JP2017057221A - Therapeutically active compositions and their methods of use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide therapeutically active compositions and their methods of use.SOLUTION: Provided are compounds with the following structure formula (I), pharmaceutically acceptable salts thereof, use of those compounds for treating cancer, and pharmaceutical compositions comprising those compounds. The compounds of formula I inhibits mutant IDH1, particularly mutant IDH1 having alpha hydroxyl neoactivity. Also described herein are pharmaceutical compositions comprising a compound of formula I or a salt thereof, and methods of using such compositions to treat cancers characterized by the presence of a mutant IDH1.SELECTED DRAWING: None

Description

This application is filed in Chinese Patent Application No. 2011101722169.1 filed on June 17, 2011, US Patent Application No. 61/509, filed on July 18, 2011, each incorporated by reference in its entirety. Priority is claimed from No. 071 and US patent application Ser. No. 61 / 584,210 filed Jan. 6, 2012.

Isocitrate dehydrogenase (IDH) is 2-oxoglutarate of isocitrate (sna,
Catalyze oxidative decarboxylation to α-ketoglutaric acid). These enzymes belong to two distinct subclasses, one using NAD (+) as an electron acceptor and the other using NADP (+). Five isocitrate dehydrogenases have been reported: three are NAD (+)-dependent isocitrate dehydrogenases located in the mitochondrial matrix and two are NADP (+)-dependent isocitrate dehydrases. An enzyme, one of which is mitochondrial and the other is mainly cytoplasmic. Each NADP (+) dependent isozyme is a homodimer.

IDH1 (isocitrate dehydrogenase 1 (NADP +), cytoplasmic) is IDH; IDP
IDCD; also known as IDPC or PICD. The protein encoded by this gene is the NADP (+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisome. This contains the PTS-1 peroxisome targeting signal sequence. The presence of this enzyme in the peroxisome is a role in the regeneration of NADPH for peroxisomal reduction, for example, conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, and peroxisomal reactions that consume 2-oxoglutarate, This suggests a role in the alpha-hydroxylation of phytanic acid. Cytoplasmic enzymes play an important role in cytoplasmic NADPH production.

The human IDH1 gene encodes a protein of 414 amino acids. Human IDH1
Nucleotide and amino acid sequences for GenBank entry NM_005
896.2 and NP_005887.2, respectively. IDH1
The nucleotide and amino acid sequences for, for example, Non-Patent Document 1; Non-Patent Document 2;
Non-patent document 3; Non-patent document 4; Non-patent document 5; Non-patent document 6;

Non-mutants, such as wild type IDH1, catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate, for example, in a positive reaction, NAD ⁺ (NADP
⁺ ) To NADP (NADPH):
Isocitrate ^{+ NAD + (NADP +) →} α-KG + CO 2 + NADH (NADPH) +
H ⁺ .

The mutation of IDH1 present in certain cancer cells is caused by R (-)-2- of α-ketoglutarate.
It has been discovered that it provides a new ability of the enzyme to catalyze NAPH-dependent reduction to hydroxyglutaric acid (2HG). 2HG is not formed by wild type IDH1. 2
HG production is thought to contribute to the formation and progression of cancer (Non-patent Document 8).

Thus, inhibition of mutant IDH1 and its new activity is a potential therapeutic treatment for cancer. Thus, there remains a need for inhibitors of IDH1 mutants with new alpha hydroxyl activity.

Nekrutenko et al. Mol. Biol. Evol. 15: 1674-1684 (1998) Geisbrecht et al. , J .; Biol. Chem. 274: 30527-30533 (1999) Wiemann et al. Genome Res. 11: 422-435 (2001) The MGC Project Team, Genome Res. 14: 2121-2127 (2004) Lubec et al. , Submitted (DEC-2008) to UniProtKB Kullmann et al. , Submitted (JUN-1996) to the EMBL / GenBank / DDBJ databases Sjoebrom et al. , Science 314: 268-274 (2006). Dang, L et al, Nature 2009, 462: 739-44

Herein, Structural Formula I:


Or a pharmaceutically acceptable salt thereof, wherein
Y represents —N (R ⁵ ) —, —N (R ⁵ ) —CH ₂ —, —CH ₂ —N (R ⁵ ) —, or —C.
H ^{(R 5)} - a and;
Each R ^1a and R ^1b is independently hydrogen, —C ₁ -C ₄ alkyl, —N (R ⁷
) _(C 1 -C _{4 ^{alkylene) -N (R 7) (C}} 1 ~C 4 alkyl), aryl, heteroaryl, ^{heterocyclyl, -C (O) N (R} 7) - aryl, -N ^(R 7) C (O) -aryl,-(C ₁ -C ₄ alkylene) -aryl,-(C ₁ -C ₄ alkylene) -heteroaryl, -O- (C ₀ -C ₄ alkylene) -aryl, -O- ( C ₀ -C ₄ alkylene) -heteroaryl, —O— (C ₀ -C ₄ alkylene) -heterocyclyl, —O— (C ₀
-C ₄ alkylene) - carbocyclyl, -N ^{(R 7)} - aryl, -N ^{(R 7)} - heteroaryl, -N ^{(R 9)} - aryl, -N ^{(R 9)} - heteroaryl, -O- ( C ₁ ~C
₄ Arukeiren ^{(alkeylene)) - N (R} 7) C (O) O- (C 1 ~C 4 alkylene) - aryl or ^{-N, (R 9) -C (} O) - (C 2 ~C 4 alkenyl) Is:
At least one of R ^1a and R ^1b is not hydrogen or methyl;
Any alkylene moiety present in R ^1a or R ^1b is optionally substituted by OH or F;
Each R ⁷ is independently selected from hydrogen and C ₁ -C ₄ alkyl;
Any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R ^1a or R ^1b is —G-L-M, halo, —NO ₂ , C ₁ -C ₆ alkyl, —C≡N, ═O, —
Optionally substituted with one or more substituents selected from CF ₃ and —OCF ₃ ;
G is a bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and optionally 1, 2 or 3 methylene units of the hydrocarbon chain are —NR ⁸ — , -O
-, - C (O) - , - OC (O) -, - C (O) O -, - S -, - SO -, - SO 2 -,
-C (= S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2)} - is replaced independently by;
L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon chain, and 1, 2 or 3 methylene units of L are cyclopropylene, —NR ⁸ — ,
^{-N (R 8) C (O} ) -, - C (O) N (R 8) -, - N (R 8) SO 2 -, SO 2 N (
^{R 8) -, - O -} , - C (O) -, - OC (O) -, - C (O) O -, - S -, - SO-
_{, -SO 2 -, - C (} = S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2}
)-, Optionally replaced independently;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur There, said ring, -D-E, oxo, NO _2, halogen, _CN, C 1 -C ₆ alkyl, _{C 2}
Substituted with 1-4 groups independently selected from -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
D is a covalent bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and one or two methylene units of D are —NR ⁸ —, —S—, -O-, -C (
O) -, - SO-, or -SO ₂ - is replaced independently by optionally;
E is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is oxo, halogen, or CN
Optionally substituted by:
Each R ⁸ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂
-C _{6 alkynyl, -S (O) 2 -C 2} ~C 4 alkenyl, _-C 1 -C ₆ alkoxy or phenyl, nitrogen, oxygen, or 1 to 2 heteroatoms independently selected from nitrogen Optionally having 4 to 7 membered heterocyclyl or optionally substituted group selected from 5 to 6 membered monocyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur Is;
R ² is selected from phenyl, 3-7 membered cycloalkyl, C ₂ -C ₄ alkyl, or CF ₃ , wherein phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
Each R ³ is halo, — (C ₁ -C ₄ alkylene) -O— (C ₁ -C ₄ alkyl),
-C ₁ -C _{4 fluoroalkyl, -C (O) -O- (C} 1 ~C 4 alkyl), - phenyl, - _heteroaryl, C 3 -C _{7 cycloalkyl,} -CH 2 -N _(C 1 ~ C ₄ alkyl)
₂ , C (O) —N— (C ₁ -C ₄ alkyl) ₂ , —C (O) —NH— (C ₁ -C ₄ alkyl), optionally substituted by one or more halo or —OH. Or independently selected from -C ₁ -C ₄ alkyl, or two R ^{3 taken} together form a 3-8 saturated ring or fused phenyl, said saturated ring or fused phenyl being 1 to 2 Optionally substituted by methyl;
R ⁴ is hydrogen, —CN, halo, C ₁ -C ₄ alkoxy, —CH ₂ NH (C ₁ -C ₄ alkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, — (C _1- C ₄ alkyl) -O-
_(C 1 -C _{4 alkyl),} C 1 -C _{4 fluoroalkyl, C (O) -N- (C} 1 ~C 4 _{alkyl) 2, -C (O) -NH-} (C 1 ~C 4 alkyl) _{, -C (O) -O- (C} 1 ~C
₄ alkyl), —C (O) —OH, —S (O) ₂ — (C ₁ -C ₄ alkyl), and 5-membered heteroaryl;
R ⁵ represents —C (O) — (C ₁ -C ₅ alkyl), —C (O) — (C ₂ -C ₆ alkenyl).
, -C (O)-(C ₀ -C ₂ alkylene) -Q, -C (O)-(C ₁ -C ₄ alkenylene) -Q, -C (O)-(C ₀ -C ₂ alkylene)- _{^{N (R 6) - (C}} 0 ~C 2 alkylene) -Q, -C (O) -O- (C 0 ~C 2 alkylene) -Q, -C (O) - (C 1 ~C 2 alkylene) -O- _(C 0 ~C ₂ alkylene) -Q, -C (O) -C (O) -Q, -S (O
) ₂ -Q, -C (O)-(C ₁ -C ₄ alkylene) -O-C (O)-(C ₁ -C ₄ alkyl), -C (O)-(C ₁ -C ₄ alkylene) _{-C (O) -O- (C 1} ~C 4 alkyl)
^{, -C (O) -N (R} 6) - (C 1 ~C 4 alkylene) -O-C (O) - (C 1 ~C 4 alkyl), - C (O) -N (R 6) - _(C 1 -C _{4 alkylene) -C (O) -O- (C} 1
-C ₄ alkyl), - C (O) - (C 0 ~C 2 _{^{alkylene) -N (R 6) - (}} C 1 ~C 6
Alkyl), -C (O)-(C ₀ -C ₂ alkylene) N (R ⁶ )-(C ₂ -C ₆ alkynyl), -C (O)-(C ₀ -C ₂ alkylene) -N (R _⁶⁾ - _(C 2 ^{~C 6} alkenyl)
, -C (O)-(C ₀ -C ₂ alkylene) -N (R ⁶ )-(C ₀ -C ₂ alkylene) -O
- _(C 1 ~C ₄ alkyl), - C (O) - (C 1 ~C 2 alkylene) -O- _(C 1 _{~C 4}
Alkyl), - C (O) - (C 1 ~C 2 alkylene) -C (O) C (O ) N (R) (C 1
-C ₄ alkyl), - C (O) -O- (C 1 ~C 4 alkylene) -O- _(C 1 ~C ₄ alkyl), - _(C 0 ~C ₄ alkylene) -O-C (O) - _(C 1 ~C ₄ alkyl), - (C
₀ -C _{4 alkylene) -C (O) -O- (C} 1 ~C 4 alkyl), - _(C 0 ~C ₄ alkylene) -O- _(C 1 ~C ₄ alkyl), - C (O) - (C ₁ -C ₂ alkylene) -S (O
₎ 0~2 - _(C 1 ~C _{4 alkyl), - S (O) 2} - (C 1 ~C 4 alkyl), - C (O
)-(C ₁ -C ₄ alkylene) -C (O) C (O) N (R ⁶ ) (C ₁ -C ₆ alkyl),
_{-C (O) - (C 1} ~C 4 _{^{alkylene) -N (R 6) S (}} O) 2 - (C 1 ~C 6 alkyl), or _{-C (O) - (C 1} ~C 4 alkylene) It is selected from ^{-N (R 6) S (O} ) 2 Q:
Any alkylene moiety present in R ⁵ is optionally substituted by OCH ₃ , OH or F;
Any terminal methyl moiety present in R ⁵ is —CH ₂ OH, CF ₃ , —CH ₂ F, —CH
₂ Cl, C (O) CH ₃ , C (O) CF ₃ , CN, —OCH ₃ , —C (O) H, —OP (
Optionally substituted by O) (OH) ₂ , —OP (O) (C ₁ -C ₄ alkoxy) ₂ or CO ₂ H;
Each R ⁶ is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
Q is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —C (O) O— (C ₁ -C ₄ alkyl), — (C ₁ -C ₄ alkylene) optionally substituted with —OH. ) - _(C 1 ~C
₄ alkoxy), optionally substituted with up to 3 substituents independently selected from —CN, —OH, fluoro, chloro and bromo;
R ⁹ is selected from aryl and heteroaryl, each aryl or heteroaryl being —GLM, halo, C ₁ -C ₆ alkyl, —C≡N, ═O, —CF ₃ and —OCF Optionally substituted with one or more substituents selected from ₃ ;
m is 0, 1, 2 or 3].

The compounds of formula I inhibit mutant IDH1, in particular mutant IDH1 having alpha hydroxyl new activity. Also described herein are pharmaceutical compositions comprising a compound of formula I or a salt thereof and methods of using such compositions to treat cancer characterized by the presence of mutant IDH1.
The present invention provides, for example:
(Item 1)
Structural formula (I):

Or a pharmaceutically acceptable salt thereof, wherein
Y is —N (R ⁵ ) —, —N (R ⁵ ) —CH ₂ —, —CH ₂ —N (R ⁵ ) — or —CH (R ⁵ ) —;
Each R ^1a and R ^1b is independently hydrogen, —C ₁ -C ₄ alkyl, —N (R ⁷ ) (C ₁ -C ₄ alkylene) —N (R ⁷ ) (C ₁ -C ₄ alkyl) ), Aryl, heteroaryl, heterocyclyl, —C (O) N (R ⁷ ) -aryl, —N (R ⁷ ) C (O) -aryl, — (C ₁ -C ₄ alkylene) -aryl, — (C ₁ -C ₄ alkylene) - heteroaryl, -O- _(C 0 ~C ₄ alkylene) - aryl, -O- _(C 0 ~C ₄ alkylene) - heteroaryl, -O- _(C 0 ~C ₄ alkylene) - heterocyclyl, -O- _(C 0 ~C ₄ alkylene) - carbocyclyl, -N ^{(R 7)} - aryl or -N ^{(R 7),} - heteroaryl, -N ^{(R 9)} - aryl, -N (R ⁹⁾ - heteroaryl, -O- C ₁ -C ₄ Arukeiren ^{(alkeylene)) - N (R} 7) C (O) O- (C 1 ~C 4 alkylene) - ^{aryl, -N (R 9) -C (} O) - (C 2 ~C ₄ alkenyl): at least one of R ^1a and R ^1b is not hydrogen or methyl;
Any alkylene moiety present in R ^1a or R ^1b is optionally substituted by OH or F;
Each R ⁷ is independently selected from hydrogen and C ₁ -C ₄ alkyl;
Any aryl, heteroaryl, or heterocyclyl of R ^1a or R ^1b is —GLM, halo, —NO ₂ , C ₁ -C ₆ alkyl, —C≡N, ═O, —CF ₃ and —. Optionally substituted with one or more substituents selected from OCF ₃ ;
G is a bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and optionally 1, 2 or 3 methylene units of the hydrocarbon chain are —NR ⁸ — , -O -, - C (O ) -, - OC (O) -, - C (O) O -, - S -, - SO -, - SO 2 -, - C (= S) -, - C ^{(= NR 8) -, -} N = N-, or -C (= _{N 2)} - is replaced independently by;
L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon chain, and 1, 2 or 3 methylene units of L are cyclopropylene, —NR ⁸ — ^{, -N (R 8) C (} O) -, - C (O) N (R 8) -, - N (R 8) SO 2 -, SO 2 N (R 8) -, - O -, - C (O) -, - OC ( O) -, - C (O) O -, - S -, - SO -, - SO 2 -, - C (= S) -, - C (= NR 8) -, -N = N-, or -C (= _{N 2)} - is replaced independently by optionally;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur There, said ring, -D-E, oxo, NO _2, halogen, _CN, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, or _C 2 -C _6. 1 to independently selected from alkynyl Substituted by four groups;
D is a covalent bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and one or two methylene units of D are —NR ⁸ —, —S—, Optionally substituted independently by —O—, —C (O) —, —SO—, or —SO ₂ —;
E is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted by oxo, halogen, or CN ;
Each R ⁸ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, -C ₁ -C ₆ alkoxy, -S (O) ₂ -C _2- C ₄ alkenyl, or a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or 1- independently selected from nitrogen, oxygen, or sulfur An optionally substituted group selected from 5-6 membered monocyclic heteroaryl rings having 4 heteroatoms;
R ² is selected from phenyl, 3-7 membered cycloalkyl, C ₂ -C ₄ alkyl, or CF ₃ , wherein phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
Each R ³ is halo, — (C ₁ -C ₄ alkylene) -O— (C ₁ -C ₄ alkyl), —C ₁ -C ₄ fluoroalkyl, —C (O) —O— (C _1- C ₄ alkyl), - phenyl, - _heteroaryl, C 3 -C _{7 cycloalkyl, -CH 2 -N (C 1 ~C} 4 _{alkyl) 2, C (O) -N-} (C 1 ~C 4 alkyl) ₂ , —C (O) —NH— (C ₁ -C ₄ alkyl), independently selected from —C ₁ -C ₄ alkyl optionally substituted by one or more halo or —OH, or 2 Two R ³ together form a 3-8 saturated ring or fused phenyl, said saturated ring or fused phenyl optionally substituted by 1 to 2 methyls;
R ⁴ is hydrogen, —CN, halo, C ₁ -C ₄ alkoxy, —CH ₂ NH (C ₁ -C ₄ alkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, — (C _1- C ₄ alkyl) -O- _(C 1 ~C _{4 alkyl),} C 1 _{~C 4 fluoroalkyl, C (O) -N- (C} 1 ~C 4 _{alkyl) 2, -C (O) -NH-} ( C ₁ -C ₄ alkyl), - C (O) -O- (C 1 ~C 4 alkyl), - C (O) -OH , -S (O) 2 - (C 1 ~C 4 alkyl), and Selected from 5-membered heteroaryl;
R ⁵ is: —C (O) — (C ₁ -C ₅ alkyl), —C (O) — (C ₂ -C ₆ alkenyl), —C (O) — (C ₀ -C ₂ alkylene) -Q _{, -C (O) - (C} 1 ~C 4 alkenylene) -Q, -C (O) - (C 0 ~C 2 _{^{alkylene) -N (R 6) - (}} C 0 ~C 2 alkylene) -Q, -C (O) -O- (C ₀ -C ₂ alkylene) -Q, -C (O)-(C ₁ -C ₂ alkylene) -O- (C ₀ -C ₂ alkylene) -Q, -C ( _{O) -C (O) -Q,} -S (O) 2 -Q, -C (O) - (C 1 ~C 4 alkylene) -O-C (O) - (C 1 ~C 4 alkyl), _{-C (O) - (C 1} ~C 4 _{alkylene) -C (O) -O- (C} 1 ~C 4 ^{alkyl), - C (O) -N} (R 6) - (C 1 ~C 4 alkylene ) -O-C (O) - (C 1 C ₄ ^{alkyl), - C (O) -N} (R 6) - (C 1 ~C 4 _{alkylene) -C (O) -O- (C} 1 ~C 4 alkyl), - C (O) - (C ₀ -C _{2 ^{alkylene) -N (R 6) - (}} C 1 ~C 6 alkyl), - C (O) - (C 0 ~C 2 _{^{alkylene) N (R 6) - (}} C 2 ~C 6 alkynyl) , -C (O)-(C ₀ -C ₂ alkylene) -N (R ⁶ )-(C ₂ -C ₆ alkenyl), -C (O)-(C ₀ -C ₂ alkylene) -N (R ⁶ ) - _(C 0 ~C ₂ alkylene) -O- _(C 1 ~C ₄ alkyl), - C (O) - (C 1 ~C 2 alkylene) -O- _(C 1 ~C ₄ alkyl), - C (O)-(C ₁ -C ₂ alkylene) -C (O) C (O) N (R) (C ₁ -C ₄ alkyl), —C (O) —O— (C ₁ -C ₄ alkylene) − O- _(C 1 ~C ₄ alkyl), - _(C 0 _{~C 4} alkylene) -O-C (O) - (C 1 ~C 4 alkyl), - _(C 0 _{~C 4} alkylene) -C (O ) -O- _(C 1 ~C ₄ alkyl), - _(C 0 ~C ₄ alkylene) -O- _(C 1 ~C ₄ alkyl), - C (O) - (C 1 ~C 2 alkylene) -S _{(O) 0~2 - (C 1} ~C 4 _{alkyl), - S (O) 2} - (C 1 ~C 4 alkyl), - C (O) - (C 1 ~C 4 alkylene) -C (O ^{) C (O) N (R} 6) (C 1 ~C 6 alkyl), - C (O) - (C 1 ~C 4 _{^{alkylene) -N (R 6) S (}} O) 2 - (C 1 ~C ₆ alkyl), or —C (O) — (C ₁ -C ₄ alkylene) —N (R ⁶ ) S (O) ₂ Q:
Any alkylene moiety present in R ⁵ is optionally substituted by OCH ₃ , OH or F;
Any terminal methyl moiety present in R ⁵ is —CH ₂ OH, CF ₃ , —CH ₂ F, —CH ₂ Cl, C (O) CH ₃ , C (O) CF ₃ , CN, —OCH _3. , —C (O) H, —OP (O) (OH) ₂ , —OP (O) (C ₁ -C ₄ alkoxy) ₂ or CO ₂ H;
Each R ⁶ is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, where Q is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —C (O) O— (C ₁ ) optionally substituted with OH. -C ₄ alkyl), - _(C 1 -C ₄ alkylene) - _(C 1 -C ₄ alkoxy), - when CN, -OH, fluoro, by up to three substituents independently selected from chloro and bromo Is replaced by;
⁹ is selected from aryl and heteroaryl, each aryl or heteroaryl, -G-L-M, _halo, C 1 -C ₆ alkyl, -C≡N, = O, -CF ₃ and -OCF ₃ Optionally substituted with one or more substituents selected from:
m is 0, 1, 2 or 3.]
(Item 2)
Y is —N (R ⁵ ) — or —CH (R ⁵ ) —;
Each R ^1a and R ^1b is independently hydrogen, —C ₁ -C ₄ alkyl, —N (R ⁷ ) (C ₁ -C ₄ alkylene) —N (R ⁷ ) (C ₁ -C ₄ alkyl) ), Aryl, heteroaryl, heterocyclyl, —C (O) N (R ⁷ ) -aryl, —N (R ⁷ ) C (O) -aryl, — (C ₁ -C ₄ alkylene) -aryl, — (C ₁ -C ₄ alkylene) - heteroaryl, -O- _(C 1 ~C ₄ alkylene) - aryl, -O- _(C 1 ~C ₄ alkylene) - heteroaryl, -O- _(C 1 ~C ₄ alkylene) - heterocyclyl, -N ^{(R 7)} - aryl or -N, ^{(R 7)} - heteroaryl:
At least one of R ^1a and R ^1b is not hydrogen or methyl;
Any alkylene moiety present in R ^1a or R ^1b is optionally substituted by OH or F;
Each R ⁷ is independently selected from hydrogen and C ₁ -C ₄ alkyl;
Any aryl, heteroaryl, or heterocyclyl of R ^1a or R ^1b is —GLM, halo, C ₁ -C ₆ alkyl, —C≡N, ═O, —CF ₃ and —OCF. Optionally substituted by one or more substituents selected from ₃ ; G is a bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain; , 1, 2 or 3 methylene units of the hydrocarbon chain are —NR ⁸ —, —O—, —C (O) —, —OC (O) —, —C (O) O—, —S—, _{-SO -, - SO 2 -,} - C (= S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2)} - is replaced independently by;
L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon chain, and 1, 2 or 3 methylene units of L are cyclopropylene, —NR ⁸ — ^{, -N (R 8) C (} O) -, - C (O) N (R 8) -, - N (R 8) SO 2 -, SO 2 N (R 8) -, - O -, - C (O) -, - OC ( O) -, - C (O) O -, - S -, - SO -, - SO 2 -, - C (= S) -, - C (= NR 8) -, -N = N-, or -C (= _{N 2)} - is replaced independently by optionally;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur There, said ring, -D-E, oxo, NO _2, halogen, _CN, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl, or _C 2 -C _6. 1 to independently selected from alkynyl Substituted by four groups;
D is a covalent bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and one or two methylene units of D are —NR ⁸ —, —S—, Optionally substituted independently by —O—, —C (O) —, —SO—, or —SO ₂ —;
E is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted by oxo, halogen, or CN ;
Each R ⁸ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or phenyl, nitrogen, oxygen, or sulfur 1 When selected from a 4-7 membered heterocyclyl having 2 heteroatoms, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur A group substituted by
R ² is selected from phenyl, 3-7 membered cycloalkyl, and C ₂ -C ₄ alkyl, wherein said phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
Each R ³ is —C ₁ -C ₄ alkyl, — (C ₁ -C ₄ alkyl) -O— (C ₁ -C ₄ alkyl), —C ₁ -C ₄ fluoroalkyl, —C (O) — O- _(C 1 ~C ₄ alkyl), - phenyl, - _heteroaryl, C 3 -C _{7 cycloalkyl, -CH 2 -N (C 1 ~C} 4 _{alkyl) 2, C (O) -N-} (C ₁ -C _{4 alkyl) 2,} and _{-C (O) -NH- (C 1} ~C 4 alkyl) independently selected from or or two ^{R 3,} is 3-8 saturated ring or together Forms a fused phenyl, said saturated ring or fused phenyl optionally substituted by 1 to 2 methyl groups;
R ⁴ is hydrogen, —CN, halo, C ₁ -C ₄ alkoxy, —CH ₂ NH (C ₁ -C ₄ alkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, — (C _1- C ₄ alkyl) -O- _(C 1 ~C _{4 alkyl),} C 1 _{~C 4 fluoroalkyl, C (O) -N- (C} 1 ~C 4 _{alkyl) 2, -C (O) -NH-} ( C ₁ -C ₄ alkyl), - C (O) -O- (C 1 ~C 4 alkyl), - C (O) -OH , -S (O) 2 - (C 1 ~C 4 alkyl), and Selected from 5-membered heteroaryl;
R ⁵ is: —C (O) — (C ₁ -C ₄ alkyl), —C (O) — (CH ₂ ) _0-2- Q, —C (O) — (CH ₂ ) _0-2- N _{^{(R 6) - (CH 2}} ) 0~2 -Q, -C (O) -O- (CH 2) 1~2 -Q, -C (O) - (CH 2) 1~2 -O- ( _{CH 2) 0~2 -Q, -C (} O) -C (O) -Q, -S (O) 2 -Q, -C (O) - (C 1 ~C 4 alkylene) -O-C ( O) - _(C 1 ~C ₄ alkyl), - C (O) - (C 1 ~C 4 _{alkylene) -C (O) -O- (C} 1 ~C 4 alkyl), - C (O) -N (R ⁶ )-(C ₁ -C ₄ alkylene) -O—C (O) — (C ₁ -C ₄ alkyl), —C (O) —N (R ⁶ )-(C ₁ -C ₄ alkylene) _{-C (O) -O- (C 1} ~C 4 alkyl), - C (O) - (CH ^{_{2) 0~2 -N (R 6)}} - (C 1 ~C 6 _{alkyl), - C (O) -} (CH 2) 0~2 -N (R 6) - (C 2 ~C 6 alkynyl), _{-C (O) - (CH 2} ) 0~2 -N (R 6) - (C 2 ~C 6 _{alkenyl), - C (O) -} (CH 2) 0~2 -N (R 6) - ( _{CH 2) 0~2 -O- (C 1} ~C 4 _{alkyl), - C (O) -} (CH 2) 1~2 -O- (C 1 ~C 4 alkyl), - C (O) -O - _(C 1 ~C ₄ alkylene) -O- _(C 1 _{~C 4 alkyl), - (CH 2) 0~4} -O-C (O) - (C 1 ~C 4 alkyl), - (CH ₂ ) _{0- 4} -C (O) -O- (C ₁ -C ₄ alkyl),-(CH ₂ ) ₀ -4 -O- (C ₁ -C ₄ alkyl), -C (O)-(CH ₂ ) 1~2 -S- _{(C 1} ~C ₄ A _{Kill), - S (O) 2} - (C 1 ~C 4 alkyl), - C (O) - (C 1 ~C 4 alkylene) -C (O) C (O ) N (R 6) (C 1 -C ₆ alkyl), - C (O) - (C 1 ~C 4 _{^{alkylene) -N (R 6) S (}} O) 2 - (C 1 ~C 6 alkyl), and -C (O) - (C ₁ -C ₄ alkylene) ^-N (R 6) is selected from S _{(O) 2} Q:
Any alkylene moiety present in R ⁵ is optionally substituted with OH or F;
Any terminal methyl moiety present in R ⁵ is optionally replaced by —CH ₂ OH, CF ₃ , —CH ₂ F, —CH ₂ Cl, C (O) CH ₃ , or C (O) CF _3. Each R ⁶ is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —CN, fluoro, chloro and bromo. Optionally substituted by a substituent;
m is 0, 1, 2 or 3.
Item 1. A compound according to item 1.
(Item 3)
R ⁴ is selected from -CN or _{C (O) -O-C 1} ~C 4 alkyl, The compound of claim 1.
(Item 4)
R ⁴ is

The compound according to item 1, wherein
(Item 5)
The compound according to item 1, wherein Y is —N (R ⁵ ) —.
(Item 6)
R ⁵ _{is, -C (O) - (C} 1 ~C 3 alkyl) -O- _(C 1 ~C ₂ alkyl), - C (O) -Q , -C (O) - (C 1 ~C 5 alkyl), - C (O) - (C 1 ~C 2 alkylene) -Q, -C (O) - (C 2 ~C 4 alkenyl), - C (O) O- (C 1 ~C 4 alkyl) Or —C (O) — (C ₁ -C ₄ alkenylene) -Q; any alkylene moiety present in R ⁵ is optionally substituted with OH; any present in R ⁵ The terminal methyl moiety is —OH, CF ₃ , OCH ₃ , —C (O) H, OP (O) (C ₁ -C ₄ alkoxy) ₂ , or —OP (O) (OH) ₂ (or —OP ( 7. The compound according to item 6, optionally substituted by O) (OH) ₂ salt).
(Item 7)
Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is C ₁ -C ₄ alkyl optionally substituted with OH, Item 6 optionally substituted with one substituent independently selected from C ₁ -C ₄ alkoxy, — (C ₁ -C ₄ alkylene)-(C ₁ -C ₄ alkoxy), and —OH. Compound described in 1.
(Item 8)
R ^1a is H and R ^1b is aryl, heteroaryl, heterocyclyl, — (C ₁ -C ₄ alkylene) -aryl, — (C ₁ -C ₄ alkylene) -heteroaryl, —O— (C ₀ -C ₄ alkylene) - aryl, -O- _(C 0 ~C ₄ alkylene) - heteroaryl, -N ^{(R 7)} - aryl, -N ^{(R 7)} heteroaryl, -N ^{(R 9)} - aryl, or -N ^{(R 9)} - heteroaryl; wherein the aryl or heteroaryl, -G-L-M, CH 3 or substituted by CN, compounds of claim 1.
(Item 9)
^9. A compound according to item 8, wherein the aryl associated with R ^1b is phenyl.
(Item 10)
Heteroaryl is related to R ^1b and includes pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzoimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyr 9. A compound according to item 8, which is dinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl.
(Item 11)
Heterocyclyl is related to R ^1b and includes benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl, and said phenyl, pyridyl , Pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridanyl, pyridazylyl Benzodioxole, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N-methylisoquinolinone, tetra 9. The compound according to item 8, which is hydropyridinyl or dihydropyrrolyl.
(Item 12)
The aryl, heteroaryl or heterocyclyl associated with R ^1b is substituted by —GLM, —CF ₃ , —OCF ₃ , halo (eg, fluoro, chloro or bromo), CH ₃ , or CN; The compound according to any one of Items 9 to 11.
(Item 13)
R ^1a is methyl and R ^1b is aryl, heteroaryl, heterocyclyl, —O— (C ₀ -C ₄ alkylene) -aryl, or —O— (C ₀ -C ₄ alkylene) -heteroaryl. The compound according to Item 1.
(Item 14)
R ^1a is methyl and R ^1b is aryl, heteroaryl, heterocyclyl, —O— (CH ₂ ) -aryl, —O—CH (CH ₃ ) -aryl, —O— (CH ₂ ) -heteroaryl. or -O-CH (CH ₃₎ - heteroaryl compound of claim 13.
(Item 15)
15. A compound according to any one of items 13 to 14, wherein aryl associated with R ^1b is phenyl or naphthyl.
(Item 16)
15. A compound according to any one of items 13 to 14, wherein the heteroaryl associated with R ^1b is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl.
(Item 17)
15. A compound according to any one of items 13 to 14, wherein the heterocyclyl associated with R ^1b is tetrahydropyridinyl and said phenyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl.
(Item 18)
Aryl associated with R ^1b, heteroaryl or heterocyclyl, -G-L-M, halo, CH ₃ or substituted by CN, a compound according to any one of items 13 to 17,.
(Item 19)
-GLM is:

C ₁ -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 1 -C ₄ alkoxy, tetrazolyl, morpholino, piperazinyl, pyrrolidinone, pyrazolyl, _{benzyl, - (CH 2) 1~4 -SH} , - (CH 2) 1 _{~4 -NH 2, -NH 2, -} (CH 2) 1~4 -OH, -N (H) C (O) OCH (CH 3) 3, - (CH 2) 1~4 -OCH 3, - NH— (CH ₂ ) _1-4 -OH, —C (O) — (C ₁ -C ₄ alkyl), —C (O) — (C ₁ -C ₄ alkenyl), —O— (CH ₂ ) _{1 ~4 -C (O) -O- (C} 1 ~C 4 _{alkyl), - C (O) NH} 2, - (CH 2) 1~4 C (O) CH 3, -N (CH 3) (CH _{3), - NHC (O)} (C 2 ~C 4 _{alkenyl), - NHC (O) (} C 2 ~C 4 alkyl) _{, -SO 2 (CH 2) 1~4} , - (CH 2) 1~4 -NHSO 2 Me, -NHSO 2 (CH 2) 1~4, -O-SO 2 CF 3, -SO 2 NH- ( C ₁ -C _{4 alkyl), - SO 2 NH- (C} 2 ~C 4 _alkenyl), a SO 2 -NH ₂ or -NHSO ₂ Me, a compound according to any one of items 8-18.
(Item 20)
A pharmaceutical composition comprising the compound according to item 1 and a pharmaceutically acceptable carrier.
(Item 21)
Item 21. The composition according to Item 20, further comprising a second therapeutic agent.
(Item 22)
In a method of treating cancer characterized by the presence of an IDH1 mutation, said IDH1 mutation is an enzyme that catalyzes a NAPH-dependent reduction of α-ketoglutarate to R (−)-2-hydroxyglutarate in a patient 21. A method comprising the step of administering the composition of item 20 to a patient that has the new ability of:
(Item 23)
24. The method of item 22, wherein the IDH1 mutation is an IDH1R132H or IDH1R132C mutation.
(Item 24)
The cancers are glioma (glioblastoma), acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer and bile duct cancer, bile duct cancer, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasia 24. The method of item 23, selected from an organism (MPN) or colon cancer.
(Item 25)
25. The method of any one of items 22-24, further comprising administering a second therapeutic agent to a patient in need of such treatment.

The present invention is not limited in its application to the details of component construction and arrangement set forth in the following detailed description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, the terminology and terminology used herein is for the purpose of description and should not be considered limiting. As used herein, “included”, “include” or “have”, “contains”,
Use of “with” and variations thereof is meant to encompass the items listed below and their equivalents, as well as additional items.

Definition:
The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be straight or branched and containing the indicated number of carbon atoms. For _example, C 1 _{-C 12} alkyl, groups 1-12 (including the end)
It may have carbon atoms in it. The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens are replaced by halo (eg, perfluoroalkyl). The term “arylalkyl” or “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which two or more hydrogen atoms have been replaced by aryl groups. Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzohydryl, and trityl groups.

The term “alkylene” refers to divalent alkyl, eg, —CH ₂ —, —CH ₂ CH ₂ —.
, And _-CH 2 _CH 2 CH ₂ - and _{-CH 2 CH (CH 3) CH} 2 - refers to.

The term “alkenyl” refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent.

The term “alkynyl” refers to a straight or branched hydrocarbon chain characterized by containing 2 to 12 carbon atoms and having one or more triple bonds. As an alkynyl group,
Non-limiting examples include ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

The term “alkoxy” refers to an —O-alkyl radical. The term “haloalkoxy” refers to an alkoxy in which one or more hydrogen atoms are replaced by halo, and includes alkoxy moieties in which all hydrogens are replaced by halo (eg, perfluoroalkoxy).

The term “aryl” refers to a fully aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl moieties are phenyl, naphthyl, and anthracenyl.
Unless otherwise stated, any ring atom in aryl may be substituted with one or more substituents.

The term “carbocyclyl” refers to a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups include fully saturated ring systems (eg, cycloalkyl),
And partially saturated ring systems.

The term “cycloalkyl” as used herein includes saturated, bicyclic, tricyclic or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom
It may be substituted (eg by one or more substituents). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

The term “heteroaryl” has 1 to 3 heteroatoms for monocyclic, 1 to 6 heteroatoms for bicyclic, or 1 to 9 heteroatoms for tricyclic, Atom is O, N, or S (or oxidized form, eg, N ⁺ -O ⁻ , S (O) and S (O)
₂ ) selected from fully aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-11
Refers to a 14-membered tricyclic ring system.

The term “heterocyclyl” has from 1 to 3 heteroatoms in the case of monocyclic, 1 to 6 heteroatoms in the case of bicyclic, or 1 to 9 heteroatoms in the case of tricyclic, Is O, N, or S (or an oxidized form such as N ⁺ -O ⁻ , S (O) and S (O)
₂ ) selected from non-aromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-1
Refers to a 4-membered tricyclic ring system. The heteroatom can optionally be the point of attachment of the heterocyclyl substituent. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups include fully saturated ring systems and partially saturated ring systems.

Bicyclic and tricyclic ring systems containing one or more heteroatoms, with the point of attachment from the ring system to the rest of the molecule being through a non-aromatic ring, both aromatic and non-aromatic rings are heterocyclyl groups Is considered. Bicyclic or tricyclic ring systems in which the aryl or heteroaryl is fused to a carbocyclyl or heterocyclyl and the point of attachment from the ring system to the rest of the molecule is through an aromatic ring are considered aryl or heteroaryl groups .

Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and heterocyclyl groups, especially at one or more substitutable atoms, either alone or as part of a group (eg, the aryl portion of an aralkyl group) Halo, -C≡N, C ₁ unless otherwise noted
-C ₄ ^{alkyl, = O, -OR b, -OR} b ', -SR b, -SR b', - (C 1 ~C 4
^{Alkyl) -N (R b) (R} b), - (C 1 ~C 4 ^{alkyl) -N (R b) (R} b '),
^{-N (R b) (R b} ), - N (R b) (R b '), - O- (C 1 ~C 4 alkyl) -N (
R ^b ) (R ^b ), —O— (C ₁ -C ₄ alkyl) -N (R ^b ) (R ^{b ′} ), — (C ₁ -C
₄ alkyl) -O- _(C 1 ~C ₄ ^{alkyl) -N (R b) (R} b), - (C 1 ~C 4 alkyl) -O- _(C 1 ~C ₄ alkyl) -N ^{(R b} ) (R ^{b ′} ), —C (O) —N (R ^b )
_{^{(R b), - (C}} 1 ~C 4 ^{alkyl) -C (O) -N (R} b) (R b), - (C 1 ~C 4
Alkyl) -C (O) -N (R ^b ) (R ^{b ′} ), —OR ^{b ′} , R ^{b ′} , —C (O) (C ₁
-C ₄ alkyl), - C (O) R b ', -C (O) N (R b') (R b), - N (R b)
^{C (O) (R b)} , - N (R b) C (O) (R b '), - N (R b) SO 2 (R b), -
^{_{SO 2 N (R b) (}} R b), - N (R b) SO 2 (R b '), and _-SO 2 N ^(R b)
Optionally substituted with a substituent independently selected from (R ^{b ′} ), and any alkyl substituent may be —OH, —O— (C ₁ -C ₄ alkyl), halo, —NH ₂ , —NH (C ₁
-C is further optionally substituted by _alkyl), or -N _(C 1 -C _{4 alkyl) 2} 1 or more;
Each R ^b is independently selected from hydrogen and —C ₁ -C ₄ alkyl; or two R ^b are taken from N, S, and O together with the nitrogen atom to which they are attached. Forming a 4- to 8-membered heterocyclyl optionally containing one additional heteroatom selected
Each R ^{b ′} is independently selected from C ₃ -C ₇ carbosilyl, phenyl, heteroaryl, and heterocyclyl, wherein one or more on said phenyl, cycloalkyl, heteroaryl or heterocyclic substituents Substitutable positions are-(C _1-
C ₄ alkyl), - _(C 1 ~C _{4 fluoroalkyl), - OH, -O- (C} 1 ~C 4 _{alkyl), - O- (C 1 ~C} 4 fluoroalkyl), halo, _-NH 2, -NH _(C 1 ~C ₄
Alkyl), or optionally further substituted by one or more of —N (C ₁ -C ₄ alkyl) ₂ .

A heterocyclyl group, optionally alone or as part of a group, is optionally substituted with oxo, —C ₁ -C ₄ alkyl, or fluoro-substituted C ₁ -C ₄ alkyl on one or more optional substitutable nitrogen atoms. ing.

  The term “substituted” refers to the replacement of a hydrogen atom with another group.

As used herein, the term “increased level of 2HG” refers to mutant ID.
10%, 20% 30%, 50%, 75 than present in subjects that do not carry the H1 allele
%, 100%, 200%, 2HG more than 500%. The term “increased level of 2HG” may refer to the amount of 2HG in a cell, a tumor, an organ containing a tumor, or a body fluid.

The term “body fluid” includes amniotic fluid surrounding the fetus, aqueous humor, blood (eg, plasma), serum, cerebrospinal fluid, earwax, chymus, cowper fluid, female juice, interstitial fluid, lymph fluid, breast milk, It includes one or more of mucus (eg, rhinorrhea or sputum), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal discharge, or vomiting.

As used herein, the term “inhibit” or “prevent” includes both complete inhibition and prevention as well as partial inhibition and prevention. An inhibitor may completely or partially inhibit the intended target.

The term “treat” reduces, inhibits, attenuates, reduces, stops or stabilizes the development or progression of a disease / disorder (eg, cancer), reduces the severity of the disease / disorder (eg, cancer). Or ameliorating symptoms associated with a disease / disorder (eg, cancer).

As used herein, an amount of a compound effective to treat a disorder, or “therapeutically effective amount” is a single or multiple dose administration to a subject, in the treatment of cells, or in a subject having a disorder. Refers to the amount of a compound that is more effective in healing, reducing, alleviating or ameliorating than expected in the absence of such treatment.

As used herein, the term “subject” is intended to include human and non-human animals. Exemplary human subjects include a human patient (referred to as a patient) having a disorder, eg, a disorder described herein, or a normal subject. The term “non-human animal” of the present invention includes all vertebrates, such as non-mammals (eg, chickens, amphibians, reptiles).
As well as mammals such as non-human primates, domestic and / or agricultural animals useful such as sheep, dogs, cats, cows, pigs.

Compound Structural Formula I:


Or a pharmaceutically acceptable salt thereof, wherein
Y represents —N (R ⁵ ) —, —N (R ⁵ ) —CH ₂ —, —CH ₂ —N (R ⁵ ) —, or —C.
H ^{(R 5)} - a and;
Each R ^1a and R ^1b is independently hydrogen, —C ₁ -C ₄ alkyl, —N (R ⁷
) _(C 1 -C _{4 ^{alkylene) -N (R 7) (C}} 1 ~C 4 alkyl), aryl, heteroaryl, ^{heterocyclyl, -C (O) N (R} 7) - aryl, -N ^(R 7) C (O) -aryl,-(C ₁ -C ₄ alkylene) -aryl,-(C ₁ -C ₄ alkylene) -heteroaryl, -O- (C ₀ -C ₄ alkylene) -aryl, -O- ( C ₀ -C ₄ alkylene) -heteroaryl, —O— (C ₀ -C ₄ alkylene) -heterocyclyl, —O— (C ₀
-C ₄ alkylene) - carbocyclyl, -N ^{(R 7)} - aryl, -N ^{(R 7)} - heteroaryl, -N ^{(R 9)} - aryl, -N ^{(R 9)} - heteroaryl, -O- ( C ₁ ~C
₄ ^{Arukeiren) -N (R 7) C (} O) O- (C 1 ~C 4 alkylene) - aryl or ^{-N (R 9,) -C (} O) - be a _(C 2 -C ₄ alkenyl):
At least one of R ^1a and R ^1b is not hydrogen or methyl;
Any alkylene moiety present in R ^1a or R ^1b is optionally substituted by OH or F;
Each R ⁷ is independently selected from hydrogen and C ₁ -C ₄ alkyl;
Any aryl, carbocyclyl, heteroaryl, or heterocyclyl of R ^1a or R ^1b is —G-L-M, halo, —NO ₂ , C ₁ -C ₆ alkyl, —C≡N, ═O, —
Optionally substituted with one or more substituents selected from CF ₃ and —OCF ₃ ;
G is a bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and optionally 1, 2 or 3 methylene units of the hydrocarbon chain are —NR ⁸ — , -O
-, - C (O) - , - OC (O) -, - C (O) O -, - S -, - SO -, - SO 2 -,
-C (= S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2)} - is replaced independently by;
L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon chain, and 1, 2 or 3 methylene units of L are cyclopropylene, —NR ⁸ — ,
^{-N (R 8) C (O} ) -, - C (O) N (R 8) -, - N (R 8) SO 2 -, SO 2 N (
^{R 8) -, - O -} , - C (O) -, - OC (O) -, - C (O) O -, - S -, - SO-
_{, -SO 2 -, - C (} = S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2}
)-, Optionally replaced independently;
M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur There, said ring, -D-E, oxo, NO _2, halogen, _CN, C 1 -C ₆ alkyl, _{C 2}
Substituted with 1-4 groups independently selected from -C ₆ alkenyl, or C ₂ -C ₆ alkynyl;
D is a covalent bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and one or two methylene units of D are —NR ⁸ —, —S—, -O-, -C (
O) -, - SO-, or -SO ₂ - is replaced independently by optionally;
E is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is oxo, halogen, or CN
Optionally substituted by:
Each R ⁸ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂
-C ₆ alkynyl, _-C 1 -C _{6 alkoxy, -S (O) 2 -C 2} ~C 4 alkenyl or phenyl, nitrogen, oxygen, or 1 to 2 heteroatoms independently selected from nitrogen Optionally having 4 to 7 membered heterocyclyl or optionally substituted group selected from 5 to 6 membered monocyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur Is;
R ² is selected from phenyl, 3-7 membered cycloalkyl, C ₂ -C ₄ alkyl, or CF ₃ , wherein phenyl or cycloalkyl is optionally substituted with a substituent selected from methyl or fluoro;
Each R ³ is halo, — (C ₁ -C ₄ alkylene) -O— (C ₁ -C ₄ alkyl),
-C ₁ -C _{4 fluoroalkyl, -C (O) -O- (C} 1 ~C 4 alkyl), - phenyl, - _heteroaryl, C 3 -C _{7 cycloalkyl,} -CH 2 -N _(C 1 ~ C ₄ alkyl)
₂ , C (O) —N— (C ₁ -C ₄ alkyl) ₂ , —C (O) —NH— (C ₁ -C ₄ alkyl), optionally substituted by one or more halo or —OH. Or independently selected from -C ₁ -C ₄ alkyl, or two R ^{3 taken} together form a 3-8 saturated ring or fused phenyl, said saturated ring or fused phenyl being 1 to 2 Optionally substituted by methyl;
R ⁴ is hydrogen, —CN, halo, C ₁ -C ₄ alkoxy, —CH ₂ NH (C ₁ -C ₄ alkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, — (C _1- C ₄ alkyl) -O-
_(C 1 -C _{4 alkyl),} C 1 -C _{4 fluoroalkyl, C (O) -N- (C} 1 ~C 4 _{alkyl) 2, -C (O) -NH-} (C 1 ~C 4 alkyl) _{, -C (O) -O- (C} 1 ~C
₄ alkyl), —C (O) —OH, —S (O) ₂ — (C ₁ -C ₄ alkyl), and 5-membered heteroaryl;
R ⁵ represents —C (O) — (C ₁ -C ₅ alkyl), —C (O) — (C ₂ -C ₆ alkenyl).
, -C (O)-(C ₀ -C ₂ alkylene) -Q, -C (O)-(C ₁ -C ₄ alkenylene) -Q, -C (O)-(C ₀ -C ₂ alkylene)- _{^{N (R 6) - (C}} 0 ~C 2 alkylene) -Q, -C (O) -O- (C 0 ~C 2 alkylene) -Q, -C (O) - (C 1 ~C 2 alkylene) -O- _(C 0 ~C ₂ alkylene) -Q, -C (O) -C (O) -Q, -S (O
) ₂ -Q, -C (O)-(C ₁ -C ₄ alkylene) -O-C (O)-(C ₁ -C ₄ alkyl), -C (O)-(C ₁ -C ₄ alkylene) _{-C (O) -O- (C 1} ~C 4 alkyl)
^{, -C (O) -N (R} 6) - (C 1 ~C 4 alkylene) -O-C (O) - (C 1 ~C 4 alkyl), - C (O) -N (R 6) - _(C 1 -C _{4 alkylene) -C (O) -O- (C} 1
-C ₄ alkyl), - C (O) - (C 0 ~C 2 _{^{alkylene) -N (R 6) - (}} C 1 ~C 6
Alkyl), -C (O)-(C ₀ -C ₂ alkylene) N (R ⁶ )-(C ₂ -C ₆ alkynyl), -C (O)-(C ₀ -C ₂ alkylene) -N (R _⁶⁾ - _(C 2 ^{~C 6} alkenyl)
, -C (O)-(C ₀ -C ₂ alkylene) -N (R ⁶ )-(C ₀ -C ₂ alkylene) -O
- _(C 1 ~C ₄ alkyl), - C (O) - (C 1 ~C 2 alkylene) -O- _(C 1 _{~C 4}
Alkyl), - C (O) - (C 1 ~C 2 alkylene) -C (O) C (O ) N (R) (C 1
-C ₄ alkyl), - C (O) -O- (C 1 ~C 4 alkylene) -O- _(C 1 ~C ₄ alkyl), - _(C 0 ~C ₄ alkylene) -O-C (O) - _(C 1 ~C ₄ alkyl), - (C
₀ -C _{4 alkylene) -C (O) -O- (C} 1 ~C 4 alkyl), - _(C 0 ~C ₄ alkylene) -O- _(C 1 ~C ₄ alkyl), - C (O) - (C ₁ -C ₂ alkylene) -S (O
₎ 0~2 - _(C 1 ~C _{4 alkyl), - S (O) 2} - (C 1 ~C 4 alkyl), - C (O
)-(C ₁ -C ₄ alkylene) -C (O) C (O) N (R ⁶ ) (C ₁ -C ₆ alkyl),
_{-C (O) - (C 1} ~C 4 _{^{alkylene) -N (R 6) S (}} O) 2 - (C 1 ~C 6 alkyl), or _{-C (O) - (C 1} ~C 4 alkylene) It is selected from ^{-N (R 6) S (O} ) 2 Q:
Any alkylene moiety present in R ⁵ is optionally substituted by OCH ₃ , OH or F;
Any terminal methyl moiety present in R ⁵ is —CH ₂ OH, CF ₃ , —CH ₂ F, —CH
₂ Cl, C (O) CH ₃ , C (O) CF ₃ , CN, —OCH ₃ , —C (O) H, —OP (
Optionally substituted by O) (OH) ₂ , —OP (O) (C ₁ -C ₄ alkoxy) ₂ or CO ₂ H;
Each R ⁶ is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
Q is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —C (O) O— (C ₁ -C ₄ alkyl), — (C ₁ -C ₄ alkylene) optionally substituted with —OH. ) - _(C 1 ~C
₄ alkoxy), optionally substituted with up to 3 substituents independently selected from —CN, —OH, fluoro, chloro and bromo;
R ⁹ is selected from aryl and heteroaryl, each aryl or heteroaryl being —GLM, halo, C ₁ -C ₆ alkyl, —C≡N, ═O, —CF ₃ and —OCF Optionally substituted with one or more substituents selected from ₃ ;
m is 0, 1, 2 or 3.] is provided.

In some embodiments, Structural Formula I:


Or a pharmaceutically acceptable salt thereof, wherein
Y is —N (R ⁵ ) — or —CH (R ⁵ ) —;
Each R ^1a and R ^1b is independently hydrogen, —C ₁ -C ₄ alkyl, —N (R ⁷
) _(C 1 -C _{4 ^{alkylene) -N (R 7) (C}} 1 ~C 4 alkyl), aryl, heteroaryl, ^{heterocyclyl, -C (O) N (R} 7) - aryl, -N ^(R 7) C (O) - aryl, - _(C 1 ~C ₄ alkylene) - aryl, - _(C 1 ~C ₄ alkylene) - heteroaryl, -O- _(C 1 ~C ₄ alkylene) - aryl, -O- ( C ₁ -C ₄ alkylene) - heteroaryl, -O- _(C 1 ~C ₄ alkylene) - heterocyclyl, -N ^(R 7)
- aryl or -N, ^{(R 7)} - heteroaryl:
At least one of R ^1a and R ^1b is not hydrogen or methyl;
Any alkylene moiety present in R ^1a or R ^1b is optionally substituted by OH or F;
Each R ⁷ is independently selected from hydrogen and C ₁ -C ₄ alkyl;
Any aryl, heteroaryl, or heterosilyl of R ^1a or R ^1b (hete
Rcylyl) is, -G-L-M, _halo, C 1 -C ₆ alkyl, -C≡N, = O, -CF
Optionally substituted with one or more substituents selected from ₃ and —OCF ₃ ;
G is a bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and optionally 1, 2 or 3 methylene units of the hydrocarbon chain are —NR ⁸ — , -O
-, - C (O) - , - OC (O) -, - C (O) O -, - S -, - SO -, - SO 2 -,
-C (= S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2)} - is replaced independently by;
L is a covalent bond or a divalent C _1-8 saturated or unsaturated, linear or branched hydrocarbon chain, and 1, 2 or 3 methylene units of L are cyclopropylene, —NR ⁸ — ,
^{-N (R 8) C (O} ) -, - C (O) N (R 8) -, - N (R 8) SO 2 -, SO 2 N (
^{R 8) -, - O -} , - C (O) -, - OC (O) -, - C (O) O -, - S -, - SO-
_{, -SO 2 -, - C (} = S) -, - C (= NR 8) -, - N = N-, or -C (= _{N 2}
)-Is optionally substituted independently; M is E, or a 3-10 membered monocyclic having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; bicyclic, saturated, partially unsaturated, or aromatic ring, said ring, -D-E, oxo, NO _2, halogen, _CN, C 1 -C _{6 alkyl,} C 2 -C ₆ alkenyl or, C
Substituted in 1 to 4 groups independently selected from _{2 to} C ₆ alkynyl;
D is a covalent bond or a divalent C ₁ -C ₆ saturated or unsaturated, linear or branched hydrocarbon chain, and one or two methylene units of D are —NR ⁸ —, —S—, -O-, -C (
O) -, - SO-, or -SO ₂ - is replaced independently by optionally;
E is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, wherein said alkyl, alkenyl or alkynyl is oxo, halogen, or CN
Optionally substituted by:
Each R ⁸ is independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂
-C ₆ alkynyl, or phenyl, nitrogen, oxygen, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from sulfur, or nitrogen, are oxygen, or independently from nitrogen selected An optionally substituted group selected from 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms;
R ² is selected from phenyl, 3-7 membered cycloalkyl, and C ₂ -C ₄ alkyl;
Phenyl or cycloalkyl is optionally substituted by a substituent selected from methyl or fluoro;
Each R ³ is -C ₁ -C ₄ alkyl,-(C ₁ -C ₄ alkyl) -O- (C ₁ -C
₄ alkyl), _- C 1 -C _{4 fluoroalkyl, -C (O) -O- (C} 1 ~C 4 alkyl), - phenyl, - _heteroaryl, C 3 -C ₇ cycloalkyl, _-CH 2 -N (C ₁ ~
C _{4 alkyl) 2, C (O) -N-} (C 1 ~C 4 _{alkyl) 2,} and -C (O) -NH
Independently selected from-(C ₁ -C ₄ alkyl), or two R ³ together form a ^3- to 8-membered ring or fused phenyl, said saturated ring or fused phenyl from 1 Optionally substituted by two methyl groups;
R ⁴ is hydrogen, —CN, halo, C ₁ -C ₄ alkoxy, —CH ₂ NH (C ₁ -C ₄ alkyl), C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, — (C _1- C ₄ alkyl) -O-
_(C 1 -C _{4 alkyl),} C 1 -C _{4 fluoroalkyl, C (O) -N- (C} 1 ~C 4 _{alkyl) 2, -C (O) -NH-} (C 1 ~C 4 alkyl) _{, -C (O) -O- (C} 1 ~C
₄ alkyl), —C (O) —OH, —S (O) ₂ — (C ₁ -C ₄ alkyl), and 5-membered heteroaryl;
R ⁵ represents —C (O) — (C ₁ -C ₄ alkyl), —C (O) — (CH ₂ ) _0-2- Q, —
^{_{C (O) - (CH 2}} ) 0~2 -N (R 6) - (CH 2) 0~2 -Q, -C (O) -O- (
_{CH 2) 1~2 -Q, -C (} O) - (CH 2) 1~2 -O- (CH 2) 0~2 -Q, -C
_{(O) -C (O) -Q} , -S (O) 2 -Q, -C (O) - (C 1 ~C 4 alkylene) -O
_{-C (O) - (C 1} ~C 4 alkyl), - C (O) - (C 1 ~C 4 alkylene) -C (O
) —O— (C ₁ -C ₄ alkyl), —C (O) —N (R ⁶ ) — (C ₁ -C ₄ alkylene)
_{-O-C (O) - (} C 1 ~C 4 ^{alkyl), - C (O) -N} (R 6) - (C 1 ~C 4 _{alkylene) -C (O) -O- (C} 1 ~C _{4 alkyl), - C (O) -} (CH 2) 0~2 -N
_{^{(R 6) - (C 1}} ~C 6 _{alkyl), - C (O) -} (CH 2) 0~2 -N (R 6) - (C
₂ -C _{6 alkynyl), - C (O) -} (CH 2) 0~2 -N (R 6) - (C 2 ~C 6 alkenyl), - C (O) - (CH 2) 0~2 - N (R ⁶ ) — (CH ₂ ) _0-2- O— (C ₁
-C _{4 alkyl), - C (O) -} (CH 2) 1~2 -O- (C 1 ~C 4 alkyl), - C
_{(O) -O- (C 1 ~C} 4 alkylene) -O- _(C 1 ~C _{4 alkyl),} - _(CH 2) _{0
~4 -O-C (O) -} (C 1 ~C 4 _{alkyl), - (CH 2) 0~4} -C (O) -O- (
C ₁ -C _{4 alkyl), - (CH 2) 0~4} -O- (C 1 ~C 4 alkyl), - C (O)
_{- (CH 2) 1~2 -S- (} C 1 ~C 4 _{alkyl), - S (O) 2} - (C 1 ~C 4 alkyl), - C (O) - (C 1 ~C 4 alkylene) ^{-C (O) C (O)} N (R 6) (C 1 ~C
₆ alkyl), - C (O) - (C 1 ~C 4 _{^{alkylene) -N (R 6) S (}} O) 2 - (C 1
-C ₆ alkyl), and _{-C (O) - (C 1} ~C 4 ^{alkylene) -N (R 6) S (} O)
₂ Selected from Q:
Any alkylene moiety present in R ⁵ is optionally substituted with OH or F;
Any terminal methyl moiety present in R ⁵ is —CH ₂ OH, CF ₃ , —CH ₂ F, —CH
Optionally substituted by ₂ Cl, C (O) CH ₃ , or C (O) CF ₃ ;
Each R ⁶ is independently selected from hydrogen and methyl;
Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
Q is optionally substituted with up to three substituents independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —CN, fluoro, chloro and bromo;
m is 0, 1, 2 or 3.] is provided.

