AU2018271297A1 - Piperidine derivatives as nk1 antagonists - Google Patents

Abstract

OF THE INVENTION A compound having the general structure shown in Formula 1: R' R2 Ar2 5 Ar' O R3 (I) or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK1 receptors, for example 10 various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.

Description

NKj ANTAGONISTS

This application claims the benefit of U.S. Provisional Application No.

60/584,502, filed July 1, 2004.

FIELD OF THE INVENTION

The present invention relates to novel neurokinin-1 (NKi or NK-1) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds, to treat ΝΚ-ι receptor mediated diseases and conditions, including, for example, emesis, depression, anxiety and cough.

BACKGROUND OF THE INVENTION

Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as ΝΚ_Ί, NK₂ and NK₃, are involved in a variety of biological processes. They can be found in a mammal’s nervous and circulatory systems, as well as in peripheral tissues. Consequently, the modulation of these types of receptors has been studied to potentially treat or prevent various mammalian disease states. For instance, NKi receptors have been reported to be involved in microvascular leakage and mucus secretion. Representative types of neurokinin receptor antagonists and the disorders that can be treated with them include, for example, sleep, pain, migraine, emesis, nociception and inflammation; see, for example, U.S. 6,329,401, U.S. 5,760,018, U.S. 5,620,989, WO 95/19344, WO 94/13639, WO 94/10165, Wu et al., Tetrahedron, 56, 6279-6290 (2000), Rombouts et al., Tetrahedron, 59, 4721-4731 (2003), and Rogiers et al., Tetrahedron, 57, 8971-8981 (2001).

It would be beneficial to provide a NKi antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to provide a NKi antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases, while minimizing side effects. This invention provides such NK-i antagonists.

-1 SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a compound of

Formula I:

2018271297 28 Nov 2018

or pharmaceutically acceptable salts and/or solvates thereof, wherein: R¹ and R² are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, -CN, alkynyl, -N(R⁶)2, -N(R⁶)-S(O2)-alkyl, -N(R⁶)-C(O)-N(R⁹)2, -alkylene-CN, 10 -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR⁵)-alkyl, -C(O)-N(R⁹)2, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R⁹)₂,

O

with the proviso that at least one of R¹ and R² is -CN, A O

W is =C(R⁸)- or =N-;

X is -C(O)- or -S(O₂)-;

Y is selected from the group consisting of-CH₂-, -O-, and -N(R^S)-C(O)~, with the proviso that:

(a) the nitrogen atom of -N(R⁶)-C(O)- is bonded to X, and

-22018271297 28 Nov 2018

(b) if R¹ and/or R² is and Y is -Ο-, X is not -S(O₂)-;

Z is -C(R⁷)₂-, -N(R⁶)-, or-O-;

R³ is selected from the group consisting of H, -CH₂OR⁵, and alkyl;

R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl;

R⁵ is H or alkyl;

R⁶ is selected from the group consisting of H, alkyl, cycloalkyl, and aryl; each R⁷ is independently H or alkyl; or each R⁷, together with the ring carbon to which they are shown attached, form a cycloalkylene ring;

R⁸ is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(R⁶)2, -N(R⁶)-S(O2)-alkyl, -N(R⁶)-S(O₂)-aryl, -N(R⁶)-C(O)-alkyl, -N(R⁶)-C(O)-aryl, alkylene-O-alkyl, and

-CN;

R⁹ is selected from the group consisting of H, alkyl, and aryl, or each

R⁹, together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring;

Ar¹ and Ar² are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with 0 to 3 substituents selected 20 from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO₂;

n is 0, 1, or 2; and m is 1, 2, or 3.

- - · In another embodiment, the presentinvention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable carrier.

In another embodiment, the present invention is directed to a kit comprising two or more containers in a single package, wherein each container in the package comprises a pharmaceutical composition. At least one container of the package comprises an effective amount of the compound

- 3 2018271297 28 Nov 2018 of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, and at least one other container of the package comprises another therapeutic agent in a pharmaceutically acceptable carrier. The pharmaceutical compositions ofthe kit may be used in combination.

In another embodiment, the present invention is directed to a method for affecting an NKi receptor in a patient. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In another embodiment, the present invention is directed to a method for treating an NKi receptor mediated condition or disease (i.e., a disease associated with an NKi receptor, or a disease involving an Nl^ receptor in part ofthe disease process) in a patient in need of such treatment. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

Other features and advantages ofthe invention will be apparent from the following detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention is directed to a compound of Formula I, or a solvate and/or salt thereof, as described herein.

In yet another embodiment, the compounds of Formula I have the following structure IA:

In yet another embodiment ofthe compounds of Formula I, R³ is Ci_₆ alkyl;

R⁴ is H;

Ar¹ is phenyl;

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Ar² is a phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1.6 alkyl, Ci.₆ alkoxy, Ci-₆ haloalkyl, haloalkoxy, -CN, and -NO2; and n is 1.

In yet another embodiment of the compounds of Formula I, R³ is alkyl;

R⁴ is H;

Ar¹ is phenyl;

Ar² is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6 alkyl, C-i.₆ alkoxy, C1.6 haloalkyl, Ci_₆ 10 haloalkoxy, -CN, and -NO₂; and n is 1.

In yet another embodiment, the compounds of Formula I have the following structure IA:

R³ is Ci-₆ alkyl;

R⁴ is H;

Ar¹ is phenyl;

Ar² is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1.6 alkyl, C-i.₆ alkoxy, Ci_₆ haloalkyl, Ci.₆ haloalkoxy, -CN, and -NO2; and n is 1,

In yet another embodiment, the compounds of Formula I have the following structure I A:

consisting of H, -CH₃, -CH₂CH₂CH₃, -CH₂CI, -CH₂F, -CHCI₂, -CHF₂, -CF₃,

wherein R¹ and R² are each independently selected from the group

-5-CH₂OH, -CH2CH2OH, -CH₂CH(OH)CH₃, -CH₂C(OH)(CH₃)2, -cn, -ch₂cn ,

-NHz, -NH-S(O₂)-CH₃, -NH-C(O)-NH_2i -CH₂OCH₃, -C(O)-CH₃ ,

-C(O)-CH₂CH₃, -C(=N-OH)-CH₃, -C(=N-OH)-CH₂CH_3i -C(=N-OCH₃)-CH₃,

-C(O)-NH_2i -C(O)-NH(CH₃), -C(O)-O-CH₃ or-C(O)-O-CH₂CH₃,

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-CH₂C(O)-NH(CH₂CH₃), -CH₂C(O)-NH₂,

Υ,-Ν

-CH₂-C(O)-CH₃, -CH₂-C(O)O-CH₃, -CH₂-C(O)O-CH₂CH₃,

och₃

R⁴ is H;

Ar¹ is phenyl;

Ar² is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci_₆ alkyl, alkoxy, Ci_₅ haloalkyl, Ci-₆ haloalkoxy, -CN, and -NO2; and n is 1.

In yet another embodiment of the compounds of Formula I, Ar¹ is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected

-62018271297 28 Nov 2018 from the group consisting of CI, F, Br, -OH, Ci^ alkyl, C·^ alkoxy, Ci^ haloalkyl, C1.6 haloalkoxy, -CN, and -NO2.

In yet another embodiment of the compounds of Formula I, Ar¹ is unsubstituted phenyl.

In yet another embodiment of the compounds of Formula I, Ar² is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected from the group consisting of Cl, F, Br, -OH, C^ alkyl, Ci.₆ alkoxy, C^s haloalkyl, Ci_₆ haloalkoxy, -CN, and -NO2.

In yet another embodiment of the compounds of Formula I, Ar² is substituted phenyl.

In yet another embodiment of the compounds of Formula I, Ar² is 3,5bis(trifluoromethyl)phenyl.

In yet another embodiment of the compounds of Formula I, R¹ is H.

In yet another embodiment of the compounds of Formula I, R¹ is a Ci.₆ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.

In yet another embodiment of the compounds of Formula I, R¹ is a Cve haloalkyl, for example -CH₂CI, -CH₂F, -CHCI₂, -CHF2, -CF₃.

In yet another embodiment of the compounds of Formula I, R¹ is a C2-6 alkynyl, for example -C=C-H, -C=C-CH₃, -C=C-CH₂CH₃, etc.

In yet another embodiment of the compounds of Formula I, R¹ is a Ci-₆ alkyl substituted with one or more hydroxy groups, for example -CH₂OH, -CH₂CH2OH, -CH₂CH(OH)CH₃, or-CH₂C(OH)(CH₃)2.

In yet another embodiment of the compounds of Formula I, R¹ is -CN or -C1-6 alky)ene-CN, for example -CH₂CN.

..........In-yetanother-embodiment of the compounds of Formula I, R¹ is-NH2.

In yet another embodiment of the compounds of Formula I, R¹ is -NH-S(O₂)-Ci-6 alkyl, for example -NH-S(O₂)-CH₃.

In yet another embodiment of the compounds of Formula I, R¹ is -NH-C(O)-NH₂.

In yet another embodiment of the compounds of Formula I, R¹ is -Ci.₆ alkylene-O-C-1.5 alkyl, for example -CH₂OCH₃.

In yet another embodiment of the compounds of Formula I, R¹ is -C(O)-Ci_6 alkyl, for example -C(O)-CH₃ or-C(O)-CH₂CH₃.

-72018271297 28 Nov 2018

In yet another embodiment of the compounds of Formula I, R¹ is

-C(=N-OH)-C₁_6 alkyl or -C(=N-O-Ci.₆ alkyl)-Ci_₆ alkyl, for example

-C(=N-OH)-CH₃, -C(=N-OH)-CH₂CH_3i or-C(=N-OCH₃)-CH₃.

In yet another embodiment of the compounds of Formula I, R¹ is

-C(O)-NH(Ci-₆ alkyl), -C(O)-N(Ci.₆ alkyl)_2> -C(0)-NH(C₆-io aryl), -C(0)-N(C₆-io aryl)₂, -C(O)-N(,Ci-6 alkyl)( C₆-io aryl), or -C(O)-NH₂, for example -C(O)-NH₂ or-C(0)-NH(CH₃).

In yet another embodiment of the compounds of Formula I, R¹ is -0(0)-0-04.6 alkyl, for example -C(O)-O-CH₃ or-0(0)-0-0H₂CH₃.

In yet another embodiment of the compounds of Formula I, R¹ is alkylene-C(O)-Ci_6 alkyl, for example -CH₂-C(O)-CH₃.

In yet another embodiment of the compounds of Formula I, R¹ is -0^ alkylene-C(O)-O-Ci.₆ alkyl, for example -CH₂-C(O)O-CH₃ or -CH₂-C(O)O-CH₂CH₃.

. In yet another embodiment of the compounds of Formula I, R¹ is -Ci-6 alkylene-C(O)-NH2, -Ci.₆ alkylene-C(O)-NH(Ci.₆ alkyl), -C-i-s alkylene-C(O)-N(Ci-6 alkyl)₂, -Ci-s alkylene-C(0)-NH(C6-io aryl),-Ci.6 alkylene-C(O)-N(C₆.₁₀ aryl)₂, or-Ci-6 alkylene-C(O)-N(Ci_6 alkyl)(C6-io aryl), for example -CH₂C(O)-NH(CH₂CH₃) or -CH₂C(O)-NH₂.

In yet another embodiment of the compounds of Formula I, R¹ is one of:

-82018271297 28 Nov 2018

alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.

In yet another embodiment of the compounds of Formula I, R² is a Ci_6 haloalkyl, for example -CH₂CI, -CH₂F, -CHCI₂, -CHF₂, -CF₃.

In yet another embodiment of the compounds of Formula I, R² is a C₂.₆ alkynyl, for example -C=C-H, -C=C-CH₃, -C=C-CH₂CH₃, etc.

In yet another embodiment of the compounds of Formula I, R² is a C1.6 alkyl substituted with one or more hydroxy groups, for example-CH₂OH, -CH₂CH₂OH, -CH₂CH(OH)CH₃, or-CH₂C(OH)(CH₃)₂.

In yet another embodiment of the compounds of Formula I, R² is -CN or -Ci-6 alkylene-CN, for example -CH₂CN or -C(CH₃)₂CN.

In yet another embodiment of the compounds of Formula I, R² is -C₃.₆

C-CN cycloalkylene-CN, for example 2A

In yet another embodiment of the compounds of Formula I, R² is -NH₂.

In yet another embodiment of the compounds of Formula I, R² is

NH-S(O₂)-Ci-₆ alkyl, -N/C^ alkyl)-S(O₂)-Ci.₆ alkyl or -N(C₆.i₀ aryl)-S(O₂)-Ci._s alkyl for example -NH-S(O₂)-CH₃.

In yet another embodiment of the compounds of Formula I, R² is

-NH-C(O)-NH₂.

-92018271297 28 Nov 2018

In yet another embodiment of the compounds of Formula I, R² is -C-i-₆ alkylene-O-Ci-6 alkyl, for example -CH2OCH3.

In yet another embodiment of the compounds of Formula I, R² is -C(O)-Ci-6 alkyl, for example -C(O)-CH3 or-C(0)-CH2CH₃.

In yet another embodiment of the compounds of Formula I, R² is

-C(=N-OH)-Ci-6 alkyl or -C(=I4-O-Ci-6 alkyl)-Ci_₆ alkyl, for example -C(=N-OH)-CH₃, -C(=N-OH)-CH₂CH₃, or-C(=N-OCH₃)-CH₃.

In yet another embodiment of the compounds of Formula I, R² is

-0(0)-1414(0^ alkyl), -0(0)-14(0^ alkyl)₂, -C(O)-NH(C₆.₁₀ aryl), -C(O)-N(C₆.₁₀ aryl)₂, -C(O)-N(Ci.₆ alkyl)( C₅-io aryl), or -C(O)-I4H₂, for example -C(O)-NH₂ or-C(0)-NH(CH₃).

In yet another embodiment of the compounds of Formula I, R² is -C(O)-O-Ci.₆ alkyl, for example -C(O)-O-CH₃ or -C(O)-O-CH₂CH₃.

In yet another embodiment of the compounds of Formula I, R² is -Ci.₆ alkylene-C(O)-Ci-6 alkyl, for example -ΟΗ₂-Ο(Ο)-ΟΗ₃.

In yet another embodiment of the compounds of Formula I, R² is -0^ alkylene-C(O)-O-Ci-₆ alkyl, for example -ΟΗ₂-Ο(Ο)Ο-ΟΗ₃ or -ΟΗ₂-Ο(0)0-ΟΗ₂ΟΗ₃.

In yet another embodiment of the compounds of Formula I, R² is -Ci.₆ alkylene-C(O)-NH₂, -C1.6 alkylene-CiOj-NH/C-i-e alkyl), -Ci-₆ alkylene-C(O)-N(Ci,6 alkyl)₂, -Ci.₆ alkylene-C(0)-NH(C_s.io aryl),--0^6 alkylene-C(0)-N(C₆-io aryl)₂, or-Ci-₆ alkylene-C(O)-N(Ci-6 alkyl)(C₆-io aryl), for example -CH₂C(O)-NH(CH₂CH₃) or-CH₂C(O)-NH₂.

In yet another embodiment of the compounds of Formula I, R² is one of:

-102018271297 28 Nov 2018

alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 5 n-pentyl, or n-hexyl.

In yet another embodiment of the compounds of Formula I, R⁴ is H.

In yet another embodiment of the compounds of Formula I, R⁴ is Ci_e alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.

In yet another embodiment of the compounds of Formula I, R⁴ is C₃.₆ cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In yet another embodiment of the compounds of Formula I, R⁴ is C₃.₆ heterocycloalkyl, for example pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, azetidinyl, morpholinyl, piperazinyl, or piperidinyl.

In yet another embodiment of the compounds of Formula I, R⁴ is C₅.₁₂ heteroaryl, for example benzimidazolyl, benzofuranyl, benzothiophenyl, Turanyl/rihdolyl/iSoqOiholylfpyrazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, thiophenyl, isoxazolyl, triazolyl, thiazolyl, or thiadiazolyl.

In yet another embodiment of the compounds of Formula I, R⁴ is C₆.io aryl, for example phenyl or naphthyl.

In yet another embodiment of the compounds of Formula I, R⁴ is C-|.₆ acyl, for example -C(O)CH₃, -C(O)CH₂CH₃, -C(O)CH₂CH₂CH₃,

-C(O)CH(CH₃)₂, -C(O)C(CH₃)₃, or -C(O)CH₂CH(CH₃)₂.

-11 2018271297 28 Nov 2018

In yet another embodiment ofthe compounds of Formula I, R⁴ is Ce-io aroyl, for example benzoyl or naphthoyl.

In yet another embodiment ofthe compounds of Formula I, R⁴ is C1.5 alkylsulfonyl, for example -S(O₂)CH₃ or-S(O₂)CH₂CH₃.

In yet another embodiment of the compounds of Formula I, R⁴ is Οθ-ιο arylsulfonyl, for example -S(O₂)-phenyl or -S(O2)-naphthyl.

In yet another embodiment of the compounds of Formula I, R⁵ is H.

In yet another embodiment ofthe compounds of Formula I, R⁵ is Ci_e alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.

In yet another embodiment ofthe compounds of Formula I, R⁶ is H.

In yet another embodiment ofthe compounds of Formula I, R⁶ is C^s alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.

In yet another embodiment ofthe compounds of Formula I, R⁶ is C₃._s cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In yet another embodiment ofthe compounds of Formula I, R⁶ is Οθ-ιο aryl, for example phenyl or naphthyl.

In yet another embodiment of the compounds of Formula I, R⁷ is H.

In yet another embodiment ofthe compounds of Formula I, R⁷ is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

In yet another embodiment ofthe compounds of Formula I, each R⁷, together with the carbon atom to which they are shown attached, form a C3.6 cycloalkyl ring, for example

In yet another embodiment ofthe compounds of Formula I, R⁸ is H.

In yet another embodiment ofthe compounds of Formula I, R⁸ is C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

-122018271297 28 Nov 2018

In yet another embodiment of the compounds of Formula I, R⁸ is

-NH-StCM-Cve alkyl, -N(C₁.₆ alkyl)-S(O₂)-C^ alkyl or-N(C₆.₁₀ aryl)-S(O₂)-C^ alkyl for example -NH-S(O₂)-CH₃.

In yet another embodiment of the compounds of Formula I, R⁸ is

-NH-S(0₂)-C₆.io aryl, -N(Ci_₆ alkyl)-S(0₂)-C6-io aryl or

-N(Cs-io aryl)-S(0₂)-C₆-io aryl, for example -NH-S(O₂)-phenyl or -NH-S(O₂)-4methylphenyl.

In yet another embodiment of the compounds of Formula I, R⁸ is -NH-C(O)-Ci-6 alkyl, -N(C^ alkyl)-C(O)-Ci_₆ alkyl or-N(C₆-io 8^1)-0(0)-0^ 10 alkyl for example -NH-S(O₂)-CH₃.

In yet another embodiment of the compounds of Formula I, R⁸ is -ΝΗ-0(0)-0₆-ιο aryl, -N(Ci-_S alkyl)-C(0)-C₆-io aryl or

-N(C₆-io aryl)-C(0)-C₆.io aryl, for example -NH-C(O)-phenyl or -NH-C(O)-4methylphenyl.

In yet another embodiment of the compounds of Formula I, R⁸ is -Ci_₆ alkylene-O-Ci_₆ alkyl, for example -CH₂OCH₃.

In yet another embodiment of the compounds of Formula I, R⁸ is a C-i-6 alkyl substituted with one or more hydroxy groups, for example -CH₂0H, . -CH₂CH₂OH,-CH₂CH(OH)CH₃, or-CH₂C(OH)(CH₃)₂.

In yet another embodiment of the compounds of Formula I, R⁸ is -CN.

In yet another embodiment of the compounds of Formula I, R⁸ is -NH₂, -N(Ci-6 alkyl)₂, -NH(Ci_₆ alkyl), -N(C₆-io aryl)₂, -NH(C₆.₁₀ aryl), -N(C₃.₆ cycloalkyl)₂, -NH(C₃-6 cycloalkyl), -N(Ci_₆ alkyl)(C₆-io aryl), -NiC^e cycloalkyl)(C_S-ioaryl), or -N(Ci_6 cycloalkyl)(Ci.₆ alkyl).

