 mL anhydrous DMF, and 56 mg of DCC-resin (0.13 mmol, 10 equiv) and 5 mg of PFP (0.028 mmol, 2 equiv) were added to the solution. The reaction mixture was stirred at room temperature overnight. LC/MS showed majority of the acid was converted to PFP ester 17. The DCC-resin was filtered off. To the solution, 6.7 mg of Tut-HCl salt (0.026 mmol, 2 eq.) and 18 μΐ_^ of TEA (10 eq.) and were added. The reaction mixture was stirred at room temperature and the reaction progress was monitored by LC/MS. After the reaction was complete, the reaction mixture was loaded on Prep-HPLC with 50 mM NH₄HC0₃ (pH 7.4)/acetonitrile gave 2.0 mg (20%) of EC2796 (18). LCMS (ESI) [M+H]⁺, calculated for Q₂H₆₆N₅O₇S: 784.47; found: 785.03; ¹H NMR (500 MHz, CD₃OD): 8.09 (s, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.3 Hz, 2H), 5.97-5.88 (m, 1H), 5.68-5.60 (m, 1H), 4.81 (d, J = 9 Hz, 1H), 4.60 (dd, J = 16.5, 9 Hz, 1H), 4.41 (d, J = 13 Hz, 1H), 4.31 (m, 1H), 3.79 (d, J = 13 Hz, 1H), 3.58 (m, 2H), 3.16 (m, 1H), 2.98 (d, br, J=11.5 Hz, 1H), 2.88-2.75 (m, 3H), 2.75-2.68 (br, d, J=10.5 Hz, 1H), 2.54-2.44 (m, 1H), 2.24 (s, 3H), 2.22-2.14 (m, 1H), 2.08-1.94 (m, 6H), 1.88- 1.74 (m, 3H), 1.72-1.50 (m, 5H), 1.40-1.18 (m, 2H), 1.25 (t, J = 7 Hz, 3H), 1.15 (d, J = 7.5 Hz, 3H), 1.01 (d, J = 6 Hz, 6H), 0.98 (t , J = 7.5 Hz, 3H), 0.93(d , J = 7.5 Hz, 3H), 0.89(t , J = 7.5 Hz, 3H), 0.81 (d , J = 6.5 Hz, 3H).

[01005] Exam le 5: Synthesis of EC2885 (19)

EC2885 (19)

[01006] EC2885 (19) was prepared using procedures similar to the method described for the synthesis of EC2796 (18). One of skill in the art will readily appreciate and envision modifications and reagents necessary for the preparation of the following conjugates.

[01007] LCMS (ESI) [M+H]⁺, calculated for C₄₃H₆8N50₇S: 798.48; found: 798.80; 1H

NMR (500 MHz, CD₃OD): 8.07 (s, 1H), 7.01 (d, J = 11.5 Hz, 2H), 6.64 (d, J = 11.5 Hz, 2H), 5.92-5.87 (m, 1H), 5.67-5.62 (m, 1H), 4.81 (1H), 4.55 (dd, J = 17, 9 Hz, 1H), 4.40 (d, J = 12 Hz, 1H), 4.29 (m, 1H), 3.79 (d, br, 1H), 3.57 (m, 2H), 2.94-2.84 (m, br, 2H), 2.80-2.72 (m, 1H), 2.54 (dd, 1H), 2.46-2.38 (m, 1H), 2.16 (s, 3H), 2.08-1.94 (m, 7H), 1.80-1.70 (m, 2H), 1.68-1.45 (m, 5H), 1.39 (m, 2H), 1.36-1.26 (m, 2H), 1.23 (t, J = 7 Hz, 3H), 1.13 (d, J = 7.5 Hz, 3H), 1.00 (d, J = 6 Hz, 6H), 0.94 (t , J = 7.5 Hz, 3H), 0.92-0.87(m, 6H), 0.80 (d , J = 6.5 Hz, 3H).

[01008] Example 6: Synthesis of EC2888 (20)

EC2888 (20)

[01009] EC2888 (20) was prepared using procedures similar to the method described for the synthesis of EC2796 (18). One of skill in the art will readily appreciate and envision modifications and reagents necessary for the preparation of the following conjugates.

[01010] LCMS (ESI) [M+H]⁺, calculated for C₄₆H₆₆N₅0₇S: 832.47; found: 832.77; 1H

NMR (500 MHz, CD₃OD): 8.06 (s, 1H), 7.40 (d, J = 7.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H), 7.26 (m, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 16.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 2H), 6.53-6.49 (m, 1H), 4.88 (d, J = 9.5 Hz, 1H), 4.78 (m, 1H), 4.52 (dd, J = 12 Hz, 1H), 4.19 (m, 1H), 4.06 (d, br, 1H), 3.63 (m, 2H), 2.91 (m, 1H), 2.80 (m, 1H), 2.70 (dd, J = 14, 5.5 Hz, 1H), 2.50-2.40 (m, 2H), 2.38-2.15 (m+s, 2H + 3H), 2.10-1.90 (m, 3H), 1.88-1.74 (m, 3H), 1.74-1.56 (m, 3H), 1.55- 1.46 (m, 1H), 1.44-1.32 (m, 2H), 1.25 (t, J = 7 Hz, 3H), 1.20-1.12(m, 2H), 1.09 (d, J = 7.5 Hz, 3H), 1.01 (d , 3H), 0.88-0.82(m, 6H), 0.75 (t , J = 7.5 Hz, 3H).