In some embodiments, m is 0, 1 or 2; each R ³ , if present, is independently selected from methyl, ethyl, CF ₃ , isopropyl, cyclopropyl and phenyl. In some embodiments, R ³ is methyl or cyclopropyl. In some embodiments, R ³ is methyl. In some embodiments, R ³ is
Cyclopropyl.

In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, m is 1 and R ³ is C _3-7 cycloalkyl (eg, cyclopropyl). In some embodiments, m is 1 and R ³ is C _1-
C ₄ (alkyl) (eg methyl or isopropyl). In some embodiments, m is 1 and R ³ is haloalkyl (eg, C ₁ -C ₄ fluoroalkyl, eg, CF ₃ ). In some embodiments, m is 2 and one R ³ is C ₁
To ₄ alkyl (eg, methyl) and the other R ³ is halo (eg, fluoro).

In some embodiments, R ⁴ is —CN or —C (O) —O— (C ₁ -C ₄ alkyl). In some embodiments, R ⁴ is CN.

In some embodiments, R ⁴ is


It is. In some embodiments, R ⁴ is


It is.

In some embodiments, Y is —N (R ⁵ ) —CH ₂ — or —CH ₂ —N (R ⁵ ).
R ⁵ is —C (O) —Q and Q is cyclopropyl.

In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) R ¹⁰ ; R ¹⁰ is heteroaryl, aryl, —CH ₂ -aryl, — CH ₂ - heteroaryl, and _{- (CH} 2) is selected from 2 -O-CH _3, any aryl or heteroaryl portion of ^{R 8} is optionally substituted by methyl.

In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C ₁
-C ₅ alkyl), - C (O) - (C 2 ~C 6 alkenyl), - C (O) - (C 0 ~C 2
Alkylene) -Q, -C (O) - (C 1 ~C 4 alkenylene) -Q, -C (O) - (C 0
-C _{2 ^{alkylene) -N (R 6) - (}} C 0 ~C 2 alkylene) -Q, -C (O) - (C 1
-C ₂ alkylene) -O- _(C 0 ~C ₂ alkylene) -Q, -C (O) - (C 1 ~C 4 alkylene) -O-C (O) - (C 1 ~C 4 alkyl), _{-C (O) - (C 1} ~C 4 _{alkylene) -C (O) -O- (C} 1 ~C 4 alkyl), - C (O) - (C 0 ~C 2 alkylene) -N ^{(R 6} )-(C ₁ -C ₆ alkyl), -C (O)-(C ₀ -C ₂ alkylene) N (
_{^{R 6) - (C 2 ~C}} 6 alkynyl), - C (O) - (C 0 ~C 2 alkylene) -N ^{(R 6}
)-(C ₂ -C ₆ alkenyl), -C (O)-(C ₀ -C ₂ alkylene) -N (R ⁶ )-
(C ₀ -C ₂ alkylene) -O— (C ₁ -C ₄ alkyl), — (C ₀ alkylene) -C (
O) O— (C ₁ -C ₄ alkyl), —C (O) — (C ₁ -C ₂ alkylene) —O— (C ₁
-C ₄ alkyl), - C (O) - (C 1 ~C 2 alkylene) -C (O) C (O ) N (R)
(C ₁ -C ₄ alkyl), or —C (O) — (C ₁ -C ₄ alkylene) -C (O) C (
O) selected from N (R ⁶ ) (C ₁ -C ₆ alkyl):
Any alkylene moiety present in R ⁵ is optionally substituted by OCH ₃ , OH or F;
Any terminal methyl moiety present in R ⁵ is —CH ₂ OH, CF ₃ , —CH ₂ F, —CH
₂ Cl, C (O) CH ₃ , C (O) CF ₃ , CN, —OCH ₃ , —C (O) H, —OP (
Optionally substituted by O) (OH) ₂ , —OP (O) (C ₁ -C ₄ alkoxy) ₂ or CO ₂ H;
Each R ⁶ is independently selected from hydrogen and methyl;
Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each member of Q is C ₁ -C ₄ alkyl optionally substituted with OH, C ₁ -C _{4 alkoxy, -C (O) O- (C} 1 ~C 4 alkyl), - _(C 1 ~C ₄ alkylene) - _(C 1 ~C ₄ alkoxy), - CN, -OH, fluoro, Optionally substituted by up to three substituents independently selected from chloro and bromo.

In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C ₁
-C ₃ alkyl) -O- _(C 1 ~C ₂ alkyl), - C (O) -Q , -C (O) - (C 1
-C ₅ alkyl), - C (O) - (C 1 ~C 2 alkylene) -Q, -C (O) - (C 2 ~
C ₄ alkenyl), —C (O) O— (C ₁ -C ₄ alkyl), or —C (O) — (C ₁
It is -C ₄ alkenylene) -Q; any alkylene moiety present in ^{R 5} is optionally substituted by OH; any terminal methyl moiety present in ^{R 5} is -OH, CF
₃ , OCH ₃ , —C (O) H, OP (O) (C ₁ -C ₄ alkoxy) ₂ , or —OP (
Optionally substituted by O) (OH) ₂ (or a salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl Each member of Q is optionally substituted by OH C ₁ -C ₄
Optionally substituted _(C 1 -C ₄ alkoxy), and by one of the substituents independently selected from -OH - _alkyl, C 1 -C ₄ alkoxy, - _(C 1 -C ₄ alkylene).

In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C ₁
-C is a _C3 alkyl) -O- _(C 1 ~C ₂ alkyl). In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (CH ₂ ) ₂ —OCH ₃ . In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) — (C ₁ -C ₃ alkyl) -CF ₃ . In some embodiments, Y is —N (R ⁵ ) — and R ⁵
Is —C (O) —CH ₂ —CF ₃ . In some embodiments, Y is —N (R ⁵ ).
R ⁵ is —C (O) —Q, Q is cyclopropyl, oxetanyl or furanyl. In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C
(O) —CH ₂ —CH ₂ O. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —Q, and Q is substituted with C _1-4 alkoxy.
In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is C _1-4 alkoxy (
For example, -C (O) -cyclopropyl substituted by -ethoxy). In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) —OCH ₃ . In some embodiments, Y is —N (R ⁵ ) —, R ⁵ is —C (O) —Q, and Q is substituted with (C _1-4 alkylene) -OCH _3. ing. In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is substituted with CH ₂ OCH ₃ —
C (O) -cyclopropyl. In some embodiments, Y is —N (R ⁵ ) —, R ⁵ is —C (O) —Q, Q is substituted with C _1-4 alkyl, and alkyl is , -OH is optionally substituted. In some embodiments, Y is-
N (R ⁵ ) —, where R ⁵ is —C (O) -cyclopropyl substituted by CH ₂ OH. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O
) -Q, where Q is substituted by OH. In some embodiments, Y is —N
(R ⁵ ) —; R ⁵ is —C (O) -cyclopropyl substituted by OH. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C
_1-4 alkyl) -OH. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —CH ₂ C (OH) (CH ₃ ) ₂ . In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —CH ₂ CH (OH) CH ₃ . In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —CH _2.
CH ₂ CH ₂ OH. In some embodiments, Y is —N (R ⁵ ) —; R ⁵
Is —C (O) —CH ₂ CH ₂ OH. In some embodiments, Y is —N (R ⁵
R ⁵ is —C (O) — (C ₁ -C ₄ alkyl). In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —CH ₃ . In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C _1-4 alkyl).
- a _{(OCH 3) 2.} In some embodiments, Y is —N (R ⁵ ) —; R ⁵
_{Is, -C (O) -CH 2 CH} 2 C (H) (OCH 3) _2. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C _1-4 alkyl) —C (O).
H. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O).
It is a _{-CH 2 CH 2 C (O)} H. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) —C (cyclopropyl) (OH). In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C _1-4 alkyl) —C (O
) Is a OCH _3. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —
C _(O) a _{-CH 2 CH 2 C (O)} OCH 3. In some embodiments, Y is —N
(R ⁵ ) —, and R ⁵ is —C (O) — (C ₀ -C ₂ alkylene) -Q. In some embodiments, Y is —N (R ⁵ ) —, R ⁵ is —C (O) — (C ₀ -C ₂ alkylene) -Q, and Q is cyclopropyl, cyclobutyl Oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl. In some embodiments, Y is —N (R ⁵ ) — and R ⁵
Is, -C (O) -CH ₂ - oxetanyl, -C (O) -CH ₂ - Azechijinoniru, -C (
O) -CH ₂ - pyrrolidinonyl, -C (O) -CH ₂ - cyclobutyl, -C (O) -CH
₂ - _{cyclopropyl, -C (O) -CH 2 CH} 2 - cyclopropyl, -C (O) -CH ₂
- tetrahydrofuranyl, -C (O) -CH ₂ - dihydrofuranone, -C (O) -CH ₂
CH ₂ - oxetanyl, -C (O) _-CH 2 CH ₂ - furanyl, -C (O) -CH ₂ - tetrahydrofuranyl, -C (O) _-CH 2 CH ₂ - tetrahydrofuranyl or -C (O
) —CH ₂ -cyclopentyl. In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) — (C ₂ -C ₄ alkenyl) —OH. In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) —CH═CH—CH ₂ CH _2.
OH. In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is — (C ₀
-C is a _{4 alkylene) -C (O) -O- (C} 1 ~C 4 alkyl). In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) —O— (t-butyl). In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) — (C ₁
-C _{4 alkyl) -OP (O) (C 1} ~C 4 _{alkoxy) 2.} In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) —CH ₂ CH ₂ CH ₂ —OP (
O) (t-butoxy) ₂ . In some embodiments, Y is —N (R ⁵ ) — and R ⁵ is —C (O) — (C ₁ -C ₄ alkyl) —OP (O) (OH) ₂ or a salt thereof. ,
For example, sodium salt. In some embodiments, Y is —N (R ⁵ ) —
R ⁵ is —C (O) —CH ₂ CH ₂ —OP (O) (t-butoxy) ₂ . In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O) — (C ₁ -C ₅ alkyl). In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is —C (O
) -Pentyl. In some embodiments, Y is —N (R ⁵ ) —; R ⁵ is
A -C (O) - _(C 1 -C ₄ alkenylene) -Q. In some embodiments, Y is
-N ^{(R 5)} - a and; ^{R 5} is -C (O) -CH = cyclobutyl.

In some embodiments, one of R ^1a or R ^1b is selected from hydrogen and methyl; the other of R ^1a or R ^1b is isopropyl, —N (CH ₃ ) — (CH ₂ ) ₂ —NH.
Selected from —CH ₃ , aryl, heteroaryl, —CH ₂ -aryl, —CH ₂ -heteroaryl, —O—CH ₂ -aryl, and —O—CH ₂ -heteroaryl; R ^1a
Or any aryl or heteroaryl of R ^1b is alkoxy, OH, halo, C ₁
-C _{6 alkyl,} optionally substituted -CF 3, CN, by one or more substituents independently selected from -OC (O) CH _3, and -OCF _3.

In some embodiments, one of R ^1a or R ^1b is selected from hydrogen and methyl; the other of R ^1a or R ^1b is aryl, heteroaryl, heterocyclyl, — (C
₁ -C ₄ alkylene) - aryl, - _(C 1 ~C ₄ alkylene) - heteroaryl, -O
- _(C 0 -C ₄ alkylene) - aryl, -O- _(C 0 _{~C 4} alkylene) - heteroaryl, -N ^{(R 7)} - aryl, -N ^{(R 7)} heteroaryl, -N ^{(R 9} ) -Aryl, or —N (R ⁹ ) -heteroaryl, said aryl, heterocyclyl,
Or _{heteroaryl, -G-L-M, CH} 3, CN, alkoxy, OH, halo, _{C 1}
-C _{6 alkyl,} -CF 3, substituted by -OC (O) CH ₃ or -OCF _3,.

In some embodiments, one of R ^1a or R ^1b is selected from hydrogen and methyl; the other of R ^1a or R ^1b is aryl, heteroaryl, heterocyclyl, — (C
₁ -C ₄ alkylene) - aryl, - _(C 1 ~C ₄ alkylene) - heteroaryl, -O
- _(C 0 -C ₄ alkylene) - aryl, -O- _(C 0 _{~C 4} alkylene) - heteroaryl, -N ^{(R 7)} - aryl, -N ^{(R 7)} heteroaryl, -N ^{(R 9} ) - aryl or -N ^{(R 9),} - a heteroaryl, wherein the aryl or heteroaryl is optionally substituted with -G-L-M, CH ₃ or CN,.

In some embodiments, R ^1a is H and R ^1b is aryl, heteroaryl, heterocyclyl, — (C ₁ -C ₄ alkylene) -aryl, — (C ₁ -C ₄ alkylene) -heteroaryl. , —O— (C ₀ -C ₄ alkylene) -aryl, or —O— (C ₀
-C ₄ alkylene) - heteroaryl, -N ^{(R 7)} - aryl, -N ^{(R 7)} heteroaryl, -N ^{(R 9)} - aryl, -N ^{(R 9)} - heteroaryl, said aryl or heteroaryl is substituted by -G-L-M, CH ₃ or CN,. In some aspects of the above embodiments, R ^1a is H and R ^1b is aryl, heteroaryl, heterocyclyl, —CH ₂ -aryl, —CH ₂ -heteroaryl, —O-aryl, —O—. heteroaryl, -O- (CH ₂₎ - _{aryl, -O-CH (CH 3)} - aryl, -O (CH) (C ( CH 3) 2) - _{aryl, -O-CH (CH 2 CH} 3) - aryl, -NH- aryl, -NH- heteroaryl, -N (CH ₃₎ - aryl, -N
(CH ₃₎ - heteroaryl, -N (aryl) - aryl, -N (heteroaryl) -
Heteroaryl, —O— (CH ₂ ) -heteroaryl or —O—CH (CH ₃ ) -heteroaryl, where aryl is phenyl, heteroaryl is pyridyl, pyrimidinyl, naphthyridyl, quinolyl, isoquinolyl, isoxazolyl , Benzoxazolyl, imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrrolopyridinyl,
Pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl, and heterocyclyl is benzodioxol, pyridazinone, benzoxazolone, indolinone, N-methylindolinone, piperazinyl, N- Methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl, said phenyl, pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl, imidazolpyrazinyl, benzothiazolyl, benzoimidazolyl, pyrrolopyridinyl, pyrazolopyridyl Dinyl, indolyl, indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole, pi Dajinon, benzoxazolone, indolinone, N- methyl-indolinone, piperazinyl, N- methyl isobutyl quinolinone, tetrahydropyridinyl,
Or dihydropyrrolyl _{is, -G-L-M, -CF} 3, -OCF 3, halo (e.g., fluoro, chloro or bromo), substituted by CH ₃ or CN,.

In some embodiments, R ^1a is methyl and R ^1b is aryl, heteroaryl, heterocyclyl, —O— (C ₀ -C ₄ alkylene) -aryl, or —O— (C
₀ -C ₄ alkylene) - heteroaryl, said aryl or heteroaryl,
It is substituted by -G-L-M, CH ₃ or CN,. In some aspects of the above embodiments, R ^1a is methyl or H and R ^1b is aryl, heteroaryl, heterocyclyl, —O— (CH ₂ ) -aryl, —O—CH (CH ₃ ) —. Aryl, -O- (
CH ₂ ) -heteroaryl or —O—CH (CH ₃ ) -heteroaryl, where aryl is phenyl or naphthyl, and heteroaryl is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl , Heterocyclyl is tetrahydropyridinyl, said phenyl, pyridyl, pyrimidinyl,
Indolyl or pyrazolyl is, -G-L-M, halo (e.g., chloro or fluoro), substituted by CH ₃ or CN,.

In some embodiments, -GLM is


C ₁ -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 1 -C ₄ alkoxy, hydrogen, tetrazolyl, morpholino, piperazinyl, pyrrolidinone, pyrazolyl, benzyl, - _{(CH 2) 1
˜4-} SH, — (CH ₂ ) _1-4 -NH ₂ , —NH ₂ , — (CH ₂ ) _1-4 -OH, —N
(H) C (O) OCH (CH ₃ ) ₃ , — (CH ₂ ) _1-4 —OCH ₃ , —NH— (CH _{2
) 1~4 -OH, -C (O)} - (C 1 ~C 4 alkyl), - C (O) - (C 1 ~C 4 _{alkenyl), - O- (CH 2)} 1~4 -C ( O) —O— (C ₁ -C ₄ alkyl), —C (O
_{) NH 2, - (CH 2} ) 1~4 C (O) CH 3, -N (CH 3) (CH 3), - NHC (
_{O) (C} 2 ~C _{4 alkenyl), - NHC (O) (} C 2 ~C 4 alkyl), - _SO 2 (C
_{H 2) 1~4, - (CH} 2) 1~4 -NHSO 2 Me, -NHSO 2 (CH 2) 1~4,
_{-O-SO 2 CF 3, -SO} 2 NH- (C 1 ~C 4 _{alkyl), - SO 2 NH- (C} 2
-C _{4 alkenyl),} a SO 2 -NH ₂ or -NHSO ₂ Me.

In some embodiments, R ² is isopropyl, cyclopropyl, cyclohexyl,
And phenyl. In some embodiments, R ² is cyclopropyl. In some embodiments, R ² is isopropyl.

In some embodiments, R ⁴ is CN; Y is —N (R ⁵ ) —; R ⁵ is —C (O) R ¹⁰ ; the compound has the structural formula II:


Or a pharmaceutically acceptable salt thereof [wherein
One of R ^1a or R ^1b is selected from hydrogen and methyl;
The other of R ^1a or R ^1b is aryl, heteroaryl, heterocyclyl, — (C _1-
C ₄ alkylene) - aryl, - _(C 1 ~C ₄ alkylene) - heteroaryl, -O- (
C ₀ -C ₄ alkylene) - aryl, -O- _(C 0 ~C ₄ alkylene) - heteroaryl, -N ^{(R 7)} - aryl, -N ^{(R 7)} heteroaryl, -N ^(R 9) - Selected from aryl, or —N (R ⁹ ) -heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is —GLM, CH ₃ , CN, alkoxy, OH, halo, C ₁ -C
Substituted with ₆ alkyl, —CF ₃ , —OC (O) CH ₃ , or —OCF ₃ ;
R ² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
Each R ³ , if present, is selected from methyl, ethyl, isopropyl, CF ₃ , cyclopropyl and phenyl;
R ¹⁰ is — (C ₁ -C ₃ alkyl) -O— (C ₁ -C ₂ alkyl), Q, (C ₁ -C _5
Alkyl), C 1 _{~C 2} alkylene) _{-Q, (C} 2 ~C ₄ alkenyl), - O- _(C 1 ~
C ₄ alkyl), or — (C ₁ -C ₄ alkenylene) -Q; any alkylene moiety present in R ¹⁰ is optionally substituted with OH; any present in R ¹⁰ terminal methyl _{moiety, -OH, CF 3, OCH 3} , -C (O) H, -OP (O)
(C ₁ -C ₄ alkoxy) ₂ , or —OP (O) (OH) ₂ (or a salt thereof, such as
Is optionally substituted by sodium salt; Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, each member of Q being O
C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, optionally substituted by H,-(C
_1- C ₄ alkylene)-(C ₁ -C ₄ alkoxy), and optionally substituted by one substituent independently selected from —OH;
m is 0, 1, or 2.

In certain embodiments, m is 1; the compound has the structural formula IIa:


Or a pharmaceutically acceptable salt thereof [wherein
R ^1a is hydrogen or methyl;
R ^1b is aryl, heteroaryl, heterocyclyl,-(C ₁ -C ₄ alkylene)-
Aryl, — (C ₁ -C ₄ alkylene) -heteroaryl, —O— (C ₀ -C ₄ alkylene) -aryl, —O— (C ₀ -C ₄ alkylene) -heteroaryl, —N (R ⁷ ) -Aryl, -N (R ⁷ ) heteroaryl, -N (R ⁹ ) -aryl, or -N (R ⁹ )-
Is selected from heteroaryl, said aryl, heterocyclyl or heteroaryl, _{are, -G-L-M, CH} 3, CN, alkoxy, OH, _halo, C 1 -C ₆ alkyl, -CF
₃ , substituted with —OC (O) CH ₃ , or —OCF ₃ ;
R ² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
Each R ³ , if present, is selected from methyl, isopropyl, and cyclopropyl;
R ¹⁰ is — (C ₁ -C ₃ alkyl) -O— (C ₁ -C ₂ alkyl), Q, (C ₁ -C _5
Alkyl), C 1 _{~C 2} alkylene) _{-Q, (C} 2 ~C ₄ alkenyl), - O- _(C 1 ~
C ₄ alkyl), or — (C ₁ -C ₄ alkenylene) -Q; any alkylene moiety present in R ¹⁰ is optionally substituted with OH; any present in R ¹⁰ terminal methyl _{moiety, -OH, CF 3, OCH 3} , -C (O) H, -OP (O)
(C ₁ -C ₄ alkoxy) ₂ , or —OP (O) (OH) ₂ (or a salt thereof, such as
Is optionally substituted by sodium salt; Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, each member of Q being O
C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, optionally substituted by H,-(C
_1- C ₄ alkylene)-(C ₁ -C ₄ alkoxy), and optionally substituted by one substituent independently selected from —OH;
m is 0, 1, or 2.

In some embodiments, R ⁴ is CN; Y is —N (R ⁵ ) —; R ⁵ is —C (O) R ¹⁰ ; the compound has the structural formula II


Or a pharmaceutically acceptable salt thereof [wherein
One of R ^1a or R ^1b is selected from hydrogen and methyl;
The other of R ^1a or R ^1b is isopropyl, —N (CH ₃ ) — (CH ₂ ) ₂ —NH—C
H ₃ , aryl, heteroaryl, —CH ₂ -aryl, —CH ₂ -heteroaryl, —
Selected from O—CH ₂ -aryl, and —O—CH ₂ -heteroaryl; any aryl or heteroaryl moiety of R ^1a or R ^1b is alkoxy, hydroxy, halo, C ₁ -C ₆ alkyl, —CF ₃ , optionally substituted with one or more substituents independently selected from —OC (O) CH ₃ , and —OCF ₃ ;
R ² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
Each R ³ , if present, is selected from methyl, ethyl, isopropyl, cyclopropyl and phenyl;
R ¹⁰ is selected from heteroaryl, aryl, —CH ₂ -aryl, —CH ₂ -heteroaryl, and — (CH ₂ ) ₂ —O—CH ₃ , wherein any aryl or heteroaryl moiety of R ¹⁰ is Optionally substituted by methyl;
m is 0, 1, or 2.

In certain embodiments, m is 1; the compound has the structural formula IIa:


Or a pharmaceutically acceptable salt thereof [wherein
R ^1a is selected from hydrogen and methyl;
R ^1b is selected from aryl and heteroaryl; aryl or heteroaryl is optionally substituted by one or more substituents independently selected from methoxy, fluoro, chloro, methyl, —CF ₃ , —OCF ₃ Has been replaced;
R ² is selected from isopropyl and cyclopropyl;
R ³ is selected from methyl, ethyl, isopropyl and cyclopropyl;
R ¹⁰ is selected from — (CH ₂ ) ₂ —O—CH ₃ , furan-3-yl, 2-methylfuran-3-yl and thien-2-yl.

In some embodiments, R ⁴ is CN; Y is —N (R ⁵ ) —; R ⁵ is —C (O) R ¹⁰ ; the compound has the structural formula II:


Or a pharmaceutically acceptable salt thereof [wherein
R ^1a is H;
R ^1b is aryl, heteroaryl, —O— (C ₁ -C ₄ alkylene) -aryl, or —O— (C ₁ -C ₄ alkylene) -heteroaryl, wherein the aryl or heteroaryl is —G -L-M, CH ₃ or substituted by CN,;
R ² is selected from isopropyl, cyclopropyl, cyclohexyl, and phenyl;
Each R ³ , if present, is selected from methyl, ethyl, isopropyl, cyclopropyl and phenyl;
R ¹⁰ is selected from heteroaryl, aryl, —CH ₂ -aryl, —CH ₂ -heteroaryl, and — (CH ₂ ) ₂ —O—CH ₃ , wherein any aryl or heteroaryl moiety of R ¹⁰ is Optionally substituted by methyl;
m is 0, 1, or 2.

In certain embodiments, m is 1; the compound has the structural formula IIa:


Or a pharmaceutically acceptable salt thereof [wherein
R ^1a is H;
R ^1b is aryl, heteroaryl, —O— (CH ₂ ) -aryl, —O—CH (CH
₃ ) -aryl, —O— (CH ₂ ) -heteroaryl or —O—CH (CH ₃ ) -heteroaryl, where aryl is phenyl, heteroaryl is pyridyl, pyrimidinyl, indolyl, or pyrazolyl There, it said phenyl, pyridyl, pyrimidinyl, indolyl or pyrazolyl is substituted by -G-L-M, CH ₃ or CN,;
R ² is selected from isopropyl and cyclopropyl;
R ³ is selected from methyl, ethyl, isopropyl and cyclopropyl;
R ¹⁰ is selected from — (CH ₂ ) ₂ —O—CH ₃ , furan-3-yl, 2-methylfuran-3-yl and thien-2-yl.

In another embodiment, the compound is selected from any one of the compounds listed in Table 1 below.

In another embodiment, the compound is selected from any one of the compounds listed in Table 5 below.

The compounds of the present invention may contain one or more asymmetric centers and thus racemates, racemic mixtures, enantiomeric scaleable mixtures, and diastereomeric mixtures, as well as other possible enantiomers or stereoisomers. Can occur as a single enantiomer or an individual stereoisomer substantially free of As used herein, the term “substantially free of other stereoisomers” means that a compound having a selected stereochemistry at one or more selected stereocenters is at least about 60%, 65% 70%, 75%, 80%, 85%, 90%, 9
A preparation that is concentrated by 5%, 96%, 97%, 98%, or 99%. The term “enriched” means that at least the indicated proportion of the preparation is a compound having a selected stereochemistry at one or more selected stereocenters. Methods for obtaining or synthesizing individual enantiomers or stereoisomers for a given compound are well known in the art and can be applied as usable in the final compound or starting material or intermediate.

Compounds of formula I, II and IIa may also contain one or more isotopic substitutions. For example, H can be in any isotopic form, for example ¹ H, ² H (D or deuterium), and ³ H (T or tritium); C is in any isotopic form, for example ¹² May be C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, such as ¹⁶ O and ¹⁸ O, and the like.

Unless otherwise stated, a disclosed compound is named or expressed by structure and has one or more chiral centers, with no stereochemistry defined, and represents all possible stereoisomers of the compound Please understand.

The compounds of the invention may also be represented in multiple tautomeric forms, in such examples
Even though only a single tautomeric form can be represented, the present invention explicitly includes all tautomeric forms of the compounds described herein (eg, alkylation of ring systems is It can result in alkylation at multiple sites, and the present invention explicitly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are disclosed in Berge et al. , 1977, “Pharmaceutically.
Acceptable Salts. "J. Pharm. Sci. Vol. 66, pp.
. 1-19.

For example, if the compound is anionic, or anionic, which may be a functional group (eg, -COOH may be -COO ^- is obtained a), then a form a salt with a suitable cation it can. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺
And Mg ²⁺ , as well as other cations such as Al ³⁺ . Examples of suitable organic cations include, but are not limited to ammonium ions (ie NH
₄ ⁺ ) and substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ²⁺ , NHR ³⁺
, NR ⁴⁺ ). Examples of some suitable substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and amino acids such as , Derived from lysine and arginine. An example of a common quaternary ammonium ion is N (CH ₃ ) ₄ ⁺ .

If the compound is cationic, or a functional group that can be cationic (eg, —NH
₂ When having is obtained) is -NH ₃ ^+, can form a salt with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, Phosphoric acid and phosphorous acid.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic acid,
Acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, Hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucin acid, oleic acid, oxalic acid, palmitic acid, pamonic acid,
Pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

  Unless otherwise stated, a reference to a particular compound includes its salt form.

Compositions and Routes of Administration The compounds used in the methods described herein are formulated into a pharmaceutically acceptable composition together with a pharmaceutically acceptable carrier or adjuvant prior to administration to a subject. be able to. In another embodiment, such pharmaceutically acceptable compositions further comprise an amount of an additional therapeutic agent effective to achieve modulation of the disease or symptom, such as those described herein. Including.

The term “pharmaceutically acceptable carrier or adjuvant” can be administered to a subject together with a compound of the present invention at a dosage sufficient to deliver a therapeutic amount of the compound without impairing its pharmacological activity. Refers to a carrier or adjuvant that is non-toxic when administered.

Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugs. Delivery system (SEDDS), eg d-α
-Tocopherol polyethylene glycol 1000 succinate, surfactant used in pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine Sorbic acid, potassium sorbate, vegetable saturated fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,
Colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate,
Mention may be made of partial glyceride mixtures of waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins such as 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives Can also be advantageously used to improve delivery of compounds of the formulas described herein.

The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. Preferably, it can be administered by oral administration or administration by injection. The pharmaceutical composition of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.
In some examples, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base or buffer to improve the stability of the compound or its delivery form. The term parenteral as used herein includes, when relevant, subcutaneous, intradermal, intravenous, intramuscular, intraarticular,
Intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques are included.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. Sterile injectable preparations are sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents,
For example, it can be a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. Useful. These oils or suspensions are long-chain alcohol diluents or dispersants, or carboxymethylcellulose, or similar ones commonly used in formulating pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. A dispersant may also be included. Other commonly used surfactants such as T
Use for the purpose of formulation of ween or span and / or other similar emulsifiers or bioavailability improvers commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms You can also.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. Can do. In the case of tablets for oral use, commonly used carriers are:
Examples include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in the oily phase and combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

The pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration. These compositions mix the compounds of the invention with suitable nonirritating excipients that are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the active compound. Can be prepared. Such materials are not limited,
Examples include cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical composition of the invention is useful when the desired treatment involves an area or organ that is easily accessible by topical application. For topical application to the skin, the pharmaceutical composition must be formulated with a suitable ointment containing the active compound suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the invention can also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically transdermal patches are also included in the present invention.

The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or in the art. It can be prepared as a solution in physiological saline using other known solubilizers or dispersants.

Where a composition of the invention comprises a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent are normally administered in a monotherapy regimen. It should be present at a dosage level of about 1 to 100%, more preferably about 5 to 95% of the dosage. Additional agents can be administered separately from the compounds of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form mixed with a compound of the invention in a single composition.

The compounds described herein may be administered at doses ranging from, for example, about 0.5 to about 100 mg / kg body weight, or at doses of 1 mg to 1000 mg / dose every 4 to 120 hours, or as specified Orally, buccal, nasal, transmucosal, topical by intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous injection; or in eye drops or by inhalation, depending on drug requirements Can be administered. The methods herein contemplate administration of an effective amount of a compound or composition of compounds to achieve a desired or defined effect. Typically, the pharmaceutical compositions of this invention are administered from about 1 to about 6 times per day, or as a continuous infusion. Such administration can be used as a long-term or emergency treatment. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the recipient treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w
). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimen for any particular subject will depend on various factors such as the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, excretion rate Depending on the combination of drugs, the severity and course of the disease, condition or symptom, the disease, condition or symptom trend of the subject, and the judgment of the attending physician.

Once the condition of the subject has improved, a maintenance dose of a compound, composition or combination of the invention can be administered as needed. Subsequently, depending on the symptoms, the dose and / or frequency of administration can be reduced to a level at which the improved pathology is retained when the symptoms are alleviated to the desired level. However, the subject will have a relapse of any symptom,
Intermittent treatment may be required on a long-term basis.

The pharmaceutical composition described above comprising a compound of structural formula I, II or IIa or a compound according to any one of the embodiments herein may further comprise another therapeutic agent useful for the treatment of cancer.

Methods of Use In a method of inhibiting mutant IDH1 activity, a subject in need of inhibition includes a compound of structural formula I, II or IIa, a compound according to any one of the embodiments herein, or There is provided a method comprising contacting a pharmaceutically acceptable salt thereof. In one embodiment, the cancer to be treated is R (−) of α-ketoglutarate in the subject with an IDH1 mutation.
It features a mutant allele of IDH1 that provides a new ability of the enzyme to catalyze NAPH-dependent reduction to 2-hydroxyglutaric acid. In one aspect of this embodiment, the mutant IDH1 has an R132X mutation. In one aspect of this embodiment, R1
The 32X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G. In another embodiment, the R132X mutation is R132H or R132C. In yet another embodiment, the R132X mutation is R132H.

In a method of treating cancer characterized by the presence of a mutant allele of IDH1, the subject in need of such treatment includes (a) Structural Formula I, II or IIa, any one of the embodiments herein. There is also provided a method comprising administering a pharmaceutical composition comprising a compound according to one or a pharmaceutically acceptable salt thereof or (b) (a) and a pharmaceutically acceptable carrier.

In one embodiment, the cancer to be treated is IDH1 wherein the IDH1 mutation results in a new ability of the enzyme to catalyze NAPH-dependent reduction of α-ketoglutarate to R (−)-2-hydroxyglutarate in the patient. Characterized by a mutant allele. In one aspect of this embodiment, the IDH1 mutation is an R132X mutation. In another aspect of this embodiment, the R132X mutation is R132H, R132C, R132L, R132V, R13.
Selected from 2S and R132G. In another embodiment, the R132X mutation is R1
32H or R132C. Cancer is determined by sequencing a cell sample and amino acid 13 of IDH1.
It can be analyzed by determining the presence and defined nature of the mutation in 2 (eg, the change in amino acids present in the mutation).

Without being bound by theory, Applicants have shown that the IDH1 mutation has a new ability of the enzyme to catalyze NAPH-dependent reduction of α-ketoglutarate to R (−)-2-hydroxyglutarate. The resulting mutant allele of IDH1, particularly the R132H mutation of IDH1, is thought to characterize a subset of all types of cancer regardless of the cellular nature of the cancer or its localization in the body. Accordingly, the compounds and methods of the present invention provide I that confer such activity.
It is useful for treating any type of cancer characterized by the presence of a mutant allele of DH1, particularly the IDH1R132H or R132C mutation.

In one aspect of this embodiment, the efficacy of cancer treatment is monitored by measuring 2HG levels in the subject. Typically, 2HG levels are measured before treatment, and elevated levels indicate the use of compounds of formula I to treat cancer. When an increase in level is confirmed,
To confirm efficacy, 2HG levels are measured during the course of treatment and / or after the end of treatment. In certain embodiments, 2HG levels are measured only during the course of treatment and / or after the end of treatment. Reduction of 2HG levels during and after the course of treatment indicates efficacy. Similarly, a determination that 2HG levels do not rise during or after the treatment is also indicative of efficacy.
Typically, these 2HG measurements are other well-known methods of determining the efficacy of cancer treatment, such as reducing the number and size of tumors and / or other cancer-related lesions, improving the general health of the subject, and cancer Used in conjunction with other biomarker changes associated with therapeutic efficacy.

2HG can be detected in a sample by LC / MS. Sample is methanol and 8
Mix at 0:20 and centrifuge at 3,000 rpm for 20 minutes at 4 degrees Celsius.
The resulting supernatant was collected and stored at -80 degrees Celsius and then 2-by LC-MS / MS.
Hydroxyglutaric acid levels can be assessed. A variety of different liquid chromatography (LC) separation methods can be used. Each method involves negative electrospray ionization (E) on a triple to quadrupole mass spectrometer operating in multiple reaction monitoring (MRM) mode with MS parameters optimized for the injected metabolite standard solution.
SI, −3.0 kV). Metabolites can be obtained using previously reported methods (Luo et al. J Chromatogr A 1147, 153-64, 2
007) can be separated by reverse phase chromatography using 10 mM tributyl-amine as an ion pairing agent in an aqueous mobile phase. One method allows degradation of TCA metabolites: t = 0, 50% B; t = 5, 95% B;
t = 7, 95% B; t = 8, 0% B, where B refers to an organic mobile phase of 100% methanol. Another method is specific for 2-hydroxyglutaric acid and runs a fast linear gradient of 50% to 95% B (buffer as defined above) over 5 minutes. As above, Sy
nergi Hydro-RP, 100 mm × 2 mm, 2.1 μm particle size (Phen
omonex) can be used as the column. Metabolites can be quantified by comparing peak areas to known concentrations of pure metabolite standards. Metabolite flux studies from ¹³ C-glutamine are described, for example, in Munger et al. Nat
Biotechnol 26, 1179-86, 2008 can be performed.

  In one embodiment, 2HG is assessed directly.

In another embodiment, 2HG derivatives formed in the course of performing the analytical method are evaluated. As an example, such a derivative may be a derivative formed in MS analysis. Derivatives can include salt adducts such as Na adducts, hydration variants, or hydration variants that are also salt adducts such as Na adducts as formed, for example, in MS analysis.

In another embodiment, metabolic derivatives of 2HG are evaluated. Examples include species that accumulate or increase or decrease as a result of the presence of 2HG, eg 2HG, eg R-2H
Glutaric acid or glutamic acid correlated with G can be mentioned.

Exemplary 2HG derivatives include dehydrated derivatives such as the compounds provided below or salt adducts thereof:

In one embodiment, the cancer is at least 30, 40, 5 of the tumor cells at the time of diagnosis or treatment.
0, 60, 70, 80 or 90% are tumors carrying IDH1 mutations, in particular IDH1R132H or R132C mutations.

The IDH1R132X mutation is known to occur in certain types of cancer as shown in Table 2 below.

IDH1R132H mutations are found in glioblastoma, acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)
), Colon cancer, and blood immunoblastic non-Hodgkin lymphoma (NHL). Thus, in one embodiment, a method described herein comprises a glioma (glioblastoma), acute myeloid leukemia, sarcoma, melanoma, non-small cell lung cancer (NSCLC) or bile duct cancer in a patient, Used to treat chondrosarcoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) or colon cancer.

Thus, in one embodiment, the cancer is a cancer selected from any one of the cancer types listed in Table 2, and the IDHR132X mutation is Table 2 for that particular cancer type.
One or more of the IDHR132X mutations listed in

The treatment methods described herein comprise various evaluation steps before and / or after treatment with a compound of structural formula I, II or IIa or a compound according to any one of the embodiments described herein. Further may be included.

In one embodiment, before and / or after treatment with a compound of structural formula I, II or IIa or a compound according to any one of the embodiments described herein, the method comprises the following: And further assessing weight, invasiveness, stage and / or other phenotype.

In one embodiment, before and / or after treatment with a compound of formula I or Ia or a compound according to any one of the embodiments described herein, the method comprises the identification of cancer.
Further comprising the step of evaluating the H1 genotype. This can be accomplished by routine methods in the art, such as DNA sequencing, immunoassay, and / or assessment of the presence, distribution or level of 2HG.

In one embodiment, before and / or after treatment with a compound of formula I or Ia or a compound according to any one of the embodiments described herein, the method comprises measuring 2HG levels in a subject. The method further includes a step of measuring. This is achieved by spectroscopic analysis, eg magnetic resonance based analysis, eg MRI and / or MRS measurements, sample analysis of body fluids, eg serum or spinal fluid analysis, or analysis of surgical materials, eg mass spectrometry. be able to.

Combination therapies In some embodiments, the methods described herein can be applied to a subject in need thereof for a second.
Treatment, eg, an additional step of co-administering an additional cancer therapeutic agent or additional cancer treatment. Exemplary additional cancer therapeutic agents include, for example, chemotherapy, targeted therapy, antibody therapy, immunotherapy, and hormone therapy. Additional cancer treatments include, for example, surgery and radiation therapy. Examples of each of these treatments are provided below.

The term “co-administration” as used herein with respect to an additional cancer therapeutic agent refers to an additional cancer therapeutic agent, together with a compound of the present invention, in a single dosage form (eg, a compound of the present invention and the second Means that it can be administered as part of a composition of the present invention comprising a therapeutic agent) or as separate dosage forms. Alternatively, the additional cancer therapeutic agent can be administered before, simultaneously with, or after administration of the compound of the present invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent are administered by conventional methods.
Administration of a composition of the present invention comprising both a compound of the present invention and a second therapeutic agent to a subject may include that same therapeutic agent, any of the subject, at another time during the course of treatment. It does not preclude separate administration of the other second therapeutic agent or any of the compounds of the present invention. The term “simultaneous administration” as used herein in connection with an additional cancer treatment refers to an additional cancer treatment prior to administration of a compound of the invention, consecutively with administration, simultaneously with administration, or administration. It means that it can be done later.

In some embodiments, the additional cancer therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents used in cancer treatment include, for example, antimetabolites (eg, folic acid, purine, and pyrimidine derivatives), alkylating agents (eg, nitrogen mustard, nitrosourea, platinum, alkyl sulfonates, Hydrazine, triazene, aziridine, spindle poison, cytotoxic agent, topoisomerase inhibitor, etc.) and hypomethylating agent (decitabine (5-aza-deoxycytidine), zebralin, isothiocyanate, azacitidine (5-azacytidine),
5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine, etc.). Exemplary drugs include aclarubicin, actinomycin, alitretinoin, artretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, Camptothecin, capecitabine, carboplatin, carbocon, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, chrysantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, celitadine, decitabine, decitabine Doxorubicin,
Efaproxiral, elescromol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucid, etoposide, floxuridine, fludarabine,
Fluorouracil (5FU), fotemustine, gemcitabine, Gliadel brain indwelling agent, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubiculosin
Mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitoblonitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omecetaxin, oltaxane, oxaliplatin, paclitaxel Gauze, pemetrexed, pentostatin, pirarubicin, pixantrone, pricamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semastine, citimadine seradenobec, strataplatin (Stratatraplain) Porphine, tegafur-uracil, temoporphy , Temozolomide, teniposide, tesetaxel, test lactone, tetranitrate, thiotepa, thiazofurin, thioguanine, tipifarnib, topotecan, trabectadine, triazicon, triethylenemelamine, triplatin, tretinoin, treosulphane, trophosphamide, uramucin, vertulbin Vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, more than one drug is often given simultaneously. Two or more chemotherapeutic agents are often used as combination chemotherapy.

In some embodiments, the additional cancer therapeutic agent is a differentiation agent. Such differentiation agents include retinoids (eg, all-trans-retinoic acid (ATRA), 9-cis retinoic acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide (4-HPR). )); Arsenic trioxide; histone deacetylase inhibitors HDACs (eg azacytidine (Vidaza) and butyrate (eg sodium phenylbutyrate)); hybrid polar compounds (eg hexamethylenebisacetamide ((HM)
BA)); vitamin D; and cytokines (eg, colony stimulating factors such as G
-CSF and GM-CSF, and interferon).

In some embodiments, the additional cancer therapeutic agent is a targeted therapeutic agent. Targeted therapy constitutes the use of drugs specific for cancer cell dysregulated proteins. Small molecule targeted therapies are generally inhibitors of enzyme domains on mutations, overexpression, or otherwise important proteins in cancer cells. Prominent examples are tyrosine kinase inhibitors, such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, restaurtinib, nilotinib, cemaksanib, sorafenib, sunitinib, and even the vandetanib inhibitor For example, arbocidib and sericivib. Monoclonal antibody therapy is another policy where the therapeutic agent is an antibody that specifically binds to a protein on the surface of the cancer cell. Examples include the anti-HER2 / neu antibody trastuzumab typically used in breast cancer (HERCEPTIN®), and the anti-CD20 antibodies rituximab and tositumomab typically used in various B cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, the targeted therapy is a compound described herein, such as a biguanide, such as metformin or phenformin,
Preferably it can be used in combination with phenformin.

Targeted therapies can also include small peptides as “homing devices” that can bind to cell surface receptors or diseased extracellular matrix surrounding the tumor. These peptides (for example,
The radionuclide attached to RGD) eventually kills the cancer cell when the nuclide decays in the vicinity of the cancer cell. An example of such a treatment is BEXAR®.

In some embodiments, the additional cancer therapeutic agent is an immunotherapeutic agent. Cancer immunotherapy refers to a diverse set of treatment strategies designed to induce the subject's own immune system and resist tumors. Modern methods of generating an immune response against tumors include intravesicular BCG immunotherapy against superficial bladder cancer and the use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma subjects. It is done.

Allogeneic hematopoietic stem cell transplantation can be considered as a form of immunotherapy because donor immune cells often attack tumors with graft-versus-tumor effects. In some embodiments,
Immunotherapeutic agents can be used in combination with the compounds or compositions described herein.

In some embodiments, the additional cancer therapeutic agent is a hormone therapy agent. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone sensitive tumors include certain types of breast cancer and prostate cancer. Estrogen or testosterone removal or blockage is often an important additional treatment. In certain cancers, administration of hormone agonists such as progestogens may be beneficial for treatment.
In some embodiments, the hormonal therapy agent can be used in combination with a compound or composition described herein.

Other possible additional therapeutic modalities include imatinib, gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.

In the following examples, reagents are obtained from commercial sources (eg, Alfa, Acros, Si
gma Aldrich, TCI and Shanghai Chemical Reag
ent Company) and used without further purification. Flash chromatography uses E-columns with 200-300 mesh silica gel particles.
Performed on z Purifier III. Analytical and preparative thin-layer chromatography plates (TLC) were used for HSGF254 (thickness 0.15-0.2 mm, Shanghai).
(Angbang Company, China). Nuclear magnetic resonance (NMR) spectra were obtained from a Brucker AMX-400 NMR (Brucker, Switzerland)
obtained by d). Chemical shift is expressed in parts per million (ppm,
reported in δ). The mass spectrum was measured using a Waters LCT TOF mass spectrometer (Wat
ers, USA) by electrospray ionization (ESI). HPL
C chromatograph is a compound AGIlent 1200 liquid chromatography (compound A
GIlent, USA, column: Ultimate 4.6 mm × 50 mm, 5 μM, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). The microwave reaction was performed on an Initiator 2.5 microwave synthesizer (Biotage, Sweden).

For exemplary compounds disclosed in this section, stereoisomer (eg, (R) or (S) stereoisomer) specifications are such that the compound is at least about 90% at a defined stereocenter,
The preparation of that compound is shown to be concentrated by 95%, 96%, 97%, 98%, or 99%.

Example 1
(R) -5-Bromo-6-isopropyl-2- (4- (3-methoxypropanoyl)-
Preparation of 3-methylpiperazin-1-yl) nicotinonitrile. (R) -5-bromo-6-
Isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine-1-
Yl) nicotinonitrile (7, wherein R ^1a is hydrogen; m is 1; R ³ is
3-methyl; R ⁸ is methoxyethyl) was prepared according to the following general scheme 1.
Scheme 1:

Step A: 1- (Dimethylamino) -4-methylpent-1-en-3-one (2)
. 150 m of commercially available 3-methylbutan-2-one (1; 8.613 g, 100 mmol)
To a solution of L in anhydrous DMF, commercially available 1,1-dimethoxy-N, N-dimethylmethanamine (
29.80 g, 250 mmol) was added. The resulting mixture was stirred at 100 ° C. overnight. After removal of DMF and excess acetal, 14 g of the title compound was obtained as a crude product and used in subsequent reactions without further purification. 1H NMR (chloroform-d) δ 7.57 (d, J = 12.8 Hz, 1H), 5.05
(D, J = 12.5 Hz, 1H), 2.80-3.10 (m, 6H
), 2.56 (dt, J = 13.7, 6.8 Hz, 1H), 1.06
-1.14 (m, 6H).

Step B: 6-Isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3). 8.8 g of 1- (dimethylamino) -4-methylpent-1-en-3-one (2; 62 mmol) and 5.3 g of commercially available cyanoacetamide (62 mmol) in 24 mL of H ₂ O Treated with 7 mL acetic acid, 1.8 mL H ₂ O, and a premixed buffer solution of piperidine sufficient to make the buffer solution basic. The resulting solution was refluxed for 2 hours and LC-MS showed formation of the desired product. After cooling to room temperature, the mixture was acidified with glacial acetic acid and a brownish yellow precipitate was formed. The filter cake was washed with H ₂ O and air dried to give 6.5 g of the title compound. MS (ES) M + H predicted value 163
. 1. Actual value 163.0. 1H NMR (DMSO-d6) δ 12.51 (br
. s. , 1H), 7.96-8.18 (m, 1H), 6.24 (d,
J = 7.5 Hz, 1H), 2.83 (spt, J = 6.9 Hz,
1H), 1.19 (s, 29H), 1.17 (s, 3H).

Step C: 5-Bromo-6-isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (4). 2-hydroxy-6-isopropylnicotinonitrile (3
To a solution of 3.0 g, 19 mmol) in 50 mL DCE, NBS (5 g, 28 mmol)
) Was added at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed that the reaction was complete, the mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (4% MeOH / DCM) gave 3.9 g of the title compound as a brown solid. MS (ES) M + H predicted value 241.0, measured value 240.9. 1H NMR (DM
SO-d6) δ 12.58 (br. S., 1H), 8.38 (s, 1H
), 3.25-3.32 (m, 1H), 1.23 (s, 3H), 1.
21 (s, 3H).

Step D: 5-Bromo-3-cyano-6-isopropylpyridin-2-yl trifluoromethanesulfonate (5). To a solution of 5-bromo-2-hydroxy-6-isopropylnicotinonitrile (4; 2.0 g, 8 mmol) in 20 mL of methylene chloride was added DMAP.
(100 mg, 0.8 mmol), and triethylamine (1.01 g, 10 mmol)
) Was added. The mixture was cooled to 0 ° C. in an ice-water bath and trifluoromethanesulfonic anhydride (
2.82 g, 10 mmol) was added dropwise by syringe. The resulting reaction mixture was stirred at 0 ° C. for 30 minutes before it was allowed to warm to room temperature and stirred for an additional 2 hours. TLC
After complete conversion of the starting material into the product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc / petroleum ether) to give 2.8 g of the title compound. 1H NMR (chloroform-d) δ 8.22 (s, 1H), 3.5
7 (spt, J = 6.7 Hz, 1H), 1.28 (d, J = 6.
8 Hz, 6H).

Step E: (R) -5-Bromo-6-isopropyl-2- (3-methylpiperazine-
1-yl) nicotinonitrile (6). Triflate 5 (1.68 g, 4.5 mmol)
), (R) -2-methylpiperazine (770 mg, 6.77 mmol), and triethylamine (1.9 mL, 13.5 mmol) suspended in 5 mL of MeCN were subjected to microwave reaction at 175 ° C. at 45 ° C. Served for a minute. After the mixture was concentrated in vacuo, the residue was purified by column chromatography (10% DCM / MeOH) to give 0.91.
g of the title compound was obtained as a pale yellow solid. MS (ES) M + H predicted value 323.1, found value 323.0. 1H NMR (chloroform-d) δ 7.79 (s, 1H),
4.35-4.40 (m, 0.5H), 4.32-4.35 (m,
1H), 4.30 (t, J = 2.4 Hz, 0.5H), 3.37 −
3.45 (m, 1H), 3.08-3.13 (m, 0.5H), 3.0
5-3.08 (m, 1H), 3.04 (d, J = 2.5 Hz, 0
. 5H), 2.96-3.01 (m, 1H), 2.89-2.96 (
m, 1H), 2.65-2.74 (m, 1H), 1.21 (dd, J
= 6.8, 0.8 Hz, 6H), 1.13 (d, J = 6.3 Hz)
, 3H).

Step F: (R) -5-Bromo-6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (7). In a 25 mL round bottom flask was added (R) -5-bromo-6-isopropyl-2- (3-methylpiperazine-
1-yl) nicotinonitrile (6; 680 mg, 2.1 mmol), 3-methoxypropanoic acid (438 mg, 4.2 mmol), HATU (1.6 g, 4.2 mmol), DIP
EA (1.1 mL, 6.31 mmol) and 5 mL of methylene chloride were added. The resulting reaction mixture was stirred at room temperature for 4 hours until TLC indicated that the reaction was complete. Saturated Na
After washing with HCO ₃ , brine, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (20% EtOAc / petroleum ether) gave 550 mg of the title compound as a pale yellow solid. MS (ES) M + H predicted value 409.1, found value 409.0. 1H NMR (chloroform-d) δ 7.8
3 (s, 1H), 4.90 (br. S., 0.5H), 4.52 (d,
J = 12.3 Hz, 0.5H), 4.19-4.39 (m, 3H)
, 3.76-3.85 (m, 0.5H), 3.73 (t, J = 6.
4 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (
s, 3H), 3.25-3.35 (m, 1H), 3.02--3.20
(M, 1H), 2.63-2.80 (m, 1H), 2.51-2.
61 (m, 1H), 1.35 (d, J = 7.0 Hz, 1.5H),
1.25 (d, J = 6.3 Hz, 1.5H), 1.21-1.23
(M, 3H), 1.19-1.21 (m, 3H)

The other intermediate 7 is prepared by similar steps according to Scheme 1: (1) Step E
(R) -2-methylpiperazine in was replaced with an alternatively substituted or unsubstituted piperazine; and / or (2) 3-methoxypropanoic acid in Step F was replaced with an alternative acid.

Example 2
(R) -5-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
Preparation of -3-methylpiperazin-1-yl) nicotinonitrile. (R) -5-Bromo-6
-Cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine-
1-yl) nicotinonitrile (17; where R ^1a is hydrogen; R ² is cyclopropyl; m is 1, R ³ is 3-methyl; R ⁸ is Methoxyethyl) was prepared according to the following general scheme 2.
Scheme 2:

Step L: 1-Cyclopropyl-3- (dimethylamino) prop-2-en-1-one (12). Commercially available 1-cyclopropylethanone (11; 8.584 g, 100 mmol
) In 200 mL anhydrous DMF was added 1,1-dimethoxy-N, N-dimethylmethanamine (29.80 g, 250 mmol). The resulting mixture was stirred at 100 ° C. overnight. After removal of DMF and excess acetal, 13.9 g of the title compound was obtained as a crude product and used in subsequent reactions without further purification. 1H NMR
(Chloroform-d) δ 7.56 (d, J = 12.8 Hz, 1H),
5.20 (d, J = 12.5 Hz, 1H), 2.78-3.08 (
m, 6H), 1.79 (tt, J = 7.9, 4.5 Hz, 1H),
0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H)
.