In yet another embodiment of the compounds of Formula I, R⁹ is H.

__________ln_yet-anothe.r_emb.o.d.iment of_the_c.ompounds_of Formula I, R⁹ is Ci.₆ alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl. .

In yet another embodiment of the compounds of Formula I, R⁹ is C₆-io 30 aryl, for example phenyl or naphthyl. .

In yet another embodiment of the compounds of Formula I, each R⁹ together with the nitrogen atom to which they are shown attached, form a C-i-e

-13heterocycloalkyl ring. For example -N(R⁹)₂ forms one of

2018271297 28 Nov 2018

In yet another embodiment of the compounds of Formula I, X is -C(O)-. In yet another embodiment of the compounds of Formula I, X is

-S(O₂)-.

In yet another embodiment of the compounds of Formula I, Y is -CH₂-. In yet another embodiment of the compounds of Formula I, Y is -O-.

In yet another embodiment ofthe compounds of Formula I, Y is -N(H)-C(O)-, -N(C₁-6 alkyl)-C(O)-, or-N(C₆-io aryl)-C(O)-, for example

-N(H)-C(O)-, -N(CH₃)-C(O)-, or -N(phenyl)-C(O)-.

In yet another embodiment of the compounds of Formula I, Z is -CH₂-.

In yet another embodiment of the compounds of Formula I, Z is -C(Ci.e alkyl)₂ or -CH(C₁.₆ alkyl), for example -C(CH₃)₂- or -CH(CH₃)-.

In yet another embodiment of the compounds of Formula I, Z is -NH-.

In yet another embodiment of the compounds of Formula I, Z is -N(Ci_₆ alkyl)-, for example -N(CH₃)- or -N(CH₂CH₃)-.

In yet another embodiment ofthe compounds of Formula I, Z is -N(C₆. io aryl)-, for example -N(phenyl)- or -N(naphthyl)-.

In yet another embodiment of the compounds of Formula I, Z is -O-.

In yet another embodiment of the compounds of Formula I, n is 0.

In yet another embodiment ofthe compounds of Formula I, n is 1.

In yet another embodiment ofthe compounds of Formula I, n is 2.

In still yet another embodiment, the compounds of Formula I have the following structure IB:

wherein each of R¹ and R^z are as shown in the following Table I:

- 142018271297 28 Nov 2018

Compound	R1	Rz
1	vp 0	-CN
2	o VV° 0	-CN
3	/= N VNy,NH 0	OH A. JL c ch3 h2
4	/= N VNy-NH 0	OH A A C CH, Hz
5	/=N	-ch2cn
6	-CH3	/= N A®
7	-CN	/=N
8	-C(O)-O-CH3	/=N
9	0	-CN
10	-C(O)-NH2	/= N
11	/=N VNyNH 0	-CH2C(OH)(CH3)2
12	-ch2oh	/= N Wn

-152018271297 28 Nov 2018

Compound	R1	R2
13	/= N Vn\^n	-ch2och3
14	-CH2OCH3	/= N VM
15	/= N YNyNH 0	-CH2-NH-S(O2)-CH3
16	/= N Vn>^nh 0	-CH2C(O)-NH(CH2CH3)
17	/=N 0	-CH2-C(O)O-CH2CH3
18	/= N VNyNH 0	-C(=N-OH)-CH2CH3
19	/= N VNy,NH 0	-C(O)-CH2CH3
20	/0 r~f YNyNH 0	-ch2och3
21	/= N VN\^NH 0	-C(O)-NH(CH3)
22	-C(O)-NH(CH3)	/= N YNyNH 0
23	/= N // 0	-ch2oh

- 162018271297 28 Nov 2018

Compound	R1
24	/= N VNy-NH O	-CH2CH2OH
25	/=N VNy,NH 0	-ch2ch2ch3
26	/= N VNyNH 0	-ch2och3
27	-CH2OCH3	/= N VN^NH 0
28	/= N KcH3 // CH3 0	H
29	/= N VNy<NH O	-CH2C(O)-NH2
30	/= N 0	-CH2-C(O)-CH3
31	/= N o	-CH2-C(O)O-CH3
32	A	-CN
33	0	-CN

- 172018271297 28 Nov 2018

Compound	R1	R2
34	-CN	v? 0
35	-CN	/== N YNyNH 0
36	-NH-S(O2)-CH3	-CN
37	-CN	-NH-S(O2)-CH3
38	/^N Vn^nh 0	-ch2cn
39	-CN	-nh2
40	-nh2	-CN
41	-NH-C(O)-NH2	-CN
42	/=N VNy,NH 0	-CN
43	/= N VNrV 0	H
44	/ z—z x II o	H
45	och3 /=n VNy-NH 0	H

-182018271297 28 Nov 2018

Compound	R1	-2
46	H	och3 ( /=N VNy-NH 0
47	°^s-ch3 / J HN )=N VN^/NH 0	H
48	H	°W-ch3 hnz )=N VNy,NH 0
49	H2N /=N y-Ny.NH 0	H
50	H	H2N /=N Vn^nh 0
51	/= N VNy,NH 0	-C(O)-NH2
52	/= N VNx^NH 0	-C(=N-OCH3)-CH3

- 192018271297 28 Nov 2018

Compound		Rz
53	/=N Yn vnh // 0	-C(O)-CH3
54 .	/= N VNyNH 0	-C(=N-OH)-CH3
55	/= N VNyNH 0	-C(O)OCH3
56	/= N Vn^nh 0	-ch2ci
57	/= N VNy-NH 0	-ch3
58	/= N VNy-NH 0	-C(=N-OCH3)-CH2CH3
59	-NHC(O)CH3	oO
60	H	Z-Z I
61	Υ-ΝγΝΗ 0	H

In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of

-202018271297 28 Nov 2018 such treatment, wherein the disease is selected from the group consisting of:

(1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact dermatitis), (4) ophthalmalogical disorders (e.g., retinitis, ocular hypertension and cataracts), (5) central nervous system conditions, such as depressions (e.g., neurotic depression), anxieties (e.g., general anxiety, social anxiety and panic anxiety disorders), phobias (e.g., social phobia), and bipolar disorder, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11)

Alzheimer’s disease, (12) AIDS related dementia, (13) Towne’s disease, (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn’s disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type II diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26) bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea, comprising administering to the patient an effective amount of at least one (e.g., one) compound of Formula I or a pharmaceutically acceptable salt and/or.solyate thereof.

In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein the disease is selected from the group consisting of:

respiratory diseases (e.g., cough), depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related

-21 2018271297 28 Nov 2018 disorders (e.g., headaches, such as migraines, neuropathic pain, postoperative pain, and chronic pain syndromes), bladder disorders, genitourinary disorders, emesis and nausea, comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically 5 acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method of treating a disease (or disorder or condition) wherein there is microvascular leakage and mucus secretion in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method of treating asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method of treating emesis, depression, anxiety and cough in a patient in 20 need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site in a patient in need of such treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method for the blockade of NK-i receptors in a patient in need of such treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.

In still an additional embodiment, the present invention also is directed to a method for treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one

-222018271297 28 Nov 2018 or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more antidepressant agents and/or one or more anti-anxiety agents.

In still an additional embodiment, the present invention also is directed to a method of treating an NKi receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors (“SSRIs”).

In still an additional embodiment, the present invention also is directed to a method of treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or 15 solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors.

In yet an additional embodiment, the present invention also is directed to a method of treating an NKi receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to 20 the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: other types of NKt receptor antagonists (e.g., NKi receptor antagonists other than those according to Formula I of the present invention), prostanoids, H-ι receptor antagonists, α-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ET_A antagonists, renin inhibitors, serotonin 5-HT₃ receptor antagonists (e.g., ondansetron), serotonin 5-HT2_C receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein

5.

-232018271297 28 Nov 2018

In yet an additional embodiment, the invention also is directed to a method for treating an NKi mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: prostanoids, such as prostaglandin E1; α-adrenergic agonists, such as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin II antagonists, such as losartan, irbesartan, valsartan and candesartan; ETa antagonists, such as bosentan and ABT-627; serotonin 5-HT₃ receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone.

In yet an additional embodiment, the invention also is directed to a method for treating an NKi mediated disease (or disorder or condition) in a 15 patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of at least one therapeutic agent selected from the group consisting of: other types of NKi receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5-HT₃ receptor antagonists, serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5.

In yet an additional embodiment, the invention also is directed to a method for treating emesis, nausea and/or vomiting in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula l or a pharmaceutically-acceptable salt and/or solvate thereof, in combination with an effective amount of at least one serotonin 5-HT₃ receptor antagonist (e.g., ondansetron) and/or at least one glucocorticoid (e.g., dexamethasone).

In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NKi receptor mediated disease (or disorder or condition), wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound

-242018271297 28 Nov 2018 of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: SSRIs, other types of NKi receptor antagonists, prostanoids, Hi receptor antagonists, α-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ET_A antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists, serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5.

In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising an antianxiety agent in a pharmaceutically acceptable carrier.

In still yet an additional embodiment, the present invention also is pharmaceutical compositions for use in combination to treat an NK1 receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.

-252018271297 28 Nov 2018

In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.

In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a serotonin 5-HT₃ receptor antagonist in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a pharmaceutically acceptable carrier.

In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein a separate container comprises ondansetron, and/or wherein a separate container comprises dexamethasone.

Another aspect ofthe invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK₁ receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition

-252018271297 28 Nov 2018 comprising a therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: other types of

NKi receptor antagonists, SSRIs, dopamine receptor agonists, serotonin 5HT₃ receptor antagonists, serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multi-drug resistance protein 5.

Except where stated otherwise, the following definitions apply throughout the specification and claims. When any variable occurs more than one time in any moiety, its definition on each occurrence is independent of its 10 definition at every other occurrence. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of alkyl applies to alkyl as well as the alkyl portions of hydroxyalkyl, haloalkyl, alkoxy, etc.

Ac means acetyl.

AcOH (or HOAc) means acetic acid.

Boc means f-butoxycarbonyl.

Bu means butyl.

t-Bu or Bu^f means tert/a/y-butyl.

Bn means benzyl.

Cbz means carbobenzoxy (i.e., Ph-CH2-O-C(O)-).

DCM means dichloromethane.

DIEA means diisopropylethyl amine.

DMF means dimethylformamide.

DMAP means dimethylaminopyridine.

DMPU means Ν,Ν H -dimethyl propylene urea.

DMSO means dimethylsulfoxide.

DPPA means diphenylphosphorazide.

Et means ethyl.

EDC means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

FAB means fast atom bombardment.

HOTs means p-toluene sulfonic acid.

-272018271297 28 Nov 2018

HATU means O-(7-azabenzotriazol-1-yl)-N,N,N’,N’tetramethy I u ron i u m hexafl u o rop hosp hate.

HPLC means High Performance Liquid Chromatography.

HRMS means high resolution mass spectroscopy.

LCMS means liquid chromatography/mass spectroscopy

LiHMDS means lithium hexamethyldisilazide.

Me means methyl.

MeOH means methanol.

MS means mass spectroscopy.

Ms or mesyl means methane sulfonyl.

Ni (Ra) means Raney Ni.

OD means optical density.

Ph means phenyl /-PA (or IPA or iPA) means /so-propyl.

PPTS means pyridinium p-toluenesulfonic acid.

PTSA means p-toluene sulfonic acid.

PYBOP means (benzotriazol-l-yloxy)tripyrrolidino phosphonium hexafluorophosphate.

RT or rt means room temperature.

TBAF means tetrabutylammonium fluoride.

TBAI means tetrabutylammonium iodide.

TFA means trifluoroacetic acid.

THF means tetrahydrofuran. .

TLC means Thin Layer Chromatography.

TMS means trimethylsilyl.

TMSCI means trimethylsilyl chloride.

“Tosyl” means toluene sulfonyl.

Patient includes both human and animals.

“Mammal” means humans and other mammalian animals.

Portions of chemical formulae enclosed in parentheses and/or brackets denote pendant groups. For example, -C(O)- refers to a carbonyl group (i.e.,

-282018271297 28 Nov 2018 ο

ιι ^—θ“), -N(alkyl)- refers to a divalent amine group with a pendant alkyl group ,OCH₃ alkyl μ (i.e., —N—) and -C(=NOCH₃)-CH₃ refers to ~c-ch₃ .

Alkyl means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.

Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain that may be straight or branched. The term substituted alkyl means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(O)O-alkyl. Non15 limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. .

“Alkylene” means a divalent aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkylene groups contain about 1 to about 12 carbon atoms in 20 the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Non-limiting examples of an alkylene group include methylene (i.e., -CH2-) and ethylidene (-CH₂CH₂- or-CH(CH₃)-).

“Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and 25 comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. Lower alkenyl means about 2 to about 6 carbon 30 atoms in the chain, which may be straight or branched. The term “alkenyl includes substituted alkenyl which means that the alkenyl group may be

-292018271297 28 Nov 2018 substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl (i.e., vinyl), propenyl, n-butenyl, 35 methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. Lower alkynyl means about 2 to about 6 carbon atoms in the chain that may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 315 methylbutynyl. The term substituted alkynyl means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.

Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more ring system substituents which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

Heteroaryl means an aromatic monocyclic or multicyclic ring system comp.rjsiog_abjaut5_to_abo.utJA.ring_atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The heteroaryl can be optionally substituted by one or more ring system substituents which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-302018271297 28 Nov 2018 limiting examples ot suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, 5 oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, tetrazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl 10 moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 215 phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A. non-limiting example of a suitable alkylaryl group is tolyl. The bond to the 20 parent moiety is through the aryl.

Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more ring 25 system substituents which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for 30 example, indanyl, tetrahydronaphthyl and the like.

“Cycloalkylene” means a divalent cycloalkyl ring system, comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkylene rings contain about 5 to about 7 ring atoms.

The cycloalkylene can be optionally substituted with one or more ring system

-31 substituents which may be the same or different, and are as defined above.

Non-limiting example of suitable monocyclic cycloalkylenes includes

2018271297 28 Nov 2018 cyclopropylene (i.e “Halogen means fluorine, chlorine, bromine, or iodine. Preferred halogens are fluorine, chlorine and bromine. “Halogen” or “halo” substituted groups (e.g., haloalkyl groups) refers to groups substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms.

Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy., aralkoxy, acyl, aroyl; halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocycloalkyl, -C(=N-CN)-NH₂, -C(=NH)-NH_2> -C(=NH)-NH(alkyl), YiY₂N-, Y^zN-alkyl-, YiY₂NC(O)-, Y^NSOa- and -SO₂NYiY₂, wherein Y-i and Y₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)₂- and the like which

- · -2-5

- · -2-5 o,

Heterocycloalkyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or

-322018271297 28 Nov 2018 sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively 5 is present as a ring atom. Any -NH in a heterocycloalkyl ring may be present in protected form such as, for example, an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected functional groups are also considered part of this invention. The heterocycloalkyl can be optionally substituted by one or more ring system substituents which may be the same or different, and are as 10 defined herein. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Nonlimiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the 15 like.

It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

H there is no -OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, the moieties:

are considered equivalent in certain embodiments of this invention. “Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety.is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.

-332018271297 28 Nov 2018

Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include . pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. The “alkyl” portion of the hydroxyalkyl is preferably a lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

Acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Nonlimiting examples of suitable acyl groups include formyl, acetyl and propanoyl. Aroyl means an aryl-C(O)- group in which the aryl group is as

15. previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl. Alkoxy means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

Aryloxy means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

Aralkyloxy means an aralkyl-O- group in which the aralkyl group is as ______pievi.o.usLy_cl.es.Gribed_NortJjmiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

Alkylthio means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

Arylthio means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups

-342018271297 28 Nov 2018 include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbony) groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

Aralkoxycarbonyl means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

Alkylsulfonyl means an alkyl-S(O₂)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

Arylsulfonyl means an aryl-S(O₂)~ group. The bond to the parent moiety is through the sulfonyl.

The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation, to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

The term isolated or in isolated form for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term purified or in purified form for a compound refers to the physical state of said compound after

-352018271297 28 Nov 2018 being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have one or more hydrogen atoms to satisfy the valences.

When a ring system (e.g., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) is substituted with a number of substituents varying within an expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions. Thus, for example, a phenyl ring substituted with “n” substituents (where “n” ranges from 0 to 5) can have 0 to 5 substituents, whereas it is understood that a pyridinyl ring substituted with “n” substituents has a number of substituents ranging from 0 to 4.

When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York, herein incorporated by reference.

. When any variable (e.g., aryl, heterocycloalkyl, R², etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. As^used..her.e.in,.thertermJlco.mpositionlisJntended_to_encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. .

“Alkylheteroaryl” means an alkyl group attached to a parent moiety via a heteroaryl group.

“Alkylsulfinyl” means an a)kyl-S(O)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl. .

-362018271297 28 Nov 2018

Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.

“Aralkylthio” means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

“Aryloxycarbonyl” means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Arylsulfinyl” means an aryl-S(O)- group. Non-limiting examples of suitable arylsulfinyl groups include phenylsulfinyl and naphthylsulfinyl. The bond to the parent moiety is through the sulfinyl.

A carbamate group means a -O-C(O)-N(alkyl or aryl)- group, and a urea group means a -N(alkyl or aryl)-C(O)-N(alkyl or aryl)- group. Representative carbamate and urea groups may include the following:

“Cycloalkenyl’’ means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more ring system substituents which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

-372018271297 28 Nov 2018 “Cycloalkylamino” means a cycloalkyl group as defined herein attached to the parent moiety through a nitrogen atom.

“Cycloalkylaminocarbonyl” means a cyclic alkyl group attached to a nitrogen atom, which is attached to a carbonyl group; the whole may be referred to as a substituted amide. .

“Heteroalkyl” means an alky) as defined herein, in which at least one the atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.

“Heteroaralkenyl” means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3yl)ethenyl. The bond to the parent moiety is through the alkenyi.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

“Heteroaralkylthio” means a heteroaryl-alkyl-S group wherein the group is attached to the parent moiety through the sulfur.

“Heteroarylsulfinyl” means a heteroaryl-S(O)- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfinyl.

“Heteroarylsulfonyl” means a heteroaryl-S(0₂) - group wherein the heteroaryl is as defined herein and the heteroarylsulfonyl group is attached to “Heteroarylthio” means a heteroaryl-S- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfur.

“Heterocycloalkenyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon

-382018271297 28 Nov 2018 double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocycloalkenyl can be optionally substituted by one or more ring system substituents, wherein ring system substituent is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N. oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocycloalkenyl groups include 1,2,3,4- tetrahydropyridine, 1,2dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocycloalkenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocycloalkenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Heterocyclic” means, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or

3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3.MQDiQrpAoJjjiyl “Sulfonamide” means a sulfonyl group attached to a parent moiety through an amide.

As is well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example:

-392018271297 28 Nov 2018

O represents Ο

It should also be noted that throughout the specification and Claims appended hereto, that any formula, compound, moiety or chemical illustration with unsatisfied valences is assumed to have the hydrogen atom to satisfy the 5 valences unless the context indicates a bond.

With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases “one or more” and “at least one” mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is 10 well within the knowledge of those skilled in the art.

The wavy line as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example,

When the stereochemistry in a structure is not expressly indicated, the structure can have a mixture of, or any of the individual possible stereoisomers. Thus, when the stereochemistry is not explicitly indicated in a structure, the structure includes all stereochemical configurations having the 20 indicated connectivity (e.g., all possible enantiomers or diastereomers), as well as mixtures of such stereoisomers (e.g., racemic mixtures). For example,

-402018271297 28 Nov 2018 means

VN /

N. .

VN

J

Lines drawn into the ring systems, such as, for exampie:

-41 2018271297 28 Nov 2018

indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term prodrug, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery

Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

Solvate means a physical association of a compound of this invention 15 with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvate encompasses both solution-phase and isolatable 20 solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A hydrate is a solvate wherein the solvent molecule is H₂O.