[01011] Example 7: Synthesis of EC2892 (21)

[01012] EC2892 (21) was prepared using procedures similar to the method described for the synthesis of EC2796 (18). One of skill in the art will readily appreciate and envision modifications and reagents necessary for the preparation of the following conjugates.

[01013] LCMS (ESI) [M+H]⁺ : Calculated for C₄₄H₆₄N₅0₇S, 806.44; found 806.32;

Selected data 1H NMR (CD30D): δ 8.06 (s, 1H), 7.53 (d, J = 7 Hz, 2H), 7.20-7.40 (series of m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8 Hz, 2 H), 2.43 (s, 3 H), 1.26 (t, J = 6.5 Hz, 7.0 Hz, 3H), 1.19 (d, J = 7.5 Hz, 3H), 0.99 (d, J = 7 Hz, 3H), 0.83 (d, J = 7 Hz, 3H), 0.70 (t, J = 7.5 Hz, 7.0 Hz, 3H), 0.60 (t, J = 6.0 Hz, 3H).

[01014] Example 8: Synthesis of EC2902 (22)

[01015] EC2902 (22) was prepared using procedures similar to the method described for the synthesis of EC2796 (18). One of skill in the art will readily appreciate and envision modifications and reagents necessary for the preparation of the following conjugates.

[01016] LCMS (ESI) [M-H]^~: calculated for C44H69N5O7S: 810.49; found 810.97. 1H

NMR (500 MHz, 298 K, CD₃OD) δ 8.091 (s, 1H), 7.029 (d, J = 8.5 Hz, 2H), 6.676 (d, J = 8.5 Hz, 2H), 5.888 (m, 1H), 5.667 (m, 1H), 4.821 (d, 7 = 9.0 Hz, 1H), 4.549 (dd, J = 8.5, 16.5 Hz, 1H), 4.441 (d, / = 12.0 Hz, 1H), 4.301 (m, 1H), 3.831 (d, / = 12.0 Hz, 1H), 3.564 (m, 2H), 3.009 (d, J = 11.5 Hz, 1H), 2.813 (m, 3H), 2.490 (m, 1H), 2.257 (s, 3H), 2.203 (m, 2H) 1.973 (m, 6H), 1.818 (m, 2H), 1.611 (m, 6H), 1.332 (m, 1H), 1.243 (t, J = 7.0 Hz, 3H), 1.181 (m, 1H), 1.168 (d, J = 7.5 Hz, 3H), 1.006 (d, J = 6.5 Hz, 3H), 0.953 (d, J = 7.0 Hz, 3H), 0.899 (m, 9H), 0.835 (d, = 7.0 Hz, 3H).

[01017] Example 9: Synthesis of EC2915 (23)

[01018] EC2915 (23) was prepared using procedures similar to the method described for the synthesis of EC2796 (18). One of skill in the art will readily appreciate and envision modifications and reagents necessary for the preparation of the following conjugates.

[01019] EC2915: LCMS (ESI) [M-H]^~: calculated for C₄₅H₆₂F₃N₅O₇S: 872.43; found

872.77. 1H NMR (500 MHz, 298 K, CD₃OD) δ 8.083 (s, 1H), 7.723 (d, = 8.0 Hz, 2H), 7.594 (d, = 8.0 Hz, 2H), 6.941 (d, = 8.0 Hz, 2H), 6.589 (d, = 8.0 Hz, 2H), 5.067 (m, 2H), 4.621 (d, = 7.5 Hz, 1H), 4.501 (d, = 9.0 Hz, 1H), 4.313 (m, 2H), 3.594 (m, 3H), 3.019 (m, 2H), 2.772 (m, 3H), 2.530 (m, 1H), 2.302 (s, 3H), 2.056 (m, 3H), 1.998 (m, 3H), 1.624 (m, 3H), 1.372 (m, 3H), 1.176 (m, 6H), 1.031 (m, 6H), 0.837 (d, = 7.0 Hz, 3H), 0.703 (t, = 7.5 Hz, 3H).

[01020] BIOLOGY EXAMPLES [01021] Example 4: In Vitro analysis of tubulysin analogs.