Step M: 6-Cyclopropyl-2-hydroxynicotinonitrile (13). 10m
3.532 g 1-cyclopropyl-3- (dimethylamino) prop-2 in L H ₂ O
-En-1-one 12 and 2.032 g cyanoacetamide with 0.33 mL acetic acid, 0.82 mL H ₂ O, and a sufficient amount of piperidine premixed buffer solution to make the solution basic. Processed. The resulting solution was refluxed for 2 hours and LC-MS showed formation of the desired product 13. After cooling to room temperature, the mixture was acidified with glacial acetic acid to form a brownish yellow precipitate. Filter the thick brown slurry and wash the filter cake with H ₂ O;
Air drying gave 1.30 g of the title compound. MS (ES) M + H predicted value 161.1, found value 161.0. 1H NMR (chloroform-d) δ 13.60 (br. S.
, 1H), 7.77 (d, J = 7.8 Hz, 1H), 5.91 (d
, J = 7.8 Hz, 1H), 1.96-2.12 (m, 1H),
1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H)
.

Step N: 5-Bromo-6-cyclopropyl-2-hydroxynicotinonitrile (1
4). 6-cyclopropyl-2-hydroxynicotinonitrile (13; 0.32 g, 2.
0 mL) in 5 mL of DCE was added NBS (0.534 g, 3.0 mmol) at room temperature. The reaction mixture was heated at reflux for 3 hours. After LC-MS showed that the reaction was complete, the reaction mixture was cooled to room temperature and poured into water. After extraction with methylene chloride (3 × 5 mL), the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (4% MeOH / DCM) gave 0.45 g of 14. MS
(ES) M + H predicted value 239.0, measured value 238.9. 1H NMR (chloroform-
d) δ 8.49-8.72 (br. s., 1H), 7.93 (s, 1H)
, 2.23-2.34 (m, 1H), 1.36-1.42 (m, 2
H), 1.29-1.36 (m, 2H).

Step O: 5-Bromo-3-cyano-6-cyclopropylpyridin-2-yl trifluoromethanesulfonate (15). 5-Bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14; 0.45 g, 1.882 mmol in 10 mL of methylene chloride.
), DMAP (23.2 mg, 0.19 mmol), and triethylamine (0.2
47 g, 2.45 mmol) was added. The mixture was cooled to 0 ° C. in an ice-water bath and trifluoromethanesulfonic anhydride (0.69 g, 2.45 mmol) was added dropwise via a syringe. The resulting reaction mixture was stirred at 0 ° C. for 30 minutes and then allowed to warm to room temperature,
Stir for another 2 hours. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% ethyl acetate / petroleum ether) to give 537 mg of 15. 1H NMR (chloroform-d) δ 8.14
-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.3
0 (dt, J = 7.8, 3.1 Hz, 2H), 1.21-1.27
(M, 2H).

Step P: (R) -5-Bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (16). Triflate 15 (1.68g, 4.6m)
mol), (R) -2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9 mL, 13.8 mmol) suspended in 5 mL of MeCN were subjected to microwave reaction at 175 ° C. Served for 60 minutes. The mixture was concentrated under reduced pressure and the residue was extracted between ethyl acetate and water. The combined organic layers were then combined with aqueous NaHCO ₃ ,
Washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give 1.26 g of composition 16. MS (ES) M + H predicted value 321.1, measured value 321.2. 1H
NMR (chloroform-d) δ 7.78 (s, 1H), 4.14-4.
24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-
3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71
(Dd, J = 12.9, 10.2 Hz, 1H), 2.42-2.52
(M, 1H), 1.16 (d, J = 6.3 Hz, 3H), 1.08
(S,, 2H), 1.07 (d, J = 3.8 Hz, 2H).

Step Q: (R) -5-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (17). 25 mL
In a round bottom flask, (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (16; 1.26 g, 3.9 mmol), 3-methoxypropane Acid (0.74 mL, 7.8 mmol), HATU (2.98 g, 7.8 mmol)
l), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylene chloride were added. The resulting reaction mixture was stirred overnight at room temperature until TLC indicated complete reaction.
The reaction mixture was washed with saturated NaHCO ₃ and brine. The combined organic layers were then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (
30% EtOAc / petroleum ether) gave 1.28 g of the title compound as a white solid. MS (ES) M + H predicted value 407.1, found value 407.0. 1H NMR (chloroform-d) δ 7.78-7.85 (m, 1H), 4.82-4.
92 (m, 0.5H), 4.50 (d, J = 13.6 Hz, 0.5H
), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H)
), 3.75-3.82 (m, 0.5H), 3.70-3.75 (m
, 2H), 3.45-3.55 (m, 0.5H), 3.36 (s, 3
H), 3.15-3.27 (m, 1H), 2.92-3.14 (m,
1H), 2.67-2.78 (m, 1H), 2.51-2.61 (
m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J
= 6.8 Hz, 1.5 H), 1.25 (d, J = 2.5 Hz, 1.
5H), 1.09 (d, J = 3.5 Hz, 2H), 1.08 (s,
2H).

And (1) replacing (R) -2-methylpiperazine in step P with an alternatively substituted or unsubstituted piperazine; and / or (2
) Prepared similarly according to Scheme 2 either by replacing 3-methoxypropanoic acid in Step Q with an alternative acid.

Example 3
(R) -5-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
Preparation of -3-methylpiperazin-1-yl) -4-methylnicotinonitrile. (R) -5
-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (28; where R ^1a is methyl R ² is cyclopropyl; m is 1; R ³ is 3-methyl;
R ⁸ is methoxyethyl) was prepared according to the following general scheme 3.
Scheme 3:

Step Aa: 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (
24). To a suspension of ammonium acetate (140 g, 1.82 mol) in 400 mL EtOH, commercially available 1-cyclopropylethanone (22; 22.5 mL, 22.7 mmol),
Acetaldehyde (21; 10 g, 22.7 mmol), and ethyl cyanoacetate (23
24.2 mL, 22.7 mmol) was added continuously. The resulting mixture was stirred at reflux temperature for 2 hours, followed by stirring overnight at room temperature. After LC-MS showed formation of the desired product, the solvent was removed under reduced pressure. Flash column chromatography (10% MeOH / DCM) gave 1.3 g of 24 as a white solid. MS (ES) M + H
Predicted value 175.1, measured value 175.1, 1H NMR (DMSO-d6) δ 12.
36 (br. S., 1H), 5.93 (s, 1H), 2.26 (s,
3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m
, 2H), 0.91-0.95 (m, 2H).

Step Bb: 5-Bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (25). To a solution of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24; 2.6 g, 15 mmol) in 10 mL DCE was added NBS (4 g, 22
. 5 mmol) was added at room temperature. The reaction mixture was then heated at reflux for 3 hours. L
After C-MS showed that the reaction was complete, the mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (4% MeOH / DCM) gave 4 g of 25 as a brown solid. MS (ES) M + H predicted value 253.0, found value 253.0. 1H NMR (chloroform-d) δ 2.68 (s, 3H), 1.79-1.88 (m,
1H), 1.03-1.09 (m, 2H), 0.93-1.01 (
m, 2H).

Step Cc: 5-Bromo-3-cyano-6-cyclopropyl-4-methylpyridine
2-yl trifluoromethanesulfonate (26). 5-Bromo-2-hydroxy-6-
To a solution of isopropylnicotinonitrile (25; 4.0 g, 14.6 mmol) in 20 mL of methylene chloride was added DMAP (178 mg, 1.46 mmol) and triethylamine (2.5 mL, 17.5 mmol). The mixture was cooled to 0 ° C. in an ice-water bath and trifluoromethanesulfonic anhydride (3.7 mL, 21.9 mmol) was added dropwise via syringe. The resulting reaction mixture was stirred at 0 ° C. for 30 minutes, then allowed to warm to room temperature and stirred overnight. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc / petroleum ether) to give 1.66 g of 26. 1H NMR (chloroform-d) δ 2.70 (s,
3H), 2.16-2.20 (m, 1H), 1.23-1.25 (m,
2H), 1.19-1.22 (m, 2H).

Step Dd: (R) -5-Bromo-6-cyclopropyl-4-methyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (27). The triflate 26 (1.6
6 g, 4.3 mmol), (R) -2-methylpiperazine (738 mg, 6.46 mmo)
l), and a mixture of triethylamine (1.8 mL, 12.9 mmol) suspended in 5 mL of MeCN was subjected to microwave reaction at 150 ° C. for 1 hour. After the solvent was removed under reduced pressure, the residue was extracted between EtOAc and water. The organic layer is then washed with saturated aqueous N
Washed with aHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography (10% DCM / MeOH) gave 33
0 mg of 27 was obtained as a pale yellow solid. MS (ES) M + H predicted value 335.1, found value 335.2. 1H NMR (chloroform-d) δ 4.08-4.16 (m
, 0.5H), 4.05-4.08 (m, 1H), 4.01-4.0
4 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (
d, J = 8.8 Hz, 2H), 2.88-2.95 (m, 1H),
2.58-2.65 (m, 1H), 2.55-2.57 (m, 3H
), 1.77 (br. S., 1H), 1.12 (s, 1.5H), 1.
10 (s, 1.5H), 1.05-1.09 (m, 2H), 1.00
-1.05 (m, 2H).

Step Ee: (R) -5-bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (2
8). To a 50 mL round bottom flask was added (R) -5-bromo-6-cyclopropyl-4-methyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (27; 1.12 g, 3
. 34 mmol), 3-methoxypropanoic acid (0.63 mL, 6.68 mmol), HA
TU (2.54 g, 6.68 mmol), DIPEA (3.8 g, 10 mmol) and 10 mL of methylene chloride were added. The resulting reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. After the reaction mixture was washed with saturated NaHCO ₃ , brine, the organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography (20% EtOAc / petroleum ether) gave 1.7 g of 28 yellowish solid. MS (ES) M + H predicted value 421.1, measured value 421.3. 1H N
MR (chloroform-d) δ 4.90 (br. S., 0.5H), 4.5
2 (d, J = 13.6 Hz, 0.5H), 4.22 (br. S.,
0.5H), 3.95-4.13 (m, 2H), 3.78 (br. S.
, 0.5H), 3.74 (t, J = 5.9 Hz, 2H), 3.50
-3.61 (m, 0.5H), 3.38 (s, 3H), 3.07-3
. 24 (m, 1.5H), 2.90-3.06 (m, 1H), 2.65
-2.79 (m, 1H), 2.60 (s, 3H), 2.52-2.6
3 (m, 1H), 2.17-2.21 (m, 1H), 1.37 (d,
J = 6.5 Hz, 1.5H), 1.27 (d, J = 6.3 Hz,
1.5H), 1.09 (s, 2H), 1.05-1.08 (m, 2H)
).

And (1) replacing (R) -2-methylpiperazine in step Dd with an alternative substituted or unsubstituted piperazine; and / or (1)
2) Prepared similarly according to Scheme 3 either by replacing 3-methoxypropanoic acid in Step Ee with an alternative acid.

Example 4
(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) -nicotinonitrile (Compound 189 ) Preparation. Bromide 7 from Example 1 (26 mg, 0.06 mmol),
4- (trifluoromethyl) phenylboronic acid (17 mg, 0.089 mmol), Pd
(PPh ₃ ) ₄ (3 mg, 0.003 mmol), and K ₂ CO ₃ (16 mg, 0.1
19 mmol) in 1 mL DMF was subjected to microwave reaction at 150 ° C. for 45 min. After the reaction, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 19 mg of compound 189 as a yellowish oil. MS (E
S) M + H predicted value 475.2, actual value 475.1. 1H NMR (chloroform-d)
δ 7.70 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H
), 7.38 (d, J = 8.0 Hz, 2H), 4.93 (br. S)
. , 0.5H), 4.56 (d, J = 11.0 Hz, 0.5H), 4
. 44 (d, J = 12.3 Hz, 1H), 4.32-4.39 (m
, 1H), 4.28 (br. S., 0.5H), 3.83 (d, J =
13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.
53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.36
(Br.s., 0.5H), 3.33 (br.s., 0.5H), 3.1
0-3.28 (m, 1.5H), 3.07 (dt, J = 13.3,
1 Hz, 1H), 2.65-2.80 (m, 1H), 2.52-2
. 65 (m, 1H), 1.40 (d, J = 6.5 Hz, 1.5H),
1.30 (d, J = 6.3 Hz, 1.5H), 1.16 (d, J
= 6.5 Hz, 6H).

R ^1b is aryl or heteroaryl; R ² is isopropyl or cyclopropyl. Other compounds of formula II listed below are intermediates 7 (Scheme 1), 1
Prepared analogously using either 7 (Scheme 2) or 28 (Scheme 3) as starting materials.

(R) -2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5- (4- (trifluoromethyl) phenylnicotinonitrile (Compound 185).
1H NMR (chloroform-d) δ 7.70 (d, J = 8.0 Hz,
2H), 7.61 (s, 1H), 7.47-7.56 (m, 1H),
7.38 (d, J = 7.8 Hz, 1H), 7.07 (d, J =
3.5 Hz, 1H), 6.48-6.55 (m, 1H), 4.86-
4.96 (m, 1H), 4.43-4.59 (m, 2H), 4.38
(Dt, J = 13.3, 2.0 Hz, 1H), 3.56 (br. S
. , 1H), 3.46 (dd, J = 13.3, 3.8 Hz, 1H),
3.28 (td, J = 12.4, 3.4 Hz, 1H), 3.07 (
quin, J = 6.7 Hz, 1H), 1.47 (d, J = 6.8)
Hz, 3H), 1.16 (dd, J = 6.7, 1.6 Hz, 6H).
LC-MS: m / z 483.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-5- (4- (trifluoromethyl) phenyl) nicotinonitrile (
Compound 187).
1H NMR (chloroform-d) δ 7.76 (s, 1H), 7.70 (
d, J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.44 −
7.49 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H),
6.56-6.63 (m, 1H), 4.75 (br.s., 1H),
4.45 (d, J = 13.1 Hz, 1H), 4.35-4.42
(M, 2H), 3.42-3.64 (m, 1H), 3.31-3.4
1 (m, 1H), 3.18 (td, J = 12.5, 3.5 Hz, 1
H), 3.07 (dt, J = 13.2, 6.6 Hz, 1H), 1.4
4 (d, J = 6.8 Hz, 3H), 1.16 (dd, J = 6.7)
, 1.9 Hz, 6H). . LC-MS: m / z 483.2 (M + H)
+.

(R) -6-Isopropyl-2- (3-methyl-4- (2- (thiophen-2-yl))
Acetyl) piperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) nicotinonitrile (Compound 188).
1H NMR (chloroform-d) δ 7.69 (d, J = 8.3 Hz,
2H), 7.59 (s, 1H), 7.37 (d, J = 8.0 Hz,
2H), 7.22 (dd, J = 5.1, 1.1 Hz, 1H), 6.
95-7.00 (m, 1H), 6.89-6.95 (m, 1H),
4.95 (br. S., 0.5H), 4.59 (d, J = 12.8 H
z, 0.5H), 4.19-4.48 (m, 3H), 3.89-4.
06 (m, 2H), 3.82 (d, J = 13.6 Hz, 0.5H),
3.57 (t, J = 11.3 Hz, 0.5H), 3.20-3.3
8 (m, 1H), 3.08-3.20 (m, 1H), 3.00-3
. 08 (m, 1H), 1.35 (d, J = 6.5 Hz, 1.5H),
1.31 (d, J = 6.5 Hz, 1.5H), 1.15 (d, J
= 6.5 Hz, 6H). LC-MS: m / z 513.1 (M + H) +
.

(R) -2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-m-tolylnicotinonitrile (Compound 190).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.51 (
d, J = 1.0 Hz, 1H), 7.31 (t, J = 7.8 Hz,
1H), 7.19 (d, J = 7.8 Hz, 1H), 7.01-7
. 09 (m, 3H), 6.51 (dd, J = 3.3, 1.8 Hz,
1H), 4.90 (br. S., 1H), 4.52 (d, J = 13.
3 Hz, 1H), 4.42 (d, J = 13.8 Hz, 1H), 4.
30-4.37 (m, 1H), 3.56 (br. S., 1H), 3.
41 (dd, J = 13.2, 3.6 Hz, 1H), 3.24 (td,
J = 12.4, 3.3 Hz, 1H), 3.15 (dt, J = 13
. 3, 6.7 Hz, 1H), 2.40 (s, 3H), 1.48 (d,
J = 6.5 Hz, 3H), 1.15 (dd, J = 6.8, 2.3)
Hz, 6H). LC-MS: m / z 429.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-m-tolylnicotinonitrile (Compound 191).
1H NMR (chloroform-d) δ 7.75 (s, 1H), 7.61 (
s, 1H), 7.46 (t, J = 1.6 Hz, 1H), 7.31 (
t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz,
1H), 7.00-7.08 (m, 2H), 6.59 (d, J =
1.0 Hz, 1H), 4.74 (br.s., 1H), 4.20-4
. 50 (m, 3H), 3.41-3.61 (m, 1H), 3.32 (
dd, J = 13.1, 3.0 Hz, 1H), 3.08-3.19 (
m, 2H), 2.40 (s, 3H), 1.45 (d, J = 6.8 H
z, 3H), 1.08-1.19 (m, 6H). LC-MS: m /
z 429.1 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2- (thiophen-2-yl))
Acetyl) piperazin-1-yl) -5-m-tolylnicotinonitrile (Compound 192)
.
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.28 −
7.35 (m, 1H), 7.16-7.25 (m, 2H), 7.00
-7.07 (m, 2H), 6.89-6.99 (m, 2H), 4.
94 (br.s., 0.5H), 4.58 (d, J = 13.3 Hz,
0.5H), 4.33-4.43 (m, 1H), 4.19-4.33.
(M, 2H), 3.90-4.05 (m, 2H), 3.80 (d,
J = 13.3 Hz, 0.5H), 3.51-3.63 (m, 0.5H)
), 3.17-3.33 (m, 1H), 3.10-3.17 (m,
1H), 2.99-3.10 (m, 1H), 2.40 (s, 3H),
1.36 (d, J = 6.3 Hz, 1.5H), 1.32 (d, J =
6.8 Hz, 1.5H), 1.14 (d, J = 6.8 Hz, 6H)
. LC-MS: m / z 459.1 (M + H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-m-tolylnicotinonitrile (Compound 193).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.31 (
t, J = 7.9 Hz, 1H), 7.19 (d, J = 7.8 Hz,
1H), 7.01-7.08 (m, 2H), 4.93 (br. S.,
0.5H), 4.56 (d, J = 13.1 Hz, 0.5H), 4.3
0-4.44 (m, 2H), 4.19-4.30 (m, 1H), 3
. 81 (d, J = 13.6 Hz, 0.5H), 3.71-3.78
(M, 2H), 3.52-3.65 (m, 0.5H), 3.38 (s,
3H), 3.24-3.36 (m, 1H), 3.10-3.23 (
m, 2H), 2.65-2.80 (m, 1H), 2.54-2.64.
(M, 1H), 2.40 (s, 3H), 1.41 (d, J = 6.5
Hz, 1.5H), 1.31 (d, J = 6.8 Hz, 1.5H),
1.15 (d, J = 6.5 Hz, 6H). LC-MS: m / z 4
21.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-isopropylpiperazine-1-
Yl) -6-isopropyl-5- (4- (trifluoromethyl) phenyl) nicotinonitrile (Compound 195).
1H NMR (chloroform-d) δ 7.67-7.84 (m, 3H),
7.57-7.64 (m, 1H), 7.45-7.53 (m, 1H
), 7.38 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H)
), 4.84 (d, J = 13.6 Hz, 1H), 4.49-4.69 (
m, 2H), 3.81-4.22 (m, 1H), 3.22-3.57 (
br. s. , 3H), 3.07 (dt, J = 13.3, 6.7 Hz,
1H), 2.19-2.38 (m, 1H), 1.18 (d, J =
6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 0
. 88-1.05 (m, 6H). LC-MS: m / z 511.1 (
M + H) +.

(R) -6-isopropyl-2- (3-isopropyl-4- (2- (thiophene-2-
Yl) acetyl) piperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) -nicotinonitrile (compound 196).
1H NMR (chloroform-d) δ 7.64-7.75 (m, 2H),
7.55-7.62 (m, 1H), 7.37-7.46 (d, J =
8.5 Hz, 2H), 7.22 (ddd, J = 4.8, 3.2, 1.
3 Hz, 1H), 6.87-7.02 (m, 2H), 4.68-4
. 82 (m, 1.5H), 4.35-4.54 (m, 1.5H), 2.
81-4.11 (m, 3H), 3.63 (d, J = 10.3 Hz,
0.5H), 3.37-3.53 (m, 0.5H), 3.08-3.
20 (m, 1H), 2.96-3.08 (m, 2H), 2.18-
2.32 (m, 0.5H), 2.04-2.17 (m, 0.5H), 1
. 17 (dd, J = 6.7, 3.6 Hz, 3H), 1.13 (d,
J = 6.5 Hz, 3H), 1.08 (dd, J = 11.0, 6.5)
Hz, 3H), 0.87-0.93 (m, 1.5H), 0.85 (d
, J = 6.8 Hz, 1.5H). LC-MS: m / z 541.1
(M + H) +.

(R) -6-isopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) nicotinonitrile (Compound 197) .
1H NMR (chloroform-d) δ 7.66-7.76 (m, 2H),
7.59 (d, J = 2.3 Hz, 1H), 7.38 (d, J =
8.0 Hz, 2H), 4.68-4.84 (m, 1.5H), 4.47.
−4.5 (s, 1.5H), 3.88 (d, J = 13.6 Hz, 0.
5H), 3.69-3.82 (m, 2H), 3.61 (d, J = 1)
0.3 Hz, 0.5H), 3.42-3.52 (m, 0.5H),
38 (d, J = 2.8 Hz, 3H), 3.12-3.27 (m,
2H), 3.02-3.12 (m, 1H), 2.90-3.02 (m
, 0.5H), 2.53-2.83 (m, 2H), 2.17-2.3
0 (m, 0.5H), 1.98-2.16 (m, 0.5H), 1.18
(D, J = 6.5 Hz, 3H), 1.14 (d, J = 6.8 H
z, 3H), 1.08 (dd, J = 6.5, 2.8 Hz, 3H),
0.91 (d, J = 6.8 Hz, 1.5H), 0.85 (d, J =
6.8 Hz, 1.5H). LC-MS: m / z 407.4 (M + H)
+.

(R) -5- (4-Fluorophenyl) -6-isopropyl-2- (3-methyl-4-
(2-Methylfuran-3-carbonyl) piperazin-1-yl) nicotinonitrile (Compound 199).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.29 (
d, J = 2.0 Hz, 1H), 7.17-7.24 (m, 2H),
7.08-7.16 (m, 2H), 6.38 (d, J = 1.8 H
z, 1H), 4.68 (br. s., 1H), 4.41 (d, J =
13.1 Hz, 1H), 4.36 (d, J = 13.1 Hz, 1H),
4.20-4.28 (d, J = 13.6 Hz, 1H), 3.39 −
3.59 (m, 1H), 3.25-3.37 (m, 1H), 3.03
-3.18 (m, 2H), 2.41 (s, 3H), 1.41 (d, J
= 6.5 Hz, 3H), 1.14 (dd, J = 6.8, 2.3 H
z, 6H). LC-MS: m / z 447.2 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2-methylfuran-3-carbonyl) piperazin-1-yl) -5-m-tolylnicotinonitrile (Compound 200).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.29 (
d, J = 2.0 Hz, 2H), 7.17-7.24 (m, 1H),
7.08-7.16 (m, 2H), 6.38 (d, J = 1.8 H
z, 1H), 4.68 (br. s., 1H), 4.41 (d, J =
13.1 Hz, 1H), 4.36 (d, J = 13.1 Hz, 1H),
4.20-4.28 (d, J = 13.6 Hz, 1H), 3.39 −
3.59 (m, 4H), 3.25-3.37 (m, 4H), 3.03
-3.18 (m, 8H), 2.41 (s, 11H), 1.41 (d,
J = 6.5 Hz, 11H), 1.14 (dd, J = 6.8, 2.3)
Hz, 6H). LC-MS: m / z 443.3 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2-methylfuran-3-carbonyl) piperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) -nicotinonitrile (Compound 201).
1H NMR (chloroform-d) δ 7.70 (d, J = 8.0 Hz,
2H), 7.57-7.64 (m, 1H), 7.37 (d, J =
8.0 Hz, 2H), 7.27-7.32 (m, 1H), 6.35-
6.42 (m, 1H), 4.68 (br. S., 1H), 4.34-
4.53 (m, 2H), 4.20-4.34 (m, 1H), 3.48
(D, J = 4.8 Hz, 1H), 3.28-3.40 (m, 1H
), 3.16 (td, J = 12.6, 3.4 Hz, 1H), 3.00
-3.11 (m, 1H), 2.41 (s, 3H), 1.38-1.
48 (m, 3H), 1.16 (dd, J = 6.8, 2.3 Hz, 6
H). LC-MS: m / z 497.2 (M + H) +.

(R) -6-isopropyl-5- (4-isopropylphenyl) -2- (3-methyl-
4- (2-Methylfuran-3-carbonyl) piperazin-1-yl) nicotinonitrile (
Compound 202).
1H NMR (chloroform-d) δ 7.58-7.65 (m, 1H),
7.28 (d, J = 8.3 Hz, 3H), 7.11-7.20 (
m, 2H), 6.37 (d, J = 2.0 Hz, 1H), 4.59-4.
. 68 (br. S., 1H), 4.30-4.43 (m, 2H), 4
. 19 (br.s., 1H), 3.40-3.54 (m, 1H), 3
. 30 (dd, J = 12.8, 3.0 Hz, 1H), 3.14-3
. 22 (m, 1H), 3.06-3.14 (m, 1H), 2.96 (
spt, J = 6.9 Hz, 1H), 2.41 (s, 3H), 1.39
-1.45 (m, 3H), 1.30 (d, J = 7.0 Hz, 6H
), 1.15 (dd, J = 6.8, 3.0 Hz, 6H). LC-M
S: m / z 471.3 (M + H) +.

(R) -5- (furan-3-yl) -6-isopropyl-2- (3-methyl-4- (2)
-Methylfuran-3-carbonyl) piperazin-1-yl) nicotinonitrile (compound 2)
03).
1H NMR (chloroform-d) δ 7.64 (s, 1H), 7.49 −
7.53 (m, 1H), 7.43-7.47 (m, 1H), 7.29
(D, J = 1.8 Hz, 1H), 6.45 (d, J = 0.8 H
z, 1H), 6.36 (d, J = 1.8 Hz, 1H), 4.68 (
br. s. , 1H), 4.39 (d, J = 13.1 Hz, 1H),
4.34 (d, J = 13.1 Hz, 1H), 4.18-4.26 (br
. s. , 1H), 3.38-3.56 (m, 1H), 3.22-3
. 35 (m, 2H), 3.11 (td, J = 12.6, 3.4 Hz,
1H), 2.36-2.47 (m, 3H), 1.39 (d, J =
6.5 Hz, 3H), 1.18 (dd, J = 6.7, 1.6 Hz,
6H). LC-MS: m / z 419.2 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-5- (furan-3-yl) -6-isopropylnicotinonitrile (Compound 204).
1H NMR (chloroform-d) δ 7.72-7.77 (m, 1H),
7.64 (s, 1H), 7.50 (t, J = 1.8 Hz, 1H),
7.44-7.47 (m, 2H), 6.58 (dd, J = 1.8,
0.8 Hz, 1H), 6.45 (dd, J = 1.8, 0.8 Hz,
1H), 5.30 (s, 1H), 4.73 (br.s., 1H), 4
. 38 (s, 1H), 4.41 (s, 1H), 4.31 (t, J =
2.1 Hz, 1H), 4.35 (t, J = 2.0 Hz, 1H), 3
. 48 (br.s., 1H), 3.32 (dd, J = 9.9, 3.1)
Hz, 1H), 3.24-3.30 (m, 1H), 3.14 (td,
J = 12.5, 3.5 Hz, 1H), 1.42 (d, J = 7.0)
Hz, 3H), 1.19 (dd, J = 6.8, 1.0 Hz, 6H).
LC-MS: m / z 405.2 (M + H) +.

(R) -5- (furan-3-yl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 205).
1H NMR (chloroform-d) δ 7.63 (s, 1H), 7.50 (
t, J = 1.8 Hz, 1H), 7.42-7.47 (m, 1H),
6.44 (dd, J = 1.8, 0.8 Hz, 1H), 4.92 (b
r. s. , 0.5H), 4.54 (d, J = 13.1 Hz, 0.5H
), 4.38 (dd, J = 12.2, 2.1 Hz, 1H), 4.17.
-4.35 (m, 2H), 3.80 (d, J = 13.1 Hz, 0
. 5H), 3.74 (t, J = 6.5 Hz, 2H), 3.51-3
. 62 (m, 0.5H), 3.36-3.39 (m, 3H), 3.23
-3.35 (m, 2H), 3.06-3.17 (m, 1H), 2.
64-2.80 (m, 1H), 2.51-2.63 (m, 1H),
1.38 (d, J = 6.3 Hz, 1.5H), 1.28 (d, J =
6.0 Hz, 1.5H), 1.19 (d, J = 6.8 Hz, 6H)
. LC-MS: m / z 397.2 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-5- (4-isopropylphenyl) nicotinonitrile (compound 20
6).
1H NMR (chloroform-d) δ 7.72-7.77 (m, 1H),
7.61 (s, 1H), 7.46 (t, J = 1.6 Hz, 1H),
7.28 (d, J = 8.0 Hz, 2H), 7.12-7.19 (
m, 2H), 6.59 (dd, J = 1.8, 0.8 Hz, 1H),
4.74 (br. S., 1H), 4.39 (d, J = 13.3 Hz,
1H), 4.33 (dt, J = 13.2, 1.9 Hz, 2H), 3
. 49 (br.s., 1H), 3.32 (dd, J = 13.2,3.
4 Hz, 1H), 3.08-3.23 (m, 2H), 2.96 (dt
, J = 13.8, 6.9 Hz, 1H), 1.45 (d, J = 6.
8 Hz, 3H), 1.30 (d, J = 7.0 Hz, 6H), 1.1
5 (dd, J = 6.5, 2.3 Hz, 6H). LC-MS: m /
z 457.2 (M + H) +.

(R) -5- (4-Fluorophenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 207
).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.17 −
7.24 (m, 2H), 7.08-7.16 (m, 2H), 4.92
(Br. S., 0.5H), 4.55 (d, J = 12.0 Hz, 0
. 5H), 4.40 (dd, J = 12.2, 1.9 Hz, 1H), 4
. 19-4.35 (m, 2H), 3.82 (d, J = 12.5 Hz
, 0.5H), 3.69-3.78 (m, 2H), 3.53-3.6
3 (m, 0.5H), 3.38 (s, 3H), 3.26-3.35 (
m, 1H), 3.13-3.22 (m, 1H), 3.03-3.12.
(M, 1H), 2.65-2.81 (m, 1H), 2.53-2.
64 (m, 1H), 1.40 (d, J = 6.3 Hz, 1.5H),
1.30 (d, J = 6.5 Hz, 1.5H), 1.14 (d, J =
6.8 Hz, 6H). LC-MS: m / z 425.2 (M + H) +.

(R) -6-isopropyl-5- (4-isopropylphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 2)
08).
1H NMR (chloroform-d) δ 7.59-7.65 (m, 1H),
7.29-7.33 (m, 2H), 7.14-7.22 (m, 2H)
), 4.95 (br. S., 0.5H), 4.58 (d, J = 13.
1 Hz, 0.5H), 4.37-4.44 (m, 1H), 4.22-
4.37 (m, 2H), 3.83 (d, J = 13.3 Hz, 0.5
H), 3.70-3.80 (m, 2H), 3.55-3.67 (m,
0.5H), 3.40 (s, 3H), 3.33 (t, J = 12.3.
Hz, 1H), 3.15-3.25 (m, 2H), 2.98 (quin
, J = 6.9 Hz, 1H), 2.67-2.83 (m, 1H),
2.55-2.67 (m, 1H), 1.43 (d, J = 5.8 Hz
, 1.5H), 1.34 (m, 1.5H), 1.32 (d, J = 7.0
Hz, 6H), 1.17 (d, J = 6.8 Hz, 6H). LC-
MS: m / z 449.2 (M + H) +.

(R) -5- (Benzofuran-2-yl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 20)
9).
1H NMR (chloroform-d) δ 8.12 (s, 1H), 7.61 (
dd, J = 7.7, 0.9 Hz, 1H), 7.48-7.56 (m
, 1H), 7.32 (td, J = 7.7, 1.5 Hz, 1H), 7
. 24-7.29 (m, 1H), 6.78-6.88 (m, 1H),
4.93 (br. S., 0.5H), 4.38-4.64 (m, 2H
), 4.27 (br. S., 0.5H), 3.83 (d, J = 12.
8 Hz, 1H), 3.75 (br.s., 2H), 3.55 (quin
, J = 6.7 Hz, 2H), 3.38 (s, 3H), 3.08 −
3.29 (m, 2H), 2.66-2.83 (m, 1H), 2.60
(Br.s., 1H), 1.38 (d, J = 6.0 Hz, 1.5H)
, 1.33 (br. S., 1.5H), 1.28 (d, J = 6.5
Hz, 6H). LC-MS: m / z 447.1 (M + H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (pyrimidin-5-yl) nicotinonitrile (Compound 210)
).
1H NMR (chloroform-d) δ 9.23-9.28 (m, 1H),
8.69 (s, 2H), 7.62 (s, 1H), 4.94 (br. S)
. , 0.5H), 4.56 (d, J = 9.5 Hz, 0.5H), 4.
37-4.53 (m, 2H), 4.29 (br. S., 0.5H),
3.84 (d, J = 13.3 Hz, 0.5H), 3.68-3.79
(M, 2H), 3.52-3.64 (m, 0.5H), 3.40-
3.46 (m, 0.5H), 3.38 (s, 3H), 3.20-3.3
2 (m, 1H), 3.16 (d, J = 9.5 Hz, 1H), 2.9
3-3.04 (m, 1H), 2.65-2.78 (m, 1H), 2
. 52-2.64 (m, 1H), 1.39 (d, J = 6.5 Hz,
1.5H), 1.29 (d, J = 6.8 Hz, 1.5H), 1.19
(Dd, J = 6.7, 1.1 Hz, 6H). LC-MS: m / z
409.2 (M + H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (naphthalen-2-yl) nicotinonitrile (Compound 211)
).
1H NMR (chloroform-d) δ 7.83-7.97 (m, 3H),
7.66-7.77 (m, 2H), 7.49-7.60 (m, 2H)
), 7.36 (dd, J = 8.4, 1.6 Hz, 1H), 4.94.
(Br. S., 0.5H), 4.57 (d, J = 12.8 Hz, 0.
5H), 4.42 (d, J = 12.8 Hz, 1H), 4.30-4
. 38 (m, 1H), 4.27 (br.s., 1H), 3.83 (d,
J = 13.3 Hz, 0.5H), 3.69-3.79 (m, 2H)
, 3.54-3.65 (m, 0.5H), 3.39 (s, 3H), 3
. 29-3.38 (m, 1H), 3.18-3.24 (m, 1H),
3.06-3.17 (m, 1H), 2.66-2.83 (m, 1H
), 2.52−2.65 (m, 1H), 1.42 (d, J = 7.3)
Hz, 1.5H), 1.32 (d, J = 6.5 Hz, 1.5H),
1.17 (d, J = 6.8 Hz, 6H). LC-MS: m / z 4
57.1 (M + H) +.

(R) -6-isopropyl-5- (3-methoxyphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 212)
).
1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.34 (
t, J = 7.9 Hz, 1H), 6.92 (dd, J = 8.3, 1
. 8 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.
74-6.79 (m, 1H), 4.93 (br.s., 0.5H),
4.56 (d, J = 12.8 Hz, 0.5H), 4.39 (d, J
= 13.6 Hz, 1H), 4.21-4.34 (m, 2H), 3.8
4 (s, 3H), 3.79 (d, J = 8.0 Hz, 0.5H), 3
. 70-3.77 (m, 2H), 3.53-3.64 (m, 0.5H
), 3.38 (s, 3H), 3.26-3.36 (m, 1H), 3.
12-3.22 (m, 2H), 2.65-2.80 (m, 1H),
2.52-2.64 (m, 1H), 1.41 (d, J = 1.5 Hz
, 4H), 1.31 (d, J = 6.5 Hz, 1.5H), 1.10
-1.19 (m, 6H). LC-MS: m / z 437.1 (M + H)
+.

(R) -2-Isopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,4'-bipyridine-5-carbonitrile (Compound 213).
1H NMR (chloroform-d) δ 8.69 (d, J = 5.3 Hz,
2H), 7.61 (s, 1H), 7.22 (d, J = 5.5 Hz,
2H), 4.93 (br.s., 0.5H), 4.56 (d, J =
9.8 Hz, 0.5H), 4.34-4.51 (m, 2H), 4.28
(Br. S., 1H), 3.83 (d, J = 13.3 Hz, 0.5
H), 3.68-3.79 (m, 2H), 3.58 (t, J = 11
. 0 Hz, 0.5H), 3.38 (s, 3H), 3.14-3.28
(M, 2H), 3.03-3.14 (m, 1H), 2.65-2.8
3 (m, 1H), 2.52-2.65 (m, 1H), 1.39 (d,
J = 6.3 Hz, 1.5H), 1.29 (d, J = 6.5 Hz,
1.5H), 1.18 (d, J = 6.5 Hz, 6H). LC-MS
: M / z 408.1 (M + H) +.

(R) -6-isopropyl-5- (4-methoxyphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 214)
).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.11 −
7.20 (m, 2H), 6.92-7.01 (m, 2H), 4.92
(Br. S., 0.5H), 4.56 (d, J = 12.8 Hz, 0
. 5H), 4.37 (d, J = 12.5 Hz, 1H), 4.29 (d
, J = 13.1 Hz, 2H), 3.86 (s, 3H), 3.81 (
d, J = 13.6 Hz, 0.5H), 3.75 (br.s., 2H)
, 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3
. 31 (t, J = 13.2 Hz, 1H), 3.11-3.20 (m
, 2H), 2.66-2.82 (m, 1H), 2.52-2.64.
(M, 1H), 1.41 (d, J = 6.0 Hz, 1.5H), 1.3
1 (d, J = 5.8 Hz, 1.5H), 1.14 (d, J = 6.
8 Hz, 6H). LC-MS: m / z 437.3 (M + H) +.

(R) -5- (4-Chlorophenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 215)
.
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.38 −
7.43 (m, 2H), 7.14-7.20 (m, 2H), 4.93
(Br. S., 0.5H), 4.55 (d, J = 12.5 Hz, 0
. 5H), 4.40 (d, J = 12.8 Hz, 1H), 4.21-
4.36 (m, 2H), 3.82 (d, J = 13.6 Hz, 0.5H
), 3.69-3.78 (m, 2H), 3.53-3.63 (m,
0.5H), 3.38 (s, 3H), 3.27-3.37 (m, 1H)
, 3.11-3.23 (m, 1H), 3.02-3.11 (m, 1
H), 2.65-2.81 (m, 1H), 2.53-2.64 (m,
1H), 1.40 (d, J = 6.5 Hz, 1.5H), 1.30 (
d, J = 6.8 Hz, 1.5H), 1.14 (d, J = 6.5 H)
z, 6H). LC-MS: m / z 441.1 (M + H) +.

5- (4-Ethylphenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 216).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.27 (
s, 1H), 7.25 (s, 1H), 7.15 (d, J = 8.0 H
z, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J
= 12.5 Hz, 0.5H), 4.38 (d, J = 12.3 Hz,
1H), 4.30 (d, J = 12.3 Hz, 2H), 3.81 (d,
J = 13.3 Hz, 0.5H), 3.75 (br.s., 2H),
3.51-3.64 (m, 0.5H), 3.38 (s, 3H), 3.3
1 (t, J = 13.6 Hz, 1H), 3.12-3.22 (m,
2H), 3.10 (d, J = 14.3 Hz, 0.5H), 2.77 (
br. s. , 0.5H), 2.71 (q, J = 7.5 Hz, 2H),
2.61 (br. S., 1H), 1.41 (d, J = 6.0 Hz,
1.5H), 1.32 (br.s., 1.5H), 1.29 (t, J
= 7.5 Hz, 3H), 1.15 (d, J = 6.8 Hz, 6H).
LC-MS: m / z 435.3 (M + H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (naphthalen-1-yl) nicotinonitrile (Compound 217)
).
1H NMR (chloroform-d) δ 7.92 (t, J = 7.4 Hz,
2H), 7.63 (s, 1H), 7.49-7.57 (m, 2H),
7.39-7.47 (m, 2H), 7.27-7.34 (m, 1H
), 4.96 (br. S., 0.5H), 4.59 (d, J = 12.
5 Hz, 0.5H), 4.45 (d, J = 13.3 Hz, 1H),
4.32-4.41 (m, 1H), 4.30 (br.s., 1H),
3.85 (d, J = 13.6 Hz, 0.5H), 3.70-3.81
(M, 2H), 3.55-3.67 (m, 0.5H), 3.39 (s
3H), 3.07-3.27 (m, 2H), 2.67-2.76.
(M, 2H), 2.53-2.66 (m, 1H), 1.45 (d, J
= 5.5 Hz, 1.5 H), 1.36 (d, J = 6.5 Hz, 1
. 5H), 1.06 (d, J = 6.5 Hz, 6H). LC-MS:
m / z 457.3 (M + H) +.

(R) -5- (3-Chlorophenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 218)
.
1H NMR (chloroform-d) δ 7.56-7.61 (m, 1H),
7.35-7.39 (m, 2H), 7.21-7.25 (m, 1H)
), 7.11-7.14 (m, 1H), 4.93 (br. S., 0.
5H), 4.55 (d, J = 11.8 Hz, 0.5H), 4.42 (
d, J = 12.5 Hz, 1H), 4.29-4.37 (m, 1H)
, 4.26 (br. S., 1H), 3.82 (d, J = 13.6 H
z, 0.5H), 3.68-3.78 (m, 2H), 3.53-3.
65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37
(M, 1H), 3.12-3.24 (m, 1H), 3.04-3.1
2 (m, 1H), 2.65-2.80 (m, 1H), 2.50-2
. 64 (m, 1H), 1.40 (d, J = 6.5 Hz, 1.5H),
1.30 (d, J = 6.5 Hz, 1.5H), 1.15 (d, J
= 6.5 Hz, 6H). LC-MS: m / z 441.2 (M + H) +
.

(R) -5- (3,4-Dimethylphenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 2)
20).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.18 (
d, J = 7.5 Hz, 1H), 7.00 (s, 1H), 6.97 (
dd, J = 7.7, 1.6 Hz, 1H), 4.93 (br.s.,
0.5H), 4.55 (d, J = 13.1 Hz, 0.5H), 4.32.
-4.42 (m, 1H), 4.29 (d, J = 12.8 Hz, 1
H), 3.78-3.85 (m, 0.5H), 3.71-3.77 (
m, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s,
3H), 3.24-3.35 (m, 1H), 3.17 (dt, J =
13.3, 6.7 Hz, 2H), 3.01-3.12 (m, 1H),
2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H)
, 2.31 (d, J = 3.0 Hz, 6H), 1.40 (d, J =
6.5 Hz, 1.5H), 1.31 (d, J = 6.8 Hz, 1.5
H), 1.14 (d, J = 6.5 Hz, 6H). LC-MS: m
/ Z 435.4 (M + H) +.

(R) -5- (3-Fluoro-4-methylphenyl) -6-isopropyl-2- (4-
(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (
Compound 221).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.23 (
t, J = 8.0 Hz, 1H), 6.90-6.95 (m, 1H),
6.89 (dd, J = 5.8, 1.3 Hz, 1H), 4.93 (b
r. s. , 0.5H), 4.55 (d, J = 12.8 Hz, 0.5H
), 4.21-4.45 (m, 3H), 3.81 (d, J = 13.
3 Hz, 0.5H), 3.70-3.77 (m, 2H), 3.52-
3.63 (m, 0.5H), 3.38 (s, 3H), 3.26-3.
37 (m, 1H), 3.10-3.18 (m, 2H), 2.65-
2.80 (m, 1H), 2.53-2.63 (m, 1H), 2.33
(D, J = 1.5 Hz, 3H), 1.40 (d, J = 6.5 Hz)
, 1.5H), 1.30 (d, J = 6.5 Hz, 1.5H), 1.1
5 (d, J = 6.8 Hz, 6H). LC-MS: m / z 439.
4 (M + H) +.

(R) -6-Isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-phenylnicotinonitrile (Compound 222).
1H NMR (chloroform-d) δ 7.56-7.61 (m, 1H),
7.35-7.39 (m, 3H), 7.21-7.25 (m, 2H)
), 4.93 (br. S., 0.5H), 4.55 (d, J = 11.
8 Hz, 0.5H), 4.42 (d, J = 12.5 Hz, 1H),
4.29-4.37 (m, 1H), 4.26 (br.s., 1H),
3.82 (d, J = 13.6 Hz, 0.5H), 3.68-3.78
(M, 2H), 3.53-3.65 (m, 0.5H), 3.38 (s
, 3H), 3.28-3.37 (m, 1H), 3.12-3.24
(M, 1H), 3.04-3.12 (m, 1H), 2.65-2.8
0 (m, 1H), 2.50-2.64 (m, 1H), 1.40 (d,
J = 6.5 Hz, 1.5H), 1.30 (d, J = 6.5 Hz, 1
. 5H), 1.15 (d, J = 6.5 Hz, 6H). LC-MS:
m / z 407.4 (M + H) +.

(R) -5- (3,4-Dimethoxyphenyl) -6-isopropyl-2- (4- (3-
Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 223).
1H NMR (chloroform-d) δ 7.61 (s, 1H), 6.92 (
d, J = 8.3 Hz, 1H), 6.78 (dd, J = 8.2, 1
. 9 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 4.
88-4.96 (m, 0.5H), 4.55 (d, J = 13.1 H
z, 0.5H), 4.18-4.46 (m, 3H), 3.93 (s,
3H), 3.89 (s, 3H), 3.78-3.86 (m, 0.5H)
, 3.71-3.78 (m, 2H), 3.52-3.64 (m, 0
. 5H), 3.38 (s, 3H), 3.31 (t, J = 10.8 Hz)
, 1H), 3.10-3.22 (m, 2H), 2.65-2.80
(M, 1H), 2.52-2.64 (m, 1H), 1.33 (s, 1
. 5H), 1.28 (s, 1.5H), 1.16 (d, J = 6.8 H
z, 6H). LC-MS: m / z 467.3 (M + H) +.

(R) -5- (Benzo [d] [1,3] dioxol-5-yl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicoti Nononitrile (Compound 224).
1H NMR (chloroform-d) δ 7.57 (s, 1H), 6.83 −
6.90 (m, 1H), 6.64-6.73 (m, 2H), 6.02
(S, 2H), 4.92 (br. S., 0.5H), 4.55 (d,
J = 12.5 Hz, 0.5H), 4.20-4.43 (m, 3H),
3.81 (d, J = 12.8 Hz, 0.5H), 3.74 (t, J
= 6.3 Hz, 2H), 3.53-3.64 (m, 0.5H), 3
. 38 (s, 3H), 3.25-3.36 (m, 1H), 3.10-
3.22 (m, 2H), 2.64-2.80 (m, 1H), 2.52
-2.64 (m, 1H), 1.40 (d, J = 6.0 Hz, 1.
5H), 1.30 (d, J = 6.5 Hz, 1.5H), 1.14 (d
, J = 6.8 Hz, 6H). LC-MS: m / z 451.3 (M
+ H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3- (trifluoromethoxy) phenyl) nicotinonitrile (Compound 230) .
1H NMR (chloroform-d) δ 7.58-7.63 (m, 1H),
7.42-7.51 (m, 1H), 7.22-7.26 (m, 1H
), 7.18 (dd, J = 7.8, 1.3 Hz, 1H), 7.11
(S, 1H), 4.93 (br. S., 0.5H), 4.55 (d, J
= 11.8 Hz, 0.5H), 4.27-4.46 (m, 3H),
3.78-3.88 (m, 0.5H), 3.75 (t, J = 6.4
Hz, 2H), 3.50-3.64 (m, 0.5H), 3.38 (s,
3H), 3.29-3.36 (m, 1H), 3.13-3.24 (
m, 1H), 3.07 (dt, J = 13.3, 6.7 Hz, 1H),
2.65-2.81 (m, 1H), 2.52-2.64 (m, 1H)
), 1.40 (d, J = 6.3 Hz, 1.5H), 1.30 (d,
J = 6.3 Hz, 1.5H), 1.16 (d, J = 6.5 Hz,
6H). LC-MS: m / z 491.3 (M + H) +.

(R) -5- (3-Fluorophenyl) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 231)
).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.39 (
td, J = 8.0, 6.1 Hz, 1H), 7.05-7.13 (m
, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.95 (d
t, J = 9.4, 2.1 Hz, 1H), 4.93 (br.s., 0
. 5H), 4.55 (d, J = 11.8 Hz, 0.5H), 4.26
-4.45 (m, 3H), 3.82 (d, J = 13.1 Hz, 0.
5H), 3.75 (t, J = 6.1 Hz, 2H), 3.51-3.
64 (m, 0.5H), 3.38 (s, 3H), 3.27-3.35
(M, 1H), 3.16-3.23 (m, 1H), 3.09-3.1
4 (m, 1H), 2.65-2.81 (m, 1H), 2.60 (t,
J = 5.9 Hz, 1H), 1.40 (d, J = 6.3 Hz, 1
. 5H), 1.30 (d, J = 6.5 Hz, 1.5H), 1.15 (
d, J = 6.8 Hz, 6H). LC-MS: m / z 443.3 (
M + H) +.

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4- (trifluoromethoxy) phenyl) nicotinonitrile (Compound 232) .
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.27 (
s, 4H), 4.93 (br. s., 0.5H), 4.49-4.61.
(M, 0.5H), 4.26-4.47 (m, 3H), 3.82 (d
, J = 13.6 Hz, 0.5H), 3.72-3.77 (m, 2H
), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H),
3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H)
, 3.08 (dt, J = 13.3, 6.7 Hz, 1H), 2.65
-2.80 (m, 1H), 2.60 (t, J = 5.9 Hz, 1H)
, 1.40 (d, J = 6.0 Hz, 1.5H), 1.30 (d, J
= 6.5 Hz, 1.5 H), 1.16 (d, J = 6.5 Hz, 6
H). LC-MS: m / z 491.3 (M + H) +.

(R) -5- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -6
-Isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine-1
-Yl) nicotinonitrile (compound 233).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.27 (
s, 4H), 4.93 (br. s., 0.5H), 4.49-4.61.
(M, 0.5H), 4.26-4.47 (m, 3H), 3.82 (d
, J = 13.6 Hz, 0.5H), 3.72-3.77 (m, 2H
), 3.51-3.65 (m, 0.5H), 3.38 (s, 3H),
3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H)
, 3.08 (dt, J = 13.3, 6.7 Hz, 1H), 2.65
-2.80 (m, 1H), 2.60 (t, J = 5.9 Hz, 1H)
, 1.40 (d, J = 6.0 Hz, 1.5H), 1.30 (d, J
= 6.5 Hz, 1.5 H), 1.16 (d, J = 6.5 Hz, 6
H). LC-MS: m / z 465.3 (M + H) +.

(R) -6-isopropyl-5- (isoquinolin-4-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 23)
4).
1H NMR (chloroform-d) δ 9.33 (s, 1H), 8.37 (
s, 1H), 8.06-8.16 (m, 1H), 7.64-7.69.
(M, 2H), 7.45-7.50 (m, 2H), 4.96 (br.
s. , 0.5H), 4.58 (br. S., 0.5H), 4.31 −
4.54 (m, 3H), 3.86 (d, J = 12.5 Hz, 0.5H
), 3.76 (t, J = 6.4 Hz, 2H), 3.56-3.67
(M, 0.5H), 3.42 (d, J = 3.8 Hz, 1H),
36-3.40 (m, 3H), 3.08-3.33 (m, 1H),
2.65-2.78 (m, 2H), 2.54-2.64 (m, 1H)
, 1.44 (d, J = 4.5 Hz, 1.5H), 1.35 (d, J
= 6.0 Hz, 1.5H), 1.05-1.11 (m, 6H).
LC-MS: m / z 458.2 (M + H) +.

(R) -6-cyclopropyl-5- (4-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 21
9).
1H NMR (chloroform-d) δ 7.57 (s, 1H), 7.31 −
7.39 (m, 2H), 7.27 (s, 1H), 7.10-7.18
(M, 2H), 4.90 (br. S., 0.5H), 4.53 (d,
J = 13.6 Hz, 0.5H), 4.07-4.33 (m, 3H),
3.77-3.84 (m, 0.5H), 3.71-3.76 (m,
2H), 3.48-3.60 (m, 0.5H), 3.36-3.41
(M, 3H), 3.25 (t, J = 10.4 Hz, 1H), 3.06
-3.18 (m, 1H), 2.63-2.79 (m, 1H), 2.
51-2.62 (m, 1H), 1.95-2.07 (m, 1H),
1.38 (d, J = 6.5 Hz, 1.5H), 1.28 (d, J =
6.8 Hz, 1.5H), 1.12-1.18 (m, 2H), 0.9
1-0.97 (m, 2H). LC-MS: m / z 423.3 (M +
H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-m-tolylnicotinonitrile (Compound 225).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.30 −
7.36 (m, 1H), 7.14-7.22 (m, 3H), 4.90
(Br. S., 0.5H), 4.52 (d, J = 13.1 Hz, 0
. 5H), 3.80-4.36 (m, 3H), 3.80 (br. S.,
0.5H), 3.74 (t, J = 6.3 Hz, 2H), 3.50 −
3.61 (m, 0.5H), 3.37 (s, 3H), 3.19-3.2
9 (m, 1H), 3.07-3.17 (m, 1H), 2.63-3
. 80 (m, 1H), 2.53-2.62 (m, 1H), 2.41 (
s, 3H), 2.03-2.13 (m, 1H), 1.39 (d, J
= 5.8 Hz, 1.5 H), 1.29 (d, J = 6.5 Hz, 1.
5H), 1.11-1.17 (m, 2H), 0.89-0.97 (m
, 2H). LC-MS: m / z 419.3 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4- (trifluoromethyl) phenyl) nicotinonitrile (Compound 226) ).
1H NMR (chloroform-d) δ 7.71 (d, J = 8.0 Hz,
2H), 7.60 (s, 1H), 7.52 (d, J = 8.0 Hz,
2H), 4.82-4.95 (m, 0.5H), 4.53 (d, J
= 12.8 Hz, 0.5H), 4.17-4.39 (m, 3H), 3
. 80 (d, J = 13.6 Hz, 0.5H), 3.74 (t, J =
6.3 Hz, 2H), 3.49-3.62 (m, 0.5H), 3.3
7 (s, 3H), 3.24-3.33 (m, 1H), 3.03-3
. 15 (m, 1H), 2.63-2.80 (m, 1H), 2.51-
2.62 (m, 1H), 1.93-2.02 (m, 1H), 1.38
(D, J = 6.5 Hz, 1.5H), 1.28 (d, J = 3.5
Hz, 1.5H), 1.14-1.20 (m, 2H), 0.93-
0.99 (m, 2H). LC-MS: m / z 473.3 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4- (trifluoromethoxy) phenyl) nicotinonitrile (Compound 227) ).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.41 −
7.44 (m, 1H), 7.38-7.41 (m, 1H), 7.30
(S, 1H), 7.28 (s, 1H), 4.90 (br. S., 0.
5H), 4.53 (d, J = 11.5 Hz, 0.5H), 4.12-
4.34 (m, 3H), 3.81 (br. S., 0.5H), 3.74
(T, J = 6.3 Hz, 2H), 3.55 (t, J = 11.4
Hz, 0.5H), 3.37 (s, 3H), 3.26 (br.s., 1
H), 3.11 (br. S., 1H), 2.63-2.78 (m, 1
H), 2.58 (d, J = 5.8 Hz, 1H), 1.95-2.0
5 (m, 1H), 1.38 (d, J = 5.8 Hz, 1.5H), 1
. 28 (d, J = 5.8 Hz, 1.5H), 1.13-1.18 (
m, 2H), 0.93-0.99 (m, 2H). LC-MS: m /
z 489.2 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3- (trifluoromethoxy) phenyl) -nicotinonitrile (compound 228).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.48 (
t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.8 Hz,
1H), 7.27 (br.s., 1H), 7.21-7.26 (m,
1H), 4.90 (br.s., 0.5H), 4.53 (d, J =
12.8 Hz, 0.5H), 4.17-4.36 (m, 3H), 3.7
7-3.86 (m, 0.5H), 3.74 (t, J = 6.1 Hz,
2H), 3.51-3.62 (m, 0.5H), 3.37 (s, 3H
), 3.28 (t, J = 8.9 Hz, 1H), 3.12 (d, J
= 10.8 Hz, 1H), 2.64-2.80 (m, 1H), 2.5
2-2.63 (m, 1H), 1.96-2.04 (m, 1H), 1
. 35-1.42 (m, 1.5H), 1.28 (d, J = 5.5 H
z, 1.5H), 1.14-1.20 (m, 2H), 0.93-1.
01 (m, 2H). LC-MS: m / z 489.2 (M + H) +.

(R) -6-cyclopropyl-5- (3-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 22
9).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.41 (
td, J = 7.8, 6.1 Hz, 1H), 7.14-7.19 (m
, 1H), 7.04-7.13 (m, 2H), 4.90 (br. S.
, 0.5H), 4.52 (d, J = 13.1 Hz, 0.5H), 4.
12-4.34 (m, 3H), 3.77-3.85 (m, 0.5H)
3.74 (t, J = 6.1 Hz, 2H), 3.48-3.61
(M, 0.5H), 3.37 (s, 3H), 3.26 (t, J = 9.
4 Hz, 1H), 3.06-3.16 (m, 1H), 2.64-2
. 79 (m, 1H), 2.51-2.62 (m, 1H), 1.99-
2.08 (m, 1H), 1.38 (d, J = 6.0 Hz, 1.5H
), 1.28 (d, J = 6.5 Hz, 1.5H), 1.12-1.
19 (m, 2H), 0.93-0.99 (m, 2H). LC-MS
: M / z 423.3 (M + H) +.