Effective amount or therapeutically effective amount is meant to describe an amount of compound or a composition of the present invention 25 effective in antagonizing the neurokinin-1 receptor and thus producing the desired therapeutic effect in a suitable patient.

The compounds of Formula I form salts that are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term 30 salt(s), as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or

-422018271297 28 Nov 2018 organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (inner salts) may be formed and are included within the term salt(s) as used herein.

Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium 10 followed by lyophilization.

Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, 15 fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, 20 propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as 25 calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine; phenylcyclohexylamine, 30 choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g, decyl, lauryl, myristyl

-432018271297 28 Nov 2018 and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S.

Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of

Pharmaceutical Salts: Properties, Selection, and Use, (2002) Inti. Union of Pure and Applied Chemistry, pp. 330-331, each of which is incorporated herein by reference.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts 15 are considered equivalent to the free forms of the corresponding compounds for purposes of the Invention.

Compounds of Formula I and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates, and/or prodrugs thereof, are intended to be included in the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and 25 the like) of the present compounds (including those of the salts, solvates and ,prodrugsOf_the_compounds.as..well as-.the_sal.ts. and so.l.v.ates_of.the.prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined

- 44 2018271297 28 Nov 2018 by the iUPAC 1974 Recommendations. The use of the terms salt, solvate prodrug and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. “At least one”, examples include 1-3, 5 1-2 or 1.

Compounds of Formula I are effective antagonists of the ΝΚ-ι receptor, and have an effect on its endogenous agonist, Substance P, at the NKi receptor site, and therefore, can be useful in treating diseases, disorders, or conditions caused or aggravated by the activity of the receptor.

The in vitro and in vivo NKi, NK₂ and NK3 activities of the compounds of Formula I can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the agonist Substance P. The percent inhibition of neurokinin agonist activity is the difference between the percent of maximum specific binding (MSB) and 100%. The percent of

MSB is defined by the following equation, wherein dpm represents disintegrations per minute:

°/ MSB = (dP^{m of} unknown) - (dpm of nonspecific binding)_______ (dpm of total binding) - (dpm of nonspecific binding)

The concentration at which the compound produces 50% inhibition of binding is then used to determine an inhibition constant (K) using the Chang-Prusoff 20 equation.

In vivo activity may be measured by inhibition of an agonist-induced foot tapping in a gerbil, as described in Science, 281, 1640-1695 (1998), which is herein incorporated by reference in its entirety. It will be recognized that compounds of Formula I can exhibit NKi antagonist activities of varying 25* de^ssTToTiffstaTOeTc'e'rtainC'ompOunds'can^_exhibit stronger NKi antagonist activities than others.

The compounds of the present invention exhibit potent affinities for the NKi receptor as measured by K, values (in nM). The activities (potencies) for the compounds of the invention are determined by measuring their Kj values.

The smaller the K, value, the more active is a compound for antagonizing the NKi receptor. Compounds of the invention exhibit a wide range of activities. The NKi average K, values for compounds of Formula I generally range from

-452018271297 28 Nov 2018

0.01 nM to about 1000 nM, preferably, from about 0.1 nM to about 100 nM, with values of from about 0.1 nM to about 10 nM being more preferred. Even more preferred are compounds having average K_f values of from 0.1 nM to about 5 nM for the NKi receptor. Especially preferred compounds have NKi average K; values of from 0.1 nM to about 1 nM. Even more especially preferred compounds have NKi average K, values of from 0.1 nM to about 0.3 nM. Compounds 2, 9, 10, 12, 14, 16, 19, 20, 23, 29, 30, 42, and 54 (see Table l above) have K, values, respectively, of 0.12, 0.18, 0.1, 0.05, 0.1, 0.13, 0.1,0.11,0.12 0.11, 0.54, 0.28, and 0.12 nM.

Compounds of the Formula I have a number of utilities. For instance, the inventive compounds can be useful as antagonists of neurokinin receptors, particularly, NKi receptors in a mammal, such as a human. As such, they may be useful in treating and preventing one or more of a variety of mammalian (human and animal) disease states (physiological disorders, symptoms and diseases) in a patient in need of such treatment, wherein the disease states are selected from the group consisting of: (1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact dermatitis), (4) ophthalmologic disorders (e.g., retinitis, ocular hypertension and cataracts), (5) centra] nervous system conditions, such as depressions (e.g., neurotic depression), anxieties (e.g., general anxiety, social anxiety and panic anxiety disorders), phobias (e.g., social phobia), and bipolar disorder, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn’s disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type II diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26)

-462018271297 28 Nov 2018 bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea.

Preferably, the inventive compounds can be useful in treating and preventing one of the foliovying mammalian (e.g., human), disease states in a patient in need of such treatment: respiratory diseases (e.g., cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive . substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders, bladder disorders, genitourinary disorders, emesis and nausea. In particular, the compounds according to Formula I are useful for treating disease states related to microvascular leakage and mucus secretion. Consequently, the compounds of the invention are especially useful in the treatment and prevention of asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders, more especially, emesis, depression, anxiety and cough.

In another aspect, the invention relates to pharmaceutical compositions comprising at least one compound (e.g., one to three compounds, preferably, one compound) represented by Formula I and at least one pharmaceutically acceptable excipient or carrier. The invention also relates to the use of such pharmaceutical compositions in the treatment of mammalian (e.g., human) disease states, such as those listed above.

In still another aspect of the invention, a method is provided for .antagonizing Jhe_e.ffects_Qf_a.S.u.bs.tan.c.e.P_at a_n.euriikini.o-1 receptor site or for the blockade of one or more neurokinin-1 receptors in a mammal (i.e., a patient, e.g., a human) in need of such treatment, comprising administering to the mammal an effective amount of at least one (e.g., one) compound according to Formula I.

In another aspect of the invention, an effective amount of one or more of the inventive NKi receptor antagonists may be combined with an effective amount of one or more anti-depressant agents and/or one or more antianxiety agents (e.g., gepirone, gepirone hydrochloride, nefazodone, and

-472018271297 28 Nov 2018 nefazoaone nyarocnioriae (e.g., Serzone®)) to treat depression and/or anxiety. U.S. 6,117,855 (2000), the disclosure of which is incorporated herein by reference, discloses a method for treating or preventing depression or anxiety with a combination therapy of a specific ΝΚ_Ί receptor antagonist together with an anti-depressant and/or anti-anxiety agent. Thus, antidepressant and/or anti-anxiety agents, such as those disclosed in U.S.

6,117,855 (2000), can be combined with one or more (e.g., one) compounds of the Formula 1 to treat depression and/or anxiety disease states in a mammal, preferably, a human.

In still another aspect of the invention, an effective amount of one or more (e.g., one) of the inventive NKi receptor antagonists may be combined with an effective amount of one or more (e.g., one) selective serotonin reuptake inhibitors (“SSRIs) to treat a variety of mammalian disease states, such as those described above. SSRIs alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. U.S. 6,162,805 (2000), the disclosure of which is incorporated herein by reference, discloses a method for treating obesity with a combination therapy of a NKi receptor antagonist and an SSRI. One or more inventive compound(s) of the Formula I can be combined together with an SSRI(s) in a single pharmaceutical composition, or it can be administered simultaneously, concurrently or sequentially with an SSRI. This combination may be useful in the treatment and prevention of obesity or another of the above-identified human and animal disease states. In particular, an effective amount of at least one (e.g., one) compound having the Formula I, alone or together with an effective amount of at least one (e.g., one) selective serotonin reuptake inhibitor, can be useful in the treatment and prevention of depression, and/or anxiety.

Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation 30 of neuronally released serotonin. Representative SSRIs include, without limitation, the following: fluoxetine, fluoxetine hydrochloride (e.g., Prozac®), fluvoxamine, fluvoxamine maleate (e.g. Luvox®), paroxetine, paroxetine hydrochloride (e.g., Paxil®), sertraline, sertraline hydrochloride (e.g., Zoloft®), citalopram, citalopram hydrobromide (e.g., Celexa™), duloxetine, duloxetine

-482018271297 28 Nov 2018 hydrochloride, venlafaxine, and venlafaxine hydrochloride (e.g., Effexor®).

Further SSRIs include those disclosed in U.S. 6,162,805 (2000). Other compounds can readily be evaluated to determine their ability to selectively inhibit serotonin reuptake. Thus, one aspect of the invention relates to a pharmaceutical composition comprising at least one (e.g., one) ΝΚ.·ι receptor antagonist having the Formula I, at least one (e.g., one) SSRI, and at least one pharmaceutically acceptable excipient or carrier. Another aspect of the invention relates to a method of treating the above identified mammalian (e.g., . human) disease states, the method comprising administering to a patient in 10 need of such treatment an effective amount of a pharmaceutical composition comprising at least one (e.g., one) NKi receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those recited above, and at least one pharmaceutically acceptable excipient or carrier.

In a preferred aspect, the invention relates to a method of treating depression and anxiety, the method comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) NKi receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those described above. When an inventive

NIG receptor antagonist is combined with an SSRI for administration to a patient in need of such treatment, the two active ingredients can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the two active ingredients are administered consecutively or sequentially, the inventive NKi receptor antagonist is,.prele^rably,^administered .betore.the.administration of the SSRI.

It is another embodiment of the invention to treat a patient suffering from multiple ailments with a combination therapy, the therapy.comprising administering to a patient (e.g., a mammal, preferably a human) in need of 30 such treatment at least one compound of Formula I, and at least one other active ingredient (i.e., drug) used for treating one or more of the ailments being suffered by the patient. The compounds of Formula I and the other active ingredients can be administered sequentially, concurrently and/or simultaneously. The compounds of Formula I and the other active ingredients

-492018271297 28 Nov 2018 can be administered separately in any suitable dosage form. Preferably, administration is accomplished using an oral dosage forms or using a transdermal patches. The compounds of Formula I and the other active ingredients can be formulated together and administered in one combined dosage form.

Thus, the compounds of the invention may be employed alone or in combination with other active agents. Combination therapy includes the administration of two or more active ingredients to a patient in need of treatment. In addition to the above described NKi receptor antagonist/SSRI 10 combination therapy, the compounds having the Formula I may be combined with one or more other active agents, such as the following: other types of NKi receptor antagonists (e.g., those that are disclosed in neurokinin receptor antagonist patents cited above), prostanoids, Hi receptor antagonists, aadrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETa antagonists, renin inhibitors, serotonin 5-HT₃ receptor antagonists (e.g., ondansetron, ondansetron hydrochloride (e.g., Zolfran®), palonosetron, granisetron, and granisetron hydrochloride (e.g., Kytril®), serotonin 5-HT2_C receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and/or inhibitors of multi-drug resistance protein 5.

Particularly useful therapeutic agents for combination therapy with compounds of the invention are the following: prostanoids, such as prostaglandin-Ei; -a-adrenergic-agonists-,-such as phentolamine mesylate; dopamine receptor agonists, such as apomorphine; angiotensin II antagonists, such as losartan, irbesartan, valsartan and candesartan; ETa antagonists, such as bosentan and ABT-627; serotonin 5-HT₃ receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of the invention, the inventive compounds can be combined with: other types of NKi receptor antagonists,

SSRIs, dopamine receptor agonists, serotonin 5-HT₃ receptor antagonists,

-502018271297 28 Nov 2018 serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids and/or inhibitors of multi-drug resistance protein 5.

Another embodiment of this invention is directed to a method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula I, and an effective amount of at least one active ingredient selected from the group consisting of: other NKi receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5, wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea.

Pharmaceutical compositions may contain from about 0.1 to about 99.9 weight percent, or from about 5 to about 95 weight percent, or from about 20 to about 80 weight percent of active ingredient (compound ofthe Formula I). For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and

Practice of Pharmacy, 20^th Edition, (2000), Lippincott Williams & Wilkins,

Baltimore, MD, herein incorporated by reference.

-51 2018271297 28 Nov 2018

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene 'glyco! solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal 5 administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form ofcreams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The term pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units, in any of the forms described herein, comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid more than one pharmaceutically active agents. The term “bulk composition” means material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present

-522018271297 28 Nov 2018 invention is also intended to encompass the administration of the aforesaid bulk composition and individual dosage units.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 4000 mg, preferably from about 0.02 mg to about 1000 mg, more preferably from about 0.3 mg to about 500 mg, and most preferably from about 0.04 mg to about 250 mg according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.02 mg/day to about 2000 mg/day, in two to four divided doses.

The pharmaceutical compositions of the invention may be administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

The quantity of receptor antagonist in combination with a selective serotonin reuptake inhibitor (“SSRI”) in a unit dose of preparation may be from 25 about 10 to about 300 mg of NKi receptor antagonist combined with from

NKi receptor antagonist in combination with a SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NKi receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another combination the quantity of NKi receptor antagonist in combination with SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NK-i receptor antagonist combined with from about 20 to about 50 mg of SSRI.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

-532018271297 28 Nov 2018

Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or 5 combination of the invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require 10 intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, 15 sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient’s disposition to the condition being treated and the judgment of the treating physician. Determination of the proper dosage regimen for a particular situation is within the skill of the art.

EXAMPLES

The invention disclosed herein is exemplified by the following preparations and examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures 25 may be apparent to those skilled in the art.

PREPARATIVEEXAMPLE-1

Stepl:

-542018271297 28 Nov 2018

In a 25 mL round-bottomed flask, Compound 42b (0.253 g, 0.42 mmol, 1.0 equiv) was taken up in 5 mL of CH2CI2, and the resulting reaction mixture was cooled to 0°C in an ice bath. Et₃N (0.088 mL, 0.63 mmol, 1.5 equiv) followed by 4-chlorobutyryl chloride (0.065 mL, 0.5 mmol, 1.2 equiv) was then added to the reaction mixture, which was subsequently slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS. Upon completion, the reaction mixture was diluted with CH2CI2, quenched with saturated aqueous NaHCO₃, followed by brine. The organic layer was dried over Na₂SO₄ and concentrated to give crude Compound 1a (0.3 g), which was used in the next step without further purification.

Electrospray MS [M+1 ] 724.4.

Step 2:

In a flame-dried 25 mL round-bottomed flask, Compound 1a (0.3 g, 0.4 mmol, 1.0 equiv) was taken up in dry THF. To this reaction mixture, 60%

NaH (0.025 g, 0.62 mmol, 1.5 equiv) was added, and reaction mixture was afirr^atT00rn'tempei^re“fof~2TfsTTIie“pTogressFonfie reaction was monitored by TLC (60:40 EtOAc/hexane) and MS. Upon completion, the reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated to give Compound 1 b (0.25 g), which was used in the next step without further purification.

Step 3:

-552018271297 28 Nov 2018

20% PdOH, MeOH, Hj(g)

Compound 1b (0.25 g, 0.37 mmol, 1.0 equiv) was dissolved in dry

MeOH (2.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert 5 atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and was monitored by TLC (60:40 EtOAc/hexane). The reaction was completed in 45 min, and the reaction mixture was then filtered through CELITE (diatomaceous earth), washed with EtOAc, and concentrated to give a crude product. Purification was carried out using preparative plate chromatography (60/40 EtOAc/hexane) to give Compound 1 (0.10 g, 49%). Electrospray MS [M+1] 554.3.

HRMS (FAB) calculated for C2_SH₂9F₆N₃O2 (M+1) 554.2242, found 554.2249.

PREPARATIVE EXAMPLE 2

Example 2 .

Step 1:

In a 25 ml round-bottomed flask, Compound 42b (0.3264 g, 0.44 mmol, 1.0 equiv) was taken up in 5 mL of THF, and the reaction mixture was cooled to 0°C in an ice bath. Et₃N (0.073 mL, 0.44 mmol, 1.2 equiv) followed

-562018271297 28 Nov 2018 by 2-chloroethyl chiororormate (0.054 mL, 0.44 mmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and stirred for 14 hrs. The progress of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. The reaction did not go to completion, and hence was diluted with EtOAc and quenched with saturated NaHCO3 followed by brine. The organic layer was dried over Na₂SO₄ and concentrated to give (0.3 g) crude product, which was subjected to BIOTAGE chromatography (40:60 EtOAc/hexane) to give Compound 2a (0.125 g).

Electrospray MS [M+1] 712.4.

Step 2:

In a flame-dried 25 ml round-bottomed flask, Compound 2a (0.125 g,

0.175 mmol, 1.0 equiv) was taken up in dry THF. To this reaction mixture, 60% NaH (0.10 g, 0.26 mmol, 1.5 equiv) was added and reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with saturated aqueous NaHCO3. The organic layer was dried over Na₂SO₄ and concentrated to give Compound 2b (0.11 g), which was used in the next step without further purification.

Electrospray MS [M+1] 676.2.

Step 3:

-572018271297 28 Nov 2018

Compound 2b (0.11 g, 0.16 mmol, 1.0 equiv) was dissolved in dry

MeOH (2.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60

EtOAc/hexane). The reaction was completed in 45 min, filtered through CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using preparative plate chromatography (45/55 EtOAc/ hexane) to give Compound 2 (0.04 g, 45%).

Electrospray MS [M+1] 542.3.

HRMS (FAB) calculated for CzsHzeFeNsOsiM+D 542.1897, found

542.1878.

PREPARATIVE Example 3 and Example 4

Ί 5 Example 3 Example 4

3 4

NaBH4 (60 mg, 1.53 mmol, 8 equiv.) was added in portions to a solution of Compound 30 (109 mg, -0.19 mmol, 1 equiv.) in absolute ethanol (2 mL) at 0°C. After stirring at 0°C for 30 minutes, TLC (MeOH/CH₂CI₂ =10%) analysis of the reaction mixture showed only product. The product was purified by BIOTAGE chromatography (2-10% MeOH in CH₂CI₂), to provide a pure mixture of two diastereomers. The two diastereomers were separated using Chiral HPLC (ChialCel OD, IPA/Hexane=10%) to give Example 3, MS [M+1]⁺ 573.1; and Example 4, MS [M+1]⁺ 573.1.

PREPARATIVE EXAMPLE 5

-582018271297 28 Nov 2018

Step A:

MsCI (0.102 mL, 1.32 mmol) was added to a solution of Compound

26a (0.375 g, 0.528 mmol) and Et₃N (0.368 mL, 2.64 mmol) in CH2CI2 (5.0 mL) at 0°C. The reaction mixture was quenched with water (15.0 mL) after 30 minutes and then diluted with CH2CI2 (50 mL). The resulting aqueous phase was extracted with CH₂CI₂ (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude mesylate was taken up in DMF (3.0 mL) and treated with KCN (0.344 g, 5.28 mmol). The resulting mixture was heated at 100°C for 12 hours before it was cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3x15 mL). The organic layer was then washed with brine (25 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified by BIOTAGE chromatography (hexane/EtOAc, v/v = 7/1) to give Compound 5b (0.14 g, 37% for 2 steps).

a. TFA

b. HC(0)NHNHC(O)H, TMSCI, Et,N, Py

A solution of Compound 5b (0.14 g, 0.195 mmol) in TFA (2.5 mL) was stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 mL) and

2018271297 28 Nov 2018 washed with a NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then dried over MgSO₄. After filtration and concentration, the crude product was passed through a short pad of silica gel with EtOAc/MeOH (v/v = 10/1) as eluent, to provide an amine (90 mg) after solvent removal. The amine was taken up in pyridine (1.0 mL) and treated with HC(O)NHNHC(O)H (38.3 mg, 0.435 mmol), TMSCI (0.276 mL, 2.175 mmol) and Et₃N (0.152 mL, 1.088 mmol) at room temperature in a sealed tube. The reaction mixture was then heated at 100°C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (40 mL) and washed with HCI (10 mL, 2.0 N). The resulting aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgS0₄. After filtration and concentration, the crude product was purified using

BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) to give Compound 5c (40 mg, 31 % for 2 steps).