[01022] KB (containing markers of human cervical cancer), KB-DR (DAVLBH resistant

KB cells) and MDA-MB-231 (human breast cancer) cells were seeded in 12-well Falcon plates and allowed to form nearly confluent monolayers overnight in FFRPMI/HIFCS. Each well then received increasing concentrations of tubulysin analogs (n=4) and the cells were incubated for 72 h at 37°C. Spent medium was aspirated, rinsed with medium and replaced with medium containing [ H]thymidine. Following a 2 h incubation, cells were washed with PBS and then treated with 5% trichloroacetic acid. The trichloroacetic acid was aspirated and cells were solubilized in 0.25 N sodium hydroxide. Each solubilized sample were transferred to scintillation vials containing Ecolume scintillation cocktail and counted in a liquid scintillation counter. Final results were expressed as the percentage of [ H] thymidine incorporation relative to untreated controls and IC50 values calculated using GraphPad Prism software. Results are shown in Table 1.

Table 1

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of the formula VII

VII

wherein

R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or

R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl;

R 2" and R 3^J are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl;

R 7' and R 8° are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

R⁹ is H or -OH;

comprising one or more of

a. contacting a compound of the formula I

wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered

heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

with a base in an organic solvent at a temperature of about -20 °C to about 50 °C, in the presence of an alkylating agent to provide a compound of the formula II

II

wherein

R¹ is a C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7- membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; and

R 2", R 3^J and R 4" are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; or

b. contacting a compound of the formula II

II

wherein

R 2", R 3^J and R 4" are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl; 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

wherein

R¹ and R⁵ are each independently C₁-C₁₂ alkyl, wherein each hydrogen atom in C₁-C₁₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or

R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or C₁-C₁₂ alkyl; and

c. contacting a compound of the formula III

wherein

2 3 4

FT, R^J and R" are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

with an activated ester of the formula

wherein

6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; and

7 8

R' and R° are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

in the presence of a palladium catalyst and a hydrogen source to provide a compound of the formula IV

IV

wherein

FT 2, R 3^J and R 4" are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

d. contacting a compound of the formula IV

wherein

R 2", R 3^J and R 4" are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆- C₁₀ aryl, and 5- to 7-membered heteroaryl;

6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

with a base in an aqueous solvent system at a temperature of about -20 °C to about 25 °C to provide a compound of the formula V

V

wherein

6 7 8

e. contacting a compound of the formula V

V

wherein

6 7 8

R 7' and R 8° are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

with an activating agent and pentafluorophenol at a temperature of from about -20 °C to about 50 °C to provide a compound of the formula VI

VI

wherein

R¹ and R⁵ are each independently C₁-C₁₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in C₁-C₁₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

2 and R 3^J are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

R 6 is -Ci-Ci₂ 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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; or

f. contacting a compound of the formula VI

VI

wherein

R¹ and R⁵ are each independently Ci-Ci₂ alkyl, wherein each hydrogen atom in Ci-Ci₂ alkyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; or

R¹ and R⁵ are each independently Ci-Ci₂ alkyl or C₂-C₆ alkenyl, wherein each hydrogen atom in Ci-Ci₂ alkyl or C₂-C₆ alkenyl is optionally substituted with a Ci-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl; wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl, C₆-Cio aryl or 5- to 7-membered heteroaryl is independently optionally substituted with fluoro, chloro, bromo, -OH, -CF₃, or Ci-Ci₂ alkyl;

R 2" and R 3^J are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; 6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-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-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

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 to provide a compound of the formula VII

VII

wherein

R 2" and R 3^J are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl;

6 7 8

R is -C₁-C₁₂ alkyl-NR R or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in 3- to 7-membered heterocycloalkyl is optionally substituted by Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, or 5- to 7-membered heteroaryl; R 7' and R 8° are each independently selected from the group consisting of H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃_C₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆-Cio aryl, and 5- to 7-membered heteroaryl; and

R⁹ is H or -OH.

2. The process of claim 1, wherein the base in step (a) is sodium hydride.

3. The process of claim 1 or 2, wherein the alkylating agent in step (a) is a methylating agent.

4. The process of claim 1 or 2, wherein the alkylating agent in step (a) is methyliodide or ethyliodide.

5. The process of any one of the preceding claims, wherein the organic solvent in step (a) is DMF.

6. The process of claim 1, wherein the base in step (b) is KHMDS.

7. The process of claim 1 or 6, wherein the alkylating agent in step (b) is bromomethyl pentyl ether.

8. The process of claim 1 or 6, 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

9. The process of claim 6, 7 or 8, wherein the organic solvent in step (b) is THF or toluene.

10. The process of claim 1, wherein the palladium catalyst in step (c) is 10% Pd/C.

11. The process of claim 1 or 10, wherein the hydrogen source in step (c) is hydrogen gas.

12. The process of claim 1, wherein the base in step (d) is lithium hydroxide.

13. The process of claim 1 or 12, wherein the aqueous solvent system in step (d) is a mixture of methanol and water.

14. The process of claim 1, wherein the activating agent in step (e) is DCC-resin.

15. The process of claim 1, wherein the amino acid in step (f) is Tup or Tut, or a salt thereof.

16. The process of claim 11 or 15, wherein the base in step (f) is di- isopropylethylamine.

17. The process of claim 15 or 16, wherein the polar organic solvent in step (f) is DMF.