(R) -6-cyclopropyl-5- (3-fluoro-4-methylphenyl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (compound 235).
1H NMR (chloroform-d) δ 7.57 (s, 1H), 7.21 −
7.26 (m, 1H), 7.06 (s, 1H), 7.01-7.05
(M, 1H), 4.89 (br. S., 0.5H), 4.52 (d,
J = 12.8 Hz, 0.5H), 4.11-4.33 (m, 3H),
3.80 (br. S., 0.5H), 3.74 (t, J = 6.3 H
z, 2H), 3.49-3.60 (m, 0.5H), 3.36-3.
41 (m, 3H), 3.25 (t, J = 9.8 Hz, 1H), 3.
03-3.15 (m, 1H), 2.63-2.79 (m, 1H),
2.51-2.61 (m, 1H), 2.32 (d, J = 1.5 Hz
, 3H), 2.01-2.09 (m, 1H), 1.38 (d, J =
6.0 Hz, 1.5H), 1.26-1.30 (m, 1.5H), 1
. 12-1.17 (m, 2H), 0.92-0.97 (m, 2H).
LC-MS: m / z 437.3 (M + H) +.

(R) -6-cyclopropyl-5- (3-methoxyphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 23)
6).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.32 −
7.38 (m, 1H), 6.94-6.99 (m, 1H), 6.87
-6.94 (m, 2H), 4.90 (br. S., 0.5H), 4.
53 (d, J = 13.1 Hz, 0.5H), 4.18-4.26 (m,
J = 12.7 Hz, 3H), 3.84 (s, 3H), 3.81 (d
, J = 5.5 Hz, 0.5H), 3.74 (t, J = 6.1 Hz)
, 2H), 3.55 (t, J = 11.0 Hz, 0.5H), 3.37.
(S, 3H), 3.25 (t, J = 10.2 Hz, 1H), 3.0
3-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2
. 51-2.62 (m, 1H), 2.05--2.15 (m, 1H),
1.39 (d, J = 6.0 Hz, 1.5H), 1.29 (d, J
= 6.3 Hz, 1.5H), 1.11-1.18 (m, 2H), 0.
91-0.96 (m, 2H). LC-MS: m / z 435.3 (M
+ H) +.

(R) -6-cyclopropyl-5- (3,4-dimethoxyphenyl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (compound 237).
1H NMR (chloroform-d) δ 7.60 (s, 1H), 6.92 −
6.95 (m, 2H), 6.88 (s, 1H), 4.89 (br. S)
. , 0.5H), 4.53 (d, J = 14.1 Hz, 0.5H), 4
. 16-4.30 (m, 3H), 3.93 (s, 3H), 3.90 (
s, 3H), 3.78-3.84 (m, 0.5H), 3.71-3.
77 (m, 2H), 3.55 (br. S., 0.5H), 3.37 (s
, 1H), 3.24 (br. S., 1H), 3.03-3.09 (m.,
1H), 2.66-2.79 (m, 1H), 2.59 (br. S.,
1H), 2.08-2.15 (m, 1.5H), 1.38 (br. S)
. , 1.5H), 1.13-1.17 (m, 2H), 0.93 (dd,
J = 8.0, 3.3 Hz, 2H). LC-MS: m / z 465.
1 (M + H) +.

(R) -6-cyclopropyl-5- (isoquinolin-4-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (compound 2
42).
1H NMR (DMSO-d6) δ 7.47 (dd, J = 5.0, 3.
0 Hz, 1H), 7.17 (dd, J = 2.8, 1.3 Hz, 1H
), 7.00 (dd, J = 5.0, 1.3 Hz, 1H), 4.91
(Br.s., 0.5H), 4.55 (d, J = 10.8 Hz, 0.
5H), 3.98−4.27 (m, 3H), 3.75 (q, J = 6)
. 0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.4
0 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3
. 06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (
d, J = 7.3 Hz, 1H), 2.25 (s, 3H), 1.71 −
1.78 (m, 1H), 1.42 (d, J = 6.5 Hz, 1.5H
), 1.32 (d, J = 6.8 Hz, 1.5H), 1.06-1.
08 (m, 2H), 0.83-0.88 (m, 2H). LC-MS
: M / z 456.2 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (thiophen-3-yl) nicotinonitrile (Compound 24)
6).
1H NMR (chloroform-d) δ 7.64 (s, 1H), 7.41 (
dd, J = 4.8, 3.0 Hz, 1H), 7.29 (dd, J =
3.0, 1.3 Hz, 1H), 7.18 (dd, J = 5.0, 1.3
Hz, 1H), 4.90 (br. S., 0.5H), 4.52 (d,
J = 13.6 Hz, 0.5H), 4.14-4.32 (m, 2.5H)
), 3.67-3.84 (m, 2.5H), 3.55 (br. S.,
0.5H), 3.18-3.34 (m, 1H), 2.96-3.18
(M, 1.5H), 2.50-2.71 (m, 2H), 2.12-2
. 23 (m, 1H), 1.34-1.41 (m, 1.5H), 1.24
-1.30 (m, 1.5H), 1.12-1.18 (m, 2H),
0.92-1.02 (m, 2H). LC-MS: m / z 411.3
(M + H) +.

(R) -5- (Benzo [b] thiophen-2-yl) -6-cyclopropyl-2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 247).
1H NMR (chloroform-d) δ 7.82-7.87 (m, 1H),
7.78-7.82 (m, 1H), 7.77 (s, 1H), 7.33
-7.42 (m, 2H), 7.32 (s, 1H), 4.90 (br.
s. , 0.5H), 4.52 (d, J = 12.8 Hz, 0.5H),
4.24-4.39 (m, 3H), 3.70-3.80 (m, 2.
5H), 3.35-3.41 (m, 3H), 3.29 (t, J = 9
. 8 Hz, 1H), 3.03-3.20 (m, 1.5H), 2.63
-2.78 (m, 1H), 2.52-2.63 (m, 1H), 2.3
4-2.44 (m, 1H), 1.37 (d, J = 6.0 Hz, 1
. 5H), 1.23-1.29 (m, 1.5H), 1.15-1.21
(M, 2H), 0.95-1.06 (m, 2H). LC-MS:
m / z 461.3 (M + H) +.

(R) -5- (3-Chloro-4-fluorophenyl) -6-cyclopropyl-2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 248).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.45 (
dd, J = 6.9, 1.9 Hz, 1H), 7.22-7.28 (m
, 2H), 4.92 (br. S., 0.5H), 4.54 (d, J =
12.8 Hz, 0.5H), 4.16-4.37 (m, 3H),
70-3.81 (m, 2.5H), 3.50-3.64 (m, 0.5
H), 3.37-3.42 (m, 3H), 3.28 (t, J = 10
. 2 Hz, 1H), 3.12 (d, J = 11.0 Hz, 1H), 2
. 65-2.87 (m, 1H), 2.55-2.65 (m, 1H),
1.94-2.05 (m, 1H), 1.39 (d, J = 6.5 H
z, 1.5H), 1.28 (d, J = 4.0 Hz, 1.5H),
14-1.21 (m, 2H), 0.94-1.03 (m, 2H).
LC-MS: m / z 457.3 (M + H) +.

(R) -6-cyclopropyl-5- (2-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 24)
9). 1H NMR (chloroform-d) δ 7.62 (s, 1H), 7.3
7-7.45 (m, 1H), 7.30-7.36 (m, 1H), 7
. 22-7.27 (m, 1H), 7.19 (t, J = 9.0 Hz,
1H), 4.92 (br.s., 0.5H), 4.54 (d, J =
13.3 Hz, 0.5H), 4.19-4.37 (m, 3H), 3.7
8-3.86 (m, 0.5H), 3.70-3.78 (m, 2H),
3.51-3.61 (m, 0.5H), 3.39 (s, 3H),
27 (t, J = 12.5 Hz, 1H), 3.02--3.16 (m,
1H), 2.65-2.82 (m, 1H), 2.54-2.64 (
m, 1H), 1.83-1.90 (m, 1H), 1.41 (d, J
= 6.3 Hz, 1.5 H), 1.30 (d, J = 6.8 Hz, 1.
5H), 1.12-1.19 (m, 2H), 0.92-0.98 (m
, 2H). LC-MS: m / z 423.3 (M + H) +.

(R) -6-cyclopropyl-5- (2,4-difluorophenyl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (compound 250).
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.26 −
7.35 (m, 1H), 6.91-7.04 (m, 2H), 4.92
(Br. S., 0.5H), 4.54 (d, J = 13.3 Hz, 0
. 5H), 4.18-4.37 (m, 3H), 3.78-3.85 (
m, 0.5H), 3.71-3.78 (m, 2H), 3.51-3.
62 (m, 0.5H), 3.39 (s, 3H), 3.23-3.33
(M, 1H), 3.14 (d, J = 10.5 Hz, 1H), 2.65
-2.80 (m, 1H), 2.53-2.63 (m, 1H),
77-1.85 (m, 1H), 1.40 (d, J = 6.3 Hz,
1.5H), 1.30 (d, J = 6.5 Hz, 1.5H), 1.11.
-1.19 (m, 2H), 0.96 (dd, J = 7.8, 3.0 H
z, 2H). LC-MS: m / z 441.3 (M + H) +.

(R) -2-cyclopropyl-6′-methoxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,3′-bipyridine-5-carbonitrile (compound 252).
1H NMR (chloroform-d) δ 8.18 (d, J = 2.3 Hz,
1H), 7.60 (dd, J = 8.5, 2.5 Hz, 1H), 7.
56 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.
90 (br. S., 0.5H), 4.52 (d, J = 13.1 Hz,
0.5H), 4.15-4.36 (m, 3H), 3.96-4.02.
(M, 3H), 3.76-3.86 (m, 0.5H), 3.74 (t
, J = 6.3 Hz, 2H), 3.53-3.61 (m, 0.5H)
3.37 (s, 3H), 3.21-3.31 (m, 1H), 3.1
2 (d, J = 11.3 Hz, 1H), 2.63-2.80 (m,
1H), 2.51-2.62 (m, 1H), 1.93-2.04 (m
, 1H), 1.38 (d, J = 6.0 Hz, 1.5H), 1.28
(D, J = 6.3 Hz, 1.5H), 1.12-1.19 (m, 2
H), 0.92-1.00 (m, 2H). LC-MS: m / z 43
6.2 (M + H) +.

(R) -6-cyclopropyl-5- (1H-indol-5-yl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (compound 253).
1H NMR (chloroform-d) δ 8.28 (br.s., 1H), 7
. 66 (s, 1H), 7.63 (s, 1H), 7.46 (d, J =
8.3 Hz, 1H), 7.29 (t, J = 2.8 Hz, 1H), 7
. 20 (dd, J = 8.3, 1.8 Hz, 1H), 6.60 (t,
J = 2.1 Hz, 1H), 4.91 (br.s., 0.5H), 4.
54 (d, J = 13.3 Hz, 0.5H), 4.12-4.33 (
m, 3H), 3.81 (br. s., 0.5H), 3.75 (t, J
= 6.4 Hz, 2H), 3.51-3.63 (m, 0.5H), 3.
38 (s, 3H), 3.22 (d, J = 14.1 Hz, 1H), 3
. 01-3.17 (m, 1H), 2.66-2.81 (m, 1H),
2.62 (t, J = 5.8 Hz, 1H), 2.11-2.21 (
m, 1H), 1.41 (d, J = 5.5 Hz, 1.5H), 1.31
(D, J = 6.3 Hz, 1.5H), 1.11-1.17 (m,
2H), 0.87-0.94 (m, 2H). LC-MS: m / z 4
44.3 (M + H) +.

(R) -6-cyclopropyl-5- (4-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (Compound 241) ).
1H NMR (chloroform-d) δ 7.17 (s, 2H), 7.16 (
d, J = 1.8 Hz, 2H), 4.90 (br.s., 0.5H),
4.53 (d, J = 13.3 Hz, 0.5H), 4.03-4.2
2 (m, 3H), 3.79 (br. S., 0.5H), 3.74 (t,
J = 6.3 Hz, 2H), 3.52-3.63 (m, 0.5H),
3.38 (s, 3H), 3.16-3.25 (m, 1H), 2.92
-3.08 (m, 1H), 2.64-2.79 (m, 1H), 2.
51-2.63 (m, 1H), 2.18 (s, 3H), 1.56-
1.63 (m, 1H), 1.41 (d, J = 6.5 Hz, 1.5H)
, 1.31 (d, J = 6.5 Hz, 1.5H), 1.03-1.0
9 (m, 2H), 0.79-0.84 (m, 2H). LC-MS:
m / z 437.2 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5-m-tolylnicotinonitrile (Compound 243)
).
1H NMR (DMSO-d6) δ 7.36 (t, J = 7.5 Hz,
1H), 7.22 (d, J = 7.5 Hz, 1H), 6.97-7.
04 (m, 2H), 4.92 (br. S., 0.5H), 4.55 (d
, J = 12.3 Hz, 0.5H), 4.24 (br.s., 0.5H)
), 4.03-4.19 (m, 2H), 3.76 (s, 0.5H),
3.75 (s, 2H), 3.55-3.64 (m, 0.5H), 3.4
0 (s, 3H), 3.11-3.26 (m, 1H), 2.93-3
. 08 (m, 1H), 2.68-2.80 (m, 1H), 2.61 (
d, J = 11.0 Hz, 1H), 2.42 (s, 3H), 2.20
(S, 3H), 1.62-1.71 (m, 1H), 1.43 (d, J
= 6.5 Hz, 1.5 H), 1.34 (d, J = 6.0 Hz, 1
. 5H), 1.01-1.11 (m, 2H), 0.80-0.85 (
m, 2H). LC-MS: m / z 433.3 (M + H) +.

(R) -6-cyclopropyl-5- (3-methoxyphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (Compound 251) ).
1H NMR (chloroform-d) δ 7.37 (t, J = 7.8 Hz,
1H), 6.93 (dd, J = 8.3, 2.5 Hz, 1H), 6.
78 (d, J = 7.5 Hz, 1H), 6.74 (s, 1H), 4.
90 (br. S., 0.5H), 4.53 (d, J = 12.8 Hz,
0.5H), 3.96-4.21 (m, 3H), 3.83 (s, 3H)
), 3.71-3.77 (m, 2H), 3.52-3.63 (m,
1H), 3.37 (s, 3H), 3.09-3.25 (m, 1H),
2.89-3.04 (m, 1H), 2.63-2.79 (m, 1H)
, 2.59 (br. S., 1H), 2.16-2.29 (m, 3H)
, 1.63-1.72 (m, 1H), 1.41 (d, J = 6.3)
Hz, 1.5H), 1.29-1.33 (m, 1.5H), 1.06 (
d, J = 7.3 Hz, 2H), 0.78-0.84 (m, 2H).
LC-MS: m / z 449.3 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (4- (trifluoromethoxy) -phenyl) nicoti Nononitrile (Compound 255).
1H NMR (chloroform-d) δ 7.31-7.36 (m, J =
8.0 Hz, 2H), 7.23-7.28 (m, J = 8.3 Hz,
2H), 4.92 (br.s., 0.5H), 4.55 (d, J =
13.8 Hz, 0.5H), 4.01-4.22 (m, 2.5H), 3
. 69-3.85 (m, 2.5H), 3.53-3.67 (m, 0.
5H), 3.36-3.43 (m, 3H), 3.12-3.28 (m
, 1.5H), 2.94-3.12 (m, 1H), 2.66-2.8
3 (m, 1H), 2.61 (br. S., 1H), 2.16-2.2
2 (m, 3H), 1.54-1.65 (m, 1H), 1.39-1
. 46 (m, 1.5H), 1.32 (d, J = 6.3 Hz, 1.5H
), 1.03-1.12 (m, 2H), 0.80-0.89 (m,
2H). LC-MS: m / z 503.3 (M + H) +.

6-Cyclopropyl-5- (2,4-difluorophenyl) -2-((R) -4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-nicotinonitrile (compound 256).
1H NMR (chloroform-d) δ 7.16-7.25 (m, 1H),
6.93-7.07 (m, 2H), 4.92 (br. S., 0.5H
), 4.55 (d, J = 13.3 Hz, 0.5H), 4.03-4
. 30 (m, 2.5H), 3.71-3.86 (m, 2.5H), 3.
51-3.67 (m, 0.5H), 3.40 (s, 3H), 3.12.
-3.30 (m, 1.5H), 2.95-3.11 (m, 1H), 2
. 73 (td, J = 15.3, 7.3 Hz, 1H), 2.54-2
. 64 (m, 1H), 2.18-2.25 (m, 3H), 1.53-
1.61 (m, 1H), 1.39-1.47 (m, 1.5H),
32 (t, J = 5.8 Hz, 1.5H), 1.03-1.17 (m
, 2H), 0.82-0.93 (m, 2H). LC-MS: m / z
455.4 (M + H) +.

(R) -6-cyclopropyl-5- (3-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (Compound 257) ).
1H NMR (chloroform-d) δ 7.41-7.51 (m, 1H),
7.12 (td, J = 8.5, 2.5 Hz, 1H), 7.01 (d
, J = 7.5 Hz, 1H), 6.95 (d, J = 9.0 Hz,
1H), 4.92 (br.s., 0.5H), 4.55 (d, J = 1)
2.8 Hz, 0.5H), 4.04-4.22 (m, 2.5H),
72-3.84 (m, 2.5H), 3.53-3.67 (m, 0.5
H), 3.40 (s, 3H), 3.12-3.29 (m, 1.5H),
2.93-3.11 (m, 1H), 2.66-2.83 (m, 1H
), 2.61 (d, J = 6.3 Hz, 1H), 2.16-2.25
(M, 3H), 1.57-1.64 (m, 1H), 1.43 (d,
J = 6.5 Hz, 1.5H), 1.33 (d, J = 6.8 Hz,
1.5H), 1.08 (t, J = 4.6 Hz, 2H), 0.80 −
0.91 (m, 2H). LC-MS: m / z 437.4 (M + H) +.

(R) -6-cyclopropyl-5- (3-fluoro-4-methylphenyl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (Compound 258).
1H NMR (chloroform-d) δ 7.23-7.33 (m, 2H),
6.89 (s, 1H), 6.87 (d, J = 3.5 Hz, 1H),
4.91 (br.s., 0.5H), 4.54 (d, J = 13.3)
Hz, 0.5H), 4.23 (br. S., 1H), 4.01-4.2.
1 (m, 1.5H), 3.70-3.84 (m, 2.5H), 3.50
-3.66 (m, 0.5H), 3.39 (s, 3H), 3.10-
3.28 (m, 1.5H), 2.92-3.09 (m, 1H), 2.6
5-2.81 (m, 1H), 2.53-2.64 (m, 1H), 2
. 32-2.39 (m, 3H), 2.20 (s, 3H), 1.60-
1.70 (m, 1H), 1.39-1.47 (m, 1.5H),
30-1.35 (m, 1.5H), 1.07 (t, J = 4.6 Hz)
, 2H), 0.83 (dt, J = 7.5, 3.5 Hz, 2H).
LC-MS: m / z 451.4 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (naphthalen-2-yl) nicotinonitrile (compound 259).
1H NMR (DMSO-d6) δ 7.96 (d, J = 8.5 Hz,
1H), 7.91-7.95 (m, 1H), 7.88 (dd, J =
6.1, 3.4 Hz, 1H), 7.71 (s, 1H), 7.53-7
. 59 (m, 2H), 7.34 (dd, J = 8.4, 1.4 Hz,
1H), 4.94 (br.s., 0.5H), 4.57 (d, J = 1)
3.3 Hz, 0.5H), 4.05-4.32 (m, 3H), 3.83
(Br. S., 0.5H), 3.77 (t, J = 6.3 Hz, 2H
), 3.56-3.67 (m, 0.5H), 3.41 (s, 3H),
3.17-3.29 (m, 1H), 2.96-3.12 (m, 1H)
, 2.67-2.83 (m, 1H), 2.55-2.65 (m, 1
H), 2.23 (s, 3H), 1.63-1.71 (m, 1H), 1
. 45 (d, J = 5.8 Hz, 1.5H), 1.35 (d, J =
5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77
-0.83 (m, 2H). LC-MS: m / z 469.4 (M + H
) +.

(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-3,4'-bipyridine-5-carbonitrile (Compound 260) ).
1H NMR (DMSO-d6) δ 8.87 (br. S., 2H), 7.
86 (br. S., 2H), 4.94 (br. S., 0.5H), 4.
71 (s, 0.5H), 4.31-4.35 (s, 3H), 3.82 (b
r. s. , 0.5H), 3.71-3.79 (m, 2H), 3.58
(Br.s., 0.5H), 3.40 (s, 3H), 3.21 (br.
s. , 1H), 3.14 (br.s., 1H), 2.68 (br.s.
, 1H), 2.61 (br. S., 1H), 2.04 (br. S.,
1H), 1.45 (d, J = 5.8 Hz, 1.5H), 1.35 (d
, J = 5.5 Hz, 1.5H), 1.05-1.14 (m, 2H)
, 0.77-0.83 (m, 2H). LC-MS: m / z 420.
5 (M + H) +.

(R) -5- (Benzo [d] [1,3] dioxol-5-yl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4
-Methylnicotinonitrile (Compound 261).
1H NMR (DMSO-d6) δ 6.91 (d, J = 8.0 Hz,
1H), 6.62-6.71 (m, 2H), 6.03-6.10 (m
, 2H), 4.92 (br. S., 0.5H), 4.55 (d, J =
13.6 Hz, 0.5H), 4.03-4.24 (m, 3H),
80 (br. S., 0.5H), 3.76 (t, J = 6.1 Hz,
2H), 3.59 (t, J = 11.7 Hz, 0.5H), 3.39 (
s, 3H), 3.18-3.25 (m, 1H), 2.92-3.08
(M, 1H), 2.65-2.80 (m, 1H), 2.54-2.
65 (m, 1H), 2.22 (s, 3H), 1.68-1.77 (m
, 1H), 1.42 (d, J = 6.5 Hz, 1.5H), 1.33
(D, J = 6.5 Hz, 1.5H), 1.06 (t, J = 5.3)
Hz, 2H), 0.84 (t, J = 6.1 Hz, 2H)
LC-MS: m / z 463.3 (M + H) +.

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (thiophen-3-yl) nicotinonitrile (compound 262).
1H NMR (DMSO-d6) δ 7.47 (dd, J = 5.0, 3.
0 Hz, 1H), 7.17 (dd, J = 2.8, 1.3 Hz, 1H
), 7.00 (dd, J = 5.0, 1.3 Hz, 1H), 4.91
(Br.s., 0.5H), 4.55 (d, J = 10.8 Hz, 0.
5H), 3.98−4.27 (m, 3H), 3.75 (q, J = 6)
. 0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.4
0 (s, 3H), 3.11-3.25 (m, 1H), 2.94-3
. 06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (
d, J = 7.3 Hz, 1H), 2.25 (s, 3H), 1.71 −
1.78 (m, 1H), 1.42 (d, J = 6.5 Hz, 1.5H
), 1.32 (d, J = 6.8 Hz, 1.5H), 1.06-1.
08 (m, 2H), 0.83-0.88 (m, 2H). LC-MS
: M / z 425.3 (M + H) +.

Example 5
(R) -5-Benzyl-6-isopropyl-2- (4- (3-methoxypropanoyl)
Preparation of -3-methylpiperazin-1-yl) nicotinonitrile (Compound 239). Bromide 7 from Example 1 (20 mg, 0.049 mmol) and PdCl ₂ (dppf). C
A mixture of H ₂ Cl ₂ (4 mg, 0.005 mmol) in 1 mL dry THF was stirred at room temperature under a nitrogen atmosphere for 5 min. Benzylzinc bromide (2 mL of a 0.5 M solution in THF, 0.098 mmol) was then added via a transfer needle and the resulting reaction mixture was then refluxed for 4 hours before the volatiles were evaporated under reduced pressure. It was. A black solid was applied to the top of the flash silica gel column, which was CH ₂ Cl ₂ then 8: 1 C
To give compound 239 5.1mg eluted as a reddish solid H ₂ Cl ₂ -EtOAc. MS (ES) M + H predicted value 421.3, found value 421.2. 1H NMR (chloroform-d) δ 7.43 (s, 1H), 7.28-7.36 (m,
2H), 7.19-7.25 (m, 1H), 7.08 (d, J = 7
. 0 Hz, 2H), 4.90 (br.s., 0.5H), 4.53 (d
, J = 13.6 Hz, 0.5H), 4.16-4.36 (m, 3H
), 3.91 (s, 2H), 3.79 (br. S., 0.5H), 3.
73 (t, J = 6.5 Hz, 2H), 3.51-3.61 (m,
0.5H), 3.37 (s, 3H), 3.22-3.30 (m, 1H)
, 3.12-3.21 (m, 1H), 2.63-2.78 (m, 1
H), 2.51-2.61 (m, 1H), 1.38 (d, J = 5.
8 Hz, 1.5H), 1.28-1.32 (m, 1.5H), 1.12.
(D, J = 6.5 Hz, 6H).

R ^1b is alkyl, —CH ₂ -aryl or —CH ₂ -heteroaryl; R
² is isopropyl or cyclopropyl other compounds of formula II listed below starting from either intermediate 7 (Scheme 1), 17 (Scheme 2) or 28 (Scheme 3) And prepared similarly.

(R) -5-Benzyl-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (Compound 245)
.
1H NMR (chloroform-d) δ 7.29-7.35 (m, 2H),
7.24 (d, J = 7.5 Hz, 1H), 7.09 (d, J =
7.3 Hz, 2H), 4.91 (br. S., 0.5H), 4.54 (
d, J = 14.1 Hz, 0.5H), 4.22 (br.s., 0.5
H), 4.16 (s, 2H), 4.09 (d, J = 15.6 Hz,
1.5H), 3.97-4.05 (m, 1H), 3.69-3.82
(M, 2H), 3.53-3.63 (m, 1H), 3.36-3.4
2 (m, 3H), 3.15 (t, J = 13.9 Hz, 1H), 2.
90-3.05 (m, 1H), 2.66-2.81 (m, 1H),
2.54-2.63 (m, 1H), 2.40 (s, 3H), 2.04
(Dd, J = 8.0, 4.8 Hz, 1H), 1.42 (d, J =
6.8 Hz, 1.5H), 1.35 (br.s., 1.5H), 1.07
-1.15 (m, 2H), 0.90-0.92 (m, 2H). L
C-MS: m / z 433.3 (M + H) +.

Example 6
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (methyl (2- (methylamino) ethyl) amino) nicotinonitrile Preparation of (Compound 238). (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (methyl (2- (methylamino) ethyl) amino) nicotinonitrile (Compound 238) was converted to bromide 7 (30 mg
, 0.074 mmol), CuI (0.7 mg, 0.004 mmol), K ₂ CO ₃ (2
0 mg, 0.147 mmol), and N1, N2-dimethylethane-1,2-diamine (3.25 mg, 0.035 mmol) were prepared by mixing in a 5 mL microwave tube capped with a rubber septum. The tube was placed under vacuum and refilled with nitrogen three times. Piperidine (19 mg, 0.22 mmol) and DMSO (1 mL) are added to the tube,
The rubber septum was quickly replaced with a microwave tube cap. The reaction was heated in an oil bath at 120 ° C. overnight before it was cooled, diluted with EtOAc, and filtered through a pad of Celite. EtOAc was removed on a rotary evaporator. Compound 238
Was obtained in an amount of 10 mg via preparative TLC (DCM: MeOH / 10: 1) separation. MS
(ES) M + H predicted value 417.3, measured value 417.5. 1H NMR (chloroform-
d) δ 7.56 (s, 1H), 4.91 (br.s., 0.5H),
4.53 (d, J = 12.3 Hz, 0.5H), 4.02-4.31
(M, 3H), 3.67-3.83 (m, 3H), 3.47-3.
64 (m, 2H), 3.34-3.41 (m, 3H), 3.16-
3.30 (m, 1H), 2.93-3.13 (m, 4H), 2.74
-2.84 (m, 2H), 2.61 (s, 3H), 2.53 (s, 3
H), 1.39 (d, J = 5.8 Hz, 1.5H), 1.30-1
. 34 (m, 1.5H), 1.17 (d, J = 6.5 Hz, 6H).

Example 7
(R) -5-amino-6-isopropyl-2- (4- (3-methoxypropanoyl)-
Preparation of 3-methylpiperazin-1-yl) nicotinonitrile. (R) -5-amino-6-
Isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine-1-
Yl) nicotinonitrile was prepared according to Scheme 4.
Scheme 4:

(R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) nicotinonitrile (30). (R) -5-Bromo-6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (7; 747 mg, 1.8 mmol) in DMF (8 mL) ) Medium solution with 4, 4,
4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2dioxaborolane) (563 mg, 2.2 mmol) and KOAc (538 mg, 5.5 mmol)
) Was added. The resulting mixture was stirred at room temperature for 5 minutes before PdCl ₂ (dpp
f). CH ₂ Cl ₂ (45 mg, 0.03 mmol) was added. After flushing with nitrogen, the reaction mixture was heated at 85 ° C. for 18 hours. LC-MS analysis showed that starting material was still present, the temperature was raised to 120 ° C. and stirred overnight. After cooling, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (25% EtOAc / petroleum ether) gave 334 mg of 30 as a white solid. MS (ES) M + H predicted value 457.3, measured value 457.4. 1H NMR (
Chloroform-d) δ 8.16 (s, 1H), 4.90 (br. S.,
0.5H), 4.52 (d, J = 12.3 Hz, 0.5H), 4.19
-4.39 (m, 3H), 3.76-3.85 (m, 0.5H),
3.73 (t, J = 6.4 Hz, 2H), 3.50-3.61 (m
, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1
H), 3.02-3.20 (m, 1H), 2.63-2.80 (m,
1H), 2.51-2.61 (m, 1H), 1.45 (d, J =
7.0 Hz, 1.5H), 1.35 (d, J = 6.3 Hz, 1.5H)
), 1.34 (s, 12H), 1.19-1.21 (dd, J = 6.8)
, 2.0 Hz, 3H), 1.23-1.25 (d, J = 6.8 Hz,
3H).

(R) -5-Azido-6-isopropyl-2- (4- (3-methoxypropanoyl)-
3-Methylpiperazin-1-yl) nicotinonitrile (31). Boronate 30 (1
0 mg, 0.022 mmol) and Cu (OAc) ₂ . H ₂ O (0.5 mg, 0.00
25 mmol) in MeOH (0.2 mL) was added NaN ₃ (2.4 mg, 0.037).
mmol) was added with slow stirring. After the addition, the reaction mixture is heated to 50 ° C.
Stir overnight. After cooling and diluting with water, the reaction mixture was extracted with methylene chloride. The organic layer was then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. 3.7 by column chromatography (25% ethyl acetate / petroleum ether)
mg of 31 was obtained as a yellowish solid. MS (ES) M + H predicted value 372.2, measured value 37
2.3.

(R) -5-amino-6-isopropyl-2- (4- (3-methoxypropanoyl)-
3-Methylpiperazin-1-yl) nicotinonitrile (32). Azide 31 (10m
g, 0.027 mmol) in 1 mL MeOH in 10% Pd / C (0.5 mg
) Was added. The resulting mixture was purged with hydrogen and stirred at room temperature for 1 hour under hydrogen atmosphere. After LC-MS analysis showed formation of the desired product, the reaction mixture was filtered and the filtrate was concentrated in vacuo. Column chromatography (25% EtOAc / petroleum ether)
Gave 9 mg of 32 as a pink solid. MS (ES) M + H predicted value 346.2, found value 346.1. 1H NMR (chloroform-d) δ 7.25 (s, 1H)
, 4.90 (br.s., 0.5H), 4.53 (d, J = 13.1)
Hz, 0.5H), 4.20 (br. S., 1H), 3.95-4.
07 (m, 1H), 3.93 (br. S., 1H), 3.75 (br.
s. , 0.5H), 3.73 (t, J = 6.4 Hz, 2H),
52-3.63 (m, 0.5H), 3.37 (s, 3H), 3.02
-3.21 (m, 2H), 2.88-3.02 (m, 1H), 2.6
2-2.78 (m, 1H), 2.59 (t, J = 5.8 Hz, 1
H), 1.41 (d, J = 5.8 Hz, 1.5H), 1.31-1.3
2 (m, 1.5H), 1.26 (s, 6H).

Example 8
Preparation of (R) -5- (benzyloxy) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 254). Compound 254 was prepared according to the following general scheme 5:
Scheme 5:


In the formula, R ^c is —CH ₂ -aryl or —CH ₂ -heteroaryl.

Step K-1: (R) -5-hydroxy-6-isopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile. To a solution of boronate 30 from Example 7 (30 mg, 0.066 mmol) in 15 mL of THF was added aqueous NaOH (2.86 g, 0.07 mmol) at room temperature. After stirring for 5 minutes, a solution of 30% H ₂ O ₂ (2.43 mg, 0.07 mmol) was added.
The reaction mixture was allowed to stir at room temperature for an additional 30 minutes before it was adjusted to neutral pH and concentrated in vacuo. Column chromatography (50% EtOAc / petroleum ether)
Gave 21 mg of 33. MS (ES) M + H predicted value 347.2, actual value 347.3
. 1H NMR (methanol-d4) δ 7.26 (s, 1H), 4.82
(Br.s., 0.5H), 4.47 (d, J = 13.1 Hz, 0.
5H), 4.39 (br.s., 0.5H), 3.95 (d, J = 1)
3.1 Hz, 0.5H), 3.79-3.92 (m, 2H), 3.55
-3.74 (m, 3H), 3.36 (s, 3H), 3.10-3.
23 (m, 1H), 2.95-3.10 (m, 1H), 2.81-
2.93 (m, 1H), 2.71-2.81 (m, 1H), 2.59
-2.69 (m, 1H), 1.45 (d, J = 6.8 Hz, 1.5
H), 1.36 (br. S., 1.5H), 1.23 (d, J = 6.
8 Hz, 6H).

Step K-2: (R) -5- (benzyloxy) -6-isopropyl-2- (4- (
3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 254). (R) -5-hydroxy-6-isopropyl-2- (3-isopropyl-
4- (3-Methoxypropanoyl) piperazin-1-yl) nicotinonitrile (33; 1
To a solution of 5 mg, 0.043 mmol) in 1 mL THF was added 60% NaH (2.1 mg
, 0.052 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, benzyl bromide (8.9 mg, 0.052 mmol) was then added. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature overnight. After the reaction mixture was concentrated, 6.5 mg of compound 254 was obtained by preparative TLC separation of the crude (50% ethyl acetate / petroleum ether).
Was obtained as a yellowish solid. MS (ES) M + H predicted value 437.3, measured value 437.4.
H NMR (chloroform-d) δ 7.33-7.43 (m, 5H),
7.23 (s, 1H), 5.02 (s, 2H), 4.90 (br. S.
, 0.5H), 4.53 (d, J = 13.3 Hz, 0.5H), 4.
21 (br. S., 0.5H), 4.02-4.09 (m, 1H),
3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H)
, 3.51-3.61 (m, 0.5H), 3.42-3.51 (m,
1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H),
2.91-3.07 (m, 1H), 2.63-2.78 (m, 1H
), 2.51-2.62 (m, 1H), 1.40 (d, J = 6.5
Hz, 1.5H), 1.31 (d, J = 6.5 Hz, 1.5H),
1.20 (d, J = 6.8 Hz, 6H).

R ^1b is —O—CH ₂ -aryl or —O—CH ₂ -heteroaryl; R ²
Is another compound of formula II listed below, which is isopropyl or cyclopropyl: (R) -6-isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine-1- Yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile 30 was prepared in a similar procedure as described in Example 7 to prepare 30. Using an alternative boronate prepared from either intermediate 7 (Scheme 1), 17 (Scheme 2), or 28 (Scheme 3) using
Were similarly prepared.

(R) -5- (Benzyloxy) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 254).
1H NMR (chloroform-d) δ 7.33-7.43 (m, 5H),
7.23 (s, 1H), 5.02 (s, 2H), 4.90 (br. S)
. , 0.5H), 4.53 (d, J = 13.3 Hz, 0.5H), 4
. 21 (br. S., 0.5H), 4.02-4.09 (m, 1H),
3.90-4.02 (m, 1H), 3.65-3.85 (m, 3H
), 3.51-3.61 (m, 0.5H), 3.42-3.51 (m
, 1H), 3.37 (s, 3H), 3.09-3.23 (m, 1H)
, 2.91-3.07 (m, 1H), 2.63-2.78 (m, 1
H), 2.51-2.62 (m, 1H), 1.40 (d, J = 6.
5 Hz, 1.5H), 1.31 (d, J = 6.5 Hz, 1.5H),
1.20 (d, J = 6.8 Hz, 6H). LC-MS: m / z
437.4 (M + H) +.

Example 9
Preparation of (R) -6-isopropyl-2- (3-methyl-4- (2-methylfuran-3-carbonyl) piperazin-1-yl) -5-phenylnicotinonitrile (Compound 164). Compound 164 (45, wherein m is 1; R ³ is 3-methyl; R ⁸ is 2
-Methylfuran-3yl) was prepared according to the general scheme described in general scheme 6 below.
Scheme 6:

Step R: 1- (Dimethylamino) -4-methyl-2-phenylpent-1-ene
3-one (41). 3-methyl-1-phenylbutan-2-one (40; 3.38 g, 2
0,1) in 40 mL anhydrous DMF was added 1,1-dimethoxy-N, N-dimethylmethanamine (5.958 g, 50 mmol). The resulting mixture was stirred at 100 ° C. overnight. After removing DMF and excess acetal, 4.3 g of 41 was obtained as a crude product and used in subsequent reactions without further purification. MS (ES) M +
H predicted value 218.2, measured value 218.0.

Step S: 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (4
2). To 20 mL anhydrous DMF solution containing 960 mg sodium hydride (22 mmol, 60% dispersion in mineral oil) was added crude 1- (dimethylamino) -4-methyl-2-phenylpent-1-en-3-one ( 41; 4.3 g, 20 mmol DMF solution), cyanoacetamide (1.72 g, 20 mmol), and 2 mL MeOH in 35 mL DMF
The medium solution was added dropwise. After the addition was complete, the resulting mixture was stirred at 80 ° C. overnight. After removing DMF under reduced pressure, the residue was redissolved in methylene chloride and washed with water and brine. The organic layer was then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography (1:10 ethyl acetate / petroleum ether) gave 3.84 g of 42 as a white solid. MS (ES) M + H predicted value 239.1, found value 239.0. 1H NMR (DMSO-d6) δ 8.03 (s, 1H),
7.43-7.50 (m, 2H), 7.37-7.43 (m, 1H
), 7.30-7.33 (m, 1H), 7.29 (s, 1H), 2.
85-2.97 (m, 1H), 1.21 (s, 3H), 1.20 (s
, 3H).

Step T: 2-Chloro-6-isopropyl-5-phenylnicotinonitrile (43)
. 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (42; 2.3 g
10 mmol), a mixture of 5 mL phosphoryl trichloride and 1 drop of DMF was added to the LC-M
Heated to reflux overnight until S showed complete conversion to product. After evaporating excess phosphoryl trichloride under reduced pressure, the residue was redissolved in methylene chloride and carefully neutralized with saturated aqueous NaHCO ₃ followed by washing with 1N HCl and brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography (1: 5 ethyl acetate / petroleum ether) gave 2.4 g of 43 as a yellowish solid. MS (ES) M + H predicted value 257.1, found value 257.0. 1H NMR (chloroform-d) [delta] 7.76-7.82 (m, 1H), 7.43-7.54.
(M, 3H), 7.28 (br. S., 1H), 7.22-7.26
(M, 1H), 3.20 (spt, J = 6.7 Hz, 1H),
22 (s, 3H), 1.20 (s, 3H).

Step U: (R) -6-isopropyl-2- (3-methylpiperazin-1-yl)-
5-Phenylnicotinonitrile (44). Chloride 43 (192.5 mg, 0.75 m
mol), (R) -2-methylpiperazine (187.8 mg, 1.875 mmol), and triethylamine (0.261 mL, 1.875 mmol) suspended in 2 mL of acetonitrile were subjected to 175 C. for 45 minutes. After the reaction mixture was concentrated in vacuo, the residue was purified by flash column chromatography to give 184 mg of 44 as a yellowish oil. MS (ES) M + H predicted value 321.2,
Found 321.1. 1H NMR (chloroform-d) δ 7.56-7.66
(M, 1H), 7.34-7.51 (m, 3H), 7.19-7.
28 (m, 2H), 4.31-4.59 (m, 2H), 3.11-
3.27 (m, 3H), 3.01-3.11 (m, 2H), 2.84
(Dd, J = 12.8, 10.3 Hz, 1H), 1.22 (d, J
= 6.3 Hz, 3H), 1.15 (dd, J = 6.7, 1.1 Hz
, 6H).

Step V: (R) -6-isopropyl-2- (3-methyl-4- (2-methylfuran-3-carbonyl) piperazin-1-yl) -5-phenylnicotinonitrile (Compound 1
64). In a 5 mL amber glass vial, (R) -6-isopropyl-2- (3-
Methylpiperazin-1-yl) -5-phenyl-nicotinonitrile (50 mg, 0.15
6 mmol), 2-methylfuran-3-carboxylic acid (39 mg, 0.312 mmol),
EDCI (60 mg, 0.312 mmol), HOBt (42 mg, 0.312 mmol)
), Triethylamine (40 mg, 0.312 mmol) and 2 mL of methylene chloride were charged. The resulting reaction mixture was stirred at room temperature overnight. The mixture was quenched with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers are saturated NaHCO 3
Washed with ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified by preparative TLC (EtOAc: petroleum ether / 100: 20) to give 28
mg of the title compound was obtained as a white solid. MS (ES) M + H predicted value 429.2, found value 429.1. 1H NMR (methanol-d4) δ 7.59-7.67 (m
, 1H), 7.37-7.50 (m, 3H), 7.31 (d, J =
2.0 Hz, 1H), 7.21-7.28 (m, 2H), 6.39.
(D, J = 2.0 Hz, 1H), 4.70 (br.s., 1H),
4.29-4.50 (m, 2H), 4.23 (br.s., 1H),
3.49 (br. S., 1H), 3.33 (dd, J = 12.9, 3
. 1 Hz, 1H), 3.08-3.23 (m, 2H), 2.40-
2.47 (m, 3H), 1.43 (d, J = 6.8 Hz, 3H),
1.16 (dd, J = 6.8, 2.8 Hz, 6H).

R ^1a is hydrogen; R ^1b is an optionally substituted phenyl, other compounds of formula II listed below: (1) Methyl-1-phenylbutan-2-one (40
) With an alternative phenyl ketone as starting material; (2) replacing (R) -2-methylpiperazine with an alternative piperazine in step U; and (3
) Prepared similarly according to Scheme 6 by one or more of replacing 2-methylfuran-3-carboxylic acid in step V with an alternative acid.

2- (4- (Furan-2-carbonyl) piperazin-1-yl) -6-isopropyl-
5-Phenylnicotinonitrile (Compound 109).
1H NMR (chloroform-d) δ 7.65 (s, 1H), 7.53 −
7.58 (m, 1H), 7.38-7.49 (m, 3H), 7.24
-7.28 (m, 2H), 7.10 (d, J = 3.3 Hz, 1H
), 6.54 (dd, J = 3.3, 1.8 Hz, 1H), 4.03
(Br. S., 4H), 3.89 (dd, J = 6.4, 3.6 Hz,
4H), 3.17 (dt, J = 13.4, 6.7 Hz, 1H), 1
. 18 (d, J = 6.5 Hz, 6H). LC-MS: m / z 40
1.1 (M + H) +.

2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 119).
1H NMR (chloroform-d) δ 7.62-7.69 (m, 1H),
7.54 (d, J = 0.8 Hz, 1H), 7.40-7.47 (
m, 3H), 7.23-7.28 (m, 2H), 7.08 (d, J
= 3.5 Hz, 1H), 6.53 (dd, J = 3.5, 1.8 Hz
, 1H), 4.93 (br. S., 1H), 4.54 (d, J = 1)
2.8 Hz, 1H), 4.45 (d, J = 12.3 Hz, 1H),
4.37 (d, J = 13.3 Hz, 1H), 3.58 (br. S.,
1H), 3.44 (dd, J = 13.3, 3.8 Hz, 1H), 3
. 27 (td, J = 12.4, 3.4 Hz, 1H), 3.16 (dt
, J = 13.3, 6.7 Hz, 1H), 1.50 (d, J = 6.
8 Hz, 3H), 1.17 (dd, J = 6.7, 1.9 Hz, 6H
). LC-MS: m / z 414.9 (M + H) +.

2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 120).
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.64 (
s, 1H), 7.40-7.51 (m, 4H), 7.24-7.28.
(M, 2H), 6.61 (d, J = 1.3 Hz, 1H), 4.76.
(Br.s., 1H), 4.33-4.52 (m, 3H), 3.51
(S, 1H), 3.35 (dd, J = 13.2, 3.1 Hz, 1H
), 3.12-3.22 (m, 2H), 1.47 (d, J = 6.8)
Hz, 3H), 1.17 (dd, J = 6.5, 2.0 Hz, 6H)
. LC-MS: m / z 414.9 (M + H) +.

2- (4- (Furan-3-carbonyl) piperazin-1-yl) -6-isopropyl-
5-Phenylnicotinonitrile (Compound 124).
1H NMR (chloroform-d) δ 7.76-7.81 (m, 1H),
7.65 (s, 1H), 7.36-7.51 (m, 4H), 7.23
-7.28 (m, 2H), 6.62 (dd, J = 1.9, 0.9
Hz, 1H), 3.91 (br. S., 4H), 3.84 (br. S.
, 4H), 3.17 (dt, J = 13.4, 6.6 Hz, 1H),
1.17 (d, J = 6.8 Hz, 6H). LC-MS: m / z 4
01.1 (M + H) +.

2- (4- (1H-indole-3-carbonyl) piperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 125).
1H NMR (chloroform-d) δ 8.97 (br.s., 1H), 7
. 74-7.81 (m, 1H), 7.64 (s, 1H), 7.53 (
br. s. , 1H), 7.38-7.50 (m, 4H), 7.28-
7.31 (m, 1H), 7.24-7.28 (m, 3H), 3.94
(Br.s., 4H), 3.85 (br.s., 4H), 3.16 (
dt, J = 13.2, 6.6 Hz, 1H), 1.17 (d, J =
6.5 Hz, 6H). LC-MS: m / z 450.2 (M + H) +.

6-Isopropyl-5-phenyl-2- (4- (2-phenylacetyl) piperazine-
1-yl) nicotinonitrile (compound 126).
1H NMR (chloroform-d) δ 7.62 (s, 1H), 7.41 −
7.47 (m, 3H), 7.38-7.41 (m, 1H), 7.37
(S, 1H), 7.34-7.36 (m, 1H), 7.32 (s,
1H), 7.30 (s, 1H), 7.25 (d, J = 1.5 Hz,
1H), 7.24 (s, 1H), 3.84-3.89 (m, 2H),
3.83 (s, 2H), 3.73-3.78 (m, 2H), 3.64
-3.68 (m, 2H), 3.58-3.63 (m, 2H), 3.1
5 (dt, J = 13.3, 6.7 Hz, 1H), 1.15 (d, J
= 6.5 Hz, 6H). LC-MS: m / z 425.1 (M + H)
+.

6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazine-1
-Yl) -5-phenylnicotinonitrile (compound 139).
1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.37 −
7.51 (m, 4H), 7.33-7.37 (m, 2H), 7.29
-7.33 (m, 2H), 7.22-7.27 (m, 2H), 4.
62 (d, J = 13.6 Hz, 0.5H), 4.42 (d, J =
12.5 Hz, 0.5H), 4.19-4.35 (m, 2H), 3.8
1 (br. S., 1H), 3.76 (d, J = 13.1 Hz, 0.
5H), 3.49 (t, J = 12.0 Hz, 0.5H), 2.91-3
. 29 (m, 3H), 1.31 (br. S., 3H), 1.15 (d,
J = 6.8 Hz, 6H). LC-MS: m / z 439.2 (M +
H) +.

2-((3S, 5R) -3,5-dimethyl-4- (2-phenylacetyl) piperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 140).
1H NMR (chloroform-d) δ 7.61-7.64 (m, 1H),
7.41-7.48 (m, 3H), 7.38-7.41 (m, 1H
), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.
32 (s, 1H), 7.30 (s, 1H), 7.27 (d, J = 1)
. 8 Hz, 1H), 7.23-7.26 (m, 1H), 4.90 (b
r. s. , 1H), 4.46 (br. S., 2H), 4.20 (br.
s. , 1H), 3.82 (s, 2H), 3.12-3.22 (m,
2H), 3.11 (br.s., 1H), 1.43 (d, J = 7.0)
Hz, 6H), 1.16 (d, J = 6.8 Hz, 6H). LC-
MS: m / z 453.1 (M + H) +.

2-((3S, 5R) -4- (furan-3-carbonyl) -3,5-dimethylpiperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 141).
1H NMR (chloroform-d) δ 7.77 (dd, J = 1.5, 0
. 8 Hz, 1H), 7.65 (s, 1H), 7.47-7.49 (m
, 1H), 7.45-7.47 (m, 1H), 7.44 (s, 1H)
, 7.40-7.43 (m, 1H), 7.24-7.28 (m, 2
H), 6.65 (dd, J = 1.9, 0.9 Hz, 1H), 4.71
(Br. S., 2H), 4.47 (s, 1H), 4.50 (s, 1H)
3.27 (dd, J = 12.9, 4.1 Hz, 2H), 3.18
(Dt, J = 13.3, 6.7 Hz, 1H), 1.55 (d, J =
7.0 Hz, 6H), 1.18 (d, J = 6.5 Hz, 6H).
LC-MS: m / z 429.2 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazin-1-yl) -5-phenylnicotinonitrile (Compound 143).
1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.39 −
7.47 (m, 3H), 7.34-7.39 (m, 2H), 7.29
-7.33 (m, 2H), 7.22-7.28 (m, 3H), 4.
98 (br.s., 0.5H), 4.62 (d, J = 13.8 Hz,
0.5H), 4.42 (d, J = 12.0 Hz, 0.5H), 4.1
5-4.35 (m, 2H), 3.81 (br. S., 2H), 3.7
2-3.79 (m, 0.5H), 3.49 (t, J = 11.3 Hz
, 0.5H), 3.29 (d, J = 10.0 Hz, 0.5H),
04-3.21 (m, 2.5H), 2.88-3.01 (m, 0.5
H), 1.27-1.34 (m, 3H), 1.15 (d, J = 6.
5 Hz, 6H). LC-MS: m / z 439.2 (M + H) +.

(S) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-phenylnicotinonitrile (Compound 144).
1H NMR (chloroform-d) δ 7.74-7.80 (m, 1H),
7.64 (s, 1H), 7.36-7.52 (m, 4H), 7.27
(Dd, J = 7.9, 6.4 Hz, 2H), 6.59-6.64
(M, 1H), 4.76 (br. S., 1H), 4.20-4.50
(M, 3H), 3.51 (br. S., 1H), 3.35 (dd, J
= 13.3, 3.3 Hz, 1H), 3.06-3.24 (m, 2H)
1.47 (d, J = 6.8 Hz, 3H), 1.17 (dd, J
= 6.5, 2.0 Hz, 6H). LC-MS: m / z 415.2 (
M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazin-1-yl) -5-phenylnicotinonitrile (Compound 145).
1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.29 −
7.47 (m, 7H), 7.22-7.28 (m, 3H), 4.98
(Br. S., 0.5H), 4.62 (d, J = 13.6 Hz, 0
. 5H), 4.42 (d, J = 12.8 Hz, 0.5H), 4.15.
-4.37 (m, 2H), 3.80-3.85 (m, 2H), 3.7
6 (d, J = 12.8 Hz, 0.5H), 3.49 (t, J = 1)
1.2 Hz, 0.5H), 3.25-3.37 (m, 0.5H), 3.
02-3.23 (m, 2.5H), 2.88-3.01 (m, 0.5
H), 1.26-1.35 (m, 3H), 1.15 (d, J = 6.
8 Hz, 6H). LC-MS: m / z 439.2 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-phenylnicotinonitrile (Compound 150).
1H NMR (chloroform-d) δ 7.77 (dd, J = 1.5, 1
. 0 Hz, 1H), 7.63-7.66 (m, 1H), 7.38-
7.50 (m, 4H), 7.23-7.28 (m, 2H), 6.61
(Dd, J = 1.8, 0.8 Hz, 1H), 4.76 (br. S.,
1H), 4.30-4.51 (m, 3H), 3.52 (br. S.,
1H), 3.35 (dd, J = 13.2, 3.6 Hz, 1H), 3
. 06-3.24 (m, 2H), 1.47 (d, J = 6.8 Hz,
3H), 1.17 (dd, J = 6.8, 2.0 Hz, 6H). L
C-MS: m / z 415.1 (M + H) +.

2- (4- (Furan-3-carbonyl) -3-phenylpiperazin-1-yl) -6-
Isopropyl-5-phenylnicotinonitrile (Compound 153).
1H NMR (chloroform-d) δ 7.59-7.74 (m, 1H),
7.56 (s, 1H), 7.33-7.50 (m, 8H), 7.29
(D, J = 7.3 Hz, 1H), 7.17-7.25 (m, 2H
), 6.54 (br.s., 1H), 5.74 (br.s., 1H),
4.79 (br.s., 1H), 4.51 (br.s., 1H), 4
. 33 (d, J = 9.5 Hz, 1H), 3.95 (d, J = 11
. 5 Hz, 1H), 3.58 (br. S., 2H), 3.12 (spt
, J = 6.6 Hz, 1H), 1.08-1.18 (m, 6H).
LC-MS: m / z 477.1 (M + H) +.

2- (4- (Furan-3-carbonyl) -2-phenylpiperazin-1-yl) -6-
Isopropyl-5-phenylnicotinonitrile (Compound 159).
1H NMR (chloroform-d) δ 7.72 (br.s., 1H), 7
. 48-7.60 (m, 5H), 7.46 (br. S., 3H), 7
. 40 (br.s., 2H), 7.27 (br.s., 1H), 7.2
0 (d, J = 6.8 Hz, 1H), 6.77 (s, 1H), 6.5
9 (s, 1H), 5.14-5.37 (m, 1H), 4.25 (br.
s. , 2H), 3.87 (br.s., 3H), 3.64 (br.s.
, 1H), 2.81-2.95 (m, 1H), 1.16 (d, J =
6.5 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H).
LC-MS: m / z 477.2 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2- (thiophen-2-yl))
Acetyl) piperazin-1-yl) -5-phenylnicotinonitrile (Compound 165).
1H NMR (methanol-d4) δ 7.62 (s, 1H), 7.35 −
7.57 (m, 3H), 7.21-7.28 (m, 3H), 6.87
-7.11 (m, 2H), 4.60 (d, J = 13.3 Hz, 1
H), 4.29-4.37 (m, 2H), 3.98 (s, 2H), 3
. 59 (t, J = 11.4 Hz, 1H), 3.04-3.27 (m
, 4H), 1.36 (dd, J = 15.2, 5.9 Hz, 3H),
1.16 (d, J = 6.5 Hz, 6H). LC-MS: m / z 4
45.0 (M + H) +.

2- (4- (Furan-2-carbonyl) -2-phenylpiperazin-1-yl) -6-
Isopropyl-5-phenylnicotinonitrile (Compound 166).
1H NMR (chloroform-d) δ 7.54-7.56 (m, 2H),
7.52 (br. S., 3H), 7.43 (br. S., 2H), 7
. 24-7.30 (m, 3H), 7.20 (d, J = 7.3 Hz,
1H), 7.08 (d, J = 3.3 Hz, 1H), 6.77 (s,
1H), 6.52 (br. S., 1H), 5.31-5.37 (br.
s. , 1H), 4.40 (br. S., 1H), 4.32 (br. S.
, 1H), 3.85-4.03 (m, 2H), 3.79 (d, J =
13.1 Hz, 1H), 3.68 (d, J = 4.8 Hz, 1H),
2.87 (dt, J = 13.4, 6.8 Hz, 1H), 1.15 (
d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.5 Hz,
3H). LC-MS: m / z 477.2 (M + H) +.

2- (4- (1H-indole-3-carbonyl) -2-phenylpiperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 168).
1H NMR (chloroform-d) δ 9.09 (br.s., 1H), 7
. 76 (br. S., 1H), 7.51 (s, 2H), 7.55 (s,
3H), 7.39 (br. S., 3H), 7.29 (s, 2H), 7
. 33 (s, 1H), 7.24 (br. S., 3H), 6.77 (br
. s. , 1H), 5.29 (br. S., 1H), 4.30 (d, J
= 11.5 Hz, 1H), 4.18 (br.s., 1H), 3.93.
(Br.s., 3H), 3.64 (br.s., 1H), 2.89 (
br. s. , 1H), 1.16 (d, J = 5.8 Hz, 3H), 1
. 07 (d, J = 5.8 Hz, 3H). LC-MS: m / z 52
6.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-isopropylpiperazine-1-
Yl) -6-isopropyl-5-phenylnicotinonitrile (compound 170).
1H NMR (chloroform-d) δ 7.74 (br.s., 1H), 7
. 61 (s, 1H), 7.47 (t, J = 1.6 Hz, 1H), 7
. 35-7.46 (m, 3H), 7.20-7.26 (m, 2H),
6.58 (s, 1H), 4.79 (d, J = 12.8 Hz, 1H)
4.54-4.68 (br.s., 1H), 4.45 (br.s.,
1H), 3.8-4.07 (m, 1H), 3.56-3.74 (m, 1
H), 3.19 (br.s., 1H), 3.06-3.18 (m, 3
H), 1.52-1.59 (m, 3H), 1.40-1.48 (m,
3H), 1.17 (d, J = 6.8 Hz, 3H), 1.13 (d,
J = 6.8 Hz, 3H). LC-MS: m / z 443.1 (M +
H) +.