Compound S

Compound 5c (40 mg, 0.0595 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH)z/C (8 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent 25 was removed under reduced pressure, and the crude product was purified using preparative TLC (EtOAc/MeOH, v/v = 40/1) to give Compound 5 (18 mg, 56%, Electrospray MS [M+1 ]⁺ 538.1.) and Compound 5d (6 mg, 19%, Electrospray MS [M+1]⁺ 538.1.).

-602018271297 28 Nov 2018

PREPARATIVE EXAMPLE 6

MsCI (75 mL, 0.969 mmol) was added to a solution of Compound 23d (0.248 g, 0.388 mmol) and Et₃N (0.27 mL, 1.94 mmol) in CH2CI2 (3.0 mL) at room temperature. The reaction was quenched with water (10.0 mL) after 30 minutes and diluted with CH₂CI₂ (30 mL). The aqueous phase was extracted with CH₂CI₂ (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude mesylate was taken up in anhydrous DMSO (3.0 mL) and treated with NaBH₄ (59.0 mg, 1.552 mmol). The reaction mixture was heated at 85°C for 48 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (50 mL) and washed with aqueous HCI (10 mL, 1.0 M). The resulting aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (3x15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 5/1) to give Compound 6a (0.11 g, 45% for 2 steps).

Step B:

-61 2018271297 28 Nov 2018

Compound 6a

a. Zn, HOAc

b. HC(O)NHNHC(O)H, TMSCI.Et,N, Py

Compound 6b

A mixture of Compound 6a (0.11 g, 0.176 mmol) and Zn dust (0.114 g,

1.76 mmol) in HOAc (1.5 mL) was heated at 60°C for 2 hours. The reaction mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the residue was taken up in EtOAc (25 mL) and washed with a NaOH solution (4.0 N, 10 mL). The resulting aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude amine (67.1 mg, 0.113 mmol) was taken up in pyridine (1.0 mL) and treated with HC(O)NHNHC(O)H (29.8 mg, 0.339 mmol), TMSCI (0.214 mL, 1.69 mmol) and Et₃N (0.118 mL, 0.847 mmol) at room temperature in a sealed tube. The mixture was then heated at 100°C for 2,5 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (40 mL) and washed with HCI (10 mL, 2.0 N). The resulting aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using

BIOTAGE chromatography (EtOAc/MeOH, v/v = 20/1) to give Compound 6b (37 mg, 33% for 2 steps).

Step C:

Compound 6b Compound 6

-622018271297 28 Nov 2018 compound on (oo.5 mg, 0.0565 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH)₂/C (7.3 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent 5 was removed under reduced pressure and the crude product was purified using preparative TLC (EtOAc/MeOH/Et₃N, v/v/v = 40/1/0.1) to give Compound 6 (20 mg, 69%). Electrospray MS [M+1]⁺ 513.1.

PREPARATIVE EXAMPLE 7

Step A:

a. Dess-Martin Periodinane

b. HONH₂.HCl_t NaOAc, EtOH

c. 1,T-oxayidiimidazole, PhH

Dess-Martin Periodinane (0.114 g, 0.268 mmol) was added to a mixture of Compound 12a (70.5 mg, 0.107 mmol) and NaHCO₃ (0.112 g, 1.34 mmol) in CH₂CI₂ (3.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with the addition of EtOAc (30 mL) and water 20 (10 mL). The organic phase was washed with saturated Na₂S₂O₃ solution (3 x mL). The combined aqueous phases were extracted with EtOAc (3x10 mL). The combined organic layers were washed with a NaOH solution (10. mL, 1.0 N), water (10 mL), brine (15 mL); and dried over MgSO₄. After filtration and concentration, the crude aldehyde (70.5 mg, 0.107 mmol) was 25 dissolved in EtOH (3.0 mL) and treated with ΗΟΝΗ₂ΉΟΙ (74.4 mg, 1.07 mmol) and NaOAc (43.9 mg, 0.535 mmol) at room temperature. The reaction mixture was stirred for 12 hours before it was diluted with EtOAc (20 mL) and

-632018271297 28 Nov 2018 washed with aqueous NaHCO₃ (10 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude oxime was obtained (63 mg, 0.093 mmol) which was taken up in benzene (2.0 mL) and treated with 1,T-oxalyldiimidazole (35.4 mg, 0.186 mmol). The reaction mixture was heated at 80°C for 3 hours before it was cooled down to room temperature and diluted with EtOAc (20 mL) and washed with aqueous HCl (0.5 N, 5 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (EtOAc) to give Compound 7a (39 mg, 55% for 3 steps).

Step B:

H₂, Pd(OH)7C, EtOH

Compound 7a (39 mg, 0.059 mmol) in EtOH (2.5 mL) was treated at room temperature with Pd(OH)₂/C (7.8 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (EtOAc/EtsN, v/v = 100/0.1) to give Compound 7 (12.2 mg, 40%). Electrospray MS [M+1]⁺ 524.3.

PREPARATIVE EXAMPLE 8

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Step A:

a. Dess-Martin Periodinana

b. 2-methyl-2-butene, NaCIO₂

NaH₂PO₄, tert-butano)

c. TMSCHN₂. MeOH, PhH

Dess-Martin Periodinane (0.325 g, 0.767 mmol) was added to a mixture of Compound 12a (0.202 g, 0.306 mmol) and NaHCO₃ (0.322 g, 3.83 mmol) in CH2CI2 (5.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic 10 phase was washed with saturated Na₂S₂O₃ solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3x15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude aldehyde (0.202 g) was taken up in tert-butanol (4.0 15 mL) and water (1.0 mL) and treated with NaH₂PO₄-H₂O (84.4 mg, 0.612 mmol), NaCIO₂ (96.8 mg, 1.07 mmol) and 2-methyl-2-butene (0.227 mL, 2.14 mmol) successively. The reaction mixture was stirred for 2 hours and then diluted with EtOAc (30 mL) and washed with aqueous NH₄Cl. The resulting aqueous phase was extracted with EtOAc (3x10 mL). The combined organic 20 layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄.

After filtration and concentration, the crude acid was dissolved in benzene (4.0 mL) and MeOH (1.0 mL). The resulting solution was treated with TMSCHN₂ (0.306 mL, 0.612 mmol) at room temperature and stirred for 20 minutes. Solvent was removed under reduced pressure and the crude product 25 was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 5/1 to 1/3) to give Compound 8a (62 mg, 29% for 3 steps).

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Step B:

Compound 8a

Compound 8a (62 mg, 0.090 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)₂/C (12.4 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v = 6/1) to give

Compound 8 (42 mg, 84%). Electrospray MS [M+1]⁺ 557.3.

PREPARATIVE EXAMPLE 9

Step 1:

Toluene

RTemp - 80 “C

In a 25 ml round-bottomed flask, Compound 42b (0.21 g, 0.35 mmol, 20 1.0 equiv) was taken up in 2 mL of toluene. 3-chloropropionyl chloride (0.037 mL, 0.38 mmol, 1.1 equiv) was then added to the reaction mixture, which was stirred at room temperature for five hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS, which showed some starting material was still present. The reaction mixture was thus heated to

-6680°C. Upon completion of the reaction after a further hour of heating, the mixture was concentrated to give crude product Compound 9a (0.2 g), which was used in the next step without further purification.

2018271297 28 Nov 2018

Step 2:

60% N'aH in

CHjCyDMF (4/1)

In a flame-dried 25 ml round-bottomed flask, Compound 9a (0.2 g,

0.287 mmol, 1.0 equiv) was taken up in a 0.5 M solution of dry CH2CI2/DMF (4/1) ratio (4.59 mL/1.15 mL). To this mixture a 0.5 M solution of 60% NaH (0.012 g, 0.316 mmol, 1.1 equiv) in dry CH₂CI₂/DMF (4/1 ratio; 5.06 mL/1.26 mL) was very slowly added using a syringe pump over a period of 3.5 hrs and the reaction mixture was stirred at room temperature overnight. The progress 15 of the reaction was monitored by TLC (40:60 EtOAc/hexane) and MS. The reaction went to 60% completion, and was then diluted with CH₂CI₂ and quenched with saturated aqueous NH4CI. The organic layer was dried over Na₂SO4 and concentrated to give crude product (0.18 g), which was purified using BIOTAGE chromatography (30/70 EtOAc/ hexane) to give Compound 20 9b (0.125 g).

Electrospray MS [M+1 ] 660.2.

Step 3:

20%PdOH. MeOH, H_a(g)

Compound 9b (0.125 g, 0.189 mmol, 1.0 equiv) was dissolved in dry

MeOH (1.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric

-67pressure and the progress of the reaction was monitored by TLC (50:40

EtOAc/hexane). The reaction was completed in 20 min, and the reaction mixture was filtered through CELITE, washed using EtOAc, and concentrated to give crude product. Purification was carried out using prep plate chromatography (45/55 EtOAc/ hexane) to give Compound 9 (0.071g, 71%). Electrospray MS [M+1] 526.3.

HRMS (FAB) calculated for CseHsgFsNsOs (M+1) 526.1932, found 526.1929.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 10

Step A:

Compound 10

A solution of Compound 8 (35 mg, 0.063 mmol) in ammonia methanol solution (3.0 mL, 7.0 M) in a Parr bomb was heated at 80°C for 5 days. The system was cooled to room temperature and solvent was removed under reduced pressure. The crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) to give Compound 10 (26.8 mg, 79%). Electrospray MS [M+1]⁺ 542.1.

PREPARATIVE EXAMPLE 11

-682018271297 28 Nov 2018

A solution of methylmagnesium bromide in tert-butylether (0.42 mL, 1.0M, 0.42 mmol, 6.2 equiv.) was syringed into a solution of Compound 30b (48 mg, 0.068 mmol, 1.0 equiv.) in anhydrous THF (1 mL) at 0°C. The reaction mixture was then warmed up to room temperature. After TLC (EtOAc eluent) showed that the reaction was complete, the reaction mixture was diluted with ether and washed with saturated aqueous NH₄CI solution. The combined organic layers were dried over MgSO₄, filtered and concentrated to give crude product, Compound 11a, which was used in the next step without purification.

Step 2:

Using the same procedure as that of Example 31, Step 6, the crude

Compound 11a was hydrogenated to give pure Example 30b (yield 52.6% from Compound 11). MS [M+1]⁺ 587.1.

PREPARATIVE EXAMPLE 12

-692018271297 28 Nov 2018

Step A:

Compound 23d

CHONHNHCHO, TMSCI, Et₃N, Py

HC(O)NHNHC(O)H (0.28 g, 3.18 mmol), TMSCI (2.0 mL, 15.9 mmol) and Et₃N (1.1 mL, 7.95 mmol) were added successively to a solution of Compound 23d (0.647 g, 1.06 mmol) in pyridine (5.0 mL) at room temperature in a sealed tube. The mixture was then heated at 100°C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with EtOAc (100 mL) and washed with HCI (35 mL, 2.0 N). The aqueous phase was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with water (15 mL), brine (25 mL), and dried over

MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (EtOAc/MeOH, v/v = 5/1) to give Compound 12a (0.48 g, 68%).

Step b:

H„ PdiOHyC, EtOH

-70Compound 12a (32.6 mg, 0.049 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH)2/C (6.5 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was then filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (EtOAc/MeOH eluent, v/v = 6/1) to give Compound 12 (17.2 mg, 66%). Electrospray MS [M+1]⁺ 529.1.

PREPARATIVE EXAMPLE 13 and 14

2018271297 28 Nov 2018

HC(O)NHNHC(O)H (67.1 mg, 0.762 mmol), TMSCI (0.484 mL, 3.81 mmol) and Et₃N (0.266 mL, 1.905 mmol) were added successively to a solution of Compound 26a (0.155 g, 0.254 mmol) in pyridine (2.0 mL) at room temperature in a sealed tube. The mixture was then heated at 100°C for

2.5 hours before it was cooled down to room temperature. The mixture was diluted with EtOAc (40 mL) and washed with HCI (15 mL, 2.0 N). The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using

BIOTAGE chromatography (EtOAc/MeOH, v/v = 10/1) eluent to give Compound 14a (0.129 g, 75%).

-71 2018271297 28 Nov 2018

Step B:

Compound 14a (129 mg, 0.19 mmol) in EtOH (4.0 mL) was treated at room temperature with Pd(OH)₂/C (25.8 mg, 10 wt%) and hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (EtOAc/Et₃N, v/v = 100/0.1) to give Compound 13 (36 mg, 35%, Electrospray MS [M+1]⁺ 543.1.) and Compound 14 (30 mg, 29%, Electrospray MS [M+1J* 543.1.).

PREPARATIVE EXAMPLE 15

a. Dess-Martin periodinane

b. p-MeOBnNHj, NaBH(OAc)_a

CICHjCHjCI

Dess-Martin Periodinane (57.7 mg, 0.136 mmol) was added to a mixture of Compound 23g (46 mg, 0.0678 mmol) and NaHCO₃ (57 mg, 0.678 mmol) in CH₂CI₂ (2.5 mL) at room temperature. The reaction mixture was

-722018271297 28 Nov 2018 stirred for 1 hour before it was diluted with EtOAc (20 mL) and water (10 mL).

The organic phase was washed with saturated Na₂S₂O₃ solution (3x10 mL).

The combined aqueous phases were extracted with EtOAc (3x10 mL). The combined organic layers were washed with NaOH solution (10 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude aldehyde (46 mg, 0.0679 mmol) was taken up in CICH₂CH₂CI (1.0 mL) and treated with 4A molecular sieves (15 mg) and paramethoxybenzyl amine (26.7 μΙ, 0.204 mmol), followed with addition of NaBH(OAc)₃ (86.4 mg, 0.408 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. The system was then diluted with EtOAc (20 mL) and washed with aqueous NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 15a. (38 mg, 70% for 2 steps).

A mixture of Compound 15a (46.6 mg, 0.0584 mmol), Pd/C (46.6 mg, 10 wt%), and NH₄CO₂H (36.8 mg, 0.584 mmol) in MeOH (2.0 mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and filtered through a short pad of CELITE, and the residue was washed with EtOH (15 25 mL). Solvent was removed under reduced pressure to give a crude product, which was taken up with EtOAc (20 mL) and washed with aqueous NaHCO₃ (10 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was

-73purified using preparative TLC (MeOH/EtOAc, v/v = 1/10) to give Compound

15b (18 mg, 57%).

Step C:

2018271297 28 Nov 2018

MsCI (2.5 pL, 0.0324 mmol) was added to a solution of Compound 15b (8.8 mg, 0.0162 mmol) and Et₃N (5.4 pL, 0.0388 mmol) in CH2CI2 (1.0 mL) at 0°C. The reaction was quenched with water (5.0 mL) in 30 minutes and diluted with EtOAc (15 mL). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/5) to give Compound 15 (7.2 mg, 72%). Electrospray MS [M+1]⁺ 622.3.

Step 1:

PREPARATIVE EXAMPLE 16

HATU, EtNH_a

DMF

-742018271297 28 Nov 2018

Using the same procedure as that of Example 30, Step 1, Compound 16a was prepared using ethylamine in the place of A/,/V-dimethylamine hydrochloride salt, and without using diisopropyl ethyl amine. The crude product was used in the next step without purification.

Step 2:

Using the same procedure as that of Example 31, Step 6, the crude

Compound 16a was hydrogenated to give pure Example 16 (yield 70.5% from Compound 16). MS [M+1]⁺600.1.

PREPARATIVE EXAMPLE 17

StepT.

DMAP, EDC

EtOH, CH₂CI₂

A solution of Compound 31h (46.3 mg, 0.066 mmol, 1.0 equiv.) in anhydrous dichloromethane (1 mL) was cooled to 0°C. To this solution was added sequentially DMAP (8 mg, 0.066 mmol, 1.0 equiv.), and ethanol (36

-752018271297 28 Nov 2018 μι). The reaction mixture was allowed to warm up to room temperature, and then concentrated to dryness. The residue was taken up into EtOAc and washed with saturated aqueous NaHCO₃ solution. The organic layer was dried over Na₂SO₄, filtered and concentrated to give the crude product,

Compound 17a, which was used in the next step without purification.

Step 2:

/Y° p-/

17a

PdfOHWC, h₂ (46% from 31h)

Using the same procedure as that of Example 31, Step 6, the crude

Compound 17a was hydrogenated to give pure 17 (yield 46% from Compound 31h). MS [M+1]⁺ 601.1.

PREPARATIVE EXAMPLE 18

Compound 18

Step A:

Compound 19 (10 mg, 0.0175 mmol) in EtOH (1.5 mL) was treated with HONH₂»HCI (12.2 mg, 0.175 mmol) and NaOAc (7.2 mg, 0.0876 mmol) at room temperature. The reaction mixture was then stirred at 60°C for 12

-76hours. The mixture was diluted with EtOAc (20 mL) and washed with aqueous

NaHCO₃. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified by preparative TLC (hexane/EtOAc, v/v = 2/3) to give Compound 18 (10 mg, 98%). Electrospray MS [M+1]⁺ 586.1.

PREPARATIVE EXAMPLE 19

2018271297 28 Nov 2018

Compound 19

a. Dess-Martin periodinane

b. VinylMgBr, THF

c. Dess-Martin periodinane

Compound 19a

Dess-Martin Periodinane (0.252 g, 0.595 mmol) was added to a mixture of Compound 23h (0.202 g, 0.297 mmol) and NaHCO₃ (0.25 g, 2.97 mmol) in CH₂CI₂ (4.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with a saturated Na₂S₂O₃ solution (3x15 mL).

The combined aqueous phases were extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and . concentration, the crude aldehyde (0.202 g) was taken up in anhydrous THF (4.0 mL) and was treated with CH₃MgBr (1.19 mL, 1.19 mmol, 1.0 M in THF) at -78°C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours by the slow addition of saturated

-772018271297 28 Nov 2018 aqueous NH4CI solution (10 mL). The reaction mixture was then diluted with

EtOAc (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic. The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude secondary alcohol (0.21 g),was taken up in CH₂CI₂,(5.0 mL) and treated with Dess-Martin Periodinane (0.379 g, 0.894 mmol) and NaHCO₃ (0.375 g, 4.47, mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na₂S₂O₃ solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3x15 mL). The combined organic layers were washed with aqueous NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 19a (90 mg, 43% for 3 steps).

Step B:

Compound 19a

H₂, Pd(OH)fC, EtOH

Compound 19a (57.4 mg, 0.0816 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)₂/C (11.5 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was was’hed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 19 (41 mg, 88%). Electrospray MS [M+1]⁺ 571.1.

PREPARATIVE EXAMPLE 20

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Step A:

Compound 26b

a. CHOCO₂Et, NaBH(OAc)₃₁

CICH_ZCH_ZCJ

b. TMSN=C=O, CICHjCHjCI

Compound 20a

Compound 20b

NaBH(OAc)₃ (81.4 mg, 0.384 mmol) was added at room temperature to a solution of Compound 26b (79.9 mg, 0.128 mmol), CHOCO₂Et (37.8 μΙ, 0.192 mmol, 45-50% in toluene), and 4 A molecular sieves (30 mg) in

CICH₂CH₂Cl (1.0 mL). The reaction mixture was stirred for 12 hours before it was diluted with EtOAc (20 mL) and washed with aqueous NaHCO₃ (10 mL). The aqueous phase was extracted with EtOAc (3 x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product (91 mg, 0.128 mmol) was taken up in ClCH₂CH₂Cl (0.5 mL) and treated with TMSN=C=O (2.5 mL). The reaction mixture was heated at 70°C for 72 hours before the solvent was removed under reduced pressure. The crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give a mixture of Compound 20a and 20b, which was further purified by OD chiral HPLC to give pure Compound 20a (30 mg, 33%) and Compound 20b (25 mg, 28%).