(R) -2- (3-Ethyl-4- (furan-3-carbonyl) piperazin-1-yl)
-6-Isopropyl-5-phenylnicotinonitrile (Compound 171).
1H NMR (chloroform-d) δ 7.74 (s, 1H), 7.58 −
7.65 (m, 1H), 7.35-7.50 (m, 4H), 7.20
-7.26 (m, 2H), 6.58 (dd, J = 1.8, 0.8
Hz, 1H), 5.02 (s, 1H), 4.69 (br.s., 1H)
, 4.50 (d, J = 13.1 Hz, 1H), 4.41 (d, J
= 12.3 Hz, 1H), 4.23-4.31 (br.s., 1H),
3.46-3.86 (m, 2H), 3.27 (dd, J = 13.3,
3.3 Hz, 1H), 3.10-3.21 (m, 2H), 1.79
-1.96 (m, 2H), 1.54 (d, J = 6.5 Hz, 1.5
H), 1.45 (d, J = 6.5 Hz, 1.5H), 1.15 (dd
, J = 6.8, 3.5 Hz, 6H). LC-MS: m / z 429
. 1 (M + H) +.

(R) -2- (3-Ethyl-4- (furan-2-carbonyl) piperazin-1-yl)
-6-Isopropyl-5-phenylnicotinonitrile (Compound 172).
1H NMR (chloroform-d) δ 7.59-7.64 (m, 1H),
7.51 (dd, J = 1.8, 0.8 Hz, 1H), 7.36 −
7.46 (m, 3H), 7.21-7.26 (m, 2H), 7.02
-7.10 (m, 1H), 6.51 (dd, J = 3.5, 1.8 H
z, 1H), 4.71 (br. s., 1H), 4.38-4.60 (
m, 3H), 3.50 (br.s., 1H), 3.35 (dd, J =
13.3, 3.5 Hz, 1H), 3.22 (td, J = 12.5,
3.4 Hz, 1H), 3.08-3.18 (m, 1H), 1.90-
2.06 (m, 1H), 1.83 (dquin, J = 14.2, 7.
2 Hz, 1H), 1.15 (dd, J = 6.7, 3.1 Hz, 6H
), 0.97 (t, J = 7.4 Hz, 3H). LC-MS: m /
z 429.1 (M + H) +.

(R) -2- (3-Ethyl-4- (2-methylfuran-3-carbonyl) piperazine-
1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 173).
1H NMR (chloroform-d) δ 7.58-7.66 (m, 1H),
7.35-7.47 (m, 3H), 7.29 (d, J = 2.0 H
z, 1H), 7.21-7.26 (m, 2H), 6.32-6.41.
(M, 1H), 4.59-4.80 (m, 1H), 4.50 (d, J
= 13.1 Hz, 1H), 4.42 (br.s., 1H), 3.91-
3.97 (br. S., 1H), 3.45-3.65 (m, 1H), 3.
27 (dd, J = 13.1, 3.3 Hz, 1H), 3.05-3.
19 (m, 2H), 2.41 (s, 3H), 1.86-1.95 (m
, 1H), 1.79 (dt, J = 14.1, 7.0 Hz, 1H),
1.15 (dd, J = 6.8, 2.0 Hz, 6H), 0.87-0
. 99 (m, 3H). LC-MS: m / z 443.1 (M + H) +.

(R) -2- (3-Ethyl-4- (2- (thiophen-2-yl) acetyl) piperazin-1-yl) -6-isopropyl-5-phenylnicotinonitrile (Compound 174).
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.35 −
7.49 (m, 3H), 7.17-7.25 (m, 3H), 6.92
-6.99 (m, 2H), 4.75 (br. S., 0.5H), 4.
59-4.71 (m, 0.5H), 4.30-4.50 (m, 2H)
, 3.79-4.07 (m, 3H), 3.46-3.56 (m, 0
. 5H), 3.17-3.30 (m, 0.5H), 2.97-3.17
(M, 3H), 1.78-1.89 (m, 1H), 1.69-1.
78 (m, 1H), 1.10-1.16 (m, 6H), 0.90-
0.97 (m, 3H). LC-MS: m / z 459.1 (M + H) +.

2- (4- (Furan-2-carbonyl) -3-methylpiperazin-1-yl) -5,6
-Diphenylnicotinonitrile (compound 117). Compound 117 was synthesized, synthesized and synthesized using 1,2-diphenylethanone as the starting material.
1H NMR (chloroform-d) δ 7.87 (s, 1H), 7.53 (
dd, J = 1.5, 0.8 Hz, 1H), 7.37-7.44 (m
, 2H), 7.27-7.35 (m, 6H), 7.12-7.19.
(M, 2H), 7.06-7.12 (m, 1H), 6.53 (dd,
J = 3.4, 1.9 Hz, 1H), 4.94 (br.s., 1H),
4.53 (t, J = 11.7 Hz, 2H), 4.36-4.46
(M, 1H), 3.62 (br.s., 1H), 3.44-3.54
(M, 1H), 3.26-3.37 (m, 1H), 1.52 (d, J
= 6.5 Hz, 3H). LC-MS: m / z 448.9 (M + H)
+.

2- (4- (Furan-3-carbonyl) -3-methylpiperazin-1-yl) -5,6
-Diphenylnicotinonitrile (compound 118). Compound 118 was synthesized using 1,2-diphenylethanone as the starting material.
1H NMR (chloroform-d) δ 7.88 (s, 1H), 7.77 (
s, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.0 H
z, 2H), 7.27-7.33 (m, 6H), 7.13-7.16.
(M, 2H), 6.61 (s, 1H), 4.71-4.79 (br. S
. , 1H), 4.47-4.50 (s, 1H), 4.38 (s, 1H),
4.41 (s, 1H), 3.48-3.64 (m, 1H), 3.38
-3.42 (m, 1H), 3.21 (td, J = 12.4, 3.0 H
z, 1H), 1.49 (d, J = 6.5 Hz, 3H). LC-MS
: M / z 448.9 (M + H) +.

2- (4- (furan-3-carbonyl) piperazin-1-yl) -5,6-diphenylnicotinonitrile (Compound 122). Compound 122 was synthesized using 1,2-diphenylethanone as the starting material.
1H NMR (chloroform-d) δ 7.88 (s, 1H), 7.78 (
s, 1H), 7.47-7.51 (m, 1H), 7.37-7.42.
(M, 2H), 7.27-7.35 (m, 6H), 7.15 (dd,
J = 6.5, 3.0 Hz, 2H), 6.62 (s, 1H), 3.92
(Br.s., 4H), 3.89 (br.s., 4H). LC-MS
: M / z 435.1 (M + H) +.

5,6-Diphenyl-2- (4- (2-phenylacetyl) piperazin-1-yl) nicotinonitrile (Compound 123). Compound 123 was synthesized using 1,2-diphenylethanone as the starting material.
1H NMR (chloroform-d) δ 7.85 (s, 1H), 7.34 −
7.39 (m, 4H), 7.28-7.33 (m, 8H), 7.22
-7.26 (m, 1H), 7.13 (dd, J = 6.5, 3.0
Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.8
4 (m, 4H), 3.66 (s, 4H). LC-MS: m / z 45
9.1 (M + H) +.

(R) -5- (3-Fluorophenyl) -2- (4- (furan-3-carbonyl) -3
-Methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 161)
. Compound 161 was synthesized using 1- (3-fluorophenyl) -3-methylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.73-7.79 (m, 1H),
7.61 (s, 1H), 7.47 (t, J = 1.6 Hz, 1H),
7.35-7.44 (m, 1H), 7.06-7.13 (m, 1H)
), 7.00-7.04 (m, 1H), 6.96 (dt, J = 9.
3, 2.1 Hz, 1H), 6.54-6.63 (m, 1H), 4.6
1-4.90 (m, 1H), 4.41 (s, 0.5H), 4.44 (
s, 0.5H), 4.19-4.39 (m, 2H), 3.42-3.49
(Br.s., 1H), 3.34 (dd, J = 13.2, 3.1 H
z, 1H), 3.14-3.23 (m, 1H), 3.06-3.14
(M, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.15
(Dd, J = 6.8, 1.8 Hz, 6H). LC-MS: m / z
433.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-5- (2-methoxyphenyl) nicotinonitrile (Compound 175)
. Compound 175 was synthesized using 1- (2-methoxyphenyl) -3-methylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.75 (s, 1H), 7.56 (
s, 1H), 7.46 (t, J = 1.5 Hz, 1H), 7.34 −
7.41 (m, 1H), 7.06-7.12 (m, 1H), 7.01
(T, J = 7.3 Hz, 1H), 6.96 (d, J = 8.3 H
z, 1H), 6.55-6.62 (m, 1H), 4.74 (br. s)
. , 1H), 4.18-4.46 (m, 3H), 3.77 (s, 3H)
), 3.49 (br. S., 1H), 3.31 (dd, J = 13.2.
, 3.1 Hz, 1H), 3.14 (td, J = 12.5, 3.0 H
z, 1H), 2.86 (quin, J = 6.7 Hz, 1H), 1.4
6 (d, J = 6.8 Hz, 3H), 1.15 (br.s., 3H)
, 1.04 (br.s., 3H). LC-MS: m / z 445.2
(M + H) +.

(R) -2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-5- (2-methoxyphenyl) nicotinonitrile (Compound 176)
. Compound 176 was synthesized using 1- (2-methoxyphenyl) -3-methylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.56 (s, 1H), 7.50 −
7.53 (m, 1H), 7.34-7.41 (m, 1H), 7.07
-7.13 (m, 1H), 7.03-7.06 (m, 1H), 6.
99-7.02 (m, 1H), 6.96 (d, J = 8.3 Hz,
1H), 6.51 (dd, J = 3.3, 1.8 Hz, 1H), 4.9
0 (br. S., 1H), 4.51 (d, J = 13.6 Hz, 1H
), 4.41 (d, J = 13.8 Hz, 1H), 4.34 (d, J
= 13.3 Hz, 1H), 3.77 (s, 3H), 3.57 (d,
J = 10.5 Hz, 1H), 3.39 (dd, J = 13.1,3.
5 Hz, 1H), 3.23 (td, J = 12.4, 3.1 Hz, 1
H), 2.86 (dt, J = 13.3, 6.7 Hz, 1H), 1.4
9 (d, J = 6.5 Hz, 3H), 1.16 (br.s., 3H)
, 1.05 (br. S., 3H). LC-MS: m / z 445.2
(M + H) +.

(R) -6-isopropyl-5- (2-methoxyphenyl) -2- (3-methyl-4-
(2- (thiophen-2-yl) acetyl) piperazin-1-yl) nicotinonitrile (
Compound 177). Compound 177 is 1- (2-methoxyphenyl) -3-methylbutane-
Synthesized using 2-one as the starting material.
1H NMR (chloroform-d) δ 7.54 (s, 1H), 7.33 −
7.41 (m, 1H), 7.20-7.24 (m, 1H), 7.05
-7.11 (m, 1H), 6.98-7.04 (m, 1H), 6.
89-6.98 (m, 3H), 4.94 (br.s., 0.5H),
4.58 (d, J = 12.8 Hz, 0.2H), 4.17-4.46
(M, 3H), 3.91-4.04 (m, 2H), 3.76 (s,
3H), 3.56 (t, J = 11.2 Hz, 0.5H), 3.27 (
d, J = 12.8 Hz, 0.5H), 3.13-3.23 (m, 1
H), 2.98-3.11 (m, 1H), 2.85 (dt, J = 1)
3.3, 6.7 Hz, 1H), 1.33-1.39 (m, 3H), 1
. 15 (br. S., 3H), 1.04 (br. S., 3H). LC
-MS: m / z 475.2 (M + H) +.

(R) -6-isopropyl-5- (2-methoxyphenyl) -2- (3-methyl-4-
(2-Methylfuran-3-carbonyl) piperazin-1-yl) nicotinonitrile (Compound 178). Compound 178 is 1- (2-methoxyphenyl) -3-methylbutane-2-
Synthesized using ON as starting material.
1H NMR (chloroform-d) δ 7.52-7.59 (m, 1H),
7.34-7.41 (m, 1H), 7.29 (d, J = 1.8 H
z, 1H), 7.08 (dd, J = 7.3, 1.8 Hz, 1H),
7.01 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 8
. 3 Hz, 1H), 6.38 (d, J = 1.8 Hz, 1H), 4.
69 (br. S., 1H), 4.29-4.43 (m, 2H), 4.
00-4.29 (m, 1H), 3.77 (s, 3H), 3.46 (b
r. s. , 1H), 3.24-3.39 (m, 1H), 3.11 (t
d, J = 12.5, 3.0 Hz, 1H), 2.86 (spt, J =
6.6 Hz, 1H), 2.41 (s, 3H), 1.43 (d, J =
6.8 Hz, 3H), 1.12-1.19 (m, 3H), 1.04
(Br.s., 3H). LC-MS: m / z 459.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-p-tolylnicotinonitrile (Compound 179). Compound 179
Was synthesized using 3-methyl-1-p-tolylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.75 (s, 1H), 7.60 (
s, 1H), 7.44-7.49 (m, 1H), 7.24 (d, J
= 7.8 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H),
6.55-6.62 (m, 1H), 4.74 (br.s., 1H),
4.20-4.49 (m, 3H), 3.38-3.57 (m, 1H
), 3.31 (dd, J = 13.1, 3.0 Hz, 1H), 3.07
-3.22 (m, 2H), 2.37-2.46 (m, 3H),
45 (d, J = 6.8 Hz, 3H), 1.07-1.20 (m,
6H). LC-MS: m / z 429.1 (M + H) +.

(R) -2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-5-p-tolylnicotinonitrile (Compound 180). Compound 180
Was synthesized using 3-methyl-1-p-tolylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.50 −
7.53 (m, 1H), 7.24 (d, J = 7.8 Hz, 2H),
7.13 (d, J = 8.0 Hz, 2H), 7.05 (d, J =
3.5 Hz, 1H), 6.46-6.55 (m, 1H), 4.90 (
br. s. , 1H), 4.51 (d, J = 13.6 Hz, 1H),
4.42 (d, J = 14.1 Hz, 1H), 4.33 (dt, J =
13.3, 2.0 Hz, 1H), 3.57 (d, J = 10.3 Hz)
, 1H), 3.40 (dd, J = 13.2, 3.6 Hz, 1H),
3.18-3.30 (m, 1H), 3.09-3.18 (m, 1H)
, 2.41 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H)
1.07-1.20 (m, 6H). LC-MS: m / z 429.
2 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2- (thiophen-2-yl))
Acetyl) piperazin-1-yl) -5-p-tolylnicotinonitrile (Compound 181)
. Compound 181 was synthesized using 3-methyl-1-p-tolylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.58 (s, 1H), 7.20 −
7.25 (m, 3H), 7.12 (d, J = 7.8 Hz, 2H),
6.88-7.00 (m, 2H), 4.94 (br. S., 0.5H
), 4.58 (d, J = 13.1 Hz, 0.5H), 4.32-4
. 43 (m, 1H), 4.27 (s, 1H), 4.30 (s, 1H),
3.91-4.05 (m, 2H), 3.80 (d, J = 13.6
Hz, 0.5H), 3.51-3.63 (m, 0.5H), 3.20-
3.33 (m, 1H), 3.11-3.20 (m, 1H), 2.98
-3.10 (m, 1H), 2.41 (s, 3H), 1.36 (d,
J = 6.3 Hz, 1.5H), 1.32 (d, J = 6.8 Hz,
1.5H), 1.13 (d, J = 6.5 Hz, 6H). LC-MS
: M / z 459.1 (M + H) +.

(R) -6-Isopropyl-2- (3-methyl-4- (2-methylfuran-3-carbonyl) piperazin-1-yl) -5-p-tolylnicotinonitrile (Compound 182). Compound 182 was synthesized using 3-methyl-1-p-tolylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.28 −
7.32 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H),
7.12 (d, J = 8.0 Hz, 2H), 6.36-6.41 (
m, 1H), 4.69 (br. s., 1H), 4.38 (d, J =
13.3 Hz, 1H), 4.33 (d, J = 13.1 Hz, 1H),
4.23 (d, J = 12.0 Hz, 1H), 3.46 (br. S.
, 1H), 3.26-3.34 (m, 1H), 3.13-3.21
(M, 1H), 3.05-3.13 (m, 1H), 2.41 (s, 6
H), 1.41 (d, J = 6.8 Hz, 3H), 1.14 (dd,
J = 6.7, 3.4 Hz, 6H). LC-MS: m / z 443.2
(M + H) +.

(R) -6-isopropyl-5- (2-methoxyphenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 183)
). Compound 183 was synthesized using 1- (2-methoxyphenyl) -3-methylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.55 (s, 1H), 7.34 −
7.42 (m, 1H), 7.05-7.12 (m, 1H), 6.99
-7.05 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H
), 4.93 (br. S., 0.5H), 4.55 (d, J = 13.
1 Hz, 0.5H), 4.19-4.43 (m, 3H), 3.82 (
d, J = 7.5 Hz, 0.5H), 3.76 (s, 3H), 3.70
-3.76 (m, 2H), 3.54-3.64 (m, 0.5H),
3.38 (s, 3H), 3.30 (t, J = 13.3 Hz, 1H),
3.02-3.22 (m, 1H), 2.82-2.92 (m, 1H
), 2.66-2.80 (m, 1H), 2.53-2.65 (m,
1H), 1.42 (d, J = 6.5 Hz, 1.5H), 1.32 (d
, J = 6.5 Hz, 1.5H), 1.16 (br.s., 3H),
1.05 (br.s., 3H). LC-MS: m / z 437.1 (M
+ H) +.

(S) -5- (2-Ethoxyphenyl) -2- (4- (furan-2-carbonyl) -2
-Methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 184)
. Compound 184 was synthesized using 1- (2-ethoxyphenyl) -3-methylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.55 (s, 1H), 7.48 −
7.53 (m, 1H), 7.31-7.38 (m, 1H), 7.05
-7.11 (m, 2H), 6.96-7.02 (m, 1H), 6.
94 (d, J = 8.3 Hz, 1H), 6.45-6.56 (m,
1H), 4.77 (br. S., 1H), 4.53 (d, J = 11.
3 Hz, 1H), 4.36 (d, J = 13.3 Hz, 1H), 4.
23-4.33 (m, 1H), 4.02 (q, J = 6.8 Hz,
2H), 3.38-3.67 (m, 3H), 2.84-2.97 (m
, 1H), 1.36 (d, J = 6.8 Hz, 3H), 1.27 −
1.30 (m, 3H), 1.24-1.27 (m, 6H). LC-M
S: m / z 459.1 (M + H) +.

(R) -6-Isopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-p-tolylnicotinonitrile (Compound 198). Compound 19
8 was synthesized using 3-methyl-1-p-tolylbutan-2-one as the starting material.
1H NMR (chloroform-d) δ 7.59 (s, 1H), 7.23 (
d, J = 7.8 Hz, 2H), 7.12 (d, J = 8.0 Hz,
2H), 4.92 (br.s., 0.5H), 4.55 (d, J =
12.8 Hz, 0.5H), 4.21-4.42 (m, 3H), 3.8
1 (d, J = 13.8 Hz, 0.5H), 3.69-3.77 (m
, 62H), 3.53-3.64 (m, 0.5H), 3.38 (s,
3H), 3.31 (t, J = 12.3 Hz, 1H), 3.11-3
. 19 (m, 2H), 2.65-2.81 (m, 1H), 2.54-
2.63 (m, 1H), 2.41 (s, 3H), 1.40 (d, J
= 6.3 Hz, 1.5 H), 1.31 (d, J = 6.5 Hz, 1.
5H), 1.14 (d, J = 6.8 Hz, 6H). LC-MS:
m / z 421.1 (M + H) +.

(R) -2- (4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) -5,6-diphenylnicotinonitrile (Compound 240). Compound 240 is 1,2-
Synthesized using diphenylethanone as the starting material.
1H NMR (chloroform-d) δ 7.84 (s, 1H), 7.33 −
7.40 (m, 2H), 7.26-7.33 (m, 4H), 7.20
-7.25 (m, 2H), 7.08-7.16 (m, 2H), 4.
94 (br. S., 0.5H), 4.56 (d, J = 12.8 Hz,
0.5H), 4.38-4.49 (m, 1H), 4.23-4.48
(M, 2H), 3.77-3.90 (m, 1H), 3.74 (t,
J = 6.0 Hz, 2H), 3.54-3.64 (m, 0.5H),
3.37 (s, 3H), 3.34 (d, J = 6.3 Hz, 0.5H)
, 3.19-3.26 (m, 1H), 3.06-3.19 (m, 1
H), 2.66-2.78 (m, 1H), 2.55-2.63 (m,
1H), 1.39-1.46 (m, 1.5H), 1.33 (d, J
= 6.0 Hz, 1.5H). LC-MS: m / z 441.3 (M + H
) +.

Example 10
(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
Preparation of -6-isopropyl-4-phenylnicotinonitrile (Compound 130). Compound 1
30 (55, where m is 1 and R ³ is methyl; R ⁸ is furan-3-yl) was synthesized according to General Scheme 7.
Scheme 7.

Step W: 2-Hydroxy-6-isopropyl-4-phenylnicotinonitrile (5
2). To a suspension of ammonium acetate (31.46 g, 0.4 mol) in 200 mL EtOH, 3-methyl-2-butanone (51; 5.38 mL, 50 mmol), benzaldehyde (50; 5.21 g, 50 mmol), and Ethyl cyanoacetate (23; 5.6 mL
, 50 mmol) was added continuously. The resulting mixture was stirred at reflux temperature for 3 hours, followed by stirring overnight at room temperature. After LC-MS showed formation of the desired product, the formed precipitate was filtered and washed with EtOH (10 mL × 3) and hexane (10 mL × 3). After air drying, 2.18 g of 52 was obtained as a white solid. MS (ES) M + H predicted value 239.1, found value 239.0. 1H NMR (chloroform-d) δ 7.6
1-7.70 (m, 2H), 7.51-7.58 (m, 3H), 6
. 33 (s, 1H), 3.06 (dt, J = 13.8, 6.9 Hz,
1H), 1.42 (d, J = 7.0 Hz, 6H).

Step X: 2-Chloro-6-isopropyl-4-phenylnicotinonitrile (53)
. 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile 52; (0.70
2 g, 2.94 mmol), 7 mL phosphoryl trichloride and 1 drop of DMF
Heated to reflux overnight until LC-MS showed complete conversion to product. After excess phosphoryl trichloride was evaporated under reduced pressure, the residue was redissolved in methylene chloride and saturated aqueous NaHCO 3.
₃ was carefully neutralized followed by washing with 1N HCl and brine. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatography (1: 5 ethyl acetate / petroleum ether) gave 717 mg of 53 as a yellowish solid. MS (ES) M + H predicted value 257.1, found value 257.0. 1H NMR
(Chloroform-d) δ 7.52-7.64 (m, 5H), 7.26 (
s, 1H), 3.09-3.21 (m, 1H), 1.37 (d, J
= 7.0 Hz, 6H).

Step Y: (R) -6-isopropyl-2- (3-methylpiperazin-1-yl)-
4-Phenylnicotinonitrile (54). Chloride 53 (192.6 mg, 0.75 m
mol), (R) -2-methylpiperazine (150 mg, 1.5 mmol), and triethylamine (0.21 mL, 1.5 mmol) suspended in 1.5 mL of acetonitrile were subjected to 175 microwave reaction. C. for 45 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography to give 197 mg of 54 as a yellowish oil. MS (ES) M + H predicted value 321.2, measured value 321.
1.1H NMR (chloroform-d) δ 7.54-7.60 (m, 2H
), 7.47-7.53 (m, 3H), 6.71 (s, 1H), 4.
21-4.35 (m, 2H), 3.03-3.18 (m, 4H),
2.99 (dt, J = 13.8, 6.9 Hz, 1H), 2.78 (d
d, J = 12.7, 10.2 Hz, 1H), 1.30 (d, J =
7.0 Hz, 6H), 1.15-1.20 (m, 3H).

Step Z: (R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 130). 5
In a mL amber glass vial, (R) -6-isopropyl-2- (3-methylpiperazin-1-yl) -4-phenyl-nicotinonitrile (54; 32 mg, 0.1 mmo).
l), furan-3-carboxylic acid (22.4 mg, 0.312 mmol), EDCI (38
. 2 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol), triethylamine (35 μL, 0.2 mmol) and 1.5 mL of methylene chloride were charged. The resulting reaction mixture was stirred at room temperature overnight. The mixture was quenched with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were washed with saturated NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Preparative TL for crude product
Purified by C (EtOAc: petroleum ether / 20: 100) to give 23 mg of compound 130
Was obtained as a pale yellow solid. MS (ES) M + H predicted value 415.2, actual value 415.1.
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.55 −
7.58 (m, 2H), 7.50-7.53 (m, 3H), 7.48
(T, J = 1.6 Hz, 1H), 6.79 (s, 1H), 6.60
-6.62 (m, 1H), 4.76 (br. S., 1H), 4.28
(S, 1H), 4.31 (s, 1H), 4.22 (d, J = 13.
1 Hz, 1H), 3.56 (br. S., 1H), 3.34 (dd,
J = 12.9, 3.6 Hz, 1H), 3.17 (td, J = 12.
5, 3.5 Hz, 1H), 3.01 (spt, J = 6.9 Hz, 1
H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 (d, J
= 6.8 Hz, 6H).

R ^1a is optionally substituted phenyl; R ^1b is hydrogen; other compounds of formula II listed below start from (1) 3-methyl-2-butanone (51) Replacing with alternative ketone as material; (2) Replacing benzaldehyde (50) with alternative aldehyde as starting material; (3) In step Y, (R) -2-
Prepared similarly according to general scheme 7 by one or more of replacing methylpiperazine with alternative piperazine; and (4) replacing 2-methylfuran-3-carboxylic acid with alternative acid in step Z. In addition, R ^1a is isopropyl; R ^1b
A compound in which R ² is hydrogen and R ² is phenyl was also prepared by the same method of general scheme 7.

2- (4-Benzoylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 100).
1H NMR (DMSO-d6) δ 7.54-7.59 (m, 2H),
7.50-7.54 (m, 3H), 7.47 (s, 5H), 6.80
(S, 1H), 4.01 (br. S., 2H), 3.74-3.89
(M, 3H), 3.66 (br. S., 3H), 3.01 (quin,
J = 6.8 Hz, 1H), 1.32 (s, 3H), 1.30 (s,
3H). LC-MS: m / z 411.1 (M + H) +.

2-((3S, 5R) -4-benzoyl-3,5-dimethylpiperazin-1-yl)-
6-Isopropyl-4-phenylnicotinonitrile (Compound 101).
1H NMR (DMSO-d6) δ 7.53-7.58 (m, 2H),
7.49-7.53 (m, 3H), 7.40-7.47 (m, 5H)
, 6.79 (s, 1H), 4.54 (br. S., 2H), 4.24
(S, 1H), 4.27 (s, 1H), 3.28 (dd, J = 13.
1, 4.3 Hz, 2H), 3.01 (dt, J = 13.6, 6.9
Hz, 1H), 1.52 (d, J = 6.8 Hz, 6H), 1.31
(D, J = 7.0 Hz, 6H). LC-MS: m / z 439.1
(M + H) +.

2-((3S, 5R) -4- (furan-2-carbonyl) -3,5-dimethylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 102).
1H NMR (chloroform-d) δ 7.54-7.61 (m, 2H),
7.45-7.54 (m, 4H), 7.08 (d, J = 3.5 H
z, 1H), 6.78 (s, 1H), 6.52 (dd, J = 3.5,
1.8 Hz, 1H), 4.90 (br.s., 2H), 4.30 (s
, 1H), 4.34 (s, 1H), 3.32 (dd, J = 12.9,
4.4 Hz, 2H), 3.01 (quin, J = 6.9 Hz, 1H
), 1.60 (d, J = 7.0 Hz, 6H), 1.31 (d, J
= 7.0 Hz, 6H). LC-MS: m / z 429.1 (M + H) +
.

2- (4- (Furan-2-carbonyl) piperazin-1-yl) -4-isopropyl-
6-Phenylnicotinonitrile (Compound 103). Compound 103 was synthesized using isobutyraldehyde and acetophenone as starting materials.
1H NMR (DMSO-d6) δ 8.02-8.08 (m, 2H),
7.50-7.56 (m, 2H), 7.46-7.50 (m, 2H)
, 7.30 (s, 1H), 7.08 (dd, J = 3.4, 0.6 H
z, 1H), 6.53 (dd, J = 3.3, 1.8 Hz, 1H),
4.05 (br. S., 4H), 3.79-3.85 (m, 4H),
3.40 (dt, J = 13.7, 6.8 Hz, 1H), 1.38 (d
, J = 6.8 Hz, 6H). LC-MS: m / z 400.8 (M
+ H) +.

2- (4- (Furan-2-carbonyl) piperazin-1-yl) -6-isopropyl-
4- (2-methoxyphenyl) nicotinonitrile (Compound 104). Compound 104 is 2
-Methoxybenzaldehyde and 3-methylbutan-2-one were synthesized using as starting materials.
1H NMR (chloroform-d) δ 7.51-7.57 (m, 1H),
7.43-7.51 (m, 1H), 7.23-7.28 (m, 1H
), 7.03-7.11 (m, 3H), 6.75 (s, 1H), 6.
53 (dd, J = 3.0, 1.5 Hz, 1H), 4.02 (br.
s. , 4H), 3.89 (s, 3H), 3.74-3.82 (m, 4
H), 3.00 (dt, J = 13.8, 6.9 Hz, 1H), 1.3
1 (d, J = 6.8 Hz, 6H). LC-MS: m / z 430.
9 (M + H) +.

2- (4-Benzoylpiperazin-1-yl) -6-isopropyl-4- (2-methoxyphenyl) nicotinonitrile (Compound 105). Compound 105 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (DMSO-d6) δ 7.43-7.50 (m, 6H),
7.25 (dd, J = 7.4, 1.6 Hz, 1H), 7.07-7
. 10 (m, 1H), 7.02-7.06 (m, 1H), 6.75 (
s, 1H), 3.99 (br. s., 2H), 3.87 (s, 3H),
3.78 (br.s., 2H), 3.64 (br.s., 4H), 2
. 99 (dt, J = 13.8, 6.9 Hz, 1H), 1.31 (s,
3H), 1.29 (s, 3H). LC-MS: m / z 440.8 (
M + H) +.

2- (4- (1H-indole-3-carbonyl) piperazin-1-yl) -6-isopropyl-4- (2-methoxyphenyl) nicotinonitrile (Compound 106). Compound 1
06 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 9.02 (br.s., 1H), 7
. 73-7.80 (m, 1H), 7.41-7.51 (m, 3H),
7.21-7.28 (m, 3H), 7.01-7.11 (m, 2H
), 6.75 (s, 1H), 3.94 (br.s., 4H), 3.87
(S, 3H), 3.75 (br. S., 4H), 3.02 (dt, J
= 13.7, 6.8 Hz, 1H), 1.31 (d, J = 6.8 H
z, 6H). LC-MS: m / z 480 (M + H) +.

2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 107).
1H NMR (chloroform-d) δ 7.55-7.60 (m, 2H),
7.48-7.54 (m, 4H), 7.06 (dd, J = 3.5,
0.8 Hz, 1H), 6.77 (s, 1H), 6.52 (dd, J
= 3.5, 1.8 Hz, 1H), 4.91 (br. S., 1H), 4
. 52 (d, J = 13.6 Hz, 1H), 4.29-4.36 (m
, 1H), 4.23 (dt, J = 13.1, 2.1 Hz, 1H),
3.62 (br.s., 1H), 3.43 (dd, J = 13.1, 3
. 8 Hz, 1H), 3.26 (td, J = 12.4, 3.5 Hz,
1H), 3.00 (quin, J = 6.9 Hz, 1H), 1.50 (
d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.8 Hz,
6H). LC-MS: m / z 415.1 (M + H) +.

2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl) -4-isopropyl-6-phenylnicotinonitrile (Compound 108). Compound 108 was synthesized using benzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 8.00-8.08 (m, 2H),
7.50-7.57 (m, 2H), 7.45-7.50 (m, 2H)
), 7.29 (s, 1H), 7.07 (dd, J = 3.5, 0.5
Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H),
4.94 (br. S., 1H), 4.54 (d, J = 13.3 Hz)
, 1H), 4.34 (dd, J = 12.5, 2.3 Hz, 1H),
4.24 (dt, J = 13.1, 2.1 Hz, 1H), 3.65 (b
r. s. , 1H), 3.41-3.46 (m, 1H), 3.38-
3.41 (m, 1H), 3.25 (td, J = 12.4, 3.3 Hz)
, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.38 (d
, J = 6.8 Hz, 6H). LC-MS: m / z 415.1 (M
+ H) +.

2- (4- (Furan-3-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 110).
1H NMR (chloroform-d) δ 8.00-8.06 (m, 2H),
7.77 (s, 1H), 7.50 (br. S., 1H), 7.48 (
d, J = 4.3 Hz, 3H), 7.30 (s, 1H), 6.61 (
s, 1H), 4.78 (br. s., 1H), 4.28 (s, 1H),
4.31 (s, 1H), 4.22 (d, J = 13.1 Hz, 1H)
, 3.58 (br. S., 1H), 3.40 (quin, J = 6.9)
Hz, 1H), 3.33 (dd, J = 12.9, 3.1 Hz, 1H
), 3.17 (td, J = 12.4, 3.3 Hz, 1H), 1.50
(D, J = 6.8 Hz, 3H), 1.38 (d, J = 6.8 H
z, 6H). LC-MS: m / z 415.0 (M + H) +.

2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -4-isopropyl-6-phenylnicotinonitrile (Compound 111). Compound 111 was synthesized using benzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.53 −
7.61 (m, 2H), 7.49-7.53 (m, 3H), 7.47
(S, 1H), 6.79 (s, 4H), 6.61 (s, 1H), 4.
71-4.76 (br. S., 1H), 4.28 (s, 1H), 4.31
(S, 1H), 4.22 (d, J = 13.1 Hz, 1H), 3.5
6 (br.s., 1H), 3.34 (dd, J = 13.1, 3.3)
Hz, 1H), 3.17 (td, J = 12.5, 3.4 Hz, 1H)
, 3.00 (dt, J = 13.7, 6.8 Hz, 1H), 1.47
(D, J = 6.8 Hz, 3H), 1.29 (d, J = 7.3 Hz)
, 6H). LC-MS: m / z 414.9 (M + H) +.

2- (4- (Furan-3-carbonyl) piperazin-1-yl) -6-isopropyl-
4- (2-methoxyphenyl) nicotinonitrile (Compound 113). Compound 113 is 2
-Methoxybenzaldehyde and 3-methylbutan-2-one were synthesized using as starting materials.
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.42 −
7.53 (m, 2H), 7.25 (dd, J = 7.5, 1.5 Hz)
, 1H), 7.02-7.13 (m, 2H), 6.76 (s, 1H)
, 6.59-6.66 (m, 1H), 3.90 (br.s., 4H)
3.88 (s, 3H), 3.73 (br. S., 4H), 3.00
(Dt, J = 13.7, 6.8 Hz, 1H), 1.30 (d, J =
6.8 Hz, 6H). LC-MS: m / z 431.0 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-2-carbonyl) piperazine-
1-yl) -6-isopropylnicotinonitrile (Compound 114). Compound 114 is 3
-Synthesized using fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.42-7.56 (m, 2H),
7.36 (dq, J = 7.7, 0.9 Hz, 1H), 7.17 −
7.27 (m, 2H), 7.09 (dd, J = 3.4, 0.9 Hz,
1H), 6.76 (s, 1H), 6.53 (dd, J = 3.5, 1
. 8 Hz, 1H), 4.03 (br.s., 4H), 3.83 (dd,
J = 6.3, 4.0 Hz, 4H), 2.95-3.10 (m, 1
H), 1.31 (d, J = 6.8 Hz, 6H). LC-MS: m
/ Z 419.1 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-3-carbonyl) piperazine-
1-yl) -6-isopropylnicotinonitrile (Compound 115). Compound 115 is 3
-Synthesized using fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.77-7.80 (m, 1H),
7.45-7.53 (m, 2H), 7.36 (dt, J = 7.7,
1.2 Hz, 1H), 7.17-7.28 (m, 2H), 6.77.
(S, 1H), 6.62 (dd, J = 1.9, 0.6 Hz, 1H),
3.92 (br.s., 4H), 3.77 (br.s., 4H), 2
. 92-3.10 (m, 1H), 1.31 (d, J = 6.8 Hz,
6H). LC-MS: m / z 419.0 (M + H) +.

2- (4- (1H-indole-3-carbonyl) piperazin-1-yl) -4- (3
-Fluorophenyl) -6-isopropylnicotinonitrile (Compound 116). Compound 1
16 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.75 (d, J = 7.0 Hz,
1H), 7.40-7.63 (m, 3H), 7.36 (d, J =
7.8 Hz, 1H), 7.17-7.28 (m, 3H), 6.77 (
s, 1H), 3.94 (br. s., 4H), 3.79 (br. s.,
4H), 3.67 (s, 1H), 3.02-3.13 (m, 1H),
1.32 (d, J = 6.8 Hz, 6H). LC-MS: m / z
468.1 (M + H) +.

6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazine-1
-Yl) -4-phenylnicotinonitrile (compound 121).
1H NMR (chloroform-d) δ 7.48-7.58 (m, 5H),
7.33-7.39 (m, 3H), 7.30 (d, J = 1.5 H
z, 1H), 7.25-7.28 (m, 1H), 6.75 (s, 1H)
), 4.71 (s, 1H), 4.27 (br.s., 1H), 4.09
-4.20 (m, 2H), 3.80 (br. S., 2H), 3.52
(S, 1H), 3.19-3.26 (s, 1H), 3.06-3.15
(M, 1H), 2.98 (dt, J = 13.7, 6.8 Hz, 1H
), 1.40 (s, 3H), 1.30 (d, J = 4.5 Hz, 19
H). LC-MS: m / z 439.2 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 127). Compound 127 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.44-7.58 (m, 2H),
7.31-7.40 (m, 1H), 7.14-7.27 (m, 2H
), 7.07 (d, J = 3.5 Hz, 1H), 6.74 (s, 1H)
), 6.53 (dd, J = 3.5, 1.8 Hz, 1H), 4.92
(Br. S., 1H), 4.52 (d, J = 13.6 Hz, 1H),
4.34 (d, J = 10.5 Hz, 1H), 4.24 (dt, J
= 13.1, 2.1 Hz, 1H), 3.62 (br. S., 1H),
3.45 (dd, J = 13.3, 3.8 Hz, 1H), 3.28 (t
d, J = 12.4, 3.4 Hz, 1H), 3.01 (dt, J =
13.6, 6.9 Hz, 1H), 1.44-1.54 (m, 3H),
1.31 (d, J = 6.8 Hz, 6H). LC-MS: m / z 4
33.0 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 128). Compound 128 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.73-7.81 (m, 1H),
7.44-7.56 (m, 2H), 7.35 (dt, J = 8.0,
1.1 Hz, 1H), 7.12-7.27 (m, 2H), 6.75.
(S, 1H), 6.61 (dd, J = 1.8, 0.8 Hz, 1H),
4.77 (br. S., 1H), 4.31 (d, J = 12.0 Hz)
, 2H), 4.23 (d, J = 13.1 Hz, 1H), 3.57 (
br. s. , 1H), 3.36 (d, J = 10.0 Hz, 1H),
3.19 (td, J = 12.4, 3.5 Hz, 1H), 3.01 (d
t, J = 13.5, 6.9 Hz, 1H), 1.46 (d, J = 6
. 8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 6H). L
C-MS: m / z 433.1 (M + H) +.

2- (4- (1H-indole-3-carbonyl) -3-methylpiperazin-1-yl) -4- (3-fluorophenyl) -6-isopropylnicotinonitrile (Compound 129
). Compound 129 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 8.85 (s, 1H), 7.75 (
d, J = 7.8 Hz, 1H), 7.40-7.54 (m, 3H),
7.35 (d, J = 7.8 Hz, 1H), 7.15-7.28 (
m, 4H), 6.74 (s, 1H), 4.84 (br.s., 1H),
4.28 (t, J = 15.3 Hz, 3H), 3.59 (d, J =
11.8 Hz, 1H), 3.41 (d, J = 11.0 Hz, 1H)
, 3.21 (t, J = 10.8 Hz, 1H), 3.00 (dt, J
= 13.8, 6.9 Hz, 1H), 1.45 (d, J = 6.5 H
z, 3H), 1.30 (d, J = 6.8 Hz, 6H). LC-MS
: M / z 482.2 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-4-phenylnicotinonitrile (Compound 130).
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.55 −
7.58 (m, 2H), 7.50-7.53 (m, 3H), 7.48
(T, J = 1.6 Hz, 1H), 6.79 (s, 1H), 6.60
-6.62 (m, 1H), 4.76 (br. S., 1H), 4.28
(S, 1H), 4.31 (s, 1H), 4.22 (d, J = 13.
1 Hz, 1H), 3.56 (br. S., 1H), 3.34 (dd,
J = 12.9, 3.6 Hz, 1H), 3.17 (td, J = 12.
5, 3.5 Hz, 1H), 3.01 (spt, J = 6.9 Hz, 1
H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 (d, J
= 6.8 Hz, 6H). LC-MS: m / z 415.1 (M + H)
+.

(R) -6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazin-1-yl) -4-phenylnicotinonitrile (Compound 131).
1H NMR (chloroform-d) δ 7.52-7.57 (m, 2H),
7.47-7.52 (m, 3H), 7.29-7.41 (m, 4H)
), 7.24-7.28 (m, 1H), 6.75 (s, 1H), 4.
98 (br. S., 0.5H), 4.62 (d, J = 13.3 Hz,
0.5H), 4.28 (d, J = 13.1 Hz, 1H), 4.06
-4.20 (m, 2H), 3.81 (br. S., 2H), 3.70
-3.79 (m, 0.5H), 3.54 (t, J = 11.3 Hz,
0.5H), 3.18-3.33 (m, 1H), 3.03-3.17
(M, 1H), 2.99 (dt, J = 13.8, 6.9 Hz, 1H)
, 1.33 (br.s., 3H), 1.29 (d, J = 7.0 Hz)
, 6H). LC-MS: m / z 439.1 (M + H) +.

(S) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-4-phenylnicotinonitrile (Compound 132).
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.54-
7.59 (m, 2H), 7.49-7.54 (m, 3H), 7.48
(T, J = 1.6 Hz, 1H), 6.79 (s, 1H), 6.59
-6.63 (m, 1H), 4.76 (br. S., 1H), 4.28
(S, 1H), 4.31 (s, 1H), 4.22 (d, J = 13.
3 Hz, 1H), 3.57 (br. S., 1H), 3.34 (dd,
J = 13.2, 3.6 Hz, 1H), 3.17 (td, J = 12.
5, 3.4 Hz, 1H), 3.01 (spt, J = 6.9 Hz, 1
H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 (d, J
= 6.8 Hz, 6H). LC-MS: m / z 415.1 (M + H)
+.

(S) -6-Isopropyl-2- (3-methyl-4- (2-phenylacetyl) piperazin-1-yl) -4-phenylnicotinonitrile (Compound 133).
1H NMR (chloroform-d) δ 7.53-7.56 (m, 2H),
7.47-7.53 (m, 3H), 7.33-7.39 (m, 2H
), 7.29-7.33 (m, 2H), 7.24-7.28 (m,
1H), 6.75 (s, 1H), 4.98 (br.s., 0.5H),
4.62 (d, J = 13.3 Hz, 0.5H), 4.28 (d, J
= 12.8 Hz, 1H), 4.08-4.20 (m, 2H), 3.8
1 (br.s., 2H), 3.70-3.79 (m, 0.5H), 3
. 54 (t, J = 11.3 Hz, 0.5H), 3.17-3.32.
(M, 1H), 3.10 (t, J = 12.7 Hz, 1H), 2.98
(Dt, J = 13.7, 6.8 Hz, 1H), 1.31-1.35
(M, 3H), 1.29 (d, J = 7.0 Hz, 6H). LC-
MS: m / z 439.1 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-3-carbonyl) -3,5-dimethylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 134).
Compound 134 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (DMSO-d6) δ 7.77 (s, 1H), 7.45 −
7.53 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H),
7.17-7.25 (m, 2H), 6.76 (s, 1H), 6.65
(D, J = 1.0 Hz, 1H), 4.71 (br.s., 1H),
4.31 (d, J = 12.8 Hz, 2H), 3.50-3.69 (
m, 1H), 3.27 (dd, J = 13.2, 4.4 Hz, 2H),
3.01 (quin, J = 7.0 Hz, 1H), 1.56 (d, J
= 7.0 Hz, 6H), 1.32 (s, 3H), 1.30 (s, 3
H). LC-MS: m / z 447.1 (M + H) +.

2- (3,5-Dimethyl-4- (2-phenylacetyl) piperazin-1-yl) -4
-(3-Fluorophenyl) -6-isopropylnicotinonitrile (Compound 135). Compound 135 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.43-7.55 (m, 1H),
7.12-7.40 (m, 8H), 6.74 (s, 1H), 4.90
(Br.s., 1H), 4.26 (br.s., 3H), 3.82 (
s, 2H), 3.14 (br. s., 2H), 3.00 (dt, J =
13.8, 6.9 Hz, 1H), 1.44 (d, J = 6.8 Hz,
6H), 1.30 (d, J = 6.8 Hz, 6H). LC-MS:
m / z 471.1 (M + H) +.

4- (3-Fluorophenyl) -2- (4- (furan-2-carbonyl) -3,5-dimethylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 136).
Compound 136 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.45-7.55 (m, 2H),
7.32-7.38 (m, 1H), 7.15-7.28 (m, 2H
), 7.08 (d, J = 3.5 Hz, 1H), 6.74 (s, 1H)
), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.90.
(Br. S., 2H), 4.34 (d, J = 13.1 Hz, 2H),
3.33 (dd, J = 13.1, 4.5 Hz, 2H), 2.93 −
3.08 (m, 1H), 1.59 (d, J = 7.0 Hz, 6H),
1.31 (d, J = 6.8 Hz, 6H). LC-MS: m / z
447.0 (M + H) +.

6-cyclohexyl-2- (4- (furan-2-carbonyl) piperazin-1-yl)
-4-phenylnicotinonitrile (Compound 137). Compound 137 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (chloroform-d) δ 7.46-7.61 (m, 6H),
7.08 (dd, J = 3.4, 0.9 Hz, 1H), 6.78 (s
, 1H), 6.53 (dd, J = 3.4, 1.9 Hz, 1H), 4
. 03 (br. S., 4H), 3.76-3.86 (m, 4H), 2
. 66 (tt, J = 11.6, 3.3 Hz, 1H), 1.92-2
. 00 (m, 2H), 1.83-1.91 (m, 2H), 1.74-
1.82 (m, 1H), 1.55 (qd, J = 12.3, 2.8 H
z, 2H), 1.41 (qt, J = 12.6, 3.1 Hz, 2H),
1.25-1.35 (m, 1H). LC-MS: m / z 441.0
(M + H) +.

6-Cyclohexyl-2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -4-phenylnicotinonitrile (Compound 138). Compound 138 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.43 −
7.61 (m, 6H), 6.77 (s, 1H), 6.61 (s, 1H)
), 4.76 (br.s., 1H), 4.29 (d, J = 12.3.
Hz, 2H), 4.20 (d, J = 13.1 Hz, 1H), 3.56
(Br.s., 1H), 3.33 (dd, J = 13.2, 3.1 H
z, 1H), 3.16 (td, J = 12.5, 3.1 Hz, 1H),
2.56-2.72 (m, 1H), 1.95 (d, J = 12.5)
Hz, 2H), 1.87 (d, J = 12.8 Hz, 2H), 1.78
(D, J = 12.8 Hz, 1H), 1.49-1.60 (m, 2
H), 1.46 (d, J = 6.5 Hz, 3H), 1.35-1.4
4 (m, 2H), 1.25-1.34 (m, 1H). LC-MS:
m / z 455.1 (M + H) +.

6-cyclohexyl-2-((3S, 5R) -4- (furan-3-carbonyl) -3,
5-Dimethylpiperazin-1-yl) -4-phenylnicotinonitrile (Compound 142)
. Compound 142 was synthesized using benzaldehyde and 1-cyclohexylethanone as starting materials.
1H NMR (chloroform-d) δ 7.77 (s, 1H), 7.54-
7.58 (m, 2H), 7.49-7.53 (m, 3H), 7.48
(T, J = 1.6 Hz, 1H), 6.79 (s, 1H), 6.65
(D, J = 2.0 Hz, 1H), 4.73 (br.s., 2H),
4.27 (d, J = 13.1 Hz, 2H), 3.25 (dd, J
= 13.1, 4.5 Hz, 2H), 2.66 (tt, J = 11.6,
3.4 Hz, 1H), 1.95 (d, J = 12.5 Hz, 2H),
1.84-1.92 (m, 2H), 1.78 (d, J = 12.5
Hz, 1H), 1.57 (d, J = 7.0 Hz, 6H), 1.49
-1.54 (m, 2H), 1.38-1.47 (m, 2H), 1.3
1-1.37 (m, 1H). LC-MS: m / z 469.1 (M +
H) +.

6-Isopropyl-4- (2-methoxyphenyl) -2- (4- (2-phenylacetyl) piperazin-1-yl) nicotinonitrile (Compound 146). Compound 146 is 2-
Synthesized using methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.42-7.48 (m, 1H),
7.28-7.40 (m, 5H), 7.23 (dd, J = 7.5,
1.8 Hz, 1H), 7.01-7.10 (m, 2H), 6.73
(S, 1H), 3.83-3.90 (m, 5H), 3.82 (s, 2
H), 3.62-3.70 (m, 4H), 3.49-3.56 (m,
2H), 2.91-3.03 (m, 1H), 1.29 (d, J =
6.8 Hz, 6H). LC-MS: m / z 455.2 (M + H) +.

2- (4- (furan-2-carbonyl) -3-methylpiperazin-1-yl) -6-isopropyl-4- (2-methoxyphenyl) nicotinonitrile (Compound 147). Compound 147 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.52 (dd, J = 1.8, 0
. 8 Hz, 1H), 7.41-7.48 (m, 1H), 7.25 (d
d, J = 7.5, 1.8 Hz, 1H), 7.00-7.16 (m,
3H), 6.73 (s, 1H), 6.52 (dd, J = 3.5, 1
. 8 Hz, 1H), 4.91 (br.s., 1H), 4.51 (d,
J = 12.3 Hz, 1H), 4.32 (d, J = 12.5 Hz,
1H), 4.22 (dt, J = 13.2, 2.0 Hz, 1H),
88 (s, 3H), 3.62 (br. S., 1H), 3.39 (dd,
J = 13.2, 3.6 Hz, 1H), 3.22 (td, J = 12
. 4, 3.5 Hz, 1H), 3.00 (dt, J = 13.7, 6.8)
Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.30
(D, J = 6.8 Hz, 6H). LC-MS: m / z 455.1
(M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-4- (2-methoxyphenyl) nicotinonitrile (Compound 148)
. Compound 148 was synthesized using 2-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.76 (dd, J = 1.5, 0
. 8 Hz, 1H), 7.40-7.51 (m, 2H), 7.22-
7.28 (m, 1H), 7.01-7.11 (m, 2H), 6.70
-6.76 (m, 1H), 6.61 (dd, J = 1.8, 0.8 H
z, 1H), 4.75 (br.s., 1H), 4.16-4.45 (
m, 3H), 3.88 (s, 3H), 3.55 (br.s., 1H),
3.31 (dd, J = 12.9, 3.4 Hz, 1H), 3.14 (
td, J = 12.5, 3.4 Hz, 1H), 3.00 (dt, J =
13.7, 6.8 Hz, 1H), 1.46 (d, J = 7.0 Hz,
3H), 1.30 (d, J = 6.8 Hz, 6H). LC-MS:
m / z 445.2 (M + H) +.

6-Isopropyl-4- (2-methoxyphenyl) -2- (3-methyl-4- (2-phenylacetyl) piperazin-1-yl) nicotinonitrile (Compound 149). Compound 1
49 was synthesized using 3-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.41-7.49 (m, 1H),
7.29-7.40 (m, 4H), 7.20-7.28 (m, 2H
), 7.01-7.09 (m, 2H), 6.71 (s, 1H), 4.
97 (br. S., 1H), 4.60 (d, J = 13.3 Hz, 1
H), 4.25 (br.s., 1H), 4.16 (d, J = 13.3)
Hz, 1H), 3.87 (s, 3H), 3.64-3.81 (m,
2H), 3.53 (t, J = 11.4 Hz, 1H), 3.14-3
. 29 (m, 1H), 2.85-3.14 (m, 2H), 1.62 (
s, 3H), 1.29 (s, 6H). LC-MS: m / z 469.1
(M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-isopropyl-4- (3-methoxyphenyl) nicotinonitrile (Compound 151)
. Compound 151 was synthesized using 3-methoxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.76 (dd, J = 1.5, 0
. 8 Hz, 1H), 7.38-7.50 (m, 2H), 7.00-
7.17 (m, 3H), 6.76-6.81 (m, 1H), 6.61
(Dd, J = 1.9, 0.9 Hz, 1H), 4.76 (br.s.,
1H), 4.29 (d, J = 12.8 Hz, 2H), 4.21 (d
, J = 13.1 Hz, 1H), 3.84-3.92 (m, 3H),
3.56 (br. S., 1H), 3.33 (dd, J = 13.2,
3.6 Hz, 1H), 3.17 (td, J = 12.5, 3.4 Hz,
1H), 3.00 (dt, J = 13.7, 6.8 Hz, 1H), 1
. 47 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 7.
0 Hz, 6H). LC-MS: m / z 445.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-4- (3-hydroxyphenyl) -6-isopropylnicotinonitrile (Compound 152)
). Compound 152 was synthesized using 3-hydroxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.74-7.81 (m, 1H),
7.41-7.51 (m, 1H), 7.34 (t, J = 7.9 H
z, 1H), 7.11 (s, 1H), 7.05 (d, J = 7.5 H
z, 1H), 6.97 (dd, J = 8.2, 2.4 Hz, 1H),
6.79 (s, 1H), 6.57-6.64 (m, 1H), 4.79
(Br.s., 1H), 4.15-4.44 (m, 3H), 3.59.
(Br.s., 1H), 3.34 (d, J = 10.5 Hz, 1H),
3.17 (td, J = 12.5, 3.1 Hz, 1H), 2.93 −
3.04 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H),
1.27-1.31 (m, 6H). LC-MS: m / z 431.2
(M + H) +.

2- (4- (Furan-3-carbonyl) -3-phenylpiperazin-1-yl) -6-
Isopropyl-4-phenylnicotinonitrile (Compound 154).
1H NMR (chloroform-d) δ 7.61 (br.s., 1H), 7
. 50-7.54 (m, 2H), 7.46-7.50 (m, 3H),
7.37-7.43 (m, 3H), 7.34 (t, J = 7.7 H
z, 2H), 7.2-2.27 (m, 1H), 6.67 (s, 1H)
), 6.52 (br.s., 1H), 5.75 (br.s., 1H),
4.57 (br. S., 2H), 4.29 (d, J = 11.5 Hz)
, 1H), 4.00 (d, J = 11.0 Hz, 1H), 3.60 −
3.74 (m, 1H), 3.55 (d, J = 10.5 Hz, 1H)
, 2.94 (dt, J = 13.6, 6.8 Hz, 1H), 1.25
-1.27 (m, 3H), 1.23 (d, J = 7.0 Hz, 3H)
. LC-MS: m / z 477.1 (M + H) +.

2- (4- (furan-2-carbonyl) -3-phenylpiperazin-1-yl) -6-
Isopropyl-4-phenylnicotinonitrile (Compound 155).
1H NMR (chloroform-d) δ 7.51-7.55 (m, 2H),
7.46-7.50 (m, 4H), 7.45 (d, J = 7.5 H
z, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.20 −
7.25 (m, 1H), 6.92-7.07 (m, 1H), 6.68
(S, 1H), 6.45 (br. S., 1H), 5.95 (t, J
= 4.5 Hz, 1H), 4.63 (s, 1H), 4.66 (s, 1H)
), 4.33 (d, J = 11.0 Hz, 1H), 4.06 (dd,
J = 13.6, 4.0 Hz, 1H), 3.69 (br.s., 1H)
, 3.56-3.65 (m, 1H), 2.97 (dt, J = 13.
7, 6.8 Hz, 1H), 1.24-1.28 (m, 6H). LC
-MS: m / z 477.1 (M + H) +.