. Step B:

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Compound 20a (23 mg, 0.0325 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH)₂/C (4.6 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3 to 1/9) to give Compound 20 (14.3 mg, 77%). Electrospray MS [M+1]⁺ 574.3

PREPARATIVE EXAMPLE 21 and 22

Compound 21a (1.0 g, 1.4 mmol, 1.0 equiv) was dissolved in CH₂CI₂ (16 mL) and the solution was cooled to 0°C. Diisopropylamine (0.54 g, 4.2 mmol, 3.0 equiv.) was added to the reaction mixture, followed by PYBOP (0.88 g, 1.7 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0°C for

5 min., then warmed to room temperature. After 20 min., excess methyl amine (7.0 mL, 14 mmol, 10.0 equiv.) was added as a 2.0M solution in THF. The flask became slightly warm, and was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (95/5 EtOAc/MeOH eluent). Upon completion of the reaction, the reaction mixture

-802018271297 28 Nov 2018 was diluted with H₂O and EtOAc, the organic and aqueous layers were separated, and the organic layer was washed with brine, dried with Na₂SO₄, and concentrated to give a crude product (1.9 g) as white solid. Purification was carried out using BIOTAGE chromatography (1:1 to 2:1 EtOAc/hexane) 5 to give Compound 21b as a white solid (0.72 g, 72%).

Electrospray MS [M+1] 738.2.

21b 21c

Compound 21c (0.7 g, 0.95 mmol, 1.0 equiv) was dissolved in CH₂CI₂ (10 mL) under a N₂ atmosphere. To the reaction was added excess TFA (2.0 g, 19.4 mmol, 20.0 equiv.), and the reaction mixture was stirred at room temperature overnight The progress of the reaction was monitored by TLC 15 (1/1 EtOAc/MeOH eluent), which indicated that some starting material was still present. Accordingly, 10.0 equiv. of TFA was added and the reaction mixture was allowed to stir for 3 h. Upon completion of the reaction, the reaction mixture was cooled to 0°C, quenched with saturated NaHCO3, and diluted with EtOAc. The organic and aqueous layers were separated, and the 20 organic layer was washed with brine, dried with Na₂SO₄, and concentrated to give Compound 21d (0.6 g, 99%) as a white foam.

Compound 21c (0.24 g, 0.38 mmol, 1.0 equiv) was dissolved in 5 mL of anhydrous THF under a nitrogen atmosphere. The solution was cooled to 0°C. In a separate round-bottomed flask was combined carbonyldiimidazole (0.15 g, 0.90 mmol, 2.4 equiv) and tezf-butyl carbazate (0.1 g, 0.76 mmol, 2.0 equiv) in anhydrous THF (2 mL). The solution was allowed to stir for 30 min

-81 and added via cannula to the solution of Compound 21c over 1 min. The cannula was rinsed with anhydrous THF (1 x 0.8 mL). The reaction mixture was heated to reflux until the starting material was consumed. The reaction mixture was then cooled to room temperature and concentrated under vacuum to afford a colorless foam. The crude mixture was purified using BIOTAGE chromatography (2%-5% MeOH/CH₂CI₂) to give Compound 21 d (0.22 g, 74%) as a white solid.

2018271297 28 Nov 2018

21d

Compound 21 d (0.22 g, 0.28 mmol, 1 equiv) was dissolved in 15 mL . of anhydrous CH₂CI₂ under a nitrogen atmosphere. The solution was cooled to 0°C. HCI (1.4 mL, 5.6 mmol, 20 equiv, 4 M solution in dioxane) was added and the solution was allowed to warm to room temperature and stirred overnight. The solution was cooled to 0°C and quenched with saturated NaHCO₃ (5 mL) solution and diluted with EtOAc. The organic and aqueous layers were separated and the organic layer was washed with brine (10 mL), and dried over Na₂SO₄. The organic layer was filtered and concentrated under vacuum to give a white solid. The crude mixture was purified using BIOTAGE chromatography (5%-8% MeOH/CH₂CI₂) to give Compound 21e (0.15 g, 79%) as a white solid.

Compound 21e (0.15 g, 0.22 mmol, 1.0 equiv) was dissolved in anhydrous DMF (1 mL). Foramidine acetate (0.126g, 1.2 mmol, 5.5 equiv.) followed by acetic acid (0.69 mL, 1.2 mmol, 5.5 equiv.) was added, and the

-822018271297 28 Nov 2018 reaction mixture was heated to 80°C for 30 min. Residual starting material was found by TLC analysis, and accordingly the reaction mixture was refluxed for an additional 6 h. The progress of the reaction was monitored by TLC (9/1

CH₂Cl2/MeOH eluent). Upon completion of the reaction, the reaction mixture was cooled to room temperature, quenched with H₂O, and diluted with EtOAc. The organic and aqueous layers were separated and the organic layer was washed with brine, dried with Na2SO₄, and concentrated to give a crude product (0.131 g) as white foam. Purification was carried out using BIOTAGE chromatography (gradient of 100% CH₂CI₂ to (95:5) MeOH) to give

Compound 21f as a white solid (0.11g, 72%).

Electrospray MS [M+1 ] 706.4.

Compound 21 f (0.02 g, 0.028 mmol, 1.0 equiv.) was dissolved in dry

MeOH (1.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.09 g, 0.14 mmol, 5.0 equiv.) under an inert atmosphere. The reaction mixture was heated to reflux and was monitored by TLC (9/1 CH₂Cl2/MeOH eluent). The reaction was completed in 1 hr. The reaction mixture was filtered through CELITE, washed using EtOAc, and concentrated under vacuum. The resulting residue was taken up in EtOAc, and washed with saturated NaHCO₃, followed by brine and H2O to give a crude product (0.019 g) as solid film. Purification was carried out by BIOTAGE chromatography (gradient of 2% to 6% MeOH/CH₂CI₂). The deaired product was converted to the HCI salt to give a mixture of Compounds

21 and 22 (0.014 g) as a white solid.

HRMS (FAB) calculated for C^sFgNsOs (M+1)572.2096, found 572.2103.

PREPARATIVE EXAMPLE 23 .

-832018271297 28 Nov 2018

Step A:

Compound 23

NaBH₄ (2.42 g, 64.1 mmol) was added in 4 portions to a solution of Compound 23a in MeOH (160 mL) at 0°C. The reaction mixture was stirred for 4 hours and the reaction temperature was slowly increased to rt. The reaction was quenched by the slow addition of saturated aqueous NH₄CI solution (50 mL). The reaction mixture was then diluted with EtOAc (400 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over MgSO₄. After filtration and concentration, the crude product was passed through a short pad of silica gel (hexane/EtOAc, v/v = 7/1). Solvent was removed under reduced pressure to give Compound 23b, 17.4 g (89%) as a light yellow syrup. '

Step B:

Compound 23b

Compound 23d

-842018271297 28 Nov 2018

TBAF (2.23 mL, 2.23 mmol, 1.0 M in THF) was added dropwise to a mixture of Compound 23b (9.1 g, 14.89 mmol) and paraformaldehyde (3.85

g) in THF (100 mL) at 0°C. The reaction mixture was stirred at 0°C for 8 hours before it was quenched with addition of saturated aqueous NH4CI solution (50 mL). The reaction mixture was then diluted with EtOAc (250 mL) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE (CH2Cl₂/EtOAc, v/v = 100/0.5) to give Compound 23c (6.0 g, 63%) and 23d (2.34 g, 24%).

Step C:

Zn, HOAc, SO °C

A mixture of Compound 23c (7.54 g, 11.76 mmol) and Zn dust (7.68 g,

117.6 mmol) in HOAc (120 mL) was heated at 60°C for 2 hours. The reaction mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with EtOH (50 mL). Solvent was removed under reduced 20 pressure and the residue was taken up in EtOAc (250 mL) and washed with

NaOH solution (50 mL, 4.0 N). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, 25 v/v = 1/3 and EtOAc/MeOH, v/v = 10/1) to give Compound 23e (6.4 g, 89%).

Step D:

BnBr, (NH₄)₄HSO₄, NaOH, THF

- 852018271297 28 Nov 2018

BnBr (0.668 mL, 5.58 mmol) was added at rt to a vigorously stirring mixture of Compound 23e (3.1 g, 5.07 mmol) and Bu₄NHSO₄ (0.334 g, 1.014 mmol) in THF (20 mL) and aqueous NaOH solution (20 mL, 50 wt%). The reaction mixture was stirred at room temperature for 12 hours before it was diluted with EtOAc (250 mL) and washed with water (100 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO₄. After . filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3 to 1/7) to give Compound 23f (2.8 g, 79%).

Step E:

era

a. \=N-NHCO₂CH_{3 E(0H}

31c

b. NaOCH₃, MeOH, 80 °C

Compound 23 g

A solution of Compound 23f (2.72 g, 3.88 mmol) and reagent 31c (i.e., N-ethoxymethylene-hydrazine carboxylic acid methyl ester) (2.83 g, 19.4 mmol) in EtOH (15 mL) was heated at 60°C for 18 hours. The reaction mixture was diluted with MeOH (15 mL) and then treated with NaOCH₃ (7.0 mL, 38.8 mmol, 30% in MeOH). The resulting reaction mixture was heated at 80°C for 4 hours before it was cooled to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and aqueous NH₄CI solution (75 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over

MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2.5/1 to 1/1) to give Compound 23g (2.54 g, 85%).

Step F:

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BCI,, CH,CI„ -78 *C

BCh (3.26 mL, 3.26 mmol, 1.0 M in hexane) was added dropwise to a stirring solution of Compound 23g (0.502 g, 0.653 mmol) in CH2CI2 (45 mL) at -78°C. The reaction was quenched in 1 hour by the addition of aqueous

NaHCO₃ solution (50 mL) at -78°C. The mixture was diluted with EtOAc (100 mL) and vigorously stirred at room temperature for 2 hours. The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3 to 1/9) to give Compound 23h (0.39 g, 91%).

Step G:

H„ PdfOWC, EtOH

Compound 23h (1007hg7071’52’rrimol) in EtOH (5.0 mL) was treated at room temperature with Pd(OH)₂/C (20 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/7) to give

Compound 23 (68 mg, 82%). Electrospray MS [M+1 ]⁺ 545.1.

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PREPARATIVE EXAMPLE 24

Example 24

31g Example 24

A solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in anhydrous dichloromethane (4 mL) was cooled to -78°C. Then O₃ was bubbled through the solution until the solution turned blue. The solution was then purged with N₂ to remove excess O₃, and the reaction mixture was concentrated to dryness. The resulting residue was then taken up in ethanol (2 mL), and treated with sodium borohydride (46 mg, 1.2 mmol, 10 equiv.). The reaction mixture was stirred at room temperature until TLC (50%

EtOAc/hexanes) showed that the starting material was completely consumed. The reaction mixture was then concentrated to dryness. The residue was dissolved in absolute ethanol (4 mL) and treated with Pd(OH)₂/C (80 mg, 20 wt%, 0.11 mmol, 0.88 equiv.) before hydrogenating with a hydrogen balloon. The reaction mixture was stirred at room temperature until TLC .(5%

MeOH/CHaCb) showed that the starting material was completely consumed. The reaction mixture was again concentrated to dryness. The residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the aqueous and organic layers separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO4, filtered, concentrated to give the crude product, which was purified using Prep-TLC (MeOH/CH₂CI₂ =5%) to give pure Compound 24 (42 mg, yield 63%). MS [M+1]⁺ 559.1.

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PREPARATIVE EXAMPLE 25

compound 25

31g

Pd(OHVC, H_z

EtOH (84%)

To a solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in absolute ethanol (3 mL) was added Pd(OH)2/C (20 mg, 20 wt%, 0.028 mmol,

0.88 equiv.) before hydrogenating with a hydrogen balloon. The reaction mixture was stirred at room temperature until TLC (50% EtOAc/hexanes) showed that starting material was completely consumed. The reaction mixture was. then concentrated to dryness. The resulting residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the aqueous and organic layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product, which was purified using Prep-TLC (50% EtOAc/hexanes) to give pure Compound 25 (15 mg, yield 84%). MS [M+1]⁺ 557.1.

PREPARATIVE EXAMPLE 26

Compound 26

-892018271297 28 Nov 2018

Step A:

Compound 26a

BoCjO, NEt₃, dioxane

Compound 26b

Et₃N (0.129 mL, 0.93 mmol) was added to a solution of Compound

26a (0.472 g, 0.77 mmol) and Boc₂0 (0.168 g, 0.77 mmol) in dioxane (3.0 mL) at room temperature. The resulting solution was stirred for 8 hours before it was diluted with EtOAc (50 mL). The organic phase was washed with 0.5 N HCI (10 mL). The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 26b (0.465 g, 85%),

Step B:

Compound 26b

CHjI. (NH^HSO- NaOH, THF

Compound 26c

CH₃I (0.372 mL, 5.98 mmol) was added at rt to a vigorously stirring 20 mixture of Compound 26b (0.425 g, 0.598 mmol) and Bu₄NHSO₄ (40.6 mg, ........~0.T2~mm0l)iri~THF (5’0 mL) and aqueous NaOH solution (5.0 mL, 50 wt%).

The reaction mixture was stirred at room temperature for 12 hours before it was diluted with EtOAc (50 mL) and washed with water (15 mL). The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers 25 were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 5/1) to give Compound 26c (0.345 g, 80%).

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Step C:

Compound 26c Compound Compound 26e

A solution of Compound 26c (0.345 g, 0.476 mmol) in TFA (3.0 mL) was stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 mL) and washed with NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude amine (0.29 g, 0.464 mmol) was dissolved in EtOH (3.0 mL) and treated with reagent 31c (0.4.6 g, 2.78 mmol). The resulting solution was heated at 60°C for 18 hours. The reaction mixture was diluted with MeOH (3.0 mL) and then treated with NaOCH₃ (0.672 mL, 3.712 mmol, 30% in MeOH). The resulting reaction mixture was heated at 80°C for 4 hours before it was cooled to room temperature. The system was diluted with addition of EtOAc (50 mL) and aqueous NH₄CI solution (15 mL). The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/3) to give a mixture of Compounds 26d and 26e (0.275 g, 83% for 3 steps) which were separated with OD chiral

HPLC (hexane/isopropanol v/v = 95/5) to give pure Compounds 26d and 26e.

Step D:

-91 2018271297 28 Nov 2018

Compound 26d (38 mg, 0.0548 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)₂/C (7.6 mg, 10 wt%) and was hydrogenated 5 using a H₂ balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/4) to give Compound 26 (25 mg, 82%). Electrospray MS [M+1]⁺ 559.1.

PREPARATIVE EXAMPLE 27

Step A:

Ha, Pd(OHWC, EtOH

Compound 26e (41 mg, 0.0592 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)₂/C (8.2 mg, 10 wt%) and was hydrogenated using a H₂ balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent

- 92was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/4) to give

Compound 27 (26 mg, 79%). Electrospray MS [M+1]⁺ 559.1.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 28

Step A:

In a 25 mL round-bottomed flask, Compound 44b (0.2 g, 0.45 mmol, 1.0 equiv) was dissolved in DMF (5.0 mL). HATU (0.342 g, 0.90 mmol, 2.0 equiv), EDC (0.172 g, 0.90 mmol, 2.0 equiv), and DIEA (0.118 mL, 0,68 mmol, 1.5 equiv) were added. The reaction mixture was cooled to 0°C and

Boc-a-methyl alanine (0.109 g, 0.54 mmol, 1.2 equiv) was added. The reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with saturated NaHCO₃ (5 mL), diluted with EtOAc (10 mL), and extracted with EtOAc (2x5 mL). The organic layer was washed with brine (10 20 mL), dried over MgSO₄, and concentrated. The resulting residue was purified by preparative TLC (9/1 hexanes/EtOAc) to give 0.12 g (43%) of Compound 28a.

Step B:

-932018271297 28 Nov 2018

Compound 28a

TEA, DCM

Compound 28b was prepared by a method similar to that the compound 45c, described below, in which a DCM solution of Compound 5 28a was reacted with TFA to remove the Boc protecting group.

Step C;

HC(OMe),

CH₃CO₂H

In a 10 mL round-bottomed flask, compound 28b (0.050 g, 0.094 mmol, 1.0 equiv) was dissolved in toluene (1 mL), and then trimethylorthoformate (0.012 mL, 0.113 mmol, 1.2 equiv) and 1 drop of acetic acid were added. The solution was heated at 60°C. The reaction mixture was allowed to stir for over 48 hours. The reaction mixture was then taken up in

EtOAc (5 mL) and washed with saturated NaHCO₃ (5 mL). The organic layer was washed with brine (5 mL), dried over MgSO₄, and concentrated. The crude product was purified by preparative TLC (EtOAc) to yield 0.010 g of Compound 28. HRMS calculated for C₂7H29FeN₃O₂ (M+H) 542.2242, found 542.2222.

PREPARATIVE EXAMPLE 29

- 942018271297 28 Nov 2018

Example 29

A solution of Compound 31h (39 mg, 0.055 mmol, 1.0 equiv.) in anhydrous dichloromethane (1 mL) was cooled to -20°C. Then triethylamine (10 mL, 0.069 mmol, 1.25 equiv.) and ethyl chloroformate (6.5 mL, 0.066 mmol, 1.2 equiv.) were added. The resulting pale green solution was stirred at -15°C for 30 minutes. Ammonia gas was bubbled through the solution for minutes. TLC (EtOAc) indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate, washed sequentially with 1N HCl (1 mL), saturated sodium carbonate aqueous solution, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The resulting residue was dissolved in absolute ethanol (6 mL), to which was added Pd(OH)₂/C (17 mg, 20 wt%, 0.024 mmol, 0.43 equiv.) before attaching a hydrogen balloon to the reaction flask. The reaction mixture was stirred at room temperature until TLC (5% MeOH/EtOAc) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness, and the residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the organic and aqueous layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the crude product, which was purified using Prep-TLC (5% MeOH/EtOAc) to give pure Example 29 (18 mg, yield 57%). MS [M+1]⁺ 572.1.

PREPARATIVE EXAMPLE 30

-952018271297 28 Nov 2018

Step 1:

compound 30

To a solution of Compound 31 h (450 mg, 0.64 mmol, 1.0 equiv.) in anhydrous DMF (3.5 mL), was added, sequentially, HATU (290.5 mg, 0.764 mmol, 1.2 equiv.), A/,A/-dimethylamine hydrochloride salt (99 mg, 1.01 mmol,

1.6 equiv.) and diisopropyl ethylamine (0.50 pL, 2.87 mmol, 4.5 equiv.). The 10 resulting orange solution was stirred at room temperature until TLC (5%

MeOH/EtOAc) showed that starting material was completely consumed. The reaction mixture was poured into dichloromethane (200 mL), washed sequentially with half-saturated citric acid aqueous solution, saturated NaHCO₃, and brine. The organic layer was dried over anhydrous Na₂SO₄, 15 filtered, and concentrated to give the crude product, which was purified using

BIOTAGE chromatography (EtOAc/Hexane =3:1) to give Compound 30a as a brown solid (208 mg, yield 43.6%).

Step 2:

Methylmagnesium bromide (1.65 mL, 1.0 M in t-butylether, 1.65 mmol,

6.0 equiv.) was added dropwise to a solution of Compound 30a (206 mg,

-960.275 mmol, 1.0 equiv.) in anhydrous THF (3 mL). TLC (EtOAc) showed that the starting material was totally gone after the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with ethyl acetate, quenched with a saturated aqueous NH₄CI solution, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give the crude product, Compound 30b.

2018271297 28 Nov 2018

Compound 30b was used in the next step without purification.

Step3:

Using the same procedure as that of Example 31, Step 6, the crude Compound 30b was hydrogenated to give pure Example 30 (150 mg, yield 95.6% from Compound 30a). MS [M+1]⁺ 571.1.

PREPARATIVE EXAMPLE 31

Step 1:

H₂NNHC(O)OCH, + (EtO)₃CH

31a 31b

88’C (>55% )

EtO \=N—NH 'c(0)OCH₃

31c

Compound 31b (32 mL) was added to a solution of Compound 31a (1.0 g, 11.1 mmol, 1.0 equiv.) in triethylorthoformate. The solution was heated at 88°C for 36 hours, and then concentrated to dryness under vacuum.

The resulting residue was recrystallized from EtOAc, to give Compound.31c (0.94 g, yield 58%).

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Step 2:

31d 31e

To a solution of Compound 23b (2.5 g, 4.1 mmol) in THF (20 mL) was added allylmethylcarbonate (0.465 ml, 8.2 mmol), and Pd(PPh3)₄ (236 mg, 0.205 mmol). The reaction vessel was purged three times with nitrogen, and then the solution was allowed to stir for 16 hours. The solvent was then removed and the residue was filtered through a short silica column using 20% EtOAC /hexanes as eluent. The filtrate was concentrated and Compounds 31d and 31e were separated using prep-HPLC. MS [M+1]⁺ 651.1 for both compounds.

¹⁵ .

Step 3:

d 31 f

A round-bottomed flask was charged with Compound 31 d (3.84 g,

5.90 mmol, 1.0 equiv.) and glacial acetic acid (20 mL). To the resulting yellowish solution at 0°C was added as several small portions of Zinc dust (3.86 g, 59.0 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 6 hours until TLC (30% EtOAc/hexane) showed that the starting material Compound 31 d was totally consumed. The reaction mixture was then diluted with ethyl acetate, and passed through a CELITE pad in a funnel. The CELITE pad was thoroughly washed with ethyl acetate, and the combined with the filtrate. The filtrate was concentrated to provide a crude product, which was purified using BIOTAGE chromatography (30%

-98EtOAc/hexanes) to give a pure colorless oil product, Compound 31 f (3 g, yield 81.9%).

2018271297 28 Nov 2018

To a solution of Compound 31 f (33.4 mg, 0.054 mmol, 1.0 equiv.) in ethanol (0.4 mL) was treated with reagent 31c (67.5 mg, 0.46 mmol, 5 equiv.) and stirred at room temperature overnight. It was then diluted with anhydrous methanol (1 mL) and treated with sodium methoxide, then heated at 88°C until TLC (EtOAc) showed only product. It was concentrated to dryness, and then taken up into ethyl acetate, washed with saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO₄, filtered, and concentrated to get the crude product, which was purified via BIOTAGE chromatography (25-40% EtOAc/hexanes) to get pure compound 31 g (22.4 mg, yield >60%).

Step 4:

Compound 31g (306 mg, 0.44 mmol, 1.0 equiv.) was dissolved in anhydrous dichloromethane (5 mL). The resulting colorless solution was cooled to -78°C, then O₃ was bubbled through until the solution turned purple.

The solution was then purged with N₂ to remove excess O₃. The solution was

-992018271297 28 Nov 2018 then concentrated to dryness. The resulting white foam was dissolved in formic acid (1.5 mL) and treated with hydrogen peroxide (1.5 mL, 30% aqueous solution) to form a white suspension, which was heated to 80°C overnight. LCMS analysis showed only the product peak. The solvent was removed under vacuum, and the residue was dissolved In ethyl acetate and washed with half saturated Na2S₂O₃ aqdeous solution. The resulting two layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO4, filtered and concentrated to give the Compound 31 h (284.2 mg, yield 90.6%).

Compound 31 h was used in the next step without purification.

Step 5:

31h ³¹¹

To a solution of Compound 31 h (104 mg, 0.147 mmol, 1.0 equiv.) in benzene (4 mL) and methanol (1 mL), was added dropwise a 2.0M solution of trimethylsilyl diazomethane in hexanes (88 pL, 0.177 mmol, 1.2 equiv.). TLC (10% MeOH/CH₂CI₂) showed that the starting material was gone completely 20 after stirring the reaction mixture at room temperature for 30 minutes. The solvent was removed to give the crude product, which was used in the next step without purification.

Step 6:

The crude product from Step 5, Compound 31i, was dissolved in absolute ethanol (4.5 mL). To this solution was added Pd(OH)₂/C (46.7 mg,

-10020 wt%, 0.067 mmoi, 0.45 equiv.), and then the reaction mixture was hydrogenated with a hydrogen balloon. The hydrogenation reaction was stopped when TLC (10% MeOH/CH₂CI₂) showed that the starting material was consumed. The diluted reaction mixture was carefully passed through a

CELITE packed funnel, and the CELITE pad was washed thoroughly with methanol. The filtrate was concentrated to dryness. The resulting residue was purified by prep-TLC (10% MeOH/CH₂CI₂) to give the pure Compound 31 (56.2 mg, yield 65% from Compound 31 g), MS [M+1f 587.1.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 32

Stepl:

In a 25 ml round-bottomed flask, Compound 42b (0.142 g, 0.23 mmol, 20 1.0 equiv) was taken up in 3 mL of dichloroethane under a N₂ atmosphere and the reaction mixture was treated with Et₃N (0.0.48 ml, 0.34 mmol, 1.5 equiv) followed by 3-chlorosulfonyl propyl chloride (0.037 ml, 0.3 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and 25 MS, which indicated no desired product was formed. Accordingly, the reaction mixture was then heated to reflux. After one hour of heating the reaction was complete. The reaction mixture was then cooled and diluted

-101 with CH₂CI₂, and quenched with 1N HCI. The organic layer was dried over

Na₂SO₄ and concentrated to give crude Compound 32a (0.11 g), which was used in the next step without further purification.

2018271297 28 Nov 2018

Step 2:

DBU, DMF

In a flame dried 15 ml round-bottomed flask, Compound 32a (0.11 g, 0.23 mmol, 1.0 equiv) was taken up in dry DMF. To this reaction mixture,

1,8-diazabicyclo[5.4.0]undec-7ene (0.044 g, 0.29 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (30:70 EtOAc/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with H₂O. The organic layer was dried over Na₂SO4 and concentrated to give crude Compound 32b (0.1g). Purification was carried out using BIOTAGE chromatography (30/70 EtOAc/hexane) to give purified Compound 32b (0.072g).

Electrospray MS [M+1] 710.2.

Step 3:

20% PdOH, MeOH, H₂(g)

Compound 32b (0.072 g, 0.1 mmol, 1.0 equiv) was dissolved in dry

MeOH (1.5 ml) and was treated with 20% Pd(OH)₂ (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 EtOAc/hexane).

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The reaction was completed in 45 min, and was filtered through CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using preparative chromatography (60/40 EtOAc/hexane) to give Compound 32 (0.04g, 70%).

Electrospray MS [M+1]576.2.

HRMS (FAB) calculated for C₂₆H_2SF₆N₃O₂(M+1) 576.1756, found 576.1764.

PREPARATIVE EXAMPLE 33

Step 1:

In a 25 ml round-bottomed flask, Compound 42b (0.322 g, 0.53 mmol, 1.0 equiv) was taken up in 5 ml of CH₂CI₂ and the reaction mixture was cooled to 0°C in an ice bath. Et₃N (0.111 mL, 0.79 mmol, 1.5 equiv) followed by 4chlorobutyryLchloride (0.072 .ml, 0.64 mmol,-1-.2-equiv)-was-then added-to the reaction mixture, which was slowly warmed to room temperature and stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with CH2CI2 and quenched with saturated NaHCO₃ followed by brine. The organic layer was dried over Na₂SO₄ and concentrated to give crude Compound 33a (0.32 g), which was used in the next step without further purification.

-1032018271297 28 Nov 2018

Step 2:

60% NaH, THF * CbzN

-O

33b

In a flame dried 25 ml round-bottomed flask, Compound 33a (0.32 g, 0.45 mmol, 1.0 equiv) was taken up in dry THF. To this solution, 60% NaH (0.025 g, 0.68 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic layer was dried over Na₂SO₄ and concentrated to give Compound 33b (0.4 g), in the form of a yellow oil, which was used in the next step without further purification.

Step 3:

Compound 33b (0.4 g, 0.59 mmol, 1.0 equiv) was dissolved in dry MeOH (4.0 mL) and was treated with 20% Pd(OH)₂ (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 EtOAc/hexane eluent). The reaction was completed in 45 min, was filtered through CELITE and washed using EtOAc and concentrated to give a crude product. Purification of the crude product was carried out using BIOTAGE chromatography (60/40 EtOAc/hexane) to give Compound 33 (0.18 g, 59%).

HRMS (FAB) calculated for CaeHssFgNsOa (M+1) 540.2086, found 540.2078.

PREPARATIVE EXAMPLE 34

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Step 1:

Example 34

etjN.CHjCI,

Cl

34a

In a 25 ml round-bottomed flask, Compound 42c (0.23 g, 0.38 mmol,

1.0 equiv) was taken up in 3 mL of CH₂Cl2, and the reaction mixture was cooled to 0°C in an ice bath. Et₃N (0.079 ml, 0.57 mmol, 1.5 equiv) followed by 4-chlorobutyryl chloride (0.051 ml, 0.45 mmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion ofthe reaction, the reaction mixture was diluted with CH2CI2 and quenched with saturated

NaHCO₃ followed by brine. The organic layer was dried over Na₂SO4 and concentrated to give crude Compound 34a (0.23 g), which was used in the next step without further purification.

........Step 2:

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In a flame dried 25 ml round-bottomed flask, Compound 34a (0.23 g,

0.38 mmol, 1.0 equiv) was taken up in dry THF (1 mL). To this reaction mixture, 60% NaH (0.022 g, 0.57 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by TLC (60:40 EtOAc/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with EtOAc and quenched with saturated NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated to give Compound 34b (0.21 g) in the form of a yellow oil, which was used in the next step without further purification.

Electrospray MS [M+1 ] 674.2.

Step 3:

Compound 34b (0.21 g, 0.31 mmol, 1.0 equiv) was dissolved in dry

MeOH (2.0 mL) and was treated with 20% Pd(OH)₂ (40% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the hydrogenation was monitored by TLC (40:60 EtOAc/hexane eluent). After 45 min, the reaction mixture was filtered through

CELITE, washed with EtOAc, and concentrated to give a crude product. The crude product was purified using BIOTAGE chromatography (60/40 EtOAc/ hexane), to give Compound 34 (0.10 g, 59%).

HRMS (FAB) calculated for C₂₆H₂₈F₆N₃O₂ (M+1 )540.2086, found 540.2078.

PREPARATIVE EXAMPLE 35

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Compound 23d

Zn, HOAc, SO C

Compound 35

Compound 35a

Compound 35 was prepared using a procedure similar to procedure for preparing Compound 23e in Example 23.

Compound 35a

BnBr, (NH₄)₄HSO₄, NaOH, THF

Compound 35b

Likewise, Compound 35b was prepared by a procedure similar to the procedure used to prepare Compound 23f in Example 23.

Compound 35b

b. NaOCH₃, MeOH, 80 ’C

EtO _a. —N-NHCO₂CH₄ ' .31c , EtOH

Compound 35c

Compound 35c was prepared by a procedure similar to the procedure used to prepare Compound 23g in Example 23.

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Compound 35c

PdiOH)» H.

MeOH

Compound 35d

Compound 35d was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23.

Compound 35d

SCi₃, DCM

-78 ^eC

Compound 35e

Compound 35e was prepared by a procedure similar to the procedure for preparing Compound 23h in Example 23.

Compound 35e

Dess-Martin periodinane

Compound 35f

Compound 35f was preparing by a procedure similar to the procedure for preparing Compound 42e in Example_42.

Compound 35f

NHgOH.HCI, NaOAc

EtOH

Compound 35g

- 108Compound 35g was prepared by a procedure similar to the procedure for preparing Compound 42g in Example 42.

2018271297 28 Nov 2018

1,1-oxalyldiimidazote

Benzene

Compound 35 was prepared by a procedure similar to the procedure for preparing Compound 42 in Example 42. HRMS calculated for C25H23FSN5O2 (M+H) 540.1834, found 540.1822.

PREPARATIVE EXAMPLE 36

Step A:

Compound 36a

Compound 36a was prepared by a procedure similar to the procedure 20 for preparing Compound 47 in Example 47.

Step B:

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Compound 36a «2, Pd(OH)₂

MeOH

Compound 36

Compound 36 was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for

C24H25F6N3O3S (M+H) 550.1599, found 550.1603.

PREPARATIVE EXAMPLE 37

Step A:

Compound 37a

Compound 37a was prepared by a procedure similar to the procedure for preparing compound 47 in Example 47.

Step-B.:20

Compound 37a

Hj, Pd(OH)₂

MeOH

Compound 37

-110Compound 37 was prepared using a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for

C2₄H₂₅F6N₃O₃S (M+H) 550.1599, found 550.1603.

PREPARATIVE EXAMPLE 38

2018271297 28 Nov 2018

1) 0,, TBAI

2) ΝΗ,ΟΗ, NaOAc

3) (lm)₂CO

Step T.

To a solution of Compound 31g (640 mg, 0.93 mmol) in 10 mL CH2CI2 maintained at -78°C was bubbled O₃ gas until the reaction mixture turn blue. The reaction mixture was then purged with nitrogen until it became colorless. TBAI (412 mg, 1.11 mmol) was then added and the reaction mixture was stirred at 20°C for 2h. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous Na₂S2O₃, water and brine, and the dried and concentrated. The resulting residue was dissolved in EtOH (22 mL) and NaOAc (262.7 mg, 3.2 mmol) and hydroxylamine hydrochloride salt (222 mg, 3.2 mmol) were added, and the mixture was stirred overnight. The reaction mixture was then concentrated and the residue was partitioned between 20 mL EtOAc and water. The organic layer was dried and concentrated. The crude intermediate was dissolved in toluene (6.8 mL) followed by the addition of 1,T-oxallyldiimidazole (165 mg, 1.8 mmol) and the mixture was heated at 80°C for 2h. After cooling the reaction mixture to 23°C, the toluene solution was loaded to a silica gel column and eluted with 20-100% EtOAc/hexanes to give product Compound 38a. MS [M+1 ]⁺ 688.1.

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Step 2:

Using a procedure similar to that of Example 31, Step 6, Compound 38a was hydrogenated to give Compound 38. MS [M+1]⁺ 554.1.

PREPARATIVE EXAMPLE 39 and 40

Compound 39

Compound 40

Step A:

Compound 42b

Compound 40

H_a, Pd(OH)₂

MeOH •h

Compound 42c +

Compound 39

Compounds 39 and 40 were prepared using a procedure similar to the procedure for preparing Compound 38. HRMS calculated for

C₂₃H₂₃F₆N₃O(M+H) 472.1824, found 472.1820. .

PREPARATIVE EXAMPLE 41

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Step A:

Compound 41a

In a 25 mL round-bottomed flask Compound 42b (0.15 g, 0.248 mmol, 1.0 equiv) was dissolved in 6 mL of DCE. Trimethylsilyl isocyanate (0.51 mL, 3.72 mmol, 15.0 equiv) was added and the reaction mixture was refluxed at 80°C overnight. The reaction mixture was cooled and quenched with saturated NaHCO₃ (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The organic layers were washed with brine (5 mL), dried over MgSO₄, and concentrated. The crude product was purified by preparative TLC (1:1 EtOAc:hexanes) to yield 0.060 g (37%) of Compound 41a.

Step B:

Compound 41a

H₂, Pd(OH)₂

MeOH

Compound 41

Compound 41 was prepared by a procedure similar to procedure for preparing Compound 23 in Example 23. HRMS calculated for C₂₄H24F₆N₄O2 (M+H) 515.1882, found 515.1874.

PREPARATIVE EXAMPLE 42

-1132018271297 28 Nov 2018

Step A:

Compound 41a (6.87 g, 11.86 mmol) in EtOH (7 mL) was added to a solution of NaCN (0.767 g), NH₄CI (0.889 g) and NH₃-H₂O (3.84 mL) in EtOH (7.0 mL) and water (7.0 mL) at room temperature in a sealed tube. The sealed 10 tube was then heated at 60^DC for 12 hours before it was cooled down to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (50 mL). The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over MgSO₄. After filtration and concentration, the crude product was 15 purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 7/2 to 5/2) to give Compound 42b (2.6 g, 36%) and Compound 42c (1.8 g, 25%).

Step B:

Compound 42b

COCyNaHCO_a then NH.NHC(O)H/Py

Phosgene (6.67 mL, 12.4 mmol, 20% in toluene) was added dropwise to a vigorously stirred mixture of Compound 42b (1.5 g, 2.48 mmol) in CH₂CI₂ (30 mL) and a saturated NaHCO₃ solution (30 mL) at 0°C. The mixture was

-1142018271297 28 Nov 2018 stirred at 0°C for 3 hours before it was diluted with CH2CI2 (50 mL) and the aqueous phase was separated from the organic phase. The organic phase was washed with a cold aqueous NH₄CI solution, brine, and dried over

MgSO₄. The solvent was reduced to a volume of about 5 mL under reduced pressure, at room temperature, to remove excess phosgene. The residue was dissolved in CH₂CI₂ (15 mL) and treated with NH₂NHC(O)H (0.446 g, 7.44 mmol) and pyridine (1.2 mL, 14.88 mmol) at room temperature. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was then diluted with EtOAc (200 mL) and washed with HCI (50 mL, 0.5 N).

The aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using BIOTAGE chromatography eluted with hexane/EtOAc (v/v = 1/2 to 1/7) to give Compound 42d (1.1 g, 64%).

Step C:

HN-NHCHO m

0=/ ΰ* 'NH

TMSCI (50 pL) was added to a stirring mixture of Compound 42d (15 mg, 0.0217 mmol) and Lil (2.9 mg, 0.0217 mmol) in HMDS (0.5 mL) at room ______temperature_The_re.su Iting.reaction. mixtur.e_was_heated-at-1-40°C-(bath temperature) for 30 hours before it was cooled down to room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with HCI (5 25 mL, 1.0 N). The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 6/4) to give Compound 42 (4 mg, 34%).

-115ALTERNATE PROCEDURE FOR EXAMPLE 42

2018271297 28 Nov 2018

Alternatively, Compound 42 can also be prepared from Compound

23g as follows

Step A:

Compound 23g

CbzN

Dess-Martin periodinane

Compound 42e

CbzN

In a 10 mL round-bottomed flask, Compound 23g (0.02 g, 0.037 mmol, 1.0 equiv) was dissolved in DCM (3 mL) and the reaction mixture was cooled to 0°C. Dess-Martin periodinane ₍0.02 g, 0.048 mmol, 1.3 equiv) was added and the reaction mixture was stirred under nitrogen at room temperature for 45 minutes. The progress of the reaction was monitored by TLC (9/1 EtOAC/MeOH eluent), and the reaction was quenched after 1.5 hrs, by pouring the reaction mixture into separatory funnel containing saturated Na2S₂O3/NaHCO₃ solution (1:1) (5 mL). The mixture in the separatory funnel was shaken vigorously, and the aqueous layer was extracted with Et₂O (2 x 5) and dried over MgSO₄ and concentrated to give crude Compound 42e (0.02 g), which was used in the next step without further purification.

Step B:

NH.OH.HCI, NaOAc

Compound 42f

CbzN

EtOH

Compound 42g

In a 25 mL round-bottomed flask, Compound 42f (0.09 g, 0.13 mmol, 1.0 equiv) and sodium acetate (0.032 g, 0.39 mmol, 3.0 equiv) were dissolved in EtOH (6 mL), to which hydroxylamine hydrochloride (0.056 g, 0.080 mmol,

-1162018271297 28 Nov 2018

6.0 equiv) was added. The reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was then diluted with EtOAc (15 mL), quenched with saturated NaHCO₃ (5 mL), and the organic layer was washed using brine (5 mL) and dried over MgSO₄ to give crude 5 Compound 42g (0.95 g), which was used in the next step without further purification.

Step C:

Benzene

1,1 ’-oxalyldjimidazoJe

In a 50 mL round-bottomed flask, Compound 42g (1.1 g, 0.59 mmol, I.Oequiv) was dissolved in benzene (25 mL). 1, T-oxalyldiimidazole (0.302 g, 1.89 mmol, 1.5 equiv) was added to the solution, and the reaction mixture was heated to 75°C under nitrogen for 4 hrs. The reaction mixture was then quenched with water (20 mL), diluted with EtOAc (30 mL), dried over MgSO₄ and concentrated to give a crude product. The crude product was purified using BJOTAGE chromatography (1/1 EtOAc/hexanes) to give Compound 42h (0.7 g, 66% over three steps).

Step D:

-TMSI,.CH₃CN.