(R) -4- (3-Fluorophenyl) -2- (4- (furan-3-carbonyl) -3
-Methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 156)
. Compound 156 was synthesized using 3-fluorobenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.77 (dd, J = 1.5, 1
. 0 Hz, 1H), 7.43-7.53 (m, 2H), 7.35 (d
q, J = 7.7, 0.9 Hz, 1H), 7.12-7.28 (m,
2H), 6.67-6.80 (m, 1H), 6.61 (dd, J =
1.9, 0.9 Hz, 1H), 4.76 (br.s., 1H), 4.
17-4.45 (m, 3H), 3.56 (br.s., 1H), 3.
36 (dd, J = 13.1, 3.5 Hz, 1H), 3.18 (td,
J = 12.5, 3.5 Hz, 1H), 2.95-3.07 (m,
1H), 1.46 (d, J = 6.8 Hz, 3H), 1.29-1.
32 (m, 6H). LC-MS: m / z 433.1 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-4- (2-hydroxyphenyl) -6-isopropylnicotinonitrile (Compound 157
). Compound 157 was synthesized using 2-hydroxybenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 8.01 (dd, J = 8.2, 1
. 4 Hz, 1H), 7.73-7.77 (m, 1H), 7.50-
7.60 (m, 1H), 7.46 (t, J = 1.6 Hz, 1H),
7.31-7.37 (m, 2H), 7.21 (s, 1H), 6.60
(Dd, J = 1.6, 0.6 Hz, 1H), 4.71 (br. S.,
1H), 4.25 (br.s., 1H), 4.07 (d, J = 13
. 3 Hz, 1H), 3.98 (d, J = 13.8 Hz, 1H), 3
. 71 (br.s., 1H), 3.45-3.56 (m, 1H), 3
. 15-3.26 (m, 1H), 3.06 (dt, J = 13.7,
6.8 Hz, 1H), 1.32-1.37 (m, 9H). LC-MS
: M / z 432.2 (M + H) +.

(R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl)
-6-Isopropyl-4-o-tolylnicotinonitrile (Compound 158). Compound 158
Was synthesized using 2-methylbenzaldehyde and 3-methylbutan-2-one as starting materials.
1H NMR (chloroform-d) δ 7.72-7.79 (m, 1H),
7.47 (t, J = 1.6 Hz, 1H), 7.29-7.40 (
m, 3H), 7.19 (d, J = 6.8 Hz, 1H), 6.65 (
s, 1H), 6.60 (dd, J = 1.9, 0.9 Hz, 1H),
4.75 (br. S., 1H), 4.17-4.46 (m, 3H),
3.42-3.67 (m, 1H), 3.34 (dd, J = 13.1,
3.5 Hz, 1H), 3.16 (td, J = 12.5, 3.5 Hz)
, 1H), 2.92-3.03 (m, 1H), 2.24 (s, 3H)
1.45 (d, J = 6.3 Hz, 3H), 1.30 (d, J =
6.8 Hz, 6H). LC-MS: m / z 429.1 (M + H) +.

2- (4- (Furan-3-carbonyl) -2-phenylpiperazin-1-yl) -6-
Isopropyl-4-phenylnicotinonitrile (Compound 160).
1H NMR (chloroform-d) δ 7.69 (br.s., 1H), 7
. 64 (s, 1H), 7.45 (br.s., 2H), 7.36-7
. 44 (m, 4H), 7.31 (br. S., 2H), 7.16-7
. 26 (m, 3H), 6.57 (br. S., 1H), 5.37 (br
. s. , 1H), 4.15 (d, J = 9.8 Hz, 2H), 3.9
6 (d, J = 8.8 Hz, 4H), 2.98-3.12 (m, 1
H), 1.13 (d, J = 6.8 Hz, 6H). LC-MS: m
/ Z 477.2 (M + H) +.

(R) -2- (3-Cyano-2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -6-isopropylpyridin-4-yl) phenyl acetate (Compound 162). Compound 162 represents (R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -4- (2-hydroxyphenyl) -6-isopropylnicotinonitrile (Compound 157). Was synthesized by reaction with acetyl chloride.
1H NMR (methanol-d4) δ 7.76 (s, 1H), 7.39 −
7.58 (m, 3H), 7.31 (t, J = 1.9 Hz, 1H),
7.24 (dd, J = 7.7, 1.9 Hz, 1H), 6.78 (s
, 1H), 6.61 (d, J = 1.3 Hz, 1H), 4.76 (b
r. s. , 1H), 4.17-4.44 (m, 3H), 3.56 (b
r. s. , 1H), 3.34 (dd, J = 12.9, 3.4 Hz,
1H), 3.17 (td, J = 12.5, 3.5 Hz, 1H), 2.
93-3.06 (m, 1H), 2.27-2.43 (m, 3H),
1.46 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 7
. 0 Hz, 6H). LC-MS: m / z 473.1 (M + H) +.

(R) -4- (2-Ethoxyphenyl) -2- (4- (furan-3-carbonyl) -3
-Methylpiperazin-1-yl) -6-isopropylnicotinonitrile (Compound 163)
. Compound 163 is (R) -2- (4- (furan-3-carbonyl) -3-methylpiperazin-1-yl) -4- (2-hydroxyphenyl) -6-isopropylnicotinonitrile (Compound 157) Was synthesized by treatment with NaH / DMF followed by ethyl bromide quench.
1H NMR (methanol-d4) δ 7.76 (s, 1H), 7.37 −
7.51 (m, 2H), 6.98-7.16 (m, 3H), 6.79
(S, 1H), 6.57-6.64 (m, 1H), 4.76 (br.
s. , 1H), 4.17-4.45 (m, 3H), 4.12 (q,
J = 7.0 Hz, 2H), 3.56 (br.s., 1H), 3.34
(Dd, J = 12.9, 3.6 Hz, 1H), 3.17 (td, J
= 12.4, 3.3 Hz, 1H), 3.00 (quin, J = 6.
9 Hz, 1H), 1.47 (dt, J = 6.8, 3.5 Hz, 6H
), 1.30 (d, J = 6.8 Hz, 6H). LC-MS: m /
z 459.1 (M + H) +.

2- (4- (Furan-2-carbonyl) -2-phenylpiperazin-1-yl) -6-
Isopropyl-4-phenylnicotinonitrile (Compound 167).
1H NMR (chloroform-d) δ 7.64 (s, 1H), 7.52 (
s, 1H), 7.36-7.48 (m, 5H), 7.31 (br. s)
. , 2H), 7.22 (d, J = 6.5 Hz, 3H), 7.07 (
d, J = 3.0 Hz, 1H), 6.52 (br.s., 1H), 5
. 37-5.59 (br.s., 1H), 4.17 (br.s., 3H)
, 3.98 (br. S., 2H), 3.92 (br. S., 1H),
3.00-3.12 (m, 1H), 1.13 (d, J = 6.5 Hz
, 3H), 0.79 (br. S., 3H). LC-MS: m / z 4
77.1 (M + H) +.

2- (4- (1H-indole-3-carbonyl) -2-phenylpiperazin-1-yl) -6-isopropyl-4-phenylnicotinonitrile (Compound 169).
1H NMR (chloroform-d) δ 9.00 (br.s., 1H), 7
. 71 (d, J = 6.3 Hz, 1H), 7.64 (s, 1H), 7
. 42 (d, J = 7.3 Hz, 6H), 7.24-7.34 (m,
4H), 7.22 (d, J = 6.3 Hz, 4H), 5.53 (br
. s. , 1H), 4.13-4.35 (m, 2H), 4.01 (br
. s. , 2H), 3.76-3.96 (m, 2H), 3.00-3
. 13 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H), 0
. 80 (d, J = 6.5 Hz, 3H). LC-MS: m / z 52
6.1 (M + H) +.

Example 11
(R) -Methyl 5- (4-fluorophenyl) -6-isopropyl-2- (4- (3-
Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinate (Compound 24)
4) Preparation. Compound 244 was prepared according to Scheme 8.
Scheme 8.

Step 1: (R) -5-Bromo-6-isopropyl-2- (4- (4-methoxybenzyl) -3-methylpiperazin-1-yl) nicotinonitrile (58). (R) -5-bromo-6-isopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (
6; Example 1; 1 g, 3.10 mmol) and triethylamine (375 mg, 3.7)
2 mmol) in 20 mL THF was added dropwise 1- (chloromethyl) -4-methoxybenzene (485 mg, 3.10 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 4 hours, then warmed to room temperature and quenched by the addition of 20 mL of water. The solvent was removed under reduced pressure and the residue was extracted with EtOAc (3 × 20 mL). The combined organic layers were then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Flash column chromatographic separation (20% EtOAc / petroleum ether) then yielded 1.3 g of 58 as a dark brown oil. MS (ES) M + H predicted value 44
3.1, measured value 443.2

Step 2: (R) -5- (4-Fluorophenyl) -6-isopropyl-2- (4-
(4-Methoxybenzyl) -3-methylpiperazin-1-yl) nicotinonitrile (59
). (R) -5-Bromo-6-isopropyl-2- (4- (4-methoxybenzyl) -3
-Methylpiperazin-1-yl) -nicotinonitrile (58; 1 g, 2.18 mmol)
And solution of 4-fluorophenylboronic acid (610 mg, 4.36 mmol) and 5 mL of DMF in Pd (PPh ₃ ) ₄ (340 mg 0.218 mmol) and K ₂ C
O ₃ (360 mg, 2.62 mmol) was added under nitrogen protection. The reaction was subjected to microwave reaction at 150 ° C. for 1 hour. After dilution with 20 mL of water, the mixture is diluted with EtOA.
Extracted with c (3 × 20 mL). The combined organic layers are washed with brine and anhydrous Na
Dried over ₂ SO _4, and concentrated in vacuo. Flash column chromatographic separation (20% EtOAc / petroleum ether) then gave 600 mg of 59 as a dark brown oil. MS (ES) M + H predicted value 459.3, actual value 459.2.

Step 3: (R) -5- (4-Fluorophenyl) -6-isopropyl-2- (4-
(4-Methoxybenzyl) -3-methylpiperazin-1-yl) nicotinic acid (60)

(R) -5- (4-Fluorophenyl) -6-isopropyl-2- (4- (4-methoxybenzyl) -3-methyl-piperazin-1-yl) nicotinonitrile (600 mg, 1
. 31 mL) in 20 mL of ethanol was added 20 mL of 50% aqueous NaOH solution. The reaction mixture was heated to 120 ° C. overnight and then with <2N aqueous HCl to pH <
Acidified to 6. Ethanol was removed under reduced pressure and the residue was washed several times with water and filtered. After air drying, 500 mg of the crude title compound was obtained as a yellowish solid. MS (ES) M + H predicted value 478.2, actual value 478.2.

Step 4: (R) -Methyl-5- (4-fluorophenyl) -6-isopropyl-2
-(4- (4-methoxybenzyl) -3-methylpiperazin-1-yl) nicotinate (
61).

A 25 mL round bottom flask was charged with 10 mL of methanol. After cooling at 0 ° C., 1 mL of thionyl chloride is added dropwise and the solution is stirred at room temperature for 30 minutes before (R) -5.
-(4-Fluorophenyl) -6-isopropyl-2- (4- (4-methoxy-benzyl) -3-methylpiperazin-1-yl) nicotinic acid (500 mg, 1.05 mmol) was added slowly. The resulting mixture was then heated to reflux temperature for 2 hours. After removal of volatiles under reduced pressure, 500 mg of the crude title compound was obtained and used without further purification. M
S (ES) M + H predicted value 492.3, actual value 492.2.

Step 5: (R) -Methyl 5- (4-fluorophenyl) -6-isopropyl-2-
(3-Methylpiperazin-1-yl) nicotinate (62). (R) -Methyl-5- (4
-Fluorophenyl) -6-isopropyl-2- (4- (4-methoxybenzyl) -3-
Methylpiperazin-1-yl) nicotinate (61; 500 mg, 1.02 mmol) was dissolved in 15 mL of 2,2,2-trifluoroacetic acid. The mixture was heated to reflux overnight. After removing excess TFA under reduced pressure, the residue was redissolved in methylene chloride and saturated Na
Washed with HCO ₃ , brine. The organic layer is then dried over anhydrous Na ₂ SO ₄
Concentrated in vacuo. 300 mg of the title compound was obtained as a yellowish oil and was used subsequently without further purification. MS (ES) M + H predicted value 372.2, measured value 372.2.

Step 6: (R) -methyl 5- (4-fluorophenyl) -6-isopropyl-2-
(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinate (Compound 244).
1H NMR (chloroform-d) δ 7.84 (s, 1H), 7.20 −
7.25 (m, 2H), 7.06-7.15 (m, 2H), 4.86
(Br. S., 0.5H), 4.43 (d, J = 12.5 Hz, 0
. 5H), 4.21 (d, J = 6.0 Hz, 0.5H), 3.92 (
d, J = 13.1 Hz, 0.5H), 3.87 (s, 3H), 3.8
1 (d, J = 16.3 Hz, 1H), 3.74 (t, J = 6.7)
Hz, 3H), 3.64 (br.s., 1H), 3.37 (s, 3H)
), 3.18-3.34 (m, 1H), 2.96-3.15 (m,
2H), 2.64-2.80 (m, 1H), 2.60 (br. S.,
1H), 1.34-1.40 (m, 1.5H), 1.29-1.32.
(M, 1.5H), 1.17 (d, J = 6.8 Hz, 3H), 1.1
2 (d, J = 6.5 Hz, 3H). LC-MS: m / z 458.
2 (M + H) +.

Example 12
Assay for IDH1R132H inhibitors.
The assay was performed in a standard 384 well plate in a 76 μl volume of assay buffer (150 mM NaCl, 10 mM MgCl ₂ , 20 mM Tris pH 7.
5, in 0.03% bovine serum albumin): 25 ul of substrate mixture (8 uM N
1 μl of test compound in DMSO was added to ADPH, 2 mM aKG). After briefly centrifuging the plate, 25 μl of enzyme mixture is added (0.2 μg / ml IDH1).
R132H), then centrifuged briefly and shaken at 100 RPM. The reaction was incubated at room temperature for 50 minutes, then 25 μl of detection mixture (30 μM resazurin, 36 μg / ml) was added and the mixture was further incubated at room temperature for 5 minutes. Conversion of resazurin to resorufin was detected by fluorescence spectroscopy at Ex544, Em590, c / o590.

Certain compounds of Formula I listed in Tables 1 and 5 were tested in this assay and the results are listed in Table 3 below. “A” used in Table 3 is IDH1 with an IC ₅₀ of ≦ 0.1 μM
Refers to inhibitory activity against R132H; “B” is an IC greater than 1 μM and ≦ 5 μM
Refers to inhibitory activity against IDH1R132H at ₅₀ ; “C” refers to inhibitory activity against IDH1R132H with an IC ₅₀ greater than 5 μM and ≦ 15 μM.

Certain compounds of Formula I listed in Table 5 were tested in this assay and in the assay in Example 13, and the results are listed in Table 4 below. “A1” used in Table 4 is ≦ 0.
Inhibitory activity against IDH1R132H with an IC ₅₀ of 5 μM or ≦ 0.5 μM 2-H
Refers to IC ₅₀ for inhibition of G production; “B1” is greater than 0.5 μM and ≦ 1
Inhibitory activity against IDH1R132H with an IC ₅₀ of μM or greater than 0.5 μM,
And refers to an IC ₅₀ for inhibition of 2-HG production of ≦ 1 μM; “C1” is an inhibitory activity against IDH1R132H with an IC ₅₀ of greater than 1 μM and ≦ 10 μM or 1 μM
Refers to the IC ₅₀ for inhibition of 2-HG production greater than M and ≦ 10 μM;
Is an inhibitory activity against IDH1R132H with an IC ₅₀ of greater than 10 μM or 10
IC ₅₀ for inhibition of 2-HG production greater than μM.

In some embodiments, the invention provides compound numbers 182, 187, 191, 207, 2
12, 219, 222, 223, 224, 225, 226, 227, 229, 234, 2
35, 236, 241, 242, 243, 246, 248, 249, 250, 251, 2
52, 253, 255, 256, 257, 258, 259, 260, 261, and 26
A compound selected from any one of 2 is provided.

In some embodiments, the invention provides compound numbers 263, 265, 266, 269, 2
71, 275, 276, 277, 280, 283, 285, 286, 287, 288, 2
89, 290, 292, 293, 294, 295, 296, 297, 299, 301, 3
02, 303, 304, 307, 308, 309, 312, 313, 315, 318, 3
19, 320, 321, 322, 323, 325, 326, 328, 330, 331, 3
33, 335, 338, 340, 341, 342, 343, 345, 346, 347, 3
48, 350, 351, 352, 353, 356, 358, 359, 360, 361, 3
62, 363, 364, 372, 373, 374, 376, 377, 378, 380, 3
81, 382, 383, 384, 386, 387, 388, 389, 390, 391, 3
92, 393, 396, 397, 398, 402, 403, 405, 406, 407, 4
08, 409, 410, 411, 412, 415, 417, 418, 419, 420, 4
24, 427, 428, 429, 433, 434, 436, 438, 439, 440, 4
42, 443, 444, 445, 446, 448, 451, 452, 453, 454, 4
56, 457, 458, 459, 460, 463, 466, 468, 469, 470, 4
71, 472, 473, 474, 475, 476, 480, 481, 482, 483, 4
85, 487, 488, 491, 494, 497, 498, 500, 503, 505, 5
08, 511, 512, 514, 516, 517, 518, 521, 524, 525, 5
27, 528, 529, 530, 531, 532, 534, 535, 536, 537, 5
38, 539, 540, 541, 542, 544, 546, 547, 549, 551, 5
52, 553, 554, 555, 556, 557, 558, 559, 560, 561, 5
62, 563, 564, 565, 566, 568, 569, 570, 571, 572, 5
73, 574, 575, 575, 578, 579, 580, 581, 582, 585, 5
86, 587, 588, 589, 590, 591, 592, 594, 595, 596, 5
97, 598, 599, 601, 602, 603, 604, 605, 606, 607, 6
08, 609, 610, 611, 612, 613, 614, 615, 616, 617, 6
18, 619, 620, 621, 624, 625, 626, 627, 628, 629, 6
31, 632, 633, 634, 635, 636, 637, 638, 639, 640, 6
41, 642, 643, 644, 645, 646, 647, 648, 649, 650, 6
51, 652, 653, 654, 655, 657, 658, 659, 660, 661, 6
62, 663, 664, 665, 666, 667, 668, 669, 670, 671, 6
74, 675, 676, 677, 678, 679, 680, 681, 682, 683, 6
84, 686, 687, 688, 689, 690, 691, 692, 693, 694, 6
95, 696, 697, 698, 699, 701, 702, 703, 704, 705, 7
06, 707, 708, 709, 710, 711, 712, 713, 714, 715, 7
16, 717, 718, 719, 720, 721, 722, 723, 724, 725, 7
26, 727, 728, 729, 730, 731, 732, 733, 734, 735, 7
36, 737, 738, 739, 740, 741, 742, 743, 744, 745, 7
46, 747, 748, 749, 750, 751, 752, 753, 754, 755, 7
56, 757, 758, 759, 760, 761, 762, 763, 764, 765, 7
66, 767, 768, 769, 770, 771, 773, 774, 775, 776, 7
77, 778, 780, 781, 782, 784, 785, 786, 787, 788, 7
89, 790, 791, 792, 793, 794, 795, 796, 797, 798, 7
99, 800, 801, 802, 803, 804, 805, 806, 807, 808, 8
09, 811, 812, 813, 815, 817, 818, 819, 820, 821, 8
A compound selected from any one of 22, 823, 824, 825, 826, 827, 828, 829, and 830 is provided.

Example 13
Cellular assay for IDH1m (R132H or R132C) inhibitors.
Cells (eg, HT1080 or U87MG) were treated with T12 in DMEM containing 10% FBS, 1 × penicillin / streptomycin and 500 ug / mL G418.
Grow in 5 flasks. These are collected by trypsin and seeded in 96-well white bottom plates at a density of 5000 cells / well in 100 ul / well in DMEM with 10% FBS. Columns 1 and 12 do not plate cells. Cells are incubated overnight at 37 ° C. in 5% CO2. The next day, compounds are made at 2 × concentration and 100 ul is added to each cell well. The final concentration of DMSO is 0.
2%, DMSO control wells are plated in row G. The plate is then placed in an incubator for 48 hours. At 48 hours, 100 μl of medium is removed from each well and analyzed by LC-MS for 2-HG concentration. Place the cell plate back in the incubator for an additional 24 hours. 72 hours after compound addition, thaw 10 mL / plate of Promega Cell Titer Glo reagent,
Mix. Remove the cell plate from the incubator and allow to equilibrate to room temperature. 100 ul of reagent is then added to the media in each well. The cell plate is then placed on an orbital shaker for 10 minutes and then left at room temperature for 20 minutes. The plate is then read for luminescence with an integration time of 500 ms.

The IC ₅₀ for the inhibition of 2-HG production in these two cell lines for the various compounds of formula I (the concentration of the test compound that reduces 2HG production by 50% compared to the control) is given in Table 4 above. To do.

Example 14
Preparation of 2,3,5,6-tetrasubstituted pyridine.
General procedure 1:


Step A: 1-Cyclopropyl-3- (dimethylamino) prop-2-en-1-one (2)


1-cyclopropylethanone (100 g, 1.2 mol) in anhydrous DMF (1300 mL)
) Was added DMFDMA (300 g, 2.5 mol). The resulting mixture is 1
Stir at 00 ° C. overnight. The solvent was removed in vacuo to give crude 2 (110 g) as a yellow solid. 1H NMR (chloroform-d) δ 7.56 (d, J = 1)
2.8 Hz, 1H), 5.20 (d, J = 12.5 Hz, 1H),
2.78-3.08 (m, 6H), 1.79 (tt, J = 7.9,
4.5 Hz, 1H), 0.94-1.04 (m, 2H), 0.67-
0.80 (m, 2H).

Step B: 6-Cyclopropyl-2-hydroxynicotinonitrile (3)


1-Cyclopropyl-3-dimethylamino-propenone (315 g, 2.3 mol) and cyanoacetamide (270 g, 2.3 mol) in 47.4 mL acetic acid and 148
Piperidine was added to a mixture of 5 mL of water in buffer solution to adjust to pH9. The mixture was then heated at reflux for 2 hours, cooled and acidified to pH 5 with less than 25 degrees with 6N HCl. The yellow precipitate was filtered, washed with water and dried to give 3 as a white solid (561 g). MS (ES) M + H predicted value 161.1, found value 161.0. 1H NMR (chloroform-d) δ 13.60 (br.s., 1H), 7.77 (d, J
= 7.8 Hz, 1H), 5.91 (d, J = 7.8 Hz, 1H),
1.96-2.12 (m, 1H), 1.29-1.36 (m, 2H
), 1.04-1.11 (m, 2H).

Step C: 5-Bromo-6-cyclopropyl-2-hydroxynicotinonitrile (4
)


A mixture of 6-cyclopropyl-2-hydroxynicotinonitrile (561 g, 3.6 mol) and NBS (624 g, 5.4 mol) in DCE (4500 mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature and the precipitate was filtered, washed with water and dried to give crude 4 (473 g) as a white solid. MS (ES) M + H predicted value 239.0, found value 238.9. 1H NMR (chloroform-d) δ 8.49-8.72 (br.
s. , 1H), 7.93 (s, 1H), 2.23-2.34 (m,
1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m
, 2H).

Step D: 5-Bromo-3-cyano-6-cyclopropylpyridin-2-yl trifluoromethanesulfonate (5)


To a 1 L flask was added 5-bromo-4-cyclopropyl-2-hydroxybenzonitrile (47.6 g, 0.2 mol), pyridine (32 g, 0.4 mo) in DCM (300 mL).
l) and catalytic DMAP (500 mg) are added and the mixture is cooled to 0 ° C. and DCM (10
Trifluoromethanesulfonic anhydride (59 g, 0.21 mol) in 0 mL) was added dropwise. After the addition, the mixture was stirred for an additional hour. TLC (PE: EtOAc = 10: 1) is
Conversion of starting material to product was shown. After reaction, dilute with DCM (300 mL), 1N
Washed with HCl. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (70 g) as a yellow solid. 1H NMR (chloroform-d) δ 8.
14-8.19 (m, 1H), 2.55-2.66 (m, 1H),
1.30 (dt, J = 7.8, 3.1 Hz, 2H), 1.21 -1
. 27 (m, 2H).

Step E: Illustrated by (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (6-1) (R ′ = methyl)


Triflate 5 (1.68 g, 4.6 mmol), (R) -2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9 mL, 13.8 mm)
ol) in 5 mL of MeCN was heated at 70 ° C. for 2 hours. After the mixture was concentrated under reduced pressure, the residue was extracted between ethyl acetate and water. The combined organic layers were then washed with aqueous NaHCO ₃ , brine, dried over anhydrous Na ₂ SO ₄ ,
Concentration in vacuo gave 1.26 g of the crude title compound. MS (ES) M + H predicted value 321
. 1. Actual value 321.2. 1H NMR (chloroform-d) δ 7.78 (s,
1H), 4.14-4.24 (m, 2H), 3.09-3.14 (
m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00.
(M, 2H), 2.71 (dd, J = 12.9, 10.2 Hz, 1
H), 2.42-2.52 (m, 1H), 1.16 (d, J = 6.
3 Hz, 3H), 1.08 (s,, 2H), 1.07 (d, J =
3.8 Hz, 2H).

(R) -5-Bromo-6-cyclopropyl-2- (3-isopropylpiperazine-1-
Yl) nicotinonitrile (6-2) (R ′ = isopropyl) was synthesized by the same procedure as above except that (R) -2-isopropylpiperazine was used instead of (R) -2-methylpiperazine. did. MS (ES) M + H predicted value 349.1, actual value 349.2. 1H NM
R (chloroform-d) δ 7.79 (s, 1H), 4.14-4.24
(M, 2H), 3.09-3.14 (m, 1H), 3.02-3.
07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (d
d, 1H), 2.12-2.22 (m, 1H), 1.26 (d, 6H)
), 1.08 (d, 2H), 1.07 (d, 2H).

(R) -5-Bromo-6-cyclopropyl-2- (3-cyclopropylpiperazine-1
-Yl) nicotinonitrile (6-3) (R '= cyclopropyl) was synthesized by the same procedure as above, except that (R) -2-cyclopropylpiperazine (building block 1)
Was used in place of (R) -2-methylpiperazine. MS (ES) M + H predicted value 347.
1. Actual value 349.1. 1H NMR (chloroform-d) δ 7.77 (s,
1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m
, 1H), 3.02-3.07 (m, 1H), 2.96-3.00
(M, 2H), 2.71 (dd, 1H), 2.12-2.24 (m,
1H), 1.25 (d, 2H), 1.16 (d, 2H), 1.08 (d
, 2H), 1.07 (d, 2H).

Step F, Method 1: (R) -5-bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (7-1)
Illustrated by (R '= methyl, R1 = c)

To a 25 mL round bottom flask was added (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (6-1) (1.26 g, 3.9 mmol).
), 3-methoxypropanoic acid (0.74 mL, 7.8 mmol), HATU (2.98 g)
7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL of methylene chloride were added. The resulting reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. The reaction mixture was saturated NaHCO ₃ and brine. The combined organic layers were then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (30% EtOAc / petroleum ether) gave 1.28 g of the title compound as a white solid. MS (ES) M + H predicted value 407.1, actual value 407.0. 1H NMR
(Chloroform-d) δ 7.78-7.85 (m, 1H), 4.82
-4.92 (m, 0.5H), 4.50 (d, J = 13.6 Hz,
0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m
, 1H), 3.75-3.82 (m, 0.5H), 3.70-3.7
5 (m, 2H), 3.45-3.55 (m, 0.5H), 3.36 (
s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14
(M, 1H), 2.67-2.78 (m, 1H), 2.51-2.
61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d
, J = 6.8 Hz, 1.5H), 1.25 (d, J = 2.5 Hz
, 1.5H), 1.09 (d, J = 3.5 Hz, 2H), 1.08
(S, 2H).

Step F, Method 2: (R) -5-bromo-2- (4- (cyclopropanecarbonyl)
-3-Methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (7-2)
(R ′ = methyl, R1 =


)

To a 25 mL round bottom flask was added (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (6-1) (1 g, 3.2 mmol), cyclopropane. Carbonyl chloride (0.4 mL, 3.3 mmol), DIPEA (0.4
mL, 3.4 mmol) and 10 mL of methylene chloride were added. The resulting reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. The reaction mixture is saturated NaH
With CO ₃ and brine. The combined organic layers were then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (10% EtOAc / petroleum ether) gave 1.1 g of the title compound as a white solid. MS (ES) M + H predicted value 38
9.1, found 389.0. 1H NMR (chloroform-d) δ 7.85 (s
, 1H), 4.18-4.21 (m, 2H), 4.07-4.16 (m
, 1H), 3.70-3.75 (m, 2H), 3.15-3.27
(M, 1H), 2.92-3.14 (m, 1H), 2.67-2.7
8 (m, 1H), 2.51-2.61 (m, 1H), 2.40 -2
. 51 (m, 1H), 1.34 (d, J = 6.8 Hz, 1.5H),
1.25 (d, J = 2.5 Hz, 1.5H), 1.25-1.36
(M, 4H), 1.09 (d, 2H), 1.08 (d, 2H).

Step F, Method 3: (R) -5-bromo-6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (7-3)
) (R ′ = methyl, R1 =


)

To a 25 mL round bottom flask was added (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (6-1) (2 g, 6.2 mmol), sodium 2 -Carboxyethanolate (0.70 g, 6.4 mmol), DIPEA (2
mL, 11.5 mmol) and 10 mL DMF were added. The resulting reaction mixture is
Stir at room temperature for 5 hours until TLC indicates complete reaction. The reaction mixture was washed with water and brine. The combined organic layers were then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatographic purification (50% EtOAc / petroleum ether) gave 1.2 g of the title compound as a white solid. MS (ES) M + H predicted value 393.1
, Found 393.1. 1H NMR (chloroform-d) δ 7.85 (m, 1
H), 4.88-4.97 (m, 0.5H), 4.75 (d, J =
13.6 Hz, 0.5H), 4.29-4.48 (m, 2H), 4.11
-4.20 (m, 1H), 3.70-3.75 (m, 2H), 3.4
5-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2
. 92-3.14 (m, 1H), 2.67-2.78 (m, 1H),
2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H)
), 1.34 (d, J = 6.8 Hz, 1.5H), 1.25 (d,
J = 2.5 Hz, 1.5H), 1.09 (d, J = 3.5 Hz,
2H), 1.08 (s, 2H).

(R) -5-Bromo-6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile (7-4) is prepared according to the method of Step F. However, 6-3 was used instead of 6-1 as a starting material. MS (ES) M + H predicted value 433.1, actual value 433.3.

(R) -5-bromo-2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (7-5)
However, 6-3 was used as a starting material in place of 6-1.
MS (ES) M + H predicted value 415.1, actual value 415.1.

(R) -5-Bromo-6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicotinonitrile (7-6) was prepared according to the method of Step F. However, 6-3 was used instead of 6-1 as a starting material. MS (ES) M + H predicted value 419.1, found value 419.1. 1H NMR (chloroform-d) δ 7.85 (m, 1H), 4.87-4.97 (m, 0
. 5H), 4.77 (d, J = 13.6 Hz, 0.5H), 4.29−
4.48 (m, 2H), 4.11-4.20 (m, 1H), 3.70
-3.75 (m, 2H), 3.45-3.55 (m, 2H), 3.1
5-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2
. 67-2.78 (m, 1H), 2.51-2.61 (m, 1H),
2.40-2.51 (m, 1H), 1.34 (d, J = 6.8 H
z, 2H), 1.25 (d, 2H), 1.09 (d, J = 3.5 H
z, 2H), 1.08 (s, 2H).

(R) -5-Bromo-6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile (7-7)
However, 6-2 was used instead of 6-1 as a starting material.
MS (ES) M + H predicted value 434.1, measured value 435.1.

(R) -5-Bromo-6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) nicotinonitrile (7-8) is prepared according to Method 1 in Step F. Except that 6-2 was used instead of 6-1 as a starting material. MS (ES) M + H predicted value 421.1, measured value 421.6.

Step G, Method 1: (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4,4,5,5-tetra Methyl
Illustrated by 1,3,2-dioxaborolan-2-yl) nicotinonitrile (8-1) (R ′ = methyl, R1 = c)

(R) -5-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl) nicotinonitrile (7-1) (747 mg, 1.8
mmol) in DMF (8 mL), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2 dioxaborolane) (563 mg, 2.2mmo
l) and KOAc (538 mg, 5.5 mmol) were added. The resulting mixture was stirred at room temperature for 5 minutes before PdCl ₂ (dppf). CH ₂ Cl ₂ (45 mg, 0.
03 mmol) was added. After flushing with nitrogen, the reaction mixture was heated at 85 ° C. for 18 hours. After cooling, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. By column chromatography (25% EtOAc / petroleum ether) 33
4 mg of the title compound were obtained as a white solid. MS (ES) M + H predicted value 455.3, measured value 455.2.

Step G, Method 2: (R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) nicotinonitrile (R ′ = methyl, R1 =


)

1.4 g (R) -5-bromo-6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazine-1- in 20 mL dioxane in a round bottom flask
Yl) nicotinonitrile (7-3) (3.3 mmol), 2.12 g of 4,4,4 ', 4
', 5,5,5', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (8.34 mmol), 0.7 g KOAc (7.4 mmol), 154 mg Xph
os (0.32 mmol) and 308 mg of Pd ₂ (dba) ₃ (0.33 mmol)
Was stirred overnight at 75 ° C. under N ₂ . The mixture was then cooled to room temperature. Concentrate,
Purification by column chromatography (petroleum ether: ethyl acetate 3: 1 to 1: 1) gave 670 mg of the title compound. MS (ES) M + H predicted value 441.2, measured value 441
. 2.

General Procedure 1, Step H: (R) -6-Cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (thiophen-2-yl) nicoti Illustrated by nononitrile (compound 273)

7-1 (26 mg, 0.06 mmol), thiophen-2-ylboronic acid (14 mg,
0.089 mmol), Pd (PPh ₃ ) ₄ (3 mg, 0.003 mmol), and K
A mixture of ₂ CO ₃ (16 mg, 0.119 mmol) suspended in 1 mL of DMF was
Subjected to microwave reaction at 150 ° C. for 45 minutes. After the reaction was complete, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 19 mg of the title compound as a yellowish oil. 1H NMR (chloroform-d) δ 7.70 (s
, 1H), 7.38 (dd, J = 3.9, 2.4 Hz, 1H), 7
. 07-7.14 (m, 2H), 4.90 (br. S., 0.5H),
4.52 (d, J = 13.1 Hz, 0.5H), 4.15-4.4
1 (m, 2.5H), 3.67-3.89 (m, 2.5H), 3.47
-3.63 (m, 0.5H), 3.34-3.43 (m, 3H),
3.20-3.33 (m, 1H), 2.99-3.17 (m, 1.5
H), 2.63-2.81 (m, 1H), 2.50-2.62 (m,
1H), 2.26-2.36 (m, 1H), 1.37 (d, J =
6.3 Hz, 1.5H), 1.27 (d, J = 6.8 Hz, 1.5H)
), 1.10-1.18 (m, 2H), 0.94-1.05 (m,
2H). LC-MS: m / z 411.1 (M + H) +.

Step I: (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl)
Illustrated by -3-methylpiperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile (Compound 603)

8-1 (95 mg, 0.197 mmol), 5-chloro-2-vinylquinazoline (25
mg, 0.131 mmol), Xphos (7 mg, 0.013 mmol), Pd ₂ (d
ba) ₃ (6 mg, 0.007 mmol) and K ₃ PO ₄ . H ₂ O (105 mg, 0.
393 mmol) is stirred at 100 ° C. for 16 h, the mixture is partitioned between EtOAc and water, the organics are washed with water, brine and concentrated to give a crude product which is purified by column chromatography. 25 mg of product was obtained. 1H NMR (chloroform-d) δ 9.16 (d, J = 3.0 Hz, 1H), 8.05
(D, J = 8.5 Hz, 1H), 7.95 (dd, J = 8.5,
7.3 Hz, 1H), 7.66 (s, 1H), 7.45-7.58 (
m, 1H), 7.06 (dd, J = 17.2, 10.4 Hz, 1H)
6.80 (dd, J = 17.3, 1.5 Hz, 1H), 5.80
-5.96 (m, 1H), 4.87-5.02 (m, 0.5H), 4
. 56 (d, J = 12.0 Hz, 0.5H), 4.35-4.44
(M, 2.5H), 3.84 (d, J = 12.8 Hz, 0.5H),
3.69-3.79 (m, 2H), 3.52-3.65 (m, 0.5
H), 3.30-3.43 (m, 4H), 3.05-3.24 (m,
1.5H), 2.65-2.81 (m, 1H), 2.48-2.64.
(M, 1H), 1.50-1.59 (m, 1H), 1.30-1.
44 (m, 3H), 1.13-1.22 (m, 2H), 0.84-
0.89 (m, 2H). LC-MS: m / z 483.2 (M + H) +

General procedure 2:


Step J: (R) -tert-butyl 4- (5-bromo-3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (
9-1, R ′ = cyclopropyl)

To a solution of 6-3 (1 g, 2.24 mmol) in DCM (8 mL) was added (Boc) ₂ O (0
. 5 g, 2.26 mmol) and Et ₃ N (0.1 mL) were added. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water. The organic layer is then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a white solid (1.5 g) that can be used directly in the next step. it can. 1H NM
R (chloroform-d) δ 7.85 (s, 1H), 4.14-4.24
(M, 2H), 3.29-3.34 (m, 1H), 3.12-3.
18 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (d
d, 1H), 2.12-2.24 (m, 1H), 1.5 (s, 9H)
, 1.25 (d, 2H), 1.16 (d, 2H), 1.08 (d,,
2H), 1.07 (d, 2H).

Step K: (R) -tert-butyl 4- (5-cyano-2-cyclopropyl- [3
, 3′-bipyridin] -6-yl) -2-cyclopropylpiperazine-1-carboxylate (R ′ = cyclopropyl, R4 = 3-pyridinyl)

(R) -tert-butyl 4- (5-bromo-3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (150 mg,
0.33 mmol) in 2 mL dioxane and 0.5 mL in water.
-Ylboronic acid (45.6 mg, 0.37 mmol), Pd (dppf) Cl2 (24 m
g, 0.033 mmol), CsF (100 mg, 0.66 mmol) was added. The resulting mixture was stirred at 100 ° C. under N 2 atmosphere and microwaved for 1 hour. TL
After C showed complete conversion to starting product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc / petroleum ether) to give 100 mg of the title compound. MS (ES) M + H predicted value 446.2, actual value 446.3.

Step L: (R) -2-cyclopropyl-6- (3-cyclopropylpiperazine-1
-Yl)-[3,3′-bipyridine] -5-carbonitrile (R ′ = cyclopropyl, R
4 = 3-pyridinyl)

(R) -tert-butyl 4- (5-cyano-2-cyclopropyl- [3,3′-bipyridin] -6-yl) -2-cyclopropylpiperazine-1-carboxylate (100
To a solution of mg, 0.22 mmol) in 3 mL DCM was added TFA (1 mL). The resulting mixture was stirred at room temperature for 2 hours. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and basified to pH = 8 with Na ₂ CO ₃ solution. The solution was then extracted with DCM (10 mL × 3). The organic layer was dried, concentrated and purified by preparative HPLC (5% DCM / MeOH) to give 70 mg of the title compound. MS
(ES) M + H predicted value 346.2, measured value 346.2.

General Procedure 2, Step M: (R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl)-[3,3 '
-Bipyridine] -5-carbonitrile (compound 524)

(R) -2-cyclopropyl-6- (3-cyclopropylpiperazin-1-yl)-[
3,3′-bipyridine] -5-carbonitrile (70 mg, 0.2 mmol) in 10 mL
Solution of 3,3,3-trifluoropropanoic acid (31 mg, 0.24 mmol) in DCM.
), And triethylamine (1 mL), HOBT (54 mg, 0.4 mmol), ED
CI (76.8 mg, 0.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and purified by preparative HPLC (50% EtOAc / petroleum ether) to give 25 mg of the title compound. 1H NMR (chloroform-d) δ 8.56-8.77 (
m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.65 (
s, 1H), 7.44 (dd, J = 7.7, 4.9 Hz, 1H),
4.56 (d, J = 13.1 Hz, 1H), 4.44 (d, J =
13.1 Hz, 1H), 4.12 (br.s., 1H), 3.63-
3.86 (m, 2H), 3.32 (d, J = 9.3 Hz, 2H),
3.20 (d, J = 13.1 Hz, 1H), 3.11 (d, J =
11.8 Hz, 1H), 1.99 (td, J = 8.0, 3.8 Hz,
1H), 1.11-1.23 (m, 3H), 1.01 (dd, J =
7.5, 3.5 Hz, 2H), 0.77-0.95 (m, 2H),
0.66 (br. S., 1H), 0.50 (d, J = 5.0 Hz,
2H) LC-MS: m / z 4 456.4 (M + H) +.

General procedure 3:

Method 1: (R) -2-chloro-N- (3- (5-cyano-2-cyclopropyl-6- (
4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridine-3-
Yl) phenyl) acetamide (Compound 403) (R ″ = H, R1 =


)

(R) -5- (3-Aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (50 mg, 0
. 119 mmol) and 2-chloroacetyl chloride (15 mg, 0.131 mmol)
) In 2 ml of DCM was added dropwise TEA (24 mg, 0.238 mmol) at 0 ° C., then the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by preparative TLC to give 20 mg of product.
1H NMR (chloroform-d) δ 8.34 (s, 1H), 7.66 −
7.75 (m, 1H), 7.62 (s, 1H), 7.50-7.55
(M, 1H), 7.42-7.48 (m, 1H), 7.22 (d,
J = 7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.
54 (m, 0.5H), 4.29-4.33 (m, 1H), 4.26
(M, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.
84 (m, 2.5H), 3.52-3.57 (m, 0.5H), 3.39
(S, 3H), 3.21-3.32 (m, 1H), 3.13 (d, J
= 11.3 Hz, 1H), 3.05 (d, J = 12.3 Hz, 0
. 5H), 2.66-2.81 (m, 1H), 2.54-2.65 (
m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J
= 6.3 Hz, 1H), 1.28-1.31 (m, 2H), 1.14
-1.19 (m, 2H), 0.94-1.00 (m, 2H). L
C-MS: m / z 496.2 (M + H) +.

Method 2: (R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) Illustrated by phenyl) propanamide (Compound 424)

To a 25 mL round bottom flask was added (R) -5- (3-aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile. (50 mg, 0.119 mmol), propionic acid (0.1 mL), HAT
U (20 mg), DIPEA (0.05 mL) and 10 mL methylene chloride were added. The resulting reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. The reaction mixture was saturated NaHCO ₃ and brine. The combined organic layers were then dried over anhydrous Na
Dried over ₂ SO _4, and concentrated in vacuo. Column chromatography purification (30% E
(tOAc / petroleum ether) gave 45 mg of the title compound as a white solid. 1H N
MR (chloroform-d) δ 7.75 (s, 1H), 7.68 (s, 1
H), 7.59 (s, 1H), 7.49 (d, J = 8.0 Hz, 1
H), 7.37 (t, J = 7.8 Hz, 1H), 7.11 (d, J
= 7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d,
J = 13.3 Hz, 0.5H), 4.14-4.35 (m, 2.5
H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (
m, 0.5H), 3.37 (s, 3H), 3.17-3.32 (m,
1H), 2.93-3.17 (m, 1.5H), 2.63-2.81
(M, 1H), 2.52-2.63 (m, 1H), 2.37-2.4
9 (m, 2H), 2.05-2.13 (m, 1H), 1.38 (d,
J = 6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1
. 14 (dt, J = 7.4, 3.6 Hz, 2H), 0.88-1.
01 (m, 2H). LC-MS: m / z 476.3 (M + H) +.

General procedure 4:

Step O: 5-Bromo-3-cyano-6-cyclopropylpyridin-2-yl 4-methylbenzenesulfonate (10)

4 (2.37 g, 10 mmol) in THF (20 mL) was added TsCl (1.9 g).
, 11 mmol) and Et ₃ N (1 mL). The reaction was stirred at room temperature for 2 hours. The resulting solution was partitioned between DCM and water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by column chromatography to 2.6 g of 1
0 was obtained. 1H NMR (chloroform-d) δ 7.86 (s, 1H), 7
. 35-7.46 (m, 2H), 7.11-7.25 (m, 2H),
1.99-2.17 (m, 1H), 1.21-1.38 (m, 2H
), 1.00-1.20 (m, 2H). LC-MS: m / z 393.0
(M + H) +.

Step P: exemplified by 6-cyclopropyl-5- (4-fluorophenyl) -2-hydroxynicotinonitrile (11-1)

10 (2.6 g, 11 mmol), 4-fluorophenylboronic acid (1.4 g, 10 m
mol), Pd (PPh ₃ ) ₄ (30 mg), and K ₂ CO ₃ (16 mg, 0.119).
mmol) in 10 mL DMF was subjected to microwave reaction at 150 ° C. for 45 min. After the reaction, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 1.9 g of the title compound as a yellow solid. LC-MS: m /
z255.0 (M + H) ⁺

Step Q:


3-Cyano-6-cyclopropyl-5- (4-fluorophenyl) pyridin-2-yl trifluoromethanesulfonate. 1H NMR (chloroform-d) δ: 7.8
7 (s, 1H), 7.32-7.57 (m, 2H), 7.13-7
. 24 (m, 2H), 1.99-2.17 (m, 1H), 1.21-
1.38 (m, 2H), 1.00-1.20 (m, 2H). LC-M
S: m / z 387.1 (M + H) +.

Step R: Same procedure as General Procedure 1, Step E, except that 12-1 was replaced with 5 as the starting material and the suitable building blocks described in the “Building Blocks” section.

Step S: Same procedure as General Procedure 1, Step G, except that the preferred building blocks described in the “Building Blocks” section were used.

General procedure 5:


Step T: With (R) -tert-butyl 4- (2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl) -2-cyclopropylpiperazine-1-carboxylate Exemplification

In a 25 mL flask, 9-1 (1000 mg 2.235 mmol), 2-chloropyridin-4-ylboronic acid (457 mg, 2.906 mmol), Pd (PPh ₃ ) ₄ (
120 mg, 0.1 mmol), K ₂ CO 3 (926 mg, 6.705 mmol), and 4 mL of DMF were added. The resulting mixture was stirred at 150 ° C. for 5 hours. After washing with saturated NaHCO ₃ , brine, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (20% EtOAc / petroleum ether) gave 640 mg of the title compound. 1H NMR (chloroform-d)
δ 8.48 (d, J = 5.0 Hz, 1H), 7.62 (s, 1H
), 7.39-7.47 (m, 1H), 7.32 (dd, J = 5.
1, 1.3 Hz, 1H), 4.59 (d, J = 12.9 Hz, 1H
), 4.45 (d, J = 13.2 Hz, 1H), 4.09 (d, J
= 13.5 Hz, 1H), 3.50 (d, J = 9.1 Hz, 1H)
), 3.34-3.43 (m, 1H), 3.27 (dd, J = 13)
. 2, 3.8 Hz, 1H), 3.11 (td, J = 12.5, 3.7)
Hz, 1H), 1.94-2.06 (m, 1H), 1.77 (br.
s. , 2H), 1.50 (s, 9H), 1.34 (br. S., 1H
), 1.04 (dd, J = 7.9, 3.2 Hz, 2H), 0.56
-0.63 (m, 2H), 0.50 (dd, J = 8.5, 3.5 H
z, 1H), 0.32-0.42 (m, 1H).

Step U: (R) -tert-butyl-4- (5-cyano-2-cyclopropyl-2
'-Vinyl-3,4'-bipyridin-6-yl) -2-cyclopropylpiperazine-1-
Illustrated by carboxylate

The flask was charged with (R) -tert-butyl 4- (2′-chloro-5-cyano-2-cyclopropyl-3,4′-bipyridin-6-yl) -2-cyclopropylpiperazine-1-carboxylate ( 640 mg 1.33 mmol), tributyl (vinyl) stannane (
550 mg, 1.73 mmol), Pd (PPh ₃ ) ₄ (120 mg, 0.1 mmol)
, K2CO3 (460 mg, 3.33 mmol), and 4 mL of DMF were added. The resulting mixture was stirred at 150 ° C. for 5 hours. After washing with saturated NaHCO ₃ , brine, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography purification (20% EtOAc / petroleum ether) gave the compound. L
C-MS: m / z 472.2 (M + H) ^<+> .

Step V: (R) -2-cyclopropyl-6- (3-cyclopropylpiperazine-1
-Yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile

The flask was charged with (R) -tert-butyl 4- (5-cyano-2-cyclopropyl-2 ′
-Vinyl-3,4'-bipyridin-6-yl) -2-cyclopropylpiperazine-1-carboxylate and 12 mL EtOH / HCl (1 M) were added. The resulting reaction mixture was stirred at room temperature for 30 min at 0 ° C. until TLC indicated that the reaction was complete, which was concentrated in vacuo to give the product as a pale yellow solid. 1H NMR (chloroform-
d) δ: 8.65 (d, J = 5.0 Hz, 1H), 7.62 (s,
1H), 7.38 (s, 1H), 7.23 (dd, J = 5.0, 1
. 8 Hz, 1H), 6.89 (dd, J = 17.3, 10.9 Hz,
1H), 6.29 (dd, J = 17.6, 1.2 Hz, 1H), 5
. 57 (dd, J = 10.9, 1.2 Hz, 1H), 4.50 (d,
J = 12.9 Hz, 1H), 4.36 (d, J = 13.2 Hz,
1H), 3.28 (br.s., 1H), 3.22 (d, J = 12
. 3 Hz, 1H), 3.10 (br. S., 1H), 2.95 (br.
s. , 1H), 1.96-2.06 (m, 1H), 1.21 (t,
J = 4.1 Hz, 1H), 0.95-1.07 (m, 3H), 0.
92 (br. S., 1H), 0.62 (d, J = 7.9 Hz, 2H
), 0.40 (d, J = 4.7 Hz, 2H).

Step W: General Procedure, Same Procedure as Step 1, except that the preferred building blocks described in the “Building Blocks” section were used.

General procedure 6:


Step A ′: 1-cyclopropylbutane-1,3-dione

CH3ONa (75.65 g, 1.25 mol) and 1-cyclopropylethanone (
A mixture of 105.0 g, 1.25 mol) in THF (1000 mL) was stirred at 35 ° C. for 1 h, then ethyl acetate (110.0 g, 1.25 mol) was added dropwise. 50 ° C
After stirring at rt for 4 h, the solvent was removed under reduced pressure and the residue was dissolved in H 2 O (500 mL) and adjusted to pH 3.5 with citric acid. The mixture was ethyl acetate (500 mL × 3
). The combined organic layers were concentrated in vacuo to give 1-cyclopropylbutane-1,
3-dione (110.0 g, 69% yield) was obtained as a yellow oil. 1H NMR (chloroform-d) δ 0.83-0.95 (m, 2H), 1.06-1.10 (m
, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H).

Step B ′: 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile

1-cyclopropylbutane-1,3-dione (126.0 g, 1.0 mol) and 2
-E of cyanoacetamide (88.0 g, 1.0 mol) and piperidine (60 mL).
The mixture in tOH (1500 mL) was stirred at reflux for 4 hours. The reaction mixture was filtered and PE (
200 mL) and dried in vacuo to give 6-cyclopropyl-2-hydroxy-
4-Methylnicotinonitrile (90.0 g, 52%) was obtained as a white solid. 1H NM
R (DMSO-d6) δ 12.36 (br. S., 1H), 5.93 (
s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H)
), 1.06-1.14 (m, 2H), 0.91-0.95 (m,
2H).

Step C ′: 5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile

6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g, 0
. 52 mol) and NBS (100.0 g, 0.57 mol) DCE (1500 mL)
The mixture was stirred for 4 hours at reflux temperature. The reaction mixture was filtered and the residue was DCE
(200 mL) and dried in vacuo to give 5-bromo-6-cyclopropyl-2
-Hydroxy-4-methylnicotinonitrile (100.0 g, 76%) was obtained as a white solid. MS (ES) M + H predicted value 253.0, found value 253.0. 1H NMR (chloroform-d) δ 2.68 (s, 3H), 1.79-1.88 (m,
1H), 1.03-1.09 (m, 2H), 0.93-1.01 (m
, 2H).

Step D ′: 5-Bromo-3-cyano-6-cyclopropyl-4-methylpyridine
2-yl trifluoromethanesulfonate

5-Bromo-2-hydroxy-6-isopropylnicotinonitrile (40 g, 0.15
mol) in 200 mL of methylene chloride, DMAP (1.78 g, 14.6 mmol).
l), and triethylamine (25 mL, 175 mmol) were added. The mixture was cooled in an ice-water bath at 0 ° C. and trifluoromethanesulfonic anhydride (37 mL, 0.21 m
ol) was added dropwise by syringe. The resulting reaction mixture was stirred at 0 ° C. for 30 minutes,
It was then warmed to room temperature and stirred overnight. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and purified by column chromatography (20% EtOAc / petroleum ether) to give 55 g of the title compound. 1H NMR (chloroform-
d) δ 2.70 (s, 3H), 2.16-2.20 (m, 1H),
1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H)

Step E ′: exemplified by (R) -5-bromo-6-cyclopropyl-4-methyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (R ′ ″ = methyl)

5-Bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yltrifluoromethanesulfonate (50.0 g, 0.13 mol) and (R) -2-methylpiperazine (15.6 g, 0.16 mol) ) And Et3N (26.0 g, 0.26 mol)
) In THF (500 mL) was stirred at 80 ° C. overnight. The resulting mixture was concentrated in vacuo to give (R) -5-bromo-6-cyclopropyl-4-methyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (34.8 g, 80% ) Was obtained as a white solid. 1H NMR (chloroform-d) δ 4.08-4.16 (m, 0
. 5H), 4.05-4.08 (m, 1H), 4.01-4.04 (
m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (d,
J = 8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.
58-2.65 (m, 1H), 2.55-2.57 (m, 3H),
1.77 (br.s., 1H), 1.12 (s, 1.5H), 1.10
(S, 1.5H), 1.05-1.09 (m, 2H), 1.00-1
. 05 (m, 2H).

Step F ′: (R) -5-bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile (R
'''= Methyl, R8 =


) Preparation.

(R) -5-Bromo-6-cyclopropyl-4-methyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (34.8 g, 0.1 mol) and 3-methoxypropanoic acid (16. A mixture of 0 g, 0.15 mol) in pyridine (500 mL) was stirred at 0 ° C. for 30 minutes and then POCl 3 (28.7 g, 0.19 mol) was added dropwise. The resulting mixture was stirred at 20 ° C. for 2 hours. The reaction mixture was concentrated and purified by chromatography to give (R) -5-bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4- Methylnicotinonitrile (25
. 0 g, 59%) was obtained as a yellow oil. 1H NMR (chloroform-d) δ
4.90 (br. S., 0.5H), 4.52 (d, J = 13.6 H
z, 0.5H), 4.22 (br. s., 0.5H), 3.95-4.
13 (m, 2H), 3.78 (br. S., 0.5H), 3.74 (t
, J = 5.9 Hz, 2H), 3.50-3.61 (m, 0.5H)
, 3.38 (s, 3H), 3.07-3.24 (m, 1.5H), 2
. 90-3.06 (m, 1H), 2.65-2.79 (m, 1H),
2.60 (s, 3H), 2.52-2.63 (m, 1H), 2.17
-2.21 (m, 1H), 1.37 (d, J = 6.5 Hz, 1.5
H), 1.27 (d, J = 6.3 Hz, 1.5H), 1.09 (s,
2H), 1.05-1.08 (m, 2H).

  Step G ′ was the same as Step H in General Procedure 1.

General procedure 7:


Step H ′: 6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile

6-cyclopropyl-2-hydroxynicotinonitrile (20 g, 0.125 mmol
) In Ac ₂ O (110 mL) to a solution of HNO ₃ (15 mL) at 0 ° C. to 40 ° C. 3
Added dropwise for 0 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0 ° C. and the solid was collected by filtration. The solid was washed with brine and dried in vacuo to give the title compound (15.5 g, 60.4%) as a pale yellow solid. 1H NMR (chloroform-d) δ 10.71 (s, 1H), 8.68 (s, 1H),
13 (tt, J = 8.6, 5.6 Hz, 1H), 1.57-1.5
2 (m, 2H), 1.44-1.37 (m, 2H). LC-MS: m
/ Z 205.9 (M + H) +

Step I ′: 3-cyano-6-cyclopropyl-5-nitropyridin-2-yl trifluoromethanesulfonate

6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile (7.6 g, 37
. 7 mmol) in DCM (150 mL) was added DMAP (30.0 mg) and TE
A (7.5 g, 74.1 mmol) was added at room temperature. Then, Tf ₂ O (15.
7 g, 55.6 mmol) was added dropwise to the above solution at −40 ° C. for 30 minutes. The reaction mixture was stirred at −40 ° C. for 2 hours. The mixture was quenched with water at -40 ° C.
The mixture was then extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (12.5 g, crude) as a pale yellow solid. LC-MS: m / z 33
7.5 (M + H) ⁺

Step J ′: (R) -6-cyclopropyl-2- (3-isopropylpiperazine-1
-Yl) -5-nitronicotinonitrile

CH _{3 of} 3-cyano-6-cyclopropyl-5-nitropyridin-2-yl trifluoromethanesulfonate (10.9 g, 32.3 mmol) and (R) -2-isopropylpiperazine (3.45 g, 27.0 mmol) To a solution in CN (100 mL), TEA (
6.5 g, 64.7 mmol) was added at room temperature. The reaction mixture is stirred at 85 ° C. for 3
Heated for hours and stirred. The mixture was concentrated in vacuo and the residue was EtOAc (50 mL x 2)
Extracted by. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (8.5 g, crude) as a brown solid. LC-MS: m / z 316.6 (M + H) ⁺

Step K ′: (R) -tert-butyl 4- (3-cyano-6-cyclopropyl-5
-Nitropyridin-2-yl) -2-isopropylpiperazine-1-carboxylate

(R) -6-cyclopropyl-2- (3-isopropylpiperazin-1-yl) -5
Nitronicotinonitrile (8.52 g, 26.2 mmol) and anhydrous Boc (8.5 g)
, 39.3 mmol) in DCM (50 mL) was added TEA (3.9 g, 39.3 mm).
ol) was added at room temperature. The reaction mixture was stirred at 30 ° C. for 3 hours. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (10.4 g, 95%) as a yellow liquid. 1H NMR
(Chloroform-d) δ 8.51 (s, 1H), 4.74 (d, J =
13.7 Hz, 1H), 4.55 (d, J = 13.1 Hz, 1H),
3.88 (s, 1H), 3.37-3.23 (m, 2H), 3.11.
(Ddd, J = 10.5, 7.7, 5.7 Hz, 2H), 1.86
(Tdd, J = 13.3, 8.5, 4.9 Hz, 1H), 1.49 (
s, 9H), 1.27 (d, J = 2.3 Hz, 2H), 1.26 −
1.17 (m, 4H), 1.01 (d, J = 6.6 Hz, 3H),
0.89 (d, J = 6.8 Hz, 3H).