Compound 42

In a 50 mL round-bottomed flask, Compound 42i (0.5 g, 0.742 mmol,

1.0 equiv) was taken up in acetonitrile (9 mL). The reaction mixture was cooled to 0°C, and TMSI (0.742 mL, 5.19 mmol, 7.0 equiv) was added dropwise via syringe. The reaction mixture was stirred overnight at room

-1172018271297 28 Nov 2018 temperature. The progress of the reaction was monitored by MS, which indicated some starting material was still present. The reaction mixture was quenched using saturated Na₂S₂O₃/NaHCO₃ (1:1) (10 mL) and diluted with EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over 5 MgSO4, and concentrated to yield a crude product. The crude product was purified using BIOTAGE chromatography (60/40 EtOAc/hexanes) to give Compound 42. (0.4 g). HRMS calculated for C₂₅H₂₃F₆N₅O₂ (Μ+Η) 540.1834, found 540.1813.

PREPARATIVE EXAMPLE 43

Step A:

HATU, EDC, DJEA

Boc-aminocyclopropyl carboxylic acid

Compound 43a

Compound 43a was prepared by a procedure similar to the procedure for preparing Compound 28a.

Step B:

TFA, DCM

R

cf₃

Compound 43b

-118 compound 43b was prepared by a procedure similar to the procedure for preparing Compound 45c.

2018271297 28 Nov 2018

Step C:

HC(0Me)₃

CH₃CO₂H

Compound 43 was prepared by a procedure similar to the procedure for preparing Compound 28 (step c).

PREPARATIVE EXAMPLE 44

Step A:

Zn, AcOH

In a 50 mL round-bottomed flask, Compound 44a (1.1 g, 2.31 mmol, 1.0 equiv) was dissolved in acetic acid (20 mL), and the resulting reaction mixture was cooled to 0°C. Zn powder (1.51 g, 23.1 mmol, 10.0 equiv) was added and the mixture was refluxed for 2.5 hr. The reaction mixture was then filtered through CELITE, concentrated, diluted with EtOAc (30 mL), and neutralized with saturated NaHCO₃ (30 mL). The aqueous phase was extracted with EtOAc (2x10 mL), washed with brine (20 mL), dried over

-119MgSO₄ and concentrated. The crude product was purified using a filter column to yield 1.0 g (99%) of Compound 44b.

2018271297 28 Nov 2018

Step B:

Compound 44b

BocNHNHj, CDI

THF ,ΝΗΒοο

Compound 44c

Compound 44c was prepared by a procedure similar to the procedure for preparing Compound 45b.

Step C:

1.TFA, DCM

2. pyridine, DCM

BnO'^y^Cl

O

Compound 44d

Compound 44d was prepared by a procedure similar to the procedure for preparing Compound 45c.

Step D:

Compound 44e was prepared by a procedure similar to the procedure for preparing Compound 45d.

Step E:

-1202018271297 28 Nov 2018

In a 10 mL round-bottomed flask, Compound 44e (0.34 g, 0.54 mmol, 1.0 equiv) was taken up in 5.5 mL of MeOH/HaO (10:1). The round-bottomed flask was degassed, and Pd/C (10 wt%, 0.18 g) was added followed by HCO2NH4 (0.174 g, 2.68 mmol, 5.0 equiv). The resulting heterogeneous mixture was refluxed overnight, cooled, filtered through CELITE, concentrated, diluted with EtOAc (10 mL), washed with saturated NaHCO3 (10 mL), and dried over Na₂SO₄. The crude product was purified by BIOTAGE chromatography (9:1 EtOAc:MeOH) to yield 0.11 g (38%) of Compound 44. HRMS calculated for C25H26F6N4O3 (M+H) 545.1987, found 545.1988.

PREPARATIVE EXAMPLE 45 and 46

Step A:

Compound 45

Compound 41a

Compound 46

Compound 41a (2.8 g, 4.59 mmol, 1.0 equiv) was taken up in ethanol (15 mL). Raney nickel was added to the solution, and the reaction mixture was hydrogenated in a Parr shaker at 60 psi. The progress of the hydrogenation was monitored by TLC (4/1 EtOAc/hexanes). After 3 hours,

-121 the reaction mixture was then filtered through CEL1TE, washed with ethanol (30 mL) and concentrated. The crude product was purified by BIOTAGE chromatography (4/1 EtOAc/hexanes), to give Compound 45a (1.75 g, 65%).

2018271297 28 Nov 2018

Step B:

Compound 45a

In a 50 mL round-bottomed flask, Compound 45a (1.0 g, 1.72 mmol,

1.0 equiv) was dissolved in dry THF (20 mL) and cooled to 0°C. A solution of fert-butyl carbazate (0.228 g, 1.72 mmol, 1.0 equiv) and carbonyl diimidazole (0.335 g, 2.06 mmol, 1.2 equiv), which was previously stirred in dry THF (10 mL), was added to the above cooled solution via cannula. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was then concentrated and purified by BIOTAGE chromatography (1/1 EtOAc/hexanes) to give Compound 45b (0.85 g, 67%).

Step C:

1. TFA, DCM

2. pyridine, DCM MeO^Y^CI 0

Compound 45c

In a 50 mL round-bottomed flask, Compound 45b (0.39 g, 0.53 mmol,

1.0 equiv) was dissolved in CH2CI2 (10.0 mL) and cooled to 0°C.

Trifluoroacetic acid (1.02 mL, 13.2 mmol, 25.0 equiv) was added to the solution, and the reaction mixture was allowed to stir at room temperature.

The progress of the reaction was monitored by MS (i.e., disappearance of starting material). The reaction mixture was concentrated after 7 h, and was

-122 used in the next step without any further purification. The crude intermediate was dissolved in THF (5 mL) and cooled to 0°C. A 20 % aqueous solution of

NaOH (5.0 mL) was added, followed by methoxyacetyl chloride (0.096 mL,

1.06 mmol, 2.0 equiv). The reaction mixture was allowed to stir at room temperature overnight, and was then diluted with H₂O (10 mL), extracted with Et₂O (2x10 mL), washed with brine (10 mL), dried over MgSO₄ and concentrated to yield crude Compound 45c (0.35 g, 95%), which was used in the next step without any further purification.

Step D:

2018271297 28 Nov 2018

Compound 45c Compound 45d

In a 25 mL round-bottomed flask, Compound 45c (0.35 g, 0.49 mmol,

1.0 equiv) was dissolved in EtOH (3.0 mL). 3.0 mL of a 6 M solution of NaOH 15 was added and the reaction mixture was refluxed overnight. The reaction mixture was then concentrated and purified by preparative TLC (EtOAc) to give 0.145 g (42%) of Compound 45d.

Step E:

In a 10 mL round-bottomed flask, Compound 45d (0.125 g, 0.18 mmol, 1.0 equiv) was dissolved in 3 mL MeOH. Pd(OH)₂ (0.010 g, 0.072 mmol, 40 wt%) was added, and the heterogeneous mixture was hydrogenated 25 at room temperature. The progress of the hydrogenation was monitored by MS. The reaction mixture was filtered through CELITE, concentrated and

-123purified by preparative TLC (EtOAc) affording a mixture of Compounds 45 and 46 (0.008 g, 8%). HRMS calculated for CaeHaeFeNAOs (M+H) 559.2144, found 559.2146.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 47 and 48

Compound47

Compound 48

Step A:

MsCI, TEA

In a 10 mL round-bottomed flask, a mixture of Compounds 49 and 50 (0.025 g, 0.047 mmol, 1.0 equiv) was dissolved in 2 mL of DCM and cooled to

0°C. Triethylamine (0.0073 mL, 0.052 mmol, 1.1 equiv) was added, followed by MeSOaCI (0.004 mL, 0.052 mmol, 1.1 equiv). The reaction mixture was allowed to stir overnight. The reaction mixture was then diluted with EtOAc (10 mL) and quenched with saturated NaHCO₃ (5 mL). The aqueous phase was extracted with EtOAc (2x5 mL), dried over Na2SO₄, and concentrated.

The crude product was purified by preparative TLC (4:1 EtOAc/hexanes) to

-124give 0.028 g (100%) of a mixture of Compounds 47 and 48. HRMS calculated for CssHayFsNgC^S (M+H) 608.1766, found 608.1785.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 49 and 50

Compound 49

Compound 50 step A:

Compound 49a (0.50 g, 0.77 mmol, 1.0 equiv) was added to a 50 mL 15 round-bottomed flask. Fuming HNO3 (3 mL) was then added to the flask, and the resulting reaction mixture was allowed to stand for 1 h. After the reaction was complete, ice (10 g) was added. The reaction mixture was diluted with EtOAc (25 mL) and neutralized with saturated NaOH (3 mL). The aqueous phase was extracted with EtOAc (2x10 mL). The organic layers were washed with brine (10 mL), dried over MgSO₄, and concentrated. The crude product was purified by ΒΙΟΤΑΘΕ Chromatography (7:3 EtOAc:hexanes) to give 0.45 g (79%) of Compound 49b,

Step B:

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Compound 49b

Compound 49

Compound SO

Compounds 49 and 50 were prepared by a procedure similar to the procedure for preparing Compound 44b. HRMS calculated for C24H25F6N5O2 5 (M+H) 530.1991, found 530.1977.

PREPARATIVE EXAMPLE 51

Compound 55 (0.078 g, 0.11 mmol, 1.0 equiv) was dissolved in 7 M ammonia in MeOH (3.0 mL) and was added to a small Parr bomb, which was 15 heated to 80°C for 2 days. The progress of the reaction was monitored by

TLC (9/1 CH2CI₂/MeOH). Upon completion of the reaction, the reaction mixture was concentrated to give a crude product in the form of a white solid. The crude product was purified using BIOTAGE chromatography (2:1 to 4:1 EtOAc/Hexane) to give Compound 51a as a white solid (0.48 g).

Electrospray MS [M+1] 692.2.

10%Pd/C, NHACH

MeOH

Compound 51

- 1262018271297 28 Nov 2018

Compound 51a (0.045 g, 0.065 mmol, 1.0 equiv.) was dissolved in dry

MeOH (2.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.02g, 0.03 mmol, 5.0 equiv.) under an inert atmosphere.

The reaction mixture was heated to reflux and the progress ofthe reaction was monitored by TLC (100% EtOAc). The reaction was completed in 1 hr. The reaction mixture was filtered through CELITE, washed with EtOAc and concentrated under vacuum. The resulting residue was taken up in EtOAc, washed with saturated NaHCO₃, followed by brine and H₂O to give the desired product, Compound 51 in the form of a white solid, which was converted to its HCI salt (0.034g, 94%).

HRMS (FAB) calculated for C₂6H₂8F6N₃O₂ (M+1 )558.19242, found 558.19398.

PREPARATIVE EXAMPLE 52

Step A:

NH₂OCH₃, EtOH

Compound 53 (18.1 mg, 0.0325 mmol) in EtOH (2.5 mL) was treated with MeONH₂.HCI (24.4 mg, 0.292 mmol) and NaOAc (12.0 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at 60°C for 12 hr, then diluted with EtOAc (20 mL) and washed with aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After

-127filtration and concentration, the crude product was purified using preparative

TLC (hexane/EtOAc, v/v = 1/1 to 1/9) to give Compound 52 (16 mg, 84%).

Electrospray MS [M+1]⁺ 586.1.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 53

Compound 53

Step A:

Compound 23h

a. Dess-Martin periodinane

b. MeMgBr.THF

c. Dess-Martin periodinane

Dess-Martin periodinane (0.234 g, 0.553 mmol) was added to a mixture of Compound 23h (0.25 g, 0.369 mmol) and NaHCO₃ (0.232 g, 2.76 mmol) in 15 CH₂CI₂ (5.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na₂S₂O₃ solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3x15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 20 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude aldehyde (0.25 g) was taken up in anhydrous THF (4.0 mL) and was treated with MeMgBr (0.49 mL, 1.48 mmol, 3.0 M in Et₂O) at -78°C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours with the slow addition of saturated aqueous 25 NH₄CI solution (10 mL). The reaction mixture was then diluted with EtOAc (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly

-1282018271297 28 Nov 2018 acidic. The aqueous phase was extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude secondary alcohol (0.26 g) was taken up in CH2CI2 (5.0 mL) and treated with Dess-Martin 5 periodinane (0.468 g, 1.11 mmol) and NaHCO₃ (0.466 g, 5.55 mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na₂S₂O₃ solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3x15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 53a (0.11g, 43% for 3 steps).

Step B:

H_s, Pd(OH)/C, EtOH

Compound 53a (107 mg, 0.155 mmol) in EtOH (5.0 mL) was treated 20 at room temperature with Pd(OH)₂/C (21.5 mg, 10 wt%) and was .

hydrogenated with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 25 1/3 to 1/9) to give Compound 53 (66 mg, 76%). Electrospray MS [M+1 ]⁺

557.3.

PREPARATIVE EXAMPLE 54

- 129 2018271297 28 Nov 2018

Compound 53

ΝΗ,ΟΗ, EtOH

Compound 54

Compound 53 (14.3 mg, 0.0257 mmol) in EtOH (2.5 mL) was treated with HONH₂.HCI (10.7 mg, 0.154 mmol) and NaOAc (6.3 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at 60°C for 12 hr, then diluted with EtOAc (20 mL) and washed with aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/2) to give Compound 54 (11 mg, 75%). Electrospray MS [M+1 ]⁺ 572.1.

PREPARATIVE EXAMPLE 55

Compound 55

Step A:

-1302018271297 28 Nov 2018

Compound 23h

a. Dess-Martin Periodinane

b. 2-methyl-2-butene, NaClOj NaH₂PO₄, tert-butanol

c. TMSCHN,, MeOH, PhH

Compound 55a

Dess-Martin Periodinane (0.12 g, 0.284 mmol) was added to a mixture of Compound 23h (96.3 mg, 0.142 mmol) and NaHCO₃ (0.12 g, 1.42 mmol) in CH2CI2 (3.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with addition of EtOAc (50 mL) and water (10 mL). The organic phase was washed with saturated Na₂S2O₃ solution (3x15 mL). The combined aqueous phases were extracted with EtOAc (3x15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude aldehyde (96.3 mg) was taken up in tert-butanol (2.0 mL) and water (0.5 mL) and treated with NaH₂PO₄*H₂O (39.2 mg, 0.284 mmol), NaCIO₂ (44.9 mg, 0.497 mmol) and 2-methyl-2-butene (0.105 mL, 0.994 mmol) successively. The reaction mixture was stirred for 2 hours and then diluted with EtOAc (20 mL) and washed with aqueous NH₄CI. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were.washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude acid (95 mg) was dissolved in benzene (2.8 mL) and MeOH (0.7 mL). The resulting solution was treated with

TMSCHN₂ (82.2 pL, 0.164 mmol) at room temperature and stirred for 20 minutes. The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3) to give Compound 55a (70 mg, 35% for 3 steps).

Step B:

Compound 55a

H₂, Pd(OH)j/C, EtOH

Compound 55

-131 2018271297 28 Nov 2018

Compound 55a (38 mg, 0.0537 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)₂/C (7.6 mg, 10 wt%) and was hydrogenated with a H₂ balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 2/3) to give Compound 55 (24 mg, 78%). Electrospray MS [M+1]⁺ 573.1.

PREPARATIVE EXAMPLE 56

Step A:

Compound 56a (15 mg, 0.0227 mmol) in EtOH (2.0 mL) was treated at room temperature with Pd(OH)₂/C (3.6 mg, 10 wt%) and was hydrogenated with a H₂ balloon for 30 minutes. The reaction solution was filtered through a 20 short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was taken up in Et₂O (0.5 mL) and treated with HCl in ether (0.23 mL, 0.23 mmol, 1.0 M in ether). The mixture was stirred at room temperature for 12 hours. The mixture was then diluted with EtOAc (20 mL) and washed with aqueous 25 NaOH (5 mL, 0.5 N). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude

-132product was purified using preparative TLC (hexane/EtOAc, v/v = 1/1) to give

Compound 56 (8.5 mg, 67%). Electrospray MS [M+1]⁺ 563.1.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 57

Compound 57

Step A:

MsCI (11.7 pL, 0.151 mmol) was added to a solution of Compound 23h (42.8 mg, 0.063 mmol) and Et₃N (26.4 pL, 0.189 mmol) in CH₂CI₂ (1.0 mL) at room temperature. The reaction mixture was quenched with water (5.0 mL) after 30 minutes and diluted with CH₂CI₂ (15 mL). The aqueous phase was extracted with CH₂CI₂ (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude mesylate (44 mg, 0.0582 mmol) was taken up in anhydrous DMF (2.0 mL) and treated with NaBH₄ (11.0 mg, 0.291 mmol). The reaction mixture was heated at 90°C for 1 hour before it was cooled down to room temperature. The reaction mixture was then diluted with EtOAc (20 mL) and washed with aqueous HCI (5 mL, 1.0 M). The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (3x10 mL), brine (10 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using

-133preparative TLC (hexane/EtOAc, v/v = 3/2) to give Compound 57a (18 mg,

43%) and Compound 56a (15 mg, 36%).

2018271297 28 Nov 2018

Step B:

Compound 57a

H₂, Pd(<WC, EtOH

Compound 57

Compound 57a (18 mg, 0.027 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)z/C (3.6 mg, 10 wt%) and was hydrogenated 10 with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 1/1) to give Compound 57 (10 mg, 70%). Electrospray MS [M+1]⁺ 529.1.

PREPARATIVE EXAMPLE 58

Compound 53

Compound 19 (10.0 mg, 0.0175 mmol) in EtOH (1.5 mL) was treated with MeONH2HCI (14.6 mg, 0.175 mmol) and NaOAc (7.2 mg, 0.0876 mmol)

-134at room temperature. The reaction mixture was stirred at 60°C for 12 hr, and was then diluted with EtOAc (20 mL) and washed with aqueous NaHCO₃. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO₄.

After filtration and concentration, the crude product was purified using preparative TLC (hexane/EtOAc, v/v = 2/3) to give Compound 58 (10.5 mg, 100%). Electrospray MS [M+1]⁺ 600.1.

2018271297 28 Nov 2018

PREPARATIVE EXAMPLE 59

Compound 59

Step A:

AcCI, EtjN, CH^Ck

Compound 59 b

To a solution of Compound 59a (0.53 g, 0.76 mmol) in CH2CI2 (4 mL) was added Et₃N (0.14 mL, 0.98 mmol). The reaction mixture was cooled to -78°C and acetyl chloride (0.065 mL, 0.91 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 72 hours. Additional Et₃N (0.068 mL) and acetyl chloride (0.033 mL) was·added to the reaction mixture, which was then stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified with BIOTAGE chromatography (hexane/EtOAc, v/v = 3/2) to give Compound 59b (0.5 g).

Step B:

-1352018271297 28 Nov 2018

Compound59b

BCIj, CH_:CI₂, -78 °C

Compound 59c

BCI3 (3.7 mL, 3.7 mmol, 1.0 M in hexane) was added dropwise to a stirring solution of Compound 59b (0.55 g, 0.74 mmol) in CH2CI2 (9 mL) at

-78°C. The reaction was quenched in 1 hour by the addition of aqueous

NaHCOs solution (50 mL) at -78°C. The reaction mixture was diluted with

EtOAc (200 mL) and washed with saturated aqueous NaHCO₃ (100 mL), and dried over Na2SO₄. The mixture was filtered and concentrated to give crude Compound 59c (0.4 g), which was used in the next reaction without further 10 purification.

Step C:

Compound 59c

Dess-Martin, NaHCO₃₍ CH₂Cl₂

Dess-Martin periodinane (0.12 g, 0.28 mmol) was added to a mixture of

Compound 59c (0.12 g, 0.18 mmol) and NaHCO3 (0.17 g, 2.0 mmol) in CH₂CI₂ (5.0 mL) at room temperature and stirred for 45 minutes. Additional Dess-Martin periodinane (50 mg) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified with BIOTAGE chromatography (hexane/EtOAc, v/v = 1/1) to give Compound 59d (0.1 g).

Step D:

-1362018271297 28 Nov 2018

TosCHjNC, KjCO„ MeOH

A mixture of Compound 59d (0.11 g, 0.17 mmol), potassium bicarbonate (26 mg, 0.19 mmol), tosylmethyl isocyanide (36 mg, 0.19 mmol) and methanol (3 mL) was heated at 80°C for 48 hours. The reaction mixture was then concentrated and diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO₃ (2 x 100 mL). The organic layer was dried over Na₂SO4, filtered and concentrated. The crude product was purified with

BIOTAGE chromatography (hexane/EtOAc, v/v = 2/3 to 0/100) to give

Compound 59e (50 mg).

Hj, Pd(OHVC, MeOH

Compound 59d (0.31 mg, 0.45 mmol) in MeOH (10.0 mL) was treated at room temperature with Pd(OH)₂/C (0.2 g, 20 wt%) and was hydrogenated with a H₂ balloon for 2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with MeOH (30 mL). The solvent was removed under reduced pressure and the crude product was purified with BIOTAGE chromatography (EtOAc/MeOH, v/v = 9/1) to give, mixture of two isomers (190 mg), which were further purified by HPLC (chiral OD column).with hexane/IPA (v/v = 9/1) to give Compound 59 (90 mg).

PREPARATIVE EXAMPLE 60

- 1372018271297 28 Nov 2018

Step A:

a. CICC.Et, EtjN, CH₂CI₂

b. NaNj, Bu.NHSO,

c. TMSNj, toluene, 110 °C

To a solution of Compound 60a (0.26 g, 0.43 mmol) in CH₂Ci₂ (4 mL) at 0°C was added Et₃N (0.071 mL, 0.51 mmol) followed by ethylchloroformate (0.052 mL, 0.56 mmol), and the reaction mixture was stirred for 1 hour. To the reaction mixture was then added sodium azide (64 mg, 0.98 mmol) and tetrabutylammonium hydrogen sulfate (43 mg, 0.13 mmol) and stirring was continued for 1 hour. The reaction mixture was then diluted with CH₂CI₂ (100 ml) and washed with water (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over Na₂SO4, filtered and concentrated. The residue was dissolved in dry toluene (4 ml) and heated to 80°C for 2 hours and then cooled to room temperature. TMSN₃ (0.13 mL, 0,94 mmol) was added and the reaction mixture was heated to -110°C for 18 hours. The reaction mixture was then cooled to room temperature, concentrated and purified by BIOTAGE chromatography (hexane/EtOAc, v/v = 2/1, followed by MeOH/EtOAc, v/v =

1/99) to give Compound 60b (0.17 g).

Step B:

-1382018271297 28 Nov 2018

H„ Pd(OH)„C, MeOH

Compound 60b (0.17 mg, 0.26 mmol) in MeOH (10.0 mL) was treated at room temperature with Pd(OH)₂/C (15 mg, 20 wt%) and was hydrogenated 5 with a H₂ balloon for'2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with MeOH (30 mL). The solvent was removed under reduced pressure and the crude product was purified by BIOTAGE chromatography (EtOAc/MeOH, v/v = 98/2) to give Compound 60 (20 mg).

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, medications and variations are intended to fall within the spirit and scope of the present invention.

Claims (67)

1. WHAT IS CLAIMED IS:

   1, A compound of Formula I:

   R¹ R² or pharmaceutically acceptable salts and/or solvates thereof, wherein:

   R¹ and R² are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, -CN, alkynyl, -N(R⁶)2, -N(R⁶)-S(O2)-alkyl, -N(R⁶)-C(O)-N(R⁹)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR⁵)-alkyl, -C(O)-N(R⁹)2, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R⁹)₂, with the proviso that at least one of R¹ and R² is -CN, Δυ

   W is =C(R⁸)- or =N-;

   X is-C(O)-or-S(O₂)-;

   Y is selected from the group consisting of-CH₂-, -0-, and -N(R⁶)-C(O)-, with the proviso that:

   (a) the nitrogen atom of -N(R⁶)-C(O)- is bonded to X, and

   -1402018271297 28 Nov 2018 (b) if R¹ and/or R² is and Y is -Ο-, X is not -S(O₂)-;

   Zis -C(R⁷)₂- -N(R⁶)-, or-O-;

   R³ is selected from the group consisting of H, -CH₂OR⁵, and alkyl;

   R⁴ is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyi, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl;

   R⁵ is H or alkyl;

   R⁶ is selected from the group consisting of H, alkyl, cycloalkyl, and aryl; each R⁷ is independently H or alkyl; or each R⁷, together with the ring carbon to which they are shown attached, form a cycloalkylene ring;

   R⁸ is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(R⁶)2, -N(R⁶)-S(O2)-alkyl, -N(R⁶)-S(O₂)-aryl, -N(R⁶)-C(O)-alkyl, -N(R⁶)-C(O)-aryl, alkylene-O-alkyl, and

   R⁹ is selected from the group consisting of H, alkyl; and aryl, or each R⁹, together with the nitrogen to which they are shown attached, form a heterocycloalkyi ring;

   Ar¹ and Ar² are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with O to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO₂;

   n is 0,1, or 2; and m is 1, 2, or 3.
2. 2. The compound according to claim 1, wherein the compound of Formula I has the following structure:

   Ar² n

   O'

   -141 2018271297 28 Nov 2018
3. 3. The compound according to ciaim 1, wherein:

   R³ is alkyl;

   R⁴ is H;

   Ar¹ is substituted or unsubstituted phenyl;

   5 Ar² is substituted or unsubstituted phenyl; and n is .1.
4. 4. The compound according to claim 2, wherein:

   R³ is alkyl;

   10 R⁴isH;

   Ar¹ is unsubstituted phenyl;

   Ar² is substituted phenyl; and n is 1.

   15 5. The compound according to claim 1, wherein:

   R³ is alkyl;

   R⁴ is H;

   Ar¹ is monosubstituted phenyl;

   Ar² is substituted phenyl; and

   20 n is 1.

   6. The compound according to claim 4, wherein:

   Ar² is 3,5-bis(trifluoromethyl)phenyl, 3,5-bis(fluoro)phenyl, 3,5bis(chloro)phenyl, 3,5-bis(methyl)phenyl, or 3,5-bis(methoxy)phenyl.

   7. The compound according to claim 6, wherein:

   R³is-CH₃.

   8. The compound according to claim 7, wherein:

   N

   30 one of R¹ or R² is «/v-v

   -1422018271297 28 Nov 2018

   The compouna according to claim 7, wherein:

   one of R¹ or R² is

   10. The compound according to claim 7, wherein:

   . 9 \
5. 5 one of R orR is

   11. The compound according to claim 7, wherein: one of R¹ or R² is —CN.
6. 10 12. The compound according to claim 8, wherein:

   Xis-S(O₂)-;

   Y is -CH₂-; and m is 2.
7. 15 13. The compound according to claim 8, wherein:

   X is -C(O)-;

   Y is -CH₂-; and m is 2.

   20 14. The compound according to claim 8, wherein:

   X is -C(O)-;

   Yis-CH₂-;and m is 3.

   25 15. The compound according to claim 8, wherein:

   X is -C(O)-;

   Y is -O-; and m is 2.

   -1432018271297 28 Nov 2018
8. 16. The compound according to claim 8, wherein:

   X is -C(O)-;

   Y is -CH₂-; and m is 1.
9. 17. The compound according to claim 8, wherein:

   X is -C(O)-;

   Y is -NH-C(O)-; and m is 1.
10. 18. The compound according to claim 9, wherein: Z is -NH-; and

    R⁸ is H.
11. 19. The compound according to claim 9, wherein: Z is -NH-; and

    R⁸ is -NH-S(O₂)-CH₃.
12. 20. The compound according to claim 9, wherein: . Z is -NH-; and

    R⁸ is -CH₂-OH.
13. 21. The compound according to claim '9, wherein: Z is -NH-; and

    R^s is -CH₂-O-CH₃.
14. 22. The compound according to claim 9, wherein:

    Z is -NH-; and

    R⁸ is -NH₂.
15. 23. The compound according to claim 9, wherein:

    and . 144R⁸ is H.
16. 24. The compound according to claim 9, wherein:

    Z is -C(CH₃)₂-; and

    5 R⁸ is H.

    2018271297 28 Nov 2018
17. 25. The compound according to claim 1, having the Formula IB

    10 wherein R¹ and R² are selected from the group consisting of:

    Compound R² 1 v-p 0 -CN 2 0 -CN 3 /= N V^Nx^NH O OH ^xc^z\h₃ h₂ . ³ 4 /= N V^Ny-NH 0 OH A A c ch₃ • ^H2 5 /= N -ch₂cn 6 -ch₃ /= N

    -1452018271297 28 Nov 2018

    Compound R¹ R² 7 -CN /= N 8 -C(O)-O-CH₃ /=N 9 vQ 0 -CN 10 -C(O)-NH₂ /= N 11 /= N Π 0 -CH₂C(OH)(CH₃)₂ 12 -ch₂oh /= N V^NX 13 /= N -ch₂och₃ 14 -CH₂OCH₃ /= N v^NX 15 /= N Vⁿ^nh O -CH₂-NH-S(O₂)-CH₃ 16 /= N V^N\^NH 0 i -CH₂C(O)-NH(CH₂CH₃) 17 /= N ν·^Ν^ΝΗ 0 -CH₂~C(O)O-CH₂CH₃ 18 /=N ν~^Ν\^ΝΗ K 0 -C(=N-OH)-CH₂CH₃

    -1462018271297 28 Nov 2018

    Compound ................R¹ R^z 19 /= N V^Ny^NH 0 -C(O)-CH₂CH₃ 20 _ZO /—f Y^NyNH o -ch₂och₃ 21 /= N Vⁿ^nh 0 -C(O)-NH(CH₃) 22 -C(O)-NH(CHa) /= N V^Ny^NH O 23 /= N V^NH 0 -CH2OH 24 /= N 0 -CH₂CH₂OH 25 /= N V^NyNH o -ch₂ch₂ch₃ 26 /= N V^Ny-NH O -ch₂och₃ 27 -CH2OCH3 /= N V^NyNH 0 28 /=N V^NJ<^CH3 T CH₃ 0 H

    -1472018271297 28 Nov 2018

    Compound R¹ R² 29 /=N V^NyNH 0 -CH₂C(O)-NH₂ 30 /=N V^NyNH 0 -CH₂-C(O)-CH₃ 31 /=N V^NyNH O -CH₂-C(O)O-CH₃ 32 -CN 33 0 -CN 34 -CN 0 35 -CN /=N V^NyNH 0 36 -NH-S(O₂)-CH₃ -CN 37 -CN -NH-S(Q₂)-CH₃ 38 /=N 0 -ch₂cn 39 -CN -nh₂ 40 -NH₂ -CN 41 -NH-C(O)-NH₂ -CN

    - 148 2018271297 28 Nov 2018

    Compound R¹ R² 42 /^N V^Ny^NH 0 -CN 43 ^VW 0 H r /=-N V^NyxNH O H 45 och₃ /=N V^N\.NH Y o H 46 H och₃ /=N V^Ny,NH 0 47 . ^“CHs HN V^Ny^NH 0 H 48 H °^s-ch₃ HN )=N V^Nx^NH 0

    - 1492018271297 28 Nov 2018

    Compound R¹ R² 49 h₂n /=N V^Ny,NH 0 H 50 H H₂N >=N 0 51 /=N V^Ny-NH 0 -C(O)-NH₂ 52 /=N V^Ny-NH 0 -C(=N-OCH₃)-GH₃ 53 . /= N V^Ny,NH 0 -C(O)-CH₃ 54 /= N V^Ny,NH O -C(=N-OH)-CH₃ 55 /= N V^Nn^NH 0 -C(O)OCH₃ 56 /= N V^Ny NH 0 -ch₂ci 57 /= N V^Ny-NH 0 -ch₃

    - 1502018271297 28 Nov 2018

    Compound R¹ R² 58 /=N Y^Ny,NH 0 -C(=N-OCH₃)-CH₂CH₃ 59 -NHC(O)CH₃ oQ 60 H Y^N\Yh Y o 61 N=:N Yⁿ>^nh 0 H
18. 26.

    A compound represented by the following formula:

    5
19. 27.

    A compound represented by the following formula:
20. 28.

    A compound represented by the following formula:

    -151 2018271297 28 Nov 2018

    HN I
21. 29. A compound represented by the following formula:
22. 30. A compound represented by the following formula:
23. 31. A compound represented by the following formula:
24. 32. A compound represented by the following formula:

    -152-

    2018271297 28 Nov 2018
25. 33. A compound represented by the following formula:

    HN
26. 34. A compound represented by the following formula:
27. 35. A compound represented by the following formula:
28. 36. A pharmaceutical composition comprising:

    at least one compound of claim 1 or a pharmaceutically acceptable salt

    10 and/or solvate thereof, and at least one pharmaceutically acceptable carrier.

    -1532018271297 28 Nov 2018
29. 37. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one serotonin reuptake inhibitor, and at least one compound of claim 1.

    5
30. 38. A method of treating a physiological disorder, symptom or disease, comprising:

    administering to a patient in need thereof an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt and/or solvate thereof,

    10 wherein the physiological disorder, symptom or disease is selected from the group consisting of respiratory diseases, inflammatory diseases, skin disorders, ophthalmalogical disorders, central nervous system conditions, depression, anxiety, phobia, bipolar disorder, addictions, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis,

    15 schizophrenia, Alzheimer’s disease, AIDS related dementia, Towne’s disease, stress related disorders, obsessive/compulsive disorders, eating disorders, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrosing disorders, obesity, Type II diabetes, pain related disorders, headache, neuropathic pain,

    20 post-operative pain, chronic pain syndrome, bladder disorders, genitourinary disorders, cough, emesis, and nausea.
31. 39. The method of claim 38, wherein the physiological disorder, symptom or disease is emesis, depression, anxiety or cough.
32. 40. The method of claim 39, wherein the physiological disorder, symptom or disease is depression or anxiety.
33. 41. The method of claim 39, wherein the physiological disorder, symptom 30 or disease is emesis and/or nausea.
34. 42. The method of claim 39, wherein the physiological disorder, symptom or disease is cough.

    -154-

    2018271297 28 Nov 2018
35. 43. The method of claim 40, further comprising administering to the patient an effective amount of at least one anti-depressant agent and/or at least one anti-anxiety agent.

    5
36. 44. The method of claim 40, further comprising:

    administering to the patient an effective amount of at least one selective serotonin reuptake inhibitor, and wherein the physiological disorder, symptom or disease is depression.

    10
37. 45. A method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for blocking at least one neurokinin-1 receptor, in a patient in need of such treatment, comprising administering to a patient an effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt and/or solvate thereof.
38. 46. The method according to claim 38, further comprising:

    administering an effective amount of at least one active ingredient selected from the group consisting of other NKi receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 20 5-HT₃ receptor antagonists, serotonin 5-HT_2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5; and wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety,

    25 phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome,

    30 bladder disorder, genitourinary disorder, cough, emesis and nausea.
39. 47. A method of treating emesis and/or nausea in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable

    -155-

    2018271297 28 Nov 2018 salt and/or solvate thereof in combination with an effective amount of at least one serotonin 5-HT₃ receptor antagonist and/or at least one glucocorticoid.
40. 48. The method of claim 47, wherein the serotonin 5-HT₃ receptor

    5 antagonist is ondansetron and the glucocorticoid is dexamethasone.
41. 49. A kit, comprising:

    two or more separate containers in a single package, wherein each container comprises a pharmaceutical composition;

    10 wherein a first container of said package comprises a first pharmaceutical composition comprising an effective amount of a compound of claim 1 and/or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, a second container of said package comprises a second

    15 pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, and the other therapeutic agent is selected from the group consisting of SSRIs, other types of NKi receptor antagonists, prostanoids, Hi receptor antagonists, α-adrenergic receptor agonists, dopamine receptor agonists,

    20 melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT₃ receptor antagonists, serotonin

    5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho

    25 kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance -protein· 5.
42. 50. A purified compound according to claim 1.

    -156-
43. 51. A process for preparing Compound 42

    2018271297 28 Nov 2018

    Compound 42 the process comprising treating Compound 42i with a reagent suitable to produce

    5 Compound 42:

    Compound 42i.
44. 52. The process of claim 51, wherein the reagent suitable to produce Compound 42 is 0 selected from: Pd(OH)₂; Pd/C; and trimethylsilyliodide.
45. 53. The process of claim 52, wherein the reagent suitable to produce Compound 42 is trimethylsilyliodide.

    15
46. 54. The process of claim 51, wherein Compound 42i is prepared by treating Compound 42g with a reagent suitable to produce Compound 42i:

    N.

    HN OH

    Compound 42g.

    oxalyldiimidazole.

    20
47. 55. The process of claim 54, wherein the reagent suitable to produce Compound 42i is 1,1’- 15710879488_1 (GHMatters) P73535.AU.4

    2018271297 28 Nov 2018
48. 56. The process of claim 54, wherein Compound 42g is prepared by treating Compound 42f with a reagent suitable to produce Compound 42g:

    Compound 42f.
49. 57. The process of claim 56, wherein the reagent suitable to produce Compound 42g is hydroxylamine hydrochloride.
50. 58. The process of claim 53, wherein Compound 42f is prepared by treating Compound 23h

    0 with a reagent suitable to produce Compound 42f:

    Compound 23h.
51. 59. The process of claim 58, wherein the reagent suitable to produce Compoud 42f is Dess-

    15 Martin periodinane.
52. 60. The process of claim 58, wherein Compound 23h is prepared by treating Compound 23g with a reagent suitable to produce Compound 23h:

    Compound 23g.

    - 158 10879488_1 (GHMatters) P73535.AU.4
53. 61. The process of claim 60, wherein the reagent suitable to produce Compound 23h is BCI3.

    2018271297 28 Nov 2018
54. 62. The process of claim 60, wherein Compound 23g is prepared by:

    a) combining Compound 23f with Compound 3lc to form a mixture:

    h₂n₄ SL^OBn CF₃ CbzN. J A EtO_K ''_//^OyAA_CF3 ^x=n-nhco₂ch₃ 1 Compound 23f Compound 31c

    wherein the mixture is heated; ; and

    b) treating the mixture with a base.
55. 63. The process of claim 62, wherein the base is NaOCHa.
56. 64. The process of claim 62, wherein Compound 23f is prepared by treating Compound 23e with a reagent suitable to produce Compound 23f:

    Compound 23e.
57. 65. The process of claim 64, wherein the reagent suitable to produce Compound 23f is BnBr.
58. 66. The process of claim 64, wherein Compound 23e is prepared by treating Compound 23c with a reagent suitable to produce Compound 23e:

    Compound 23 c.
59. 67. The process of claim 66, wherein the reagent suitable to produce Compound 23e is zinc.

    - 15910879488_1 (GHMatters) P73535.AU.4

    2018271297 28 Nov 2018
60. 68. The process of claim 66, wherein Compound 23c is prepared by treating Compound 23b with a reagent suitable to produce Compound 23c:

    Compound 23b.
61. 69. The process of claim 68, wherein the reagent suitable to produce Compound 23c is paraformaldehyde.
62. 70. The process of claim 68, wherein Compound 23b is prepared by treating Compound 23a

    0 with a reagent suitable to produce Compound 23b:

    Compound 23 a.
63. 71. The process of claim 70, wherein the reagent suitable to produce Compound 23b is

    5 NaBH₄.

    the process comprising treating Compound 42d with a reagent suitable to produce

    Compound 42:

    - 16010879488_1 (GHMatters) P73535.AU.4

    2018271297 28 Nov 2018

    Compound 42d.
64. 73. The process of claim 72, wherein the reagent suitable to produce Compound 42 is

    5 trimethylsilylchloride.
65. 74. The process of claim 72, wherein Compound 42d is prepared by:

    a) treating Compound 42b with phosgene to thereby form a mixture:

    0 Compound 42b

    b) removing excess phosgene from the mixture; and

    c) treating the mixture with NH2NHC(O)H.
66. 75. The process of claim 74, wherein Compound 42b is prepared by treating Compound 41a

    5 with a reagent suitable to produce Compound 42b:

    O

    Compound 41a.
67. 76. The process of claim 75, wherein the reagent suitable to produce Compound 42b is

    20 NaCN.