Step L ′: (R) -tert-butyl 4- (5-amino-3-cyano-6-cyclopropylpyridin-2-yl) -2-isopropylpiperazine-1-carboxylate

(R) -tert-butyl 4- (3-cyano-6-cyclopropyl-5-nitropyridin-2-yl) -2-isopropylpiperazine-1-carboxylate (19 g, 45.
8 mmol) in EtOH (200 mL) and H ₂ O (100 mL) was dissolved in zinc (3
0 g, 458 mmol) and NH ₄ Cl (24.5 g, 458 mmol) were added at room temperature. The reaction mixture was stirred at 40 ° C. overnight. The mixture was filtered through a pad of silica and the filtrate was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (13.1 g, 74.3%) as a yellow solid. 1H NMR (
Chloroform-d) δ: 7.10 (d, J = 2.9 Hz, 1H), 4.
02 (t, J = 19.0 Hz, 3H), 3.81 (t, J = 16
. 8 Hz, 3H), 3.13 (td, J = 12.8, 2.4 Hz,
1H), 2.99-2.86 (m, 2H), 2.25 (tt, J =
12.9, 6.5 Hz, 1H), 1.97-1.83 (m, 1H),
1.49 (d, J = 2.2 Hz, 9H), 1.13-1.06 (m
, 2H), 1.06-1.01 (m, 2H), 0.98 (t, J =
9.2 Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H).
LC-MS: m / z 386.6 (M + H) +

Step M ′: (R) -tert-butyl 4- (5-((4-chloropyridin-2-yl) amino) -3-cyano-6-cyclopropylpyridin-2-yl) -2-isopropylpiperazine- 1-carboxylate

(R) -tert-butyl 4- (5-amino-3-cyano-6-cyclopropylpyridin-2-yl) -2-isopropylpiperazine-1-carboxylate (600 mg, 8
1.6 mmol) and 2-bromo-4-chloropyridine (390.3 mg, 2.03 m)
mol) in 1,4-dioxane (15 mL), Pd ₂ (dba) ₃ (142.7
mg, 0.156 mmol) and xanthophos (135.3 mg, 0.234 mmol)
) And Cs ₂ CO ₃ (1.02 g, 3.12 mmol) were added at room temperature under N ₂ . The resulting mixture was heated in a microwave at 115 ° C. under N ₂ for 1 hour and stirred. The solvent is removed in vacuo and the residue is subjected to reverse phase silica gel column chromatography (MeOH).
: H ₂ O) to give the title compound (137 mg, 18%) as a pale yellow solid. 1H NMR (chloroform-d) δ: 8.07 (d, J = 5.4 Hz)
, 1H), 7.72 (d, J = 3.3 Hz, 1H), 6.75 (d
d, J = 5.5, 1.7 Hz, 1H), 6.39 (d, J = 1.
6 Hz, 1H), 6.25 (s, 1H), 4.45 (d, J = 13
. 2 Hz, 1H), 4.26 (d, J = 9.2 Hz, 1H), 4.
21-3.61 (m, 2.5H), 3.11 (dt, J = 13.5,
6.8 Hz, 2.5H), 2.22-1.98 (m, 2H), 1.5
2-1.47 (m, 9H), 1.28 (s, 1H), 1.14 (dt
, J = 8.1, 4.5 Hz, 1H), 1.08 (dd, J = 9.
7, 4.7 Hz, 1H), 1.01 (dd, J = 10.9, 5.2)
Hz, 4H), 0.90 (d, J = 6.8 Hz, 3H). LC-M
S: m / z 497.6 (M + H) +

Step N ′: (R) -tert-butyl 4- (3-cyano-6-cyclopropyl-5
-((4-vinylpyridin-2-yl) amino) pyridin-2-yl) -2-isopropylpiperazine-1-carboxylate

(R) -tert-butyl 4- (5-((4-chloropyridin-2-yl) amino)-
3-cyano-6-cyclopropylpyridin-2-yl) -2-isopropylpiperazine-
1-carboxylate (600 mg, 1.21 mmol) isopropanol (15 mL)
) And H ₂ O (3 mL) in a solution of vinyl trifluoroboronic acid potassium salt (324.
2 mg, 2.42 mmol), Pd (dppf) Cl ₂ (98.7 mg, 0.121 mm)
ol) and DIPEA (312.2mg, 2.42mmol) was added under _{N 2} at room temperature. The reaction mixture was heated in microwave at 125 ° C. under N ₂ for 1.5 hours and stirred. The solvent was removed in vacuo and the residue was chromatographed on silica gel column (DCM
: MeOH) to give the title compound (513 mg, 87%) as a yellow solid. LC-MS: m / z 489.6 (M + H) ⁺

Step O ′: (R) -6-cyclopropyl-2- (3-isopropylpiperazine-1
-Yl) -5-((4-vinylpyridin-2-yl) amino) nicotinonitrile

(R) -tert-butyl 4- (3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl) amino) pyridin-2-yl) -2-isopropylpiperazine-
To a solution of 1-carboxylate (513 mg, 1.05 mmol) in anhydrous DCM (10 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was adjusted to pH> 7.0. The residual mixture is EtOAc
Extracted with (15 mL × 2). The combined organic layers are washed with brine and Na ₂ SO
₄ was dried. The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (crude, 40
6 mg) was obtained as a yellow liquid. 1H NMR (chloroform-d) δ: 7.9
(D, J = 6.6 Hz, 1H), 7.72 (s, 1H), 7.04
(Dd, J = 6.6, 1.3 Hz, 1H), 6.64 (dd, J =
17.4, 10.8 Hz, 1H), 6.47 (s, 1H), 6.12
(D, J = 17.5 Hz, 1H), 5.81 (d, J = 10.8)
Hz, 1H), 5.24 (s, 1H), 4.59 (d, J = 13.9
Hz, 1H), 4.45 (d, J = 14.3 Hz, 1H), 3.6
3-3.48 (m, 2H), 3.30 (dd, J = 14.1, 11
. 1 Hz, 2H), 3.18 (s, 1H), 2.15-2.01 (m
, 2H), 1.28 (d, J = 4.8 Hz, 1H), 1.16 (d
d, J = 10.2, 6.9 Hz, 8H), 1.12-1.09 (m
, 1H). LC-MS: m / z 389.5 (M + H) +

Step P ′: (R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino ) Nicotinonitrile (Compound 757)

(R) -6-cyclopropyl-2- (3-isopropylpiperazin-1-yl) -5
((4-Vinylpyridin-2-yl) amino) nicotinonitrile (300 mg, 0.77
mmol) in DMF (15 mL) and sodium 3-hydroxypropanoate (
208.8 mg, 1.55 mmol), HATU (442.5 mg, 1.2 mmol) and DIPEA (200 mg, 1.55 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (138 mg, 38.
8%) was obtained as a pale yellow solid. 1H NMR (chloroform-d) δ: 8.12
(D, J = 5.4 Hz, 1H), 7.85 (d, J = 5.5 Hz)
, 1H), 6.84 (d, J = 5.4 Hz, 1H), 6.59 (d
d, J = 17.6, 10.8 Hz, 1H), 6.46 (s, 1H),
6.42 (s, 1H), 5.91 (d, J = 17.5 Hz, 1H)
, 5.48 (d, J = 10.9 Hz, 1H), 4.69 (d, J
= 10.4 Hz, 0.5 H), 4.44 (d, J = 12.6 Hz,
1.5H), 4.31-4.23 (m, 1H), 3.93 (s, 2H)
3.75 (d, J = 13.5 Hz, 0.5H), 3.51-3.
38 (m, 2H), 3.14-2.97 (m, 2H), 2.61 (d
t, J = 5.7, 4.8 Hz, 2H), 2.36-2.25 (m,
0.5H), 2.19 (ddd, J = 12.9, 8.1, 4.9 Hz)
, 1H), 1.29 (t, J = 16.6 Hz, 1H), 1.18 −
0.97 (m, 7H), 0.95-0.88 (m, 1.5H), 0.
86 (d, J = 6.8 Hz, 1.5H). LC-MS: m / z 46
1.6 (M + H) +

General procedure 8

Step Q ′: ((R) -tert-butyl 4- (3-cyano-6-cyclopropyl-
5-hydroxypyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate

(R) -tert-butyl 4- (5-bromo-3-cyano-6 in a 50 mL flask
-Cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (0.35 g, 1.0 mmol), potassium hydroxide (0.22 g, 4 mmol)
To the mixture of Pd ₂ (dba) ₃ (0.092 g, 0.1 mmol), t-Bu-Xph.
os (0.082 g, 0.2 mol) was added. Then 10 mL of 1,4-dioxane and 1.0 mL of water are added and the mixture is stirred at 80 ° C. for 16 hours, cooled, 2
Acidified to pH 6 (temperature kept below 25 ° C.) with N HCl. The mixture was then extracted with ethyl acetate (15 mL × 2) and the organic phases combined and concentrated to give a brown oil which was further purified by silica gel chromatography (PE: EA = 3: 1) to 1
6 g of (1) was obtained as a white solid (41% yield). LC-MS: m / z 386.0 (M
+ H) ⁺

Step R ′: (R) -tert-butyl 4- (5- (2-chloropyridin-4-yloxy) -3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1- Carboxylate

(R) -tert-butyl 4- (5-bromo-3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (0.16 g,
0.41 mol), 2-chloro-4-iodopyridine (0.15 g, 0.62 mol),
A mixture of 9 mg Cu (I) Br (0.06 mmol) and 12 mg 2,2,6,6-tetramethylheptane-3,5-dione (0.06 mmol), 0.28 g Cs ₂ CO ₃ , Heated in 4 mL DMSO under microwave for 30 minutes. The mixture was cooled to room temperature, washed with water and purified by silica gel chromatography (DCM: MeOH = 20: 1) to give 0.10 g of (2) as a yellow solid (52% yield). LC-MS: m /
z486.0 (M + H) ⁺

Step S ′: (R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (3-cyclopropylpiperazin-1-yl) nicotinonitrile

(R) -tert-butyl 4- (5- (2-chloropyridin-4-yloxy) -3-
Cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1
-A mixture of carboxylate (0.10 g, 0.21 mmol) and TFA (0.35 mL) was stirred in DCM (10 mL) for 2 h. The solvent is removed and the residue is washed with NaHCO3.
Basified with ₃ solutions, extracted with DCM (10 mL), the organic phase was separated and concentrated to give a yellow solid (3) (0.075 g, 0.19 mmol, crude yield 90%). LC-
MS: m / z 397.1 (M + H) ⁺

Step T ′: (R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine-
1-yl) nicotinonitrile (Compound 694)

(R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (
3-Cyclopropylpiperazin-1-yl) nicotinonitrile (0.35 g, 0.88 m
mol), sodium 3-hydroxypropanoate (0.10 g, 0.88 mmol)
, HATU (0.50 g, 1.32 mmol) and 0.23 g DIEA (1.76 m
mol) was stirred in 8 mL of DMF for 4 hours. The mixture was then quenched by the addition of 6 mL of water, extracted with EA (15 mL × 2), the organic phases were combined and concentrated to give a yellow oil that was chromatographed on silica gel (DCM: MeOH = 20: 1).
) To give 0.10 g of product as a yellow solid (52% yield). 1H
NMR (chloroform-d) δ: 8.30 (d, J = 5.6 Hz,
1H), 7.48-7.49 (m, 0.5H), 6.81 (dt, J =
5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41 (d,
J = 13.0 Hz, 1H), 4.29 (d, J = 13.0 Hz,
1H), 4.12 (dd, J = 18.6, 7.4 Hz, 1H), 3
. 93 (s, 2H), 3.84-3.67 (m, 1H), 3.18 (
d, J = 12.8 Hz, 1H), 3.13-2.99 (m, 1H)
, 2.61 (s, 2H), 2.32-2.22 (m, 0.5H), 2
. 02 (t, J = 4.6 Hz, 1H), 1.35 (s, 1H), 1
. 29 (d, J = 9.4 Hz, 3H), 1.14 (dd, J = 7
. 4, 3.0 Hz, 2H), 1.04 (dt, J = 7.9, 3.1)
Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m
, 2H). LC-MS: m / z 468.1 (M + H) +

Step U ′: (R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-
Hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylpyridin-4-yloxy) nicotinonitrile (Compound 692)

(R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (
3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicotinonitrile (4) 0.35 g, (0.75 mmol), potassium trifluoro (vinyl) borate (0.15 g, 1. 1 mmol), PdCl ₂ dppf (80 mg, 0.07
5 mmol) and DIEA (0.24 mL, 1.5 mmol) were heated to reflux in isopropanol at 85 ° C. under nitrogen for 5 h. The mixture was then concentrated under reduced pressure to give a yellow solid which was chromatographed on silica (PE / EA / MeOH = 150 /
120/8) gave 0.19 g of product as a white solid (55% yield). 1H NMR (chloroform-d) δ: 8.47 (d, J = 5.6)
Hz, 1H), 7.48-7.49 (m, 0.5 H), 6.86 (d,
J = 2.3 Hz, 1H), 6.77 (dd, J = 17.4, 10.
8 Hz, 1H), 6.66 (dd, J = 5.6, 2.4 Hz, 1H
), 6.22 (dd, J = 17.4, 0.9 Hz, 1H), 5.53
(Dd, J = 10.8, 0.8 Hz, 1H), 4.68 (d, J
= 11.7 Hz, 1H), 4.38 (d, J = 12.9 Hz, 1H)
), 4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H)
1H), 3.92 (s, 2H), 3.75 (d, J = 20.7 Hz,
1H), 3.47 (d, J = 21.7 Hz, 1H), 3.25 −
3.12 (m, 1H), 3.09-2.95 (m, 1H), 2.60
(S, 2H), 2.32-2.22 (m, 0.5 H), 2.11-
2.05 (m, 1H), 1.37 (d, J = 20.5 Hz, 1H),
1.27 (d, J = 2.0 Hz, 1H), 1.16-1.10 (
m, 2H), 1.01 (ddd, J = 10.1, 6.7, 3.3 Hz)
, 2H), 0.65 (t, J = 33.7 Hz, 2H), 0.45-0
. 48 (m, 2H). LC-MS: m / z 460.1 (M + H) +

General procedure 9:

Core 7-1 (120 mg, 0.295 mmol) and amine (0.295 mmol)
Was dissolved in toluene (2 mL). K3PO4 (125.0 mg, 0.590 mmo
l), xanthophos (catalyst) and Pd2 (dba) 3 (catalyst) were added to the above mixture under N2. The mixture was shaken at 120 ° C. for 16 hours. The crude product was purified by preparative HPLC.

Example 15
Building Block Synthesis Building Block 1: (R) -2-Cyclopropylpiperazine:

Step 1: (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl)
To a solution of -3-methylpiperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile (100 g, 0.87 mol) in water (1250 mL) was added NaHCO _3.
(175 g, 2.08 mol) was added at room temperature and then (Boc) ₂ O in THF (
Solution in 1250 mL) was added and the reaction mixture was heated to reflux overnight. The resulting mixture was then concentrated to remove THF under reduced pressure. EtOAc (1250 mL) was added to the residue and the resulting mixture was cooled to 5 ° C. and then adjusted to pH 3 with saturated aqueous NaHSO ₄ . The layers were separated and the aqueous layer was extracted with EtOAc (1000 mL × 3). Combined EtO
The Ac layer was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (R) -2- (tert-butoxycarbonylamino) -2-cyclopropylacetic acid (16
5 g, 88% yield). 1H NMR (MeOD 400 MHz) δ 3.16
-3.14 (d, J = 8.8, 1H), 1.11 (s, 9H), 0.73
-0.78 (m, 1H), 0.28-0.2 (m, 3H), 0.18-0.
15 (m, 1H) 100 ee%.

Step 2: Isobutyl chloroformate (81.6 g, 0.6 mol) is added to (R)-
2- (tert-Butoxycarbonylamino) -2-cyclopropylacetic acid (129 g, 0
. 6 moL) and Et ₃ N (67 g, 0.66 moL) in DCM (1000 mL) was added over 1 hour at 0 ° C. to 5 ° C. and the reaction mixture was stirred at 0 ° C. to 5 ° C. for 1 hour. In a separate flask, glycine methyl ester hydrochloride (82.8 g, 0
. 66 moL), Et ₃ N (73 g, 0.72 moL) and DCM (1000 mL) were stirred for 1 h, then the mixture was added to the flask over 2 h. After the addition was complete, the mixture was stirred at room temperature overnight for 40 hours, then washed with water and brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by column chromatography ( R) -Methyl 2- (2- (tert-butoxycarbonylamino) -2
-Cyclopropylacetamido) acetate (100 g, 58% yield) was obtained as a white solid. 100ee%. 1H NMR (DMSO 400 MHz) δ 8.2-8.1
6 (t, J = 5.6, 1H), 6.66-6.86 (d, J = 8.8, 9
H), 3.71-3.92 (m, 2H), 3.62 (s, 3H), 3.4
6-3.51 (t, J = 8.4, 1H), 1.36 (s, 9H), 0.97-
1.01 (m, 1H), 0.38-0.44 (m, 3H), 0.25-0.2
8 (m, 1H).

Step 3: (R) -methyl 2- (2- (tert-butoxycarbonylamino) -2
-Cyclopropylacetamide) acetate (290 g, 1.014 mol) in DCM (
To the solution in 1740 mL), TFA (870 mL) was added dropwise at 0 ° C. The reaction solution was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure to give (R) -methyl 2- (2-amino-2-cyclopropylacetamide) acetate (511 g of crude product).

Step 4: (R) -Methyl 2- (2-amino-2-cyclopropylacetamide) acetate (255.5 g crude, 0.507 mol) in a solution of MeOH (1250 ml) in Et ₃ N (750 ml, 10 .78 mol) was added dropwise at 0 ° C. The reaction solution was then stirred at room temperature for 2 days. The resulting mixture was filtered and the precipitate was washed with MTBE and dried under high vacuum to give (R) -3-cyclopropylpiperazine-2,5-dione (60 g, 76.9% yield). . 1H NMR (DMSO 400MHz)
δ 7.98 (s, 1H), 7.74 (s, 1H), 3.68-6.64
(D, J = 17.6, 1H), 3.30-3.36 (m, 1H), 2.9-
2.93 (dd, J = 3.2, 1H), 0.87-0.92 (m, 1H),
0.21-0.27 (m, 3H), 0.18-0.21 (m, 1H).

Step 5: (R) -3-cyclopropylpiperazine-2,5-dione (30 g,.
To a suspension mixture of 195 mmol) in THF (1000 mL) was added AlLiH ₄ (45 g,
1.184 mol) was added in portions at 0 ° C. over 1.5 hours. The reaction mixture was then heated to 70 ° C. overnight. After cooling, water (45 mL) was added dropwise at 0 ° C. and then a solution of KOH (45 mL, 1%) was added dropwise at 0 ° C. The resulting mixture was filtered, the residue was washed with EtOAc and MeOH (3: 1), and the filtrate was concentrated under reduced pressure to give the crude product. The crude product is then washed with DCM and the filtrate is concentrated under reduced pressure (R
) -2-cyclopropylpiperazine (18.5 g, yield 75.5%) was obtained. 99.5e
e%. 1H NMR (MeOD 400 MHz) δ 2.9-2.96 (m, 1
H), 2.8-2.88 (m, 1H), 2.7-2.8 (m, 1H),
55-2.68 (m, 2H), 2.4-2.5 (q, J = 10.4, 1H)
, 1.65-1.73 (m, 1H), 0.55-0.67 (m, 1H),
0.35-0.45 (m, 2H), 0.05-0.25 (m, 2H).

Building block 2: 2- (2,2,2-trifluoroethyl) piperazine

Step 1: 2-amino-4,4,4-trifluorobutanoic acid (450 mg, 3 mmo
l) in 5 mL H ₂ O and 5 mL THF was added NaHCO ₃ (504 mg, 6 m
mol) followed by di-tert-butyl dicarbonate (650 mg, 3 mmo).
l) in THF (3 mL) was added. The resulting mixture was stirred at 80 ° C. overnight. After removal of THF, the mixture was poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. 723 mg of 2- (tert-butoxycarbonylamino) -4,4,4-trifluorobutanoic acid was obtained as a crude product and used in the subsequent reaction without further purification. MS (ES) M + H predicted value 258, measured value 2
58.1H NMR (chloroform-d) δ 5.25 (d, J = 7.8)
Hz, 1H), 4.40-4.67 (m, 1H), 2.60-2.9
0 (m, 2H), 1.46 (s, 9H).

Step 2: In a 25 mL round bottom flask was added 2- (tert-butoxycarbonylamino) -4,4,4-trifluorobutanoic acid (723 mg, 2.8 mmol), Et ₃ N (5
60 mg, 5.6 mmol), isobutyl carbonochloridate (380 g, 2.8 mm)
ol) of 5 mL of methylene chloride was added. The resulting reaction mixture was stirred at 0 ° C. for 0.5 hour. Methyl 2-aminoacetate (352 mg, 2.8 mmol) was added.
The resulting mixture was stirred at room temperature overnight. After washing with saturated NaHCO ₃ , brine, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. 900mg
Of methyl 2- (2- (tert-butoxycarbonylamino) -4,4,4-trifluorobutanamide) acetate was obtained as a crude product and used in the subsequent reaction without further purification. MS (ES) M + H predicted value 329.1, found value 329.0. 1H NMR
(Chloroform-d) δ 7.11 (br.s., 1H), 5.28 (b
r. s. , 1H), 4.44-4.67 (m, 1H), 3.84-
4.07 (m, 2H), 3.69-3.83 (s, 3H), 2.72
-2.95 (m, 1H), 2.42-2.64 (m, 1H), 1.3
8-1.50 (m, 9H).

Step 3: Methyl 2- (2- (tert-butoxycarbonylamino) -4,4,4
-Trifluorobutanamide) acetate (900 mg, 2.7 mmol) 5 mL 1
The mixture in 2-dichlorobenzene was heated to 180 ° C. overnight. Cool mixture and MTB
E (5 mL) was added. A brownish yellow precipitate was formed. The filter cake was washed with MTBE and air dried to give 200 mg of 3- (2,2,2-trifluoroethyl) piperazine-2,5-dione. 1H NMR (DMSO-d6) δ 8.28 (d,
J = 9.3 Hz, 2H), 4.00-4.26 (m, 1H), 3
. 68-3.87 (m, 2H), 2.66-2.88 (m, 2H).

Step 4: Add 3- (2,2,2-trifluoroethyl) piperazine-2,
5-dione (200 mg, 1 mmol) in THF (5 mL), and LAH (2.5 mL)
6 mmol) was added dropwise at 0 ° C. under N ₂ . The mixture was heated to 65 ° C. overnight. After the reaction, the mixture was cooled. Add 0.23 mL H ₂ O, then 0.2 × 3 mL 10%
NaOH and 0.46 mL H ₂ O were added and the mixture was filtered. Cake with EtOAc
Washed with The organic phase was concentrated to give 140 mg of 2- (2,2,2-trifluoroethyl) piperazine, which was used without further purification. 1H NMR (chloroform-
d) δ 2.75-3.02 (m, 7H), 2.52 (dd, J =
11.7, 9.9 Hz, 1H), 2.10-2.17 (m, 2H).

Building block 3: 2- (difluoromethyl) piperazine

1,4-dibenzyl-2- (difluoromethyl) piperazine (Synthetic C
communications, 2011, vol. 41, # 14, 2031-2035) (80 mg, 0.253 mmol) in a solution of 40 mL EtOH in Pd (
OH) ₂ / C (15 mg) was added. The resulting mixture was stirred at room temperature under 50 Psi for 2
Hydrogenated for days. The reaction mixture was filtered and the filtrate was concentrated to give 2- (difluoromethyl) piperazine, which was used directly without further purification. LC-MS: m / z 137.1 (M
+ H) ⁺

Building block 4: 6-fluoro-1,4-diazepan

Step 1: 1,4-ditosyl-1,4-diazepan-6-ol (Synthesi)
s, 2003, 2, 223-226) (200 mg, 0.47 mmol) in 5 mL of DCM was added DAST (190 mg, 1.18 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous NaHCO ₃ . The aqueous layer was extracted with DCM and the combined organic phases were dried and concentrated. The residue was purified by preparative TLC and the residue was purified by preparative TLC to give 6-fluoro-1,4-ditosyl-1,4-diazepane (120 mg). 1H NMR (chloroform-d)
δ 7.66-7.71 (m, 4H), 7.34 (d, J = 8.0)
Hz, 4H), 5.02-4.92 (m, 1H), 3.60 (dd, J
= 18.1, 5.3 Hz, 4H), 3.34-3.53 (m, 4H)
, 2.46 (s, 6H).

Step 2: 6-Fluoro-1,4-ditosyl-1,4-diazepane (82 mg, 0.
19 mmol) in HOAc-HBr (3 mL, 30 wt%) was heated to 100 ° C. for 3 min in a pressure tube using microwave irradiation. The solvent is removed in vacuo and the residue is removed with Et.
Pulverized by ₂ O, and washed with Et ₂ O to give the 6-fluoro-1,4-diazepane, which was used directly without further purification. LC-MS: m / z 119.1 (M + H) ⁺

Building block 5: 6-fluoro-2-methyl-1,4-diazepan

Step 1: 6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane (1
20 mg) of 2-methyl-1,4-ditosyl-1,4-diazepan-6-ol (Sy
synthesis, according to nthesis, 2003, 2, 223-226) (200 mg, 0.47
mmol) (200 mg) from 6-fluoro-1,4-ditosyl-1,4-diazepane. 1H NMR (chloroform-d) δ 7.62-7.
75 (m, 4H), 7.30-7.37 (m, 4H), 5.00-4.
84 (m, 1H), 4.09-4.37 (m, 2H), 3.73-3
. 95 (m, 1H), 3.37-3.62 (m, 2H), 3.12-
3.32 (m, 1H), 3.05 (ddd, J = 13.6, 7.2)
4.0 Hz, 1H), 2.43-2.46 (m, 6H), 1.05
-1.14 (m, 3H).

Step 2: 6-Fluoro-2-methyl-1,4-diazepane is converted to 6-fluoro-2-
It was obtained from methyl-1,4-ditosyl-1,4-diazepane in the same manner as 6-fluoro-1,4-ditosyl-1,4-diazepane. LC-MS: m / z 133.1 (M + H
) ⁺

Building block 6: 2- (oxetan-2-yl) acetic acid

Step 1: 3-buten-1-ol (18.03 g, 0.25 mol), TEA (2
. A mixture of 4 mL, 0.02 mol) and sodium hydroxide (15 g, 0.38 mol) in hexane (200 mL) was stirred at 50 ° C. for 0.5 h. Hexane (50m
Benzyl bromide (32.7 mL, 0.27 mol) in L) was added dropwise over a period of 0.5 hours. The resulting mixture was then heated to reflux overnight (oil temperature: 85 ° C.). The precipitate was removed via filtration and washed twice with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The product thus obtained was sufficiently pure for the next reaction step. Yield: 38.21 g, 94.2%, colorless oil. 1H NMR
(400 MHz, CDCl3) δ 7.46-7.29 (m, 6H), 5
. 89 (ddt, J = 17.0, 10.1, 6.7 Hz, 1H), 5
. 21-5.03 (m, 2H), 4.56 (s, 2H), 3.57 (
t, J = 6.8 Hz, 2H), 2.43 (qd, J = 6.7, 1
. 1 Hz, 2H).

Step 2: ((But-3-en-1-yloxy) methyl) benzene (38.21 g
, 0.24 mol) in dichloromethane (400 mL), mCPBA (77.15
g, 0.38 mol) was added in portions at −20 ° C. as a solid. The resulting suspension was then allowed to warm to room temperature and stirred overnight. The precipitate was filtered off and washed with dichloromethane. The combined organic phases were then washed with saturated NaHCO ₃ and Na 2 SO ₃ and brine. A white precipitate was formed while the solvent was removed under reduced pressure. Further n-
Hexane was added and most of the white solid that appeared was filtered off. This procedure was repeated three times. The crude product is mixed with a mixture of ethyl acetate and petroleum ether as eluent (EtOAc: P
Column chromatography on silica gel using E = 1/50 to 1/5) gave the title compound. Yield: 35.26 g, 84.0%, pale yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.41-7.29 (m, 5H),
4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15
-3.06 (m, 1H), 2.85-2.77 (m, 1H), 2.5
5 (dd, J = 5.0, 2.7 Hz, 1H), 1.95 (dddd,
J = 13.4, 7.2, 6.2, 4.7 Hz, 1H), 1.81 (
dq, J = 14.3, 5.9 Hz, 1H). LC-MS: m / z 22
0.0 (M + CH3CN) +.

Step 3: A round bottom flask charged with HOAc (60.1 mg, 1.0 mol%) in toluene (20 mL) was charged with a Jacob sensorene Co (II) catalyst (0.30 g, 0.5 m).
ol%) at room temperature and the resulting solution was stirred at room temperature for 0.5 hour,
The flask was exposed to air to absorb oxygen. Volatiles were removed under reduced pressure to give a dark solid.
Racemic epoxide (17.82 g, 100 mmol) is added undiluted and then distilled water (
1.0 mL, 56 mmol) was added dropwise at 0 ° C. The resulting reaction mixture was allowed to warm slowly to room temperature and stirred overnight at room temperature. The reaction mixture was diluted with n-hexane and then passed through a pad of celite. The epoxide was obtained by using petroleum ether and the diol was obtained by using a mixture of methanol and dichloromethane (1/30). The resulting epoxide (red oil) is distilled to give the desired product 145
Obtained at ˜165 ° C. (oil temperature); similarly, the diol was obtained at 185-205 ° C. (oil temperature). Epoxide yield: 7.83 g, 43.9%, light yellow oil; diol yield: 8.46 g, 43.1%, light yellow oil. For chiral epoxides: 1H NMR
(400 MHz, CDCl3) δ 7.41-7.29 (m, 5H),
4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15
-3.06 (m, 1H), 2.85-2.77 (m, 1H), 2.55
(Dd, J = 5.0, 2.7 Hz, 1H), 1.95 (dddd,
J = 13.4, 7.2, 6.2, 4.7 Hz, 1H), 1.81 (d
q, J = 14.3, 5.9 Hz, 1H). LC-MS: m / z 220
. 0 (M + CH3CN) +. For chiral diols: 1H NMR (400
MHz, CDCl3) δ 7.41-7.29 (m, 5H), 4.53
(S, 2H), 3.94 (s, 1H), 3.86-3.41 (m, 5
H), 3.18 (s, 1H), 1.91-1.66 (m, 2H). L
C-MS: m / z 219.0 (M + Na) +. ee> 99%.

Step 4: A mixture of potassium tert-butoxide (1.68 g, 15 mmol) and trimethyloxosulfonium iodide (3.30 g, 15 mmol) in tert-butoxide (35 mL) was stirred at 50 ° C. for 1 hour. Chiral epoxide (0.8
A solution of 9 g, 5 mmol) in tert-butoxide (15 mL) was added dropwise while maintaining the temperature at about 50 ° C. The resulting reaction mixture was then stirred at 50 ° C. overnight. The precipitate was removed via filtration and washed with ethyl acetate. The combined organic phases were dried under reduced pressure and diluted with ethyl acetate. The diluted solution was washed with brine and dried over sodium sulfate. The crude product was subjected to column chromatography on silica gel using EtOAc: PE = 1/10 as the eluent to give the title compound. Yield: 0.55g, 5
7.7%; colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.4
1-7.29 (m, 5H), 5.09-4.94 (m, 1H), 4.70
(Dd, J = 14.0, 7.8 Hz, 1H), 4.62-4.38 (m
, 3H), 3.67-3.51 (m, 2H), 2.72 (dq, J =
13.9, 7.8 Hz, 1H), 2.43 (dt, J = 10.7, 7
. 6 Hz, 1H), 2.16 (td, J = 13.3, 5.8 Hz,
1H), 2.02 (td, J = 13.6, 6.0 Hz, 1H). LC
-MS: m / z 234.1 (M + CH3CN) +. ee> 99%.

Step 5: (R) -2- (2- (benzyloxy) ethyl) oxetane (4.35 g)
, 22.63 mmol) and palladium hydroxide on carbon (20%, with 50% water,
0.80 g, 2.5 mol%) methanol (50 mL) and dichloromethane (15 m
The mixture in L) was stirred overnight at room temperature with addition of hydrogen gas. Celi deposit
Removed through filtration through a pad of te and washed with dichloromethane. The combined organic phases were dried at 30 ° C. using a water pump and confirmed to be pure enough for the next reaction. Yield: 2.28 g, 98.7%; colorless oil. 1H NMR (400
MHz, CDCl3) δ 5.09 (qd, J = 7.5, 4.6 Hz)
, 1H), 4.70 (td, J = 8.0, 6.0 Hz, 1H), 4
. 57 (dt, J = 9.1, 5.9 Hz, 1H), 3.82 (ddd
, J = 11.8, 7.3, 4.6 Hz, 1H), 3.74 (ddd,
J = 11.1, 6.5, 4.9 Hz, 1H), 3.11-2.77
(M, 1H), 2.77-2.62 (m, 1H), 2.45 (ddt, J
= 11.0, 9.1, 7.4 Hz, 1H), 2.13-1.98 (m,
1H), 1.91 (ddt, J = 14.3, 7.3, 4.7 Hz,
1H). ee> 99%.

Step 6: Oxetane (3.10 g, 30.48 mmol), sodium periodate (19.56 g, 91.44 mmol), water (30 mL), acetonitrile (60 mL)
And carbon tetrachloride (30 mL) to a ruthenium trichloride trihydrate (79.7 mg,
1 mol%) was added at 0-5 ° C. The resulting mixture was then allowed to warm to room temperature and stirred at this temperature for 2 hours. The precipitate was removed via filtration through a pad of celite and washed with diethyl ether (ca. 100 mL × 5). The combined organic phases were washed with brine (50 mL × 3) and then dried at 35 ° C. using a water pump to ensure that it was pure enough for the next reaction. Yield: 2.26 g, 63.
8%; pale yellow oil. 1H NMR (400 MHz, methanol-d4) δ 5
. 26-5.15 (m, 1H), 4.69 (ddd, J = 8.3, 7.
8, 5.9 Hz, 1H), 4.58 (dt, J = 9.2, 5.9 H
z, 1H), 2.88-2.70 (m, 3H), 2.51 (ddt, J
= 11.2, 9.1, 7.3 Hz, 1H). ee> 99%.

Building block 7: 5-bromoisoquinoline 2-oxide

5-Bromoisoquinoline (1.5 g, 7.2 mmol) in dichloromethane (20 mL)
To the medium solution, mCPBA (1.5 g, 8.6 mmol) was added all at once at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then washed with water (20 mL) and brine (20 mL) and dried over Na ₂ SO ₄ . The solvent was removed and the residue was purified by column chromatography on silica gel (EtOAc) to give 0.97 g of the title compound as a pale yellow solid. 1H NMR (chloroform-d) δ 8.7
1-8.80 (m, 1H), 8.22 (dd, J = 7.3, 1.5
Hz, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.81
-7.91 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H
), 7.43-7.54 (m, 1H). LC-MS: m / z 222.9
(M + H) +

Building block 8: 5-bromo-1-chloroisoquinoline

5-Bromoisoquinoline 2-oxide (0.4 g, 2.4 mmol) of CHCl ₃ (1
To the solution in 0 mL) was added POCl ₃ (0.7 mL, 3 eq). The mixture is then
Reflux for hours. After cooling to room temperature, the reaction mixture was poured into ice water, neutralized with saturated NaHCO 3 (aq) and extracted with EtOAc. The solvent was removed to give 0.45 g of crude product that was used in the next step without further purification. 1H NMR (chloroform-d) δ 8.33-8.44 (m, 2H), 8.02-8.0
8 (m, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.5
2-7.61 (m, 1H). LC-MS: m / z 242.9 (M + H)
+.

Building block 9: 5-bromo-1-methoxyisoquinoline

5-Bromo-1-chloroisoquinoline (1.2 g, 5.0 mmol) in methanol (1
To the solution in 0 mL) was added NaOMe (324 mg, 6.0 mmol). Mix 2
Reflux for hours. The solvent is removed and the residue is chromatographed on silica gel (1
(0-20% EtOAc / petroleum ether) to give 600 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.26 (d, J =
8.3 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 7
. 95 (dd, J = 7.5, 1.0 Hz, 1H), 7.58 (d,
J = 6.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H)
), 4.17 (s, 3H). LC-MS: m / z 237.0 (M + H) +

Building block 10: 5-bromo-1-methoxyisoquinoline

5-Bromo-1-chloroisoquinoline (300 mg, 1.2 mmol) in water (10 mL)
To the suspension in) was added NaOH (240 mg, 6 mmol). The mixture was refluxed for 2 hours. After cooling to room temperature, the pH of the mixture was adjusted to 7 with 2N HCl. The precipitate was filtered and dried to give 205 mg of crude product as a white solid that was used directly in the next step. LC-MS: m / z 222.9 (M + H) ⁺

Building block 11: 5-bromo-1-methoxyisoquinoline

5-bromoisoquinoline 2-oxide (224 mg, 1.0 mmol), diethylphosphorusanidate (489 mg, 3.0 mmol) and Et3N (101 mg, 1.0 mmol).
mmol) in CH 3 CN (5 mL) was heated in a microwave oven at 150 ° C. for 1.5 h. After cooling to room temperature, the precipitate was filtered and dried to give 110 mg of product as a yellow solid. 1H NMR (chloroform-d) δ 8.79 (d,
J = 5.8 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H)
), 8.29 (d, J = 5.8 Hz, 1H), 8.14 (d, J
= 7.5 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H).
LC-MS: m / z 231.9 (M + H) +

Building block 12: 5-bromo-3-chloroisoquinoline

Step 1: 1,3-dichloroisoquinoline (4 g, 20.2 mmol) in CH3CN
To a solution in (100 mL) H2SO4 (4 mL) was added followed by NBS (4.4 g, 2
4.2 mmol) was added. The mixture was stirred at room temperature for 90 hours. The precipitate was then collected by filtration, washed with water and dried to give 3.4 g of 5-bromo-1,3-dichloroisoquinoline as a pale yellow solid. 1H NMR (chloroform-d) δ
8.33 (d, J = 8.5 Hz, 1H), 8.03-8.10 (m
, 2H), 7.56 (dd, J = 8.4, 7.7 Hz, 1H). LC
-MS: m / z 276.9 (M + H) +

Step 2: 5-Bromo-1,3-dichloroisoquinoline (3 g, 10.8 mmol)
To a suspension of AcOH (30 mL) and concentrated HCl (6 mL) was added Sn powder (3.86 g).
32.4 mmol) was added. The mixture was stirred at 60 ° C. for 20 minutes. After cooling to room temperature, the mixture was neutralized with NaOH (aq) and filtered through celite. The filtrate was extracted with EtOAc (2 × 30 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (5-10% EtOAc / petroleum ether) to give 0.8 g of 5-bromo-3-chloroisoquinoline as a white solid. 1H NMR
(Chloroform-d) δ 9.04 (s, 1H), 8.04 (s, 1H)
, 7.90-8.02 (m, 2H), 7.47 (t, J = 7.9
Hz, 1H).

Building block 13: 4-chloro-2-vinyl-1,7-naphthyridine

Step 1: Sodium tert-butoxide (1.45 g, 15.1 mmol) was added to a stirred solution of ethyl-2-aminonicotinate (1 g, 6.02 mmol) and ethyl acetate (13 g, 147.7 mmol) in 15 mL anhydrous THF. Was added in portions over 1 minute. The resulting mixture was stirred at room temperature for 40 minutes and stirred at 100 ° C. for 4 hours. After this time, the reaction was cooled to room temperature and evaporated in vacuo. The solid obtained was water (20 m
L) and neutralized to pH 7 with 1.0 M aqueous HCl. The resulting solid was filtered and dried under vacuum overnight to give ethyl 3- (3-acetamidoisonicotinamide) isonicotinate as a tan solid (0.58 g, 59%). LC-MS: m / z 3
29.1 (M + H) + 1H NMR (chloroform-d) δ: 11.96
(S, 1H), 10.74 (br. S., 1H), 10.12 (s, 1
H), 9.99 (s, 1H), 8.56 (d, J = 5.3 Hz, 1
H), 8.59 (d, J = 5.0 Hz, 1H), 7.89-7.9.
6 (m, 1H), 7.66 (d, J = 5.3 Hz, 1H), 4.5
1 (q, J = 7.0 Hz, 2H), 2.24-2.33 (m, 3
H), 2.19 (s, 2H), 1.43-1.54 (t, 3H).

Step 2: Ethyl 3- (3-acetamidoisonicotinamide) isonicotinate (
A stirred solution of 400 mg, 2.47 mmol) in phosphorus oxychloride (2.5 mL)
Heated to 0 ° C. for 3 hours. After this time, the reaction was cooled to room temperature and evaporated in vacuo. The resulting solution is carefully basified to pH> 10 with an aqueous solution of Na ₂ CO ₃ and the resulting solid is filtered, washed with water and dried under vacuum to give 2,4-dichloro-1,7. -Naphthyridine (
200 mg, 83%). 1H NMR (chloroform-d) δ: 9.48
(S, 1H), 8.79 (d, J = 5.9 Hz, 1H), 8.01
(D, J = 5.9 Hz, 1H), 7.74 (s, 1H). LC-M
S: m / z 200 (M + H) +

Step 3: 5 mg of PdCl ₂ (dppf) in a reaction tube under nitrogen. CH ₂ Cl ₂
3 mL isopropanol, 1 mL water, 93.6 mg (0.8 mmol) DIPEA
, 52 mg (0.39 mmol) potassium vinyl trifluoroborate and 78 mg
(0.39 mmol) of 4-chloro-2-vinyl-1,7-naphthyridine was added. The reaction solution was heated to 100 ° C. for half an hour under microwave irradiation. The reaction mixture is extracted into ethyl acetate, washed several times with water and purified by preparative TLC (petroleum: ethyl acetate = 1: 1).
50 mg (66.8%) of -chloro-2-vinyl-1,7-naphthyridine were obtained. 1H N
MR (chloroform-d) δ: 9.51 (d, J = 0.6 Hz, 1H
), 8.70 (d, J = 5.6 Hz, 1H), 7.98-8.04.
(M, 1H), 7.89 (s, 1H), 7.02 (dd, J = 17
. 6, 10.9 Hz, 1H), 6.41 (d, J = 17.6 Hz,
1H), 5.83 (d, J = 11.2 Hz, 1H). LC-MS: m
/ Z 191.6 (M + H) +

Building block 14: 5-chloro-2-vinylquinoxaline

Step 1: To a solution of 5-chloroquinoxaline (1.4 g, 8.54 mmol) in 50 mL of dichloromethane was added mCPBA (1.62 g, 9.39 mmol). The resulting mixture was stirred at room temperature overnight. After removal of dichloromethane, the resulting crude product was purified by performing column chromatography (100% DCM) to give 1.5 g of 5-
Chloroquinoxaline 1-oxide was obtained as a white solid.

Step 2: 5-Chloro-Quinoxaline 1-oxide (450 mg, 2.5 mmol) in chloroform solution of 5mL of _was added POCl 3 (1.9g, 12.5mmol) slowly.
The resulting mixture was heated to 80 ° C. and kept stirring at 80 ° C. overnight. After removing chloroform and excess POCl ₃ , the resulting crude product was subjected to column chromatography (5
% PE / EA) to give 240 mg of 2,5-dichloroquinoxaline as a white solid. MS (ES) M + H predicted value 198, measured value 199. 1H NMR (
Chloroform-d) δ: 8.89 (s, 1H), 7.98 (d, 1H),
7.92 (d, 1H), 7.76 (t, 1H).

Step 3: Into a flask, 2,5-dichloroquinoxaline (315 mg, 1.59 mm
ol), potassium trifluoro (vinyl) borate (234 mg, 1.75 mmol),
PdCl ₂ DPPF (130 mg, 0.16 mmol), K ₂ CO ₃ (442 mg, 3.
18 mmol), propan-2-ol (4 mL), and H ₂ O (1 mL) are added,
The mixture was degassed with N ₂ and then heated to 90 ° C. with stirring for about 3 hours. TLC (
5% PE / EA) showed consumption of starting material and appearance of new spots. Then
The mixture was filtered through celite and the cake was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (1-5% PE / EA) to give 256 mg of 5-chloro-2-vinylquinoxaline as a white solid. 1H NM
R (chloroform-d) δ: 9.10 (s, 1H), 8.02 (d, 1
H), 7.85 (d, 1H), 7.71 (t, 1H), 7.09 (q,
1H), 6.57 (d, 1H), 5.89 (d, 1H). MS (ES
) M + H predicted value 190, actually measured value 191.

Building block 15: 2-((R) -4- (cyclopropanecarbonyl) -3-
Methylpiperazin-1-yl) -6-cyclopropyl-5- (morpholin-2-yl) nicotinonitrile

Step 1: 7-2 (500 mg, 1.28 mmol), potassium vinyl trifluoroborate (258 mg, 1.93 mmol), TEA (650 mg, 6.4 mmol) and Pd (dppf) Cl ₂ (52 mg, 0.064 mmol). The i-PrOH and water mixture was heated at 100 ° C. for 0.5 h under microwave irradiation. The reaction mixture is concentrated and the residue is purified by column chromatography (50% PE / EA).
mg of the title compound was obtained. 1H NMR (chloroform-d) δ 7.80 (s,
1H), 6.99 (dd, J = 17.3, 10.8 Hz, 1H),
5.58 (dd, J = 17.3, 0.8 Hz, 1H), 5.36 (d
d, J = 11.0, 0.8 Hz, 1H), 4.86 (br. s.,
0.5H), 4.53 (br. S., 0.5H), 4.44 (br. S.
, 0.5H), 4.09-4.29 (m, 2.5H), 3.65 (br.
s. , 0.5H), 3.41 (br. S., 0.5H), 3.12-3.2
4 (m, 2H), 2.14-2.26 (m, 1H), 1.76 (br
. s. , 1H), 1.25-1.42 (m, 3H), 1.10-1.1
7 (m, 2H), 0.96-1.10 (m, 4H), 0.82 (dd
, J = 7.8, 1.8 Hz, 2H).

Step 2: (R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5-vinylnicotinonitrile (200 mg, .0.
59 mmol), N- (2-hydroxyethyl) -4-nitrobenzenesulfonamide (
174 mg, 0.71 mmol, Organic Letters, 2011, 13, #
4, p. Synthesized according to 728-731), and NIS (159 mg, 0.71 mmol)
) In 10 mL of MeCN was stirred at room temperature for 2 hours. After the mixture was concentrated in vacuo, the residue was purified by column chromatography (50% PE / EA) to give 100 mg of N- (2- (1- (5-cyano-6-((R) -4). -(Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) -2-iodoethoxy) ethyl) -4-nitrobenzenesulfonamide was obtained as a pale yellow solid. 1H NMR (chloroform-d) δ 8.36-8.
45 (m, J = 8.8 Hz, 2H), 8.08-8.17 (m,
J = 8.8 Hz, 2H), 7.60 (s, 1H), 5.57 (br.
s. , 1H), 4.83 (br. S., 0.5H), 4.60-4.
71 (m, 1H), 4.53 (br. S., 0.5H), 4.40 (b
r. s. , 0.5H), 4.19-4.34 (m, 2.5H), 3.5
4-3.72 (m, 1H), 3.15-3.48 (m, 8H), 1
. 88-1.98 (m, 1H), 1.75 (br.s., 1H), 1
. 34-1.40 (m, 3H), 1.00-1.18 (m, 6H), 0
. 81 (d, J = 7.8 Hz, 2H).

Step 3: N- (2- (1- (5-cyano-6-((R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) ) -2-Iodoethoxy) ethyl) -4-nitrobenzenesulfonamide (100 mg)
0.14 mmol), K ₂ CO ₃ (97 mg, 0.71 mmol) in 10 mL MeC
The mixture in N was stirred overnight at room temperature. After the mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography (50% PE / EA) to give 66 mg of 2-((
R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (4-((4-nitrophenyl) sulfonyl) morpholin-2-yl) nicotinonitrile Obtained as a pale yellow solid. 1H NMR (chloroform-d)
δ 8.39-8.49 (m, J = 8.5 Hz, 2H), 7.90
-8.02 (m, J = 8.3 Hz, 2H), 7.70 (s, 1H)
, 4.91 (dd, J = 10.2, 2.1 Hz, 1H), 4.84
(Br.s., 0.5H), 4.52 (br.s., 0.5H), 4.4
2 (br. S., 0.5H), 4.16 (dd, J = 11.8, 2.
5 Hz, 4H), 3.86-4.00 (m, 2H), 3.76 (d,
J = 11.5 Hz, 1H), 3.61 (br. S., 0.5H),
3.14-3.38 (m, 3H), 2.52-2.69 (m, 1H),
1.97-2.09 (m, 1H), 1.74 (br.s., 1H),
1.28-1.48 (m, 3H), 1.19-1.25 (m, 2H)
, 1.11-1.19 (m, 2H), 1.04-1.11 (m, 2
H), 0.81 (d, J = 7.5 Hz, 2H).

Step 4: 2-((R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (4-((4-nitrophenyl) sulfonyl) morpholine-2 -Yl) nicotinonitrile (50 mg, 0.075 mmol), butane-1-thiol (3d) and LiOH. A mixture of H ₂ O (20 mg) in 10 mL MeCN was stirred overnight at room temperature. After the mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography (10% DCM / MeOH) to give 21 mg 2-((
R) -4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (morpholin-2-yl) nicotinonitrile was obtained. 1H NMR
(Chloroform-d) δ 7.81 (br.s., 1H), 4.96 (b
r. s. , 1H), 4.34-4.63 (m, 1H), 4.14 (b
r. s. 3H), 3.97 (br. S., 1H), 3.46 (br.
s. , 3H), 3.32 (br.s., 2H), 3.09 (br.s)
. , 3H), 2.75 (br.s., 1H), 2.09 (br.s.,
1H), 1.74 (br.s., 1H), 1.26 (br.s., 5
H), 1.03 (br.s., 4H), 0.80 (br.s., 2H)
.

Building block 16: 5-chloro-2-vinylquinazoline

Step 1: 1-chloro-2-methyl-3-nitrobenzene (10.0 g, 58.3 m
mol) in 150 mL anhydrous DMF was added 1,1-dimethoxy-N, N-dimethylmethanamine (21.0 g, 175 mmol). The resulting mixture was stirred at 140 ° C. for 16 hours. After cooling to 0 ° C., the mixture was poured into NaIO ₄ (37.4 g, 175 m
mol) in H ₂ O and DMF was added slowly. The mixture was stirred for an additional 6 hours. The mixture was filtered and partitioned between EtOAc and water. The organic layer is washed with water and N
Dried over a ₂ SO ₄ and concentrated to give the crude, which was purified by column to give 6.5 g of 2-chloro-6-nitrobenzaldehyde. 1H NMR (chloroform-d)
δ 10.39 (s, 1H), 7.95-8.04 (m, 1H), 7
. 74-7.80 (m, 1H), 7.64 (t, J = 8.0 Hz,
1H). LC-MS: m / z 186.0 (M + H) +

Step 2: 2-Chloro-6-nitrobenzaldehyde (1 g, 0.0054 mmol)
) In ethanol, Fe (1.8 g, 0.032 mmol), AcOH (10 ml)
) And 2N aqueous HCl (5 mL). The resulting mixture was stirred at 25 ° C. for 2 hours. The mixture was filtered and the filtrate was partitioned between DCM and water. The organic layer was washed with water and brine and concentrated to give 2-amino-6-chlorobenzaldehyde at 25 ° C., which was used in the next step without purification. LC-MS: m / z 156.01 (
M + H).

Step 3: Compound 2-amino-6-chlorobenzaldehyde (2.8 g, 0.018
mol), guanidine (3.43 g, 0.36 mol) and Na ₂ CO ₃ (3.82 g).
, 0.36 mol) of the mixture in naphthalene was stirred at 180 ° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the solid was washed with water and DCM to give a yellow solid 5-chloroquinazolin-2-amine that was used in the next step without purification. 1H NMR (D
MSO-d6) δ □ 9.28 (s, 1H), 7.65 (dd, J = 8.
5, 7.8 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H)
, 7.31 (d, J = 7.5 Hz, 1H), 7.16 (s, 2H)
. LC-MS: m / z 180.0 (M + H).

Step 4: 5-chloroquinazolin-2-amine (2.2 g, 12.2 mmol), isoamyl nitrite (4.30 g, 36.7 mmol), CuI (1.17 g, 6.12 mm)
ol) and CH ₂ I ₂ (16.4 g, 61.2 mmol) in THF at 60 ° C.
For 72 hours. After cooling to room temperature, the mixture was filtered, the filtrate was partitioned between EtOAc and water, the organic layer was washed with water and brine, and dried over Na ₂ SO ₄ . The organic layer is then concentrated to give a crude product, which is purified by column to give 5-chloro-2-
Iodoquinazoline was obtained as a yellow solid. 1H NMR (chloroform-d) δ 9
. 46 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7
. 86 (dd, J = 8.5, 7.5 Hz, 1H), 7.72 (dd,
J = 7.4, 1.1 Hz, 1H). LC-MS: m / z 291.1
(M + H).

Step 5: 5-chloro-2-iodoquinazoline (1.3 g, 4.48 mmol), potassium vinyl trifluoroborate (600 mg, 4.48 mmol), Pd (dppf
) Cl ₂ (165 mg, 0.224 mmol) and CsF (2.04 g, 13.4 mm)
ol) in dioxane / H ₂ O was stirred at 80 ° C. for 16 h. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give a crude product that was purified by column to 500
mg of 5-chloro-2-vinylquinazoline was obtained as a yellow solid. 1H NMR (chloroform-d) δ 9.75 (s, 1H), 7.93 (d, J = 8.5)
Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.63
(D, J = 7.5 Hz, 1H), 7.06 (dd, J = 17.2
, 10.4 Hz, 1H), 6.85 (dd, J = 17.3, 1.8
Hz, 1H), 5.90 (dd, J = 10.5, 1.5 Hz, 1H)
. LC-MS: m / z 191.0 (M + H).

Building block 17: 4-chloro-2-vinyl-1,8-naphthyridine

Step 1: 2-Amino nicotinic acid (0.18 mol) of 25g, _K 2 CO ₃ 25g of
(0.18 mol) of a mixture in 250 mL of DMF was stirred at 140 ° C. for 30 minutes, then cooled to 10 ° C. in ice / H ₂ O, and 11 mL of MeI (0.18 mol) was added at 10 ° C.
The mixture was stirred at room temperature overnight. Filter the mixture, concentrate the filtrate,
The residue was dissolved in EtOAc, filtered again through a pad of silica gel and the filtrate was concentrated to give 15 g of methyl 2-aminonicotinate. 1H NMR (400 MHz,
CHLOROFORM-d) δ: 7.67 (d, J = 7.0 Hz, 1
H), 7.69 (d, J = 7.8 Hz, 1 H), 7.60-7.
44 (m, 1 H), 3.54 (br. S., 3 H).

Step 2: Methyl 2-aminonicotinate (7.48 g, 49 mmol) in EtOAc / THF (150 mL / 150 mL) was added to 13.8 g of KtOBu (123 mmol).
) Was slowly added in portions at room temperature and the mixture was stirred at room temperature for 50 minutes before it was refluxed for 4 hours. After cooling to room temperature, the mixture is concentrated and the residue is washed with 200 mL of H
Dissolve in ₂ O and adjust pH to pH = 7 with 1N HCl with vigorous stirring;
The resulting suspension was filtered and the resulting solid was dried in vacuo to give 7 g of 1,8-naphthyridine-2,4-diol.

Step 3: A mixture of 8.0 g of 1,8-naphthyridine-2,4-diol (49 mmol) in 80 mL of POCl _{3 is} refluxed for 1.5 hours, excess POCl ₃ is removed under reduced pressure, and the residue Is slowly poured into saturated NaHCO ₃ with vigorous stirring and the mixture is poured into EtOA.
extracted with c, the organic layer was dried over Na ₂ SO ₄ and concentrated to give 2 g of 2,4-dichloro-1,8-naphthyridine, which was used in the subsequent reaction without further purification.
1H NMR (400 MHz, CHLOROFORM-d) δ: 9.21 −
9.12 (m, 1 H), 8.59 (dd, J = 1.8, 8.3 Hz)
, 1 H), 7.67-7.58 (m, 2 H).

Step 4: 100 mg 2,4-dichloro-1,8-naphthyridine (0.5 mmol), 68 mg potassium vinyl trifluoroborate (0.5 mmol), 130 mg DIPEA in iPrOH / H ₂ O (3 mL / 1 mL) (1 mmol) to Pd (dpp
f) ₂ Cl ₂ was added and the mixture was then stirred in a sealed tube at 105 ° C. for 1 hour. T
When LC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete, the mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated to 120 mg of crude 4-chloro-2. -Vinyl-1,8-naphthyridine was obtained and used in subsequent reactions without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ:
9.17 (dd, J = 1.8, 4.3 Hz, 1 H), 8.58 (
dd, J = 1.9, 8.4 Hz, 1 H), 7.62-7.49 (
m, 2 H), 7.13-6.94 (m, 1 H), 6.52 (d,
J = 17.6 Hz, 1 H), 5.81 (d, J = 10.8 Hz,
1 H).

Building block 18: 5-chloro-3-vinylpyridazine

5-chloropyridazin-3-ol (500 mg, 3.36 mmol), potassium vinyl trifluoroborate (450 mg, 3.36 mmol), Pd (dppf) Cl ₂ (
A mixture of 124 mg, 0.168 mmol) and CsF (1.5 g, 10.07 mmol) in dioxane / H ₂ O (8 mL / 2 mL) was stirred at 100 ° C. for 16 h.
The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with EtOAc (50 mL
) And water (30 mL) and the organic layer is washed with water (30 mL), brine,
Dry over Na ₂ SO ₄ and concentrate to give the crude, which is purified by preparative TLC to yield 20
0 mg of product was obtained.
1H NMR (chloroform-d) δ 9.06 (d, J = 2.3 Hz,
1H), 7.60 (d, J = 2.3 Hz, 1H), 7.02 (dd
, J = 17.8, 11.0 Hz, 1H), 6.32 (d, J = 1)
7.6 Hz, 1H), 5.77 (d, J = 10.9 Hz, 1H).
LC-MS: m / z 141.0 (M + H) +

Building blocks 19 and 20: tert-butyl 6-chloropyridazine-4-
Ylcarbamate and tert-butyl 5-chloropyridazin-3-ylcarbamate

3,5-dichloropyridazine (400 mg, 2.68 mmol), BocNH2 (31
4 mg, 2.68 mmol), Pd (dppf) Cl2 (99 mg, 0.134 mmol)
), Xanthophos (155 mg, 0.268 mmol) and Cs ₂ CO ₃ (2.61 g).
, 8.05 mmol) in toluene was stirred at 80 ° C. for 16 hours. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was partitioned between EtOAc (50 mL) and water (30 mL) and the organic layer was washed with water (30 mL), brine, Na ₂
Dry over SO ₄ and concentrate to give the crude, which is purified by preparative TLC to 150 mg
Of 19 and 120 mg of 20 were obtained.

tert-Butyl 6-chloropyridazin-4-ylcarbamate 1H NMR (chloroform-d) δ 8.86 (d, J = 2.0 Hz, 1H), 8.37
(D, J = 2.3 Hz, 1H), 8.12 (br.s., 1H),
1.56 (s, 9H). LC-MS: m / z 230.1 (M + H) +

tert-Butyl 5-chloropyridazin-3-ylcarbamate 1H NMR (chloroform-d) δ 8.94 (s, 1H), 8.04 (s, 1H), 7.
37 (br. S., 1H), 1.48-1.63 (s, 9H). LC
-MS: m / z 230.1 (M + H) +

Building block 21: 4-chloro-6-vinyl-1H-pyrrolo [2,3-b] pyridine

4,6-Dichloro-1H-pyrrolo [2,3-b] pyridine (20 mg, 0.1 mmol
), Potassium vinyl trifluoroborate (13 mg, 0.1 mmol), 5 mg Pd
Cl ₂ (dppf). A solution of CH ₂ Cl ₂ and CsF (45 mg, 0.3 mmol) in 3 mL of dioxane / H 2 O (5: 1) was stirred at 100 ° C. for 1 hour. The mixture was then partitioned between EtOAc and water and the organics were washed with water, brine and concentrated to give a crude that was purified by column to give 14 mg of product. 1H NMR (chloroform-d) δ: 11.19 (br. S., 1H), 7.39 (br.
s. , 1H), 7.28 (s, 2H), 6.91 (dd, J = 17.
3, 10.9 Hz, 1H), 6.62 (br.s., 1H), 6.21
(D, J = 17.3 Hz, 1H), 5.55 (d, J = 10.9
Hz, 1H). LC-MS: m / z 179.6 (M + H) +

Building block 22: 2-vinyl-1,7-naphthyridin-5-yl trifluoromethanesulfonate

Step 1: To a suspension of 5- (4-methoxybenzyloxy) -1,7-naphthyridin-2-ol (180 mg, 0.64 mmol) in DMF (5 mL) was added POCl3 (29
3 mg, 1.92 mmol) was added. The mixture was heated at 45 ° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice water, neutralized with NaHCO3, and EtOAc (3
X 20 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The solvent was removed to give 150 mg of the crude product that was used in the next step without further purification. LC-MS: m / z 300 (M + H) +

Step 2: To a solution of 2-chloro-5- (4-methoxybenzyloxy) -1,7-naphthyridine (150 mg, 0.5 mmol) in EtOH (10 mL) was added 1N HCl (2
. 5 mL) was added. The mixture was then heated at 90 ° C. for 2 hours. After cooling to room temperature, 190 mg of K2CO3 was added followed by 10 mL of methanol. The mixture was stirred vigorously for 1 hour at which time silica gel was added. The solvent was removed and the residue was purified by column chromatography (5% methanol / dichloromethane)
0 mg of the title compound (83%) was obtained. LC-MS: m / z 180 (M + H) +

Step 3: 2-Chloro-1,7-naphthyridin-5-ol (70 mg, 0.39 m
mol), potassium vinyl trifluorobrate (Potassium vinylltr)
ifluorolate) (104 mg, 0.78 mmol), Pd (dppf) Cl
A mixture of 2 (32 mg, 0.039 mmol) and CsF (119 mg, 0.78 mmol) in dioxane: H ₂ O = 5: 1 (5 ml + 1 ml) was purged with N 2 three times. The mixture was then heated at 100 ° C. for 2 hours. The solvent was removed and the residue was purified by column chromatography (5% methanol / dichloromethane) to give 30 mg of the title compound (45%). LC-MS: m / z 173 (M + H) +

Step 4: 2-Vinyl-1,7-naphthyridin-5-ol (30 mg, 0.17 m
mol) and Et3N (35 mg, 0.34 mmol) in dichloromethane (3 mL) were added Tf2O (59 mg, 0.21 mmol) at 0 ° C. The temperature was then raised to room temperature and stirred for 2 hours. Solvent was removed and the residue was purified by preparative TLC (EtOAc
/ Petroleum ether = 3/7) to give 10 mg of the title compound (20%). LC
-MS: m / z 305 (M + H) +

Building block 23: 4-chloro-1-methyl-6-vinyl-1H-pyrazolo [
3,4-b] pyridine

4,6-dichloro-1-methyl-1H-pyrazolo [3,4-b] pyridine (0.8 g,
4.0 mmol), potassium vinyl trifluorobrate (540 mg, 4.0 mmol)
), Pd (dppf) Cl2 (98 mg, 0.12 mmol) and CsF (1.22 g)
8 mmol) in dioxane: H 2 O = 5: 1 (10 mL + 2 mL) was purged with N 2 three times. The mixture was then heated at 100 ° C. for 2 hours. The solvent was removed and the residue was purified by column chromatography (30% EtOAc / petroleum ether) to give 500 mg of the title compound (65%). 1H NMR (chloroform-d)
δ 8.03 (s, 1H), 7.24 (s, 1H), 6.89 (dd,
J = 17.5, 10.7 Hz, 1H), 6.36 (d, J = 17.
3 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 4.
16 (s, 3H). LC-MS: m / z 193 (M + H) +

Building block 24: 7-bromo-2-vinylquinoline

Step 1: 7-bromoquinoline 1-oxide: 7-bromoquinoline (1.04 g, 5
mmol) in 20 mL DCM was added m-chloroperbenzoic acid (1.01 g, 5 mmo).
l) was added at room temperature. The reaction mixture was then stirred overnight at room temperature. LC-
After MS showed the reaction was complete, the mixture was poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (hexane / ethyl acetate = 3/1) gave 1.0 g of the title compound as a white solid. LC-MS: m / z 225.1 (M + H) +

Step 2: 7-bromo-2-chloroquinoline: 7-bromoquinoline 1-oxide (1
. 0 g, 4.5 mmol) in 20 mL of chloroform was added phosphorous oxychloride (3.4).
2 g, 22 mmol) was added at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed that the reaction was complete, the mixture was poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (hexane / ethyl acetate = 3/1) gave 0.75 g of the title compound as a white solid. LC-MS: m / z 244.1 (M + H) +

Step 3: 7-bromo-2-vinylquinoline: 7-bromo-2-chloroquinoline (0
. To a solution of 75 g, 3 mmol) in 1,4-dioxane (10 mL), potassium vinyl trifluoroborate (0.42 g, 3 mmol), dichlorobis (triphenylphosphine) palladium (II) (143 mg) and cesium fluoride (1. 40 g, 9 mmol
) Was added and the mixture was stirred at 100 ° C. under nitrogen for 10 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate = 4/1) to give 0.42 g of the title compound as a white solid. LC-MS: m / z 234.9 (M + H) +

Building block 25: (R) -2- (tetrahydrofuran-2-yl) acetic acid

Step 1: (R) -2- (2- (benzyloxy) ethyl) tetrahydrofuran: 1
. To a well-stirred suspension in 28 g (52 mmol) NaH dry diglyme (15 mL), 6.86 g (31.2 mmol) trimethylsulfoxonium iodide was added at room temperature. The mixture was gently heated to 120 ° C. to give compound 1 (3 mL) in diglyme (3 mL).
Step 4 product in building block 6 scheme) (1 g, 5.2 mmol)
Was added at once. The reaction mixture was stirred at 120 ° for 4 hours, cooled, carefully quenched with water and extracted three times with n-hexane. The combined extracts were washed with water and brine and dried over Na2SO4. The solvent was removed and purified by chromatography on silica gel to give compound 2 (0.5 g, 46%). 1H NMR
(Chloroform-d) δ 7.34-7.42 (m, 4H), 7.26
-7.34 (m, 1H), 4.43-4.63 (m, 2H), 3.9
1-4.05 (m, 1H), 3.83-3.91 (m, 1H), 3
. 74 (td, J = 7.9, 6.5 Hz, 1H), 3.62 (t,
J = 6.6 Hz, 2H), 1.96-2.05 (m, 1H),
73-1.95 (m, 4H), 1.52 (dd, J = 11.9, 8
. 7 Hz, 1H).

Step 2: (R) -2- (Tetrahydrofuran-2-yl) ethanol: Compound 2 (
0.3 g, 1.45 mmol) in MeOH (15 mL) in 10% Pd (OH)
2 / C (20 mg) was added. The reaction mixture was purged with hydrogen and 2 in an atmosphere of hydrogen.
Stir for days. The black suspension was passed through a plug of celite and eluted with MeOH, then the solution was concentrated to give the desired product as a colorless oil (0.15 g, 89%). 1
1 H NMR (CHLOROFORM-d, 400 MHz): δ 4.00-4
. 08 (m, 1 H), 3.86-4.00 (m, 1 H), 3.66
-3.86 (m, 3 H), 2.87 (br. S., 1 H),
98-2.10 (m, 1 H), 1.84-1.98 (m, 2 H)
, 1.70-1.84 (m, 2 H), 1.46-1.63 ppm
(M, 1 H).

Step 3: (R) -2- (Tetrahydrofuran-2-yl) acetic acid: Compound 3 (0.1
5 g, 1.3 mmol), sodium periodate (0.72 G, 2.6 mmol), water (
To a mixture of 10 mL), acetonitrile (20 mL) and carbon tetrachloride (20 mL) was added ruthenium trichloride (29 mg, 10 mol%) at 0-5 ° C. The resulting mixture was then allowed to warm to room temperature and stirred at this temperature for 2 hours. Celi deposit
Removed through filtration through a pad of te and washed with diethyl ether (ca. 100 mL × 5). The combined organic phases were washed with brine (50 mL × 3) and then dried under reduced pressure to give compound 4 (60 mg, containing about 8% by-product).
1H NMR (CHLOROFORM-d, 400 MHz): δ 4.19 −
4.33 (m, 1 H), 3.89-4.06 (m, 1 H), 3.8
3 (td, J = 7.8, 6.5 Hz, 1 H), 2.62 (dd, J =
6.5, 1.5 Hz, 2 H), 2.07-2.23 (m, 1 H),
1.89-2.06 (m, 2 H), 1.54-1.72 (m, 1
H).

Example 16
The following compounds were made according to methods similar to those for compound 273.

(R) -5- (2-Cyanophenyl) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile (Compound 274; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 7.
76-7.82 (m, 1H), 7.69 (td, J = 7.7,
4 Hz, 1H), 7.58-7.63 (m, 1H), 7.52 (td
, J = 7.7, 1.1 Hz, 1H), 7.46 (d, J = 7.8
Hz, 1H), 4.56-4.79 (m, 1.5H), 4.44 (t
, J = 10.3 Hz, 1.5H), 3.86 (d, J = 13.8)
Hz, 0.5H), 3.70-3.79 (m, 2H), 3.51-3
. 65 (m, 0.5H), 3.34-3.49 (m, 3.5H), 3.
03-3.24 (m, 2H), 2.87-3.00 (m, 0.5H)
, 2.53-2.82 (m, 2H), 2.05-2.29 (m, 1
H), 1.63-1.77 (m, 1H), 1.26 (br. S., 1
H), 0.93-1.23 (m, 7H), 0.87-0.92 (m,
1.5H), 0.84 (d, J = 6.8 Hz, 1.5H). LC-M
S: m / z 458.2 (M + H) +

(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-methoxyphenyl) nicotinonitrile (Compound 275; General Procedure) 1, Step H): 1H NMR (chloroform-d) δ 7
. 58 (d, J = 2.5 Hz, 1H), 7.39 (td, J = 7
. 9, 1.8 Hz, 1H), 7.18-7.25 (m, 1H), 7.
04 (td, J = 7.4, 1.0 Hz, 1H), 6.99 (d, J
= 8.0 Hz, 1H), 4.69 (d, J = 12.8 Hz, 0.
5H), 4.49-4.60 (m, 1H), 4.44 (d, J = 1)
0.5 Hz, 0.5H), 4.25-4.38 (m, 1H), 3.79
-3.89 (m, 4H), 3.68-3.78 (m, 2H), 3.
51-3.63 (m, 0.5H), 3.34-3.42 (m, 3H)
, 2.90-3.16 (m, 2.5H), 2.53-2.82 (m,
2H), 2.09-2.36 (m, 1H), 1.75-1.88 (
m, 1H), 1.02-1.18 (m, 5H), 0.79-0.96
(M, 5H). LC-MS: m / z 463.2 (M + H) +

  Compound AGI-0007758 / NB162-086 (General Procedure 1, Step H)

(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2- (trifluoromethoxy) phenyl) nicotinonitrile (Compound 276) General procedure 1, step H): 1H NMR (chloroform-d) δ 7.54 (d, J = 2.0 Hz, 1H), 7.43 −
7.48 (m, 1H), 7.33-7.41 (m, 3H), 4.69
(D, J = 13.3 Hz, 0.5H), 4.60 (t, J = 13.
3 Hz, 1H), 4.41 (dd, J = 16.8, 13.3 Hz,
1.5H), 3.85 (d, J = 13.3 Hz, 0.5H), 3.70
-3.79 (m, 2H), 3.52-3.62 (m, 0.5H),
3.35-3.49 (m, 3.5H), 3.03-3.23 (m, 2
H), 2.89-3.02 (m, 0.5H), 2.53-2.82 (
m, 2H), 1.67-1.78 (m, 1H), 1.04-1.12.
(M, 5H), 0.77-0.98 (m, 6H). LC-MS: m
/ Z 517.2 (M + H) +

(R) -1- (4- (6-Cyclopropyl-5- (4-fluorophenyl) -3- (3
-Methyl-1,2,4-oxadiazol-5-yl) pyridin-2-yl) -2-methylpiperazin-1-yl) -3-methoxypropan-1-one (compound 831)

To a solution of N′-hydroxyacetimidamide (221 mg, 2 mmol) hydrochloride in 10 mL anhydrous THF was added NaH (48 mg, 2 mmol). 0.5 reaction mixture
Heat to reflux for an hour and (R) -methyl 6-cyclopropyl-5- (4-fluorophenyl)-
2- (4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinate (455 mg, 1 mmol) was added to this solution. The reaction was kept at reflux for 2 hours.
The reaction was cooled to room temperature and filtered. The filtrate was concentrated to dryness and 120 mg of product was collected in preparative TL.
Obtained by C. 1H NMR (chloroform-d) δ 7.9 (s, 1H),
7.33-7.49 (m, 2H), 7.05-7.23 (m, 2H)
), 4.85 (br. S., 0.5H), 4.42 (d, J = 13.
1 Hz, 0.5H), 4.17 (br.s., 0.5H), 3.77 −
3.93 (m, 2H), 3.47-3.77 (m, 6H), 3.37
(S, 4H), 3.06-3.26 (m, 2H), 2.81-3.
06 (m, 1H), 2.51-2.80 (m, 3H), 2.31-
2.49 (m, 3H), 1.87-2.11 (m, 1H), 1.28
-1.43 (m, 1.5H), 1.15-1.28 (m, 3.5H),
1.12 (br. S., 1H), 0.80-1.06 (m, 2H).

(R) -5- (3-Cyanophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 283)
General procedure 1, step H): 1H NMR (chloroform-d) δ 7.66
-7.71 (m, 2H), 7.62-7.65 (m, 1H), 7.5
5-7.60 (m, 2H), 4.90 (br. S., 0.5H), 4
. 53 (d, J = 12.8 Hz, 0.5H), 4.18-4.40
(M, 2.5H), 3.67-3.88 (m, 2.5H), 3.46-
3.62 (m, 0.5H), 3.38 (s, 3H), 3.24-3.
35 (m, 1H), 2.99-3.20 (m, 1.5H), 2.64
-2.81 (m, 1H), 2.49-2.63 (m, 1H), 1.8
5-1.97 (m, 1H), 1.38 (d, J = 6.5 Hz, 1
. 5H), 1.27 (d, J = 6.5 Hz, 1.5H), 1.14 −
1.21 (m, 2H), 0.94-1.04 (m, 2H). LC-M
S: m / z 430.2 (M + H) +

(R) -5- (3-Aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 285)
General procedure 1, step H): 1H NMR (chloroform-d) δ 7.57
-7.60 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H)
, 6.77 (d, J = 7.8 Hz, 1H), 6.68-6.74
(M, 2H), 4.89 (br. S., 0.5H), 4.52 (d, J
= 13.3 Hz, 0.5H), 4.09-4.31 (m, 2.5H)
3.67-3.81 (m, 2.5H), 3.47-3.60 (m,
0.5H), 3.37 (s, 3H), 3.18-3.29 (m, 1H
), 2.95-3.16 (m, 1.5H), 2.63-2.78 (m
, 1H), 2.52-2.61 (m, 1H), 2.09-2.17
(M, 1H), 1.38 (d, J = 6.5 Hz, 1.5H), 1.2
8 (d, J = 6.8 Hz, 1.5H), 1.06-1.16 (m,
2H), 0.88-0.99 (m, 2H). LC-MS: m / z 42
0.1 (M + H) +

(R) -6-cyclopropyl-5- (isoquinolin-5-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 2)
86; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 9.3
4 (s, 1H), 8.53 (d, J = 6.0 Hz, 1H), 8.0
6 (d, J = 8.0 Hz, 1H), 7.68-7.75 (m, 1
H), 7.61-7.68 (m, 2H), 7.43 (t, J = 5.
6 Hz, 1H), 4.94 (br.s., 0.5H), 4.57 (d,
J = 13.1 Hz, 0.5H), 4.18-4.47 (m, 2.5
H), 3.69-3.86 (m, 2.5H), 3.54-3.67 (
m, 0.5H), 3.37-3.44 (m, 3H), 3.34 (dd,
J = 13.1, 6.3 Hz, 1H), 3.04-3.25 (m,
1.5H), 2.67-2.78 (m, 1H), 2.54-2.67.
(M, 1H), 1.48-1.58 (m, 1H), 1.39-1.4
7 (m, 1.5H), 1.29-1.39 (m, 1.5H), 1.09
-1.21 (m, 2H), 0.75-0.89 (m, 2H). L
C-MS: m / z 456.1 (M + H) +

(R) -6-cyclopropyl-5- (1H-indol-4-yl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 287; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 8
. 40 (br. S., 1H), 7.74 (s, 1H), 7.44 (d,
J = 8.3 Hz, 1H), 7.24-7.29 (m, 1H), 7
. 02-7.10 (m, 1H), 6.37-6.45 (m, 1H),
4.92 (br. S., 0.5H), 4.55 (d, J = 13.6)
Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.71-
3.86 (m, 2.5H), 3.51-3.65 (m, 0.5H),
3.35-3.44 (m, 3H), 3.20-3.32 (m, 1H)
, 2.98-3.17 (m, 1.5H), 2.66-2.81 (m,
1H), 2.54-2.64 (m, 1H), 1.94-2.04 (
m, 1H), 1.40-1.46 (m, 1.5H), 1.32 (d,
J = 6.5 Hz, 1.5H), 1.08-1.17 (m, 2H),
0.80-0.91 (m, 2H). LC-MS: m / z 444.2 (
M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinolin-5-yl) nicotinonitrile (Compound 288)
General procedure 1, step H): 1H NMR (chloroform-d) δ 8.97;
(Dd, J = 4.1, 1.6 Hz, 1H), 8.23 (d, J =
8.5 Hz, 1H), 7.94-8.05 (m, 1H), 7.82 (
dd, J = 8.5, 7.0 Hz, 1H), 7.61-7.66 (m
, 1H), 7.48-7.55 (m, 1H), 7.40-7.48.
(M, 1H), 4.83-5.06 (m, 0.5H), 4.56 (d,
J = 13.1 Hz, 0.5 H), 4.15-4.43 (m, 2.5
H), 3.69-3.91 (m, 2.5H), 3.57 (d, J =
10.5 Hz, 0.5H), 3.36-3.45 (m, 3H), 3.3
3 (dd, J = 13.1, 3.5 Hz, 1H), 3.01-3.2
6 (m, 1.5H), 2.65-2.82 (m, 1H), 2.52-
2.64 (m, 1H), 1.48-1.56 (m, 1H), 1.39
-1.47 (m, 1.5H), 1.29-1.38 (m, 1.5H)
, 1.07-1.18 (m, 2H), 0.74-0.91 (m, 2
H). LC-MS: m / z 456.1 (M + H) +

(R) -6-cyclopropyl-5- (1H-indol-6-yl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 289; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 8
. 41 (br. S., 1H), 7.69 (d, J = 8.0 Hz, 1
H), 7.66 (s, 1H), 7.39 (s, 1H), 7.27-7
. 30 (m, 1H), 7.13 (dd, J = 8.0, 1.5 Hz,
1H), 6.60 (t, J = 2.1 Hz, 1H), 4.91 (br.
s. , 0.5H), 4.53 (d, J = 13.6 Hz, 0.5H),
4.13-4.32 (m, 2.5H), 3.68-3.84 (m,
2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3
H), 3.17-3.31 (m, 1H), 2.93-3.16 (m,
1.5H), 2.64-2.82 (m, 1H), 2.53-2.63
(M, 1H), 2.13-2.23 (m, 1H), 1.40 (d,
J = 6.5 Hz, 1.5H), 1.30 (d, J = 6.8 Hz,
1.5H), 1.09-1.17 (m, 2H), 0.84-0.98
(M, 2H). LC-MS: m / z 444.2 (M + H) +

(R) -6-cyclopropyl-5- (4-fluoronaphthalen-1-yl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 290; General Procedure 1, Step H): 1H NMR (chloroform-d)
δ 8.19 (d, J = 8.0 Hz, 1H), 7.50-7.65
(M, 4H), 7.30-7.37 (m, 1H), 7.22 (dd,
J = 10.2, 7.9 Hz, 1H), 4.93 (br. S., 0.5
H), 4.56 (d, J = 13.3 Hz, 0.5H), 4.15 −
4.42 (m, 2.5H), 3.69-3.90 (m, 2.5H), 3
. 50-3.68 (m, 0.5H), 3.36-3.43 (m, 3H
), 3.24-3.34 (m, 1H), 3.00-3.23 (m,
1.5H), 2.65-2.85 (m, 1H), 2.55-2.64
(M, 1H), 1.54-1.61 (m, 1H), 1.40-1.4
8 (m, 1.5H), 1.33 (dd, J = 6.3, 3.5 Hz,
1.5H), 1.07-1.18 (m, 2H), 0.72-0.85
(M, 2H). LC-MS: m / z 473.1 (M + H) +

(R) -Methyl 2- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) Acetate (Compound 291; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.36-7.45 (m, 1H
), 7.25-7.34 (m, 3H), 4.90 (br. S., 0.
5H), 4.53 (d, J = 13.1 Hz, 0.5H), 4.26 (
t, J = 12.5 Hz, 2.5H), 3.64-3.85 (m, 7
H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H),
3.19-3.30 (m, 1H), 2.93-3.18 (m, 2H
), 2.63-2.81 (m, 1H), 2.49-2.63 (m,
1H), 2.02-2.12 (m, 1H), 1.39 (d, J = 6
. 3 Hz, 1.5H), 1.28 (d, J = 6.5 Hz, 1.5H)
, 1.10-1.20 (m, 2H), 0.89-1.00 (m, 2
H). LC-MS: m / z 477.1 (M + H) +

(R) -6-cyclopropyl-5- (1H-indazol-5-yl) -2- (4- (
3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 295; General Procedure 2, Step M): 1H NMR (chloroform-d) δ
8.14 (br. S., 1H), 7.75 (s, 1H), 7.65 (s
, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.42 (d
d, J = 8.7, 1.4 Hz, 1H), 4.91 (br.s., 0
. 5H), 4.54 (d, J = 13.3 Hz, 0.5H), 4.12
-4.39 (m, 2.5H), 3.69-3.89 (m, 2.5H),
3.50-3.64 (m, 0.5H), 3.38 (s, 3H),
20-3.33 (m, 1H), 2.97-3.20 (m, 1.5H)
, 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1
H), 1.99-2.14 (m, 1H), 1.36-1.46 (m,
1.5H), 1.30 (d, J = 6.8 Hz, 1.5H), 1.13
-1.21 (m, 2H), 0.90-0.99 (m, 2H). LC
-MS: m / z 445.4 (M + H) +

(R) -4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) benzamide (Compound 296; general General Procedure 1, Step H): 1H NMR (chloroform-d) δ 7.
84-7.96 (m, J = 8.5 Hz, 2H), 7.57-7.
66 (m, 1H), 7.45-7.56 (m, 2H), 6.27 (b
r. s. , 1H), 5.99 (br. S., 1H), 4.90 (br.
s. , 0.5H), 4.52 (d, J = 13.3 Hz, 0.5H),
4.14-4.38 (m, 2.5H), 3.70-3.87 (m,
2.5H), 3.47-3.62 (m, 0.5H), 3.33-3.4
3 (m, 3H), 3.27 (t, J = 10.3 Hz, 1H),
99-3.21 (m, 1.5H), 2.64-2.83 (m, 1H)
, 2.50-2.64 (m, 1H), 1.95-2.09 (m, 1
H), 1.38 (d, J = 6.3 Hz, 1.5H), 1.25-1
. 31 (m, 1.5H), 1.13-1.21 (m, 2H), 0.92
-1.02 (m, 2H). LC-MS: m / z 448.5 (M + H)
+

(R) -6-cyclopropyl-5- (3- (2-hydroxyethyl) phenyl) -2-
(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 297; General Procedure 1, Step H): 1H NMR (chloroform-d
) Δ 7.60 (s, 1H), 7.35-7.42 (m, 1H), 7
. 23-7.27 (m, 3H), 4.89 (br. S., 0.5H),
4.52 (d, J = 13.1 Hz, 0.5H), 4.14-4.3
1 (m, 2.5H), 3.91 (t, J = 6.7 Hz, 2H), 3
. 68-3.83 (m, 2.5H), 3.49-3.61 (m, 0.
5H), 3.37 (s, 3H), 3.19-3.29 (m, 1H),
2.97-3.18 (m, 1.5H), 2.91-2.97 (m, 2
H), 2.64-2.81 (m, 1H), 2.52-2.62 (m,
1H), 2.02-2.14 (m, 1H), 1.39 (d, J =
6.3 Hz, 1.5H), 1.27-1.32 (m, 1.5H), 1.
08-1.19 (m, 2H), 0.89-1.02 (m, 2H).
LC-MS: m / z 449.6 (M + H) +

(R) -3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) benzamide (Compound 305; general General Procedure 1, Step H): 1H NMR (methanol-d4) δ 7.
96 (t, J = 1.5 Hz, 1H), 7.91 (dt, J = 7.
7, 1.6 Hz, 1H), 7.81 (s, 1H), 7.62-7.6
7 (m, 1H), 7.56-7.62 (m, 1H), 4.82 (br
. s. , 0.5H), 4.38-4.48 (m, 1H), 4.16-
4.29 (m, 2H), 3.97 (d, J = 13.6 Hz, 0.5
H), 3.68-3.76 (m, 2H), 3.54-3.67 (m,
0.5H), 3.36 (s, 4H), 3.05-3.26 (m, 1.
5H), 2.72-2.89 (m, 1H), 2.57-2.70 (m
, 1H), 1.99-2.10 (m, 1H), 1.40 (d, J =
6.5 Hz, 1.5H), 1.29 (d, J = 6.8 Hz, 1.5
H), 1.20 (dq, J = 4.4, 3.1 Hz, 2H), 0.93
-1.04 (m, 2H). LC-MS: m / z 448.3 (M + H)
+

(R) -6-cyclopropyl-5- (3- (hydroxymethyl) phenyl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 306; General Procedure 1, Step H): 1H NMR (methanol-d4)
δ 7.71 (br. s., 1H), 7.37-7.48 (m, 3H)
, 7.32 (d, J = 7.5 Hz, 1H), 4.80 (br. S.
, 1H), 4.68 (s, 3H), 4.36-4.51 (m, 1H)
, 4.13-4.30 (m, 2H), 3.95 (d, J = 13.6
Hz, 0.5H), 3.67-3.78 (m, 2H), 3.50-
3.65 (m, 0.5H), 3.27-3.35 (m, 2.5H), 2
. 99-3.20 (m, 1.5H), 2.70-2.84 (m, 1H
), 2.61-2.67 (m, 1H), 2.06-2.13 (m,
1H), 1.40 (d, J = 6.5 Hz, 1.5H), 1.28 (d
, J = 6.8 Hz, 1.5H), 1.12-1.24 (m, 2H)
, 0.96 (dd, J = 7.3, 3.5 Hz, 2H). LC-MS
: M / z 435.3 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-oxoindoline-6-yl) nicotinonitrile (
Compound 313; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
8.40 (s, 1H), 7.53-7.64 (m, 1H), 7.29
(D, J = 7.8 Hz, 1H), 6.98-7.07 (m, 1H
), 6.87-6.93 (m, 1H), 4.90 (br. S., 0.
5H), 4.53 (d, J = 13.4 Hz, 0.5H), 4.13-
4.37 (m, 2.5H), 3.68-3.88 (m, 2.5H),
3.49-3.65 (m, 2.5H), 3.34-3.43 (m, 3
H), 3.20-3.31 (m, 1H), 2.95-3.18 (m,
1.5H), 2.51-2.81 (m, 2H), 2.02-2.15
(M, 1H), 1.38-1.40 (m, 1.5H), 1.26-
1.31 (m, 1.5H), 1.07-1.20 (m, 2H), 0.9
0-1.04 (m, 2H). LC-MS: m / z 460.2 (M + H)
+

(R) -6′-amino-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,3′-bipyridine-5-carbonitrile (
Compound 314; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
8.10 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H),
7.44-7.50 (m, 1H), 6.55-6.64 (m, 1H)
), 4.89 (br.s., 0.5H), 4.72 (br.s., 2H)
), 4.52 (d, J = 13.3 Hz, 0.5H), 4.15-4
. 31 (m, 2.5H), 3.69-3.85 (m, 2.5H), 3.
49-3.63 (m, 0.5H), 3.34-3.43 (m, 3H)
3.19-3.31 (m, 1H), 2.96-3.17 (m, 1
. 5H), 2.51-2.81 (m, 2H), 1.99-2.08 (
m, 1H), 1.23-1.41 (m, 3H), 1.11-1.18.
(M, 2H), 0.90-0.99 (m, 2H). LC-MS: m /
z 421.4 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinolin-4-yl) nicotinonitrile (Compound 315)
General procedure 1, step H): 1H NMR (chloroform-d) δ 8.9.
(D, J = 4.5 Hz, 1H), 8.23 (d, J = 8.5 Hz)
, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.61 −
7.71 (m, 2H), 7.53-7.61 (m, 1H), 7.36
(D, J = 4.0 Hz, 1H), 4.93 (br.s., 0.5H)
, 4.56 (d, J = 12.5 Hz, 0.5H), 4.25-4.
45 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.5
7 (d, J = 9.3 Hz, 0.5H), 3.29-3.45 (m,
4H), 3.01-3.27 (m, 1.5H), 2.65-2.84.
(M, 1H), 2.51-2.65 (m, 1H), 1.54 (td,
J = 8.2, 4.1 Hz, 1H), 1.42 (d, J = 5.5
Hz, 1.5H), 1.32 (t, J = 5.0 Hz, 1.5H), 1
. 05-1.21 (m, 2H), 0.74-0.92 (m, 2H).
LC-MS: m / z 456.0 (M + H) +

(R) -6-cyclopropyl-5- (2,6-dimethoxyphenyl) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 316; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 7
. 51-7.57 (m, 1H), 7.30-7.38 (m, 1H),
6.65 (d, J = 8.3 Hz, 2H), 4.90 (br. S.,
0.5H), 4.52 (d, J = 13.6 Hz, 0.5H), 4.1
1-4.34 (m, 2.5H), 3.67-3.84 (m, 8.5H)
), 3.47-3.62 (m, 0.5H), 3.32-3.43 (m
3H), 2.95-3.24 (m, 2.5H), 2.63-2.8
4 (m, 1H), 2.51-2.63 (m, 1H), 1.65-1
. 72 (m, 1H), 1.41 (d, J = 6.5 Hz, 1.5H),
1.31 (d, J = 6.8 Hz, 1.5H), 1.00-1.12.
(M, 2H), 0.75-0.86 (m, 2H). LC-MS: m
/ Z 465.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3- (2,2,2-trifluoroacetyl) -1H -Indol-5-yl) nicotinonitrile (compound 317; general procedure 1, step H):
1H NMR (chloroform-d) δ 8.44 (s, 1H), 8.10 −
8.18 (m, 1H), 7.67 (s, 1H), 7.56 (d, J
= 8.5 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H),
4.92 (br. S., 0.5H), 4.55 (d, J = 12.8)
Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.69-
3.88 (m, 2.5H), 3.52-3.69 (m, 0.5H),
3.35-3.45 (m, 3H), 3.22-3.35 (m, 1H)
, 2.98-3.20 (m, 1.5H), 2.54-2.82 (m,
2H), 2.04-2.13 (m, 1H), 1.38-1.47 (
m, 1.5H), 1.31 (d, J = 6.5 Hz, 1.5H),
14-1.19 (m, 2H), 0.90-0.97 (m, 2H).
LC-MS: m / z 540.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinolin-8-yl) nicotinonitrile (Compound 342)
General procedure 1, step H): 1H NMR (chloroform-d) δ 8.94;
(Dd, J = 4.1, 1.6 Hz, 1H), 8.23 (dd, J =
8.3, 1.8 Hz, 1H), 7.90 (dd, J = 8.2,
4 Hz, 1H), 7.73 (s, 1H), 7.66-7.71 (m,
1H), 7.59-7.66 (m, 1H), 7.45 (dd, J =
8.3, 4.3 Hz, 1H), 4.92 (br.s., 0.5H),
4.54 (d, J = 13.3 Hz, 0.5H), 4.13-4.38
(M, 2.5H), 3.68-3.87 (m, 2.5H), 3.50
-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24 (t,
J = 12.8 Hz, 1H), 2.96-3.17 (m, 1.5H)
, 2.52-2.82 (m, 2H), 1.59-1.68 (m, 1
H), 1.43 (d, J = 6.5 Hz, 1.5H), 1.33 (d,
J = 6.5 Hz, 1.5H), 1.07 (br.s., 2H), 0
. 78 (br. S., 2H)

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) acetamide (Compound 284; General Procedure 3, Step N, Method 1) 1H NMR (chloroform-d) δ 7.64 (s, 1H), 7.58 (s, 2H), 7.4
6 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.8)
Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 4.89
(Br. S., 0.5H), 4.52 (d, J = 13.3 Hz, 0.
5H), 4.11-4.36 (m, 2.5H), 3.67-3.86
(M, 2.5H), 3.54 (t, J = 10.9 Hz, 0.5H),
3.33-3.43 (m, 3H), 3.18-3.31 (m, 1H)
, 2.94-3.17 (m, 1.5H), 2.63-2.79 (m,
1H), 2.51-2.63 (m, 1H), 2.17-2.28 (
m, 3H), 2.06-2.14 (m, 1H), 1.38 (d, J
= 6.5 Hz, 1.5 H), 1.27 (d, J = 7.0 Hz, 1.
5H), 1.08-1.17 (m, 2H), 0.91-1.00 (m
, 2H). LC-MS: m / z 462.2 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) acrylamide (Compound 343; General Procedure 3, Step N, Method 1): 1H NMR (chloroform-d) δ 7.70-7.79 (m, 2H), 7.54-7
. 63 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7
. 16 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 1)
6.8, 1.0 Hz, 1H), 6.31 (dd, J = 16.8, 10
. 0 Hz, 1H), 5.81 (dd, J = 10.2, 1.1 Hz,
1H), 4.91 (br.s., 1H), 4.54 (d, J = 13.
1 Hz, 0.5H), 4.12-4.36 (m, 2.5H), 3.69
-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H)
3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.9
6-3.17 (m, 1.5H), 2.54-2.81 (m, 2H),
2.07-2.16 (m, 1H), 1.39 (d, J = 6.5 H
z, 1.5H), 1.25-1.35 (m, 1.5H), 1.15 (q
uin, J = 3.6 Hz, 2H), 0.89-1.02 (m, 2H
). LC-MS: m / z 474.6 (M + H) +

(R, E) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl )
But-2-enamide (Compound 415; General Procedure 3, Step N, Method 2): 1H NM
R (chloroform-d) δ 7.64-7.76 (m, 2H), 7.60
-7.63 (m, 1H), 7.49-7.53 (m, 1H), 7.
37-7.44 (m, 1H), 7.30-7.35 (m, 1H),
7.14 (d, J = 7.8 Hz, 1H), 6.95-7.10 (m
, 1H), 5.99 (dd, J = 15.1, 1.8 Hz, 1H),
4.92 (s, 0.5H), 4.54 (d, J = 12.8 Hz, 0.
5H), 4.20-4.32 (m, 2.5H), 3.76 (t, J =
6.3 Hz, 2H), 3.50-3.62 (m, 0.5H), 3.3
9 (s, 3H), 3.18-3.34 (m, 1.5H), 2.97-
3.16 (m, 1.5H), 2.65-2.80 (m, 1H), 2.5
3-2.65 (m, 1H), 2.09-2.16 (m, 1H), 1
. 95 (dd, J = 6.8, 1.5 Hz, 3H), 1.40 (d,
J = 6.3 Hz, 1H), 1.29-1.31 (m, 2H),
12-1.19 (m, 2H), 0.92-1.01 (m, 2H)
LC-MS: m / z 487.3 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl)- 2
Oxopropanamide (Compound 416; General Procedure 3, Step N, Method 2): 1H
NMR (chloroform-d) δ 7.38-7.66 (m, 4H), 7.
32 (dd, J = 3.9, 1.9 Hz, 1H), 7.12-7.2
5 (m, 1H), 4.89 (s, 0.5H), 4.52 (d, J =
10.8 Hz, 0.5 H), 4.22-4.34 (m, 2 H), 4.
10-4.22 (m, 0.5H), 3.66-3.85 (m, 2.5
H), 3.55 (d, J = 3.5 Hz, 0.5H), 3.39 (d,
J = 1.5 Hz, 3H), 3.20-3.31 (m, 1H), 3
. 10-3.14 (m, 1.5H), 2.97-3.09 (m, 1H),
2.66-2.80 (m, 1H), 2.53-2.64 (m, 1H
), 1.97-2.07 (m, 1H), 1.55-1.58 (m, 3H)
), 1.35-1.42 (m, 2H), 1.10-1.17 (m,
1H), 1.05-1.10 (m, 1H), 0.73-0.96 (m
, 4H). LC-MS: m / z 490.2 (M + H) +

(R) -2-Chloro-N- (3- (5-cyano-2-cyclopropyl-6- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) acetamide (Compound 403; General Procedure 3, Step N, Method 1): 1H N
MR (chloroform-d) δ 8.34 (s, 1H), 7.66-7.
75 (m, 1H), 7.62 (s, 1H), 7.50-7.55 (m
, 1H), 7.42-7.48 (m, 1H), 7.22 (d, J =
7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54
(M, 0.5H), 4.29-4.33 (m, 1H), 4.26 (m
, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84
(M, 2.5H), 3.52-3.57 (m, 0.5H), 3.39 (s,
3H), 3.21-3.32 (m, 1H), 3.13 (d, J =
11.3 Hz, 1H), 3.05 (d, J = 12.3 Hz, 0.5H
), 2.66-2.81 (m, 1H), 2.54-2.65 (m,
1H), 2.07-2.12 (m, 1H), 1.40 (d, J = 6
. 3 Hz, 1H), 1.28-1.31 (m, 2H), 1.14-
1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS
: M / z 495.2 (M + H) +

(R) -1-Chloro-N- (3- (5-cyano-2-cyclopropyl-6- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) methanesulfonamide (Compound 404; General Procedure 3, Step N, Method 1):
1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.44
-7.52 (m, 1H), 7.36-7.41 (m, 1H), 7.2
9-7.36 (m, 2H), 7.11 (br.s., 1H), 4.9
2 (s, 1H), 4.45-4.63 (m, 2.5H), 4.18-
4.40 (m, 2.5H), 3.66-3.89 (m, 2.5H), 3
. 50-3.57 (m, 0.5H), 3.39 (s, 3H), 3.29
(T, J = 10.2 Hz, 1H), 2.99-3.20 (m, 1.5
H), 2.65-2.83 (m, 1H), 2.52-2.64 (m,
1H), 1.99-2.06 (m, 1H), 1.40 (d, J =
6.3 Hz, 1H), 1.30 (s, 2H), 1.15-1.22 (
m, 2H), 0.96-1.03 (m, 2H). LC-MS: m / z
531.2 (M + H) +

(R) -2-chloro-N- (3- (5-cyano-2-cyclopropyl-6-((R)-
4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridine-3-
Yl) phenyl) propanamide (Compound 462; General Procedure 3, Step N, Method 2)
: 1H NMR (chloroform-d) δ 8.54 (s, 1H), 7.67
-7.73 (m, 1H), 7.60 (s, 1H), 7.49-7.5
7 (m, 1H), 7.38-7.45 (m, 1H), 7.14-7
. 22 (m, 1H), 4.90 (br. S., 0.5H), 4.44-
4.64 (m, 1.5H), 4.16-4.37 (m, 2.5H),
3.68-3.86 (m, 2.5H), 3.50-3.63 (m, 0
. 5H), 3.37 (s, 3H), 3.19-3.32 (m, 1H),
2.96-3.17 (m, 1.5H), 2.53-2.78 (m,
2H), 2.05-2.12 (m, 1H), 1.83 (d, J = 7
. 0 Hz, 3H), 1.39 (d, J = 6.5 Hz, 1.5H),
1.28 (dd, J = 6.9, 2.6 Hz, 1.5H), 1.10 −
1.19 (m, 2H), 0.90-1.02 (m, 2H). LC-
MS: m / z 510.2 (M + H) +

(R) -N- (4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) acetamide (Compound 412; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 7.55-7.67 (m, 3H), 7.31-7.44 (
m, 3H), 4.91 (s, 0.5H), 4.54 (d, J = 13.6).
Hz, 0.5H), 4.14-4.33 (m, 2.5H), 3.65
-3.93 (m, 2.5H), 3.46-3.65 (m, 0.5H),
3.39 (s, 3H), 3.20-3.30 (m, 1H), 2.98
-3.19 (m, 1.5H), 2.51-2.81 (m, 1H),
2.16-2.31 (m, 3H), 1.98-2.13 (m, 1H)
, 1.24-1.44 (m, 4H), 1.08-1.18 (m, 2
H), 0.84-0.99 (m, 2H). LC-MS: m / z 462
. 6 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) propion Amide (Compound 424; General Procedure 3, Step N, Method 2): 1H NMR (
Chloroform-d) δ 7.75 (s, 1H), 7.68 (s, 1H),
7.59 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H),
7.37 (t, J = 7.8 Hz, 1H), 7.11 (d, J =
7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J
= 13.3 Hz, 0.5H), 4.14-4.35 (m, 2.5H),
3.67-3.85 (m, 2.5H), 3.49-3.62 (m,
0.5H), 3.37 (s, 3H), 3.17-3.32 (m, 1H)
, 2.93-3.17 (m, 1.5H), 2.63-2.81 (m,
1H), 2.52-2.63 (m, 1H), 2.37-2.49 (
m, 2H), 2.05-2.13 (m, 1H), 1.38 (d, J
= 6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14
(Dt, J = 7.4, 3.6 Hz, 2H), 0.88-1.01
(M, 2H). LC-MS: m / z 476.3 (M + H) +

(R) -1-cyano-N- (3- (5-cyano-2-cyclopropyl-6- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) cyclopropanecarboxamide (Compound 425; General Procedure 3, Step N, Method 2): 1H NMR (chloroform-d) δ 8.11 (s, 1H), 7
. 65 (s, 1H), 7.61 (s, 1H), 7.42-7.50 (
m, 2H), 7.19-7.25 (m, 1H), 4.92 (s, 0.
5H), 4.55 (d, J = 12.3 Hz, 0.5H), 4.17 −
4.39 (m, 2.5H), 3.71-3.76 (m, 2.5H), 3.
55-3.58 (m, 0.5H), 3.36-3.46 (m, 3H),
3.21-3.33 (m, 1H), 3.14 (d, J = 13.3 H
z, 1.5H), 3.05 (d, J = 12.0 Hz, 1H), 2. .
63-3.75 (s, 1H), 2.61-3.63 (m, 1H), 2.02
-2.12 (m, 1H), 1.81-1.91 (m, 2H), 1.
66 (q, J = 4.5 Hz, 2H), 1.40 (d, J = 5.5)
Hz, 1H), 1.25-1.33 (m, 2H), 1.12-1.
20 (m, 2H), 0.92-1.01 (m, 2H). LC-MS:
m / z 513.2 (M + H) +

Compound 427 (General Procedure 3, Step N, Method 1): 1H NMR (chloroform-d) δ 7.62 (s, 1H), 7.47-7.56 (m, 1H),
7.35-7.44 (m, 1H), 7.18-7.25 (m, 2H
), 6.42 (dd, J = 16.8, 2.0 Hz, 1H), 6.16
(Dd, J = 16.6, 10.3 Hz, 1H), 5.57 (dd,
J = 10.2, 1.6 Hz, 1H), 4.92 (d, J = 12.8).
Hz, 0.5H), 4.55 (d, J = 12.8 Hz, 0.5H),
4.13-4.41 (m, 3H), 3.69-3.90 (m, 3H)
), 3.58 (d, J = 9.3 Hz, 1H), 3.39 (s, 3H)
), 3.42 (s, 3H), 3.29 (t, J = 9.5 Hz, 1H
), 3.01-3.21 (m, 2H), 2.65-2.80 (m,
1H), 2.47-2.65 (m, 1H), 1.88-2.07 (m
, 1H), 1.65 (br.s., 3H), 1.35-1.44 (m
, 2H), 1.25-1.35 (m, 2H), 1.09-1.25.
(M, 2H), 0.92-1.09 (m, 2H). LC-MS: m /
z 488.2 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) propi Olamide (Compound 428; General Procedure 3, Step N, Method 2): 1H NMR (
Chloroform-d) δ 7.63-7.69 (m, 2H), 7.61 (
s, 1H), 7.41-7.50 (m, 2H), 7.20 (d, J
= 7.3 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d,
J = 11.8 Hz, 0.5H), 4.12-4.40 (m, 2.5H)
), 3.72-3.79 (m, 2.5H), 3.51-3.57 (m,
0.5H), 3.40 (s, 3H), 3.23-3.32 (m, 1H)
, 3.14 (d, J = 13.1 Hz, 1H), 3.05 (d, J
= 11.0 Hz, 1H), 2.99 (s, 1H), 2.65-2.8
1 (m, 1H), 2.54-2.65 (m, 1H), 2.05-2
. 13 (m, 1H), 1.40 (d, J = 6.5 Hz, 1H), 1
. 14-1.19 (m, 2H), 0.95-1.01 (m, 2H),
0.88-0.93 (m, 2H). LC-MS: m / z 472.2
(M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) ethene Sulfonamide (Compound 429; General Procedure 3, Step N, Method 1): (R) -5
(3-Aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (20 mg, 0.048 mmol)
l) To a solution of 2-chloroethanesulfonyl chloride (8.6 mg, 0.052 mmol) in 5 ml DCM was added dropwise TEA (15 mg, 0.143 mmol) at 0 ° C., then the resulting mixture was added to room temperature. Allow to warm and stir for 2 hours. EtOAc mixture
And partitioned between water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by preparative TLC to give 15 mg of product. 1H NMR (chloroform-
d) δ 7.55-7.61 (m, 1H), 7.37-7.46 (
m, 1H), 7.15-7.26 (m, 3H), 6.70 (d, J
= 12.8 Hz, 1H), 6.62 (dd, J = 16.4, 9.9).
Hz, 1H), 6.34 (d, J = 16.3 Hz, 1H), 6.02
(D, J = 9.8 Hz, 1H), 4.92 (s, 0.5H), 4.
54 (d, J = 13.3 Hz, 0.5H), 4.19-4.37 (
m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.
61 (m, 0.5H), 3.39 (s, 3H), 3.28 (t, J =
10.4 Hz, 1H), 3.02-3.14 (m, 1H), 2.65 −
2.80 (m, 1H), 2.55-2.64 (m, 1H), 1.98
-2.07 (m, 1H), 1.27 (s, 3H), 1.14-1.
19 (m, 2H), 0.95-1.01 (m, 2H).

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl)- 2
-Fluoroacrylamide (Compound 431; General Procedure 3, Step N, Method 2): 1H
NMR (chloroform-d) δ 8.19 (d, J = 4.5 Hz, 1
H), 7.75 (s, 1H), 7.61 (s, 1H), 7.57 (dd
, J = 8.0, 1.3 Hz, 1H), 7.43 (t, J = 7.9
Hz, 1H), 7.16-7.23 (m, 1H), 5.84 (dd,
J = 18.0 Hz, J = 3.3 Hz, 0.5H), 5.21 −
5.35 (m, 1H), 4.90 (br. S., 0.5H), 4.52
(D, J = 13.1 Hz, 0.5H), 4.10-4.38 (m,
2.5H), 3.66-3.86 (m, 2.5H), 3.50-3.6
4 (m, 0.5H), 3.38 (s, 3H), 3.19-3.33 (
m, 1H), 2.95-3.18 (m, 1.5H), 2.56-2.
78 (m, 2H), 2.04-2.16 (m, 1H), 1.39 (d
, J = 6.3 Hz, 1.5H), 1.28 (d, J = 6.8 Hz
, 1.5H), 1.11-1.22 (m, 2H), 0.91-1.0.
3 (m, 2H). LC-MS: m / z 492.7 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl)- 2
, 2-difluoroacetamide (Compound 432; General Procedure 3, Step N, Method 2):
1H NMR (chloroform-d) δ 8.79 (br. S., 1H), 7
. 77 (s, 1H), 7.55-7.65 (m, 2H), 7.44 (
t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.8 Hz,
1H), 6.05 (t, J = 56.0 Hz, 1H), 4.89 (b
r. s. , 0.5H), 4.51 (d, J = 13.3 Hz, 0.5H
), 4.08-4.37 (m, 2.5H), 3.66-3.88 (m
, 2.5H), 3.49-3.63 (m, 0.5H), 3.36 (s,
3H), 2.96-3.25 (m, 2.5H), 2.81 (s, 6H)
), 2.50-2.79 (m, 2H), 2.03-2.13 (m,
1H), 1.32-1.45 (m, 1.5H), 1.27 (d, J =
6.8 Hz, 1.5H), 1.10-1.17 (m, 2H), 0.9
1-1.02 (m, 2H)
LC-MS: m / z 498.8 (M + H) +

(R) -5- (4-Aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 383)
General procedure 1, step H): 1H NMR (chloroform-d) δ 7.53
-7.62 (m, 1H), 7.11-7.21 (m, 2H), 6.7
0-6.83 (m, 2H), 4.89 (br. S., 0.5H), 4
. 52 (d, J = 13.6 Hz, 0.5H), 4.04-4.28
(M, 2.5H), 3.64-3.88 (m, 4.5H), 3.47-
3.64 (m, 0.5H), 3.30-3.43 (m, 3H), 3.
14-3.27 (m, 1H), 2.92-3.14 (m, 1.5H)
, 2.50-2.79 (m, 2H), 2.08-2.15 (m, 1
H), 1.34-1.43 (m, 1.5H), 1.28-1.30 (
m, 1.5H), 1.06-1.15 (m, 2H), 0.84-0.
95 (m, 2H). LC-MS: m / z 420.1 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-oxoindoline-5-yl) nicotinonitrile (
Compound 384; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
8.22 (s, 1H), 7.50-7.64 (m, 1H), 7.21
-7.26 (m, 2H), 6.85-7.03 (m, 1H), 4.
90 (br. S., 0.5H), 4.53 (d, J = 13.6 Hz,
0.5H), 4.10-4.37 (m, 2.5H), 3.68-3.
86 (m, 2.5H), 3.48-3.64 (m, 2.5H), 3.3
5-3.44 (m, 3H), 3.19-3.31 (m, 1H), 2
. 94-3.17 (m, 1.5H), 2.52-2.82 (m, 2H)
), 1.99-2.09 (m, 1H), 1.39 (d, J = 6.5
Hz, 1.5H), 1.28 (d, J = 6.8 Hz, 1.5H),
1.09-1.20 (m, 2H), 0.91-0.99 (m, 2H)
. LC-MS: m / z 460.5 (M + H) +

(R) -6-cyclopropyl-5- (1H-indazol-6-yl) -2- (4- (
3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 385; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
8.14 (br. S., 1H), 7.82 (d, J = 8.3 Hz,
1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.16 −
7.24 (m, 1H), 4.91 (br. S., 0.5H), 4.54
(D, J = 12.5 Hz, 0.5H), 4.16-4.39 (m,
2.5H), 3.69-3.85 (m, 2.5H), 3.50-3.6
5 (m, 0.5H), 3.38 (s, 3H), 3.20-3.32 (
m, 1H), 2.98-3.14 (m, 1.5H), 2.52-2.
82 (m, 2H), 2.04-2.13 (m, 1H), 1.28-
1.43 (m, 3H), 0.91-0.98 (m, 2H), 0.81
-0.89 (m, 2H). LC-MS: m / z 445.5 (M + H) +

(R) -6-cyclopropyl-5- (isoquinolin-5-yl) -2- (3-methyl-
4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) nicotinonitrile (Compound 386; General Procedure 2, Step M): 1H NMR (chloroform-d)
δ 9.30-9.40 (m, 1H), 8.49-8.58 (m,
1H), 8.06 (d, J = 8.3 Hz, 1H), 7.67-7.
75 (m, 1H), 7.62-7.67 (m, 2H), 7.36-
7.45 (m, 1H), 4.95 (br. S., 0.5H), 4.58
-4.61 (m, 0.5H), 4.27-4.49 (m, 2H), 4
. 14 (br. S., 0.5H), 3.59-3.73 (m, 1H),
3.11-3.39 (m, 4.5H), 1.45-1.55 (m,
2.5H), 1.37 (dd, J = 6.4, 4.4 Hz, 1.5H),
1.07-1.19 (m, 2H), 0.77-0.87 (m, 2H
). LC-MS: m / z 480.1 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (Compound 387; General Procedure 2, Step M): 1H NMR (chloroform-d) δ 9.40 (br.s., 1H), 8.56 (d, J = 4
. 5 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.
72-7.78 (m, 1H), 7.64-7.71 (m, 2H),
7.46 (dd, J = 12.5, 5.8 Hz, 1H), 4.58 (d
t, J = 13.1, 2.1 Hz, 1H), 4.47 (d, J = 1)
2.0 Hz, 1H), 4.09-4.26 (m, 0.5H), 3.80
-3.86 (m, 1.5H), 3.08-3.44 (m, 5H),
1.49-1.57 (m, 1H), 1.33 (br. S., 1H),
1.08-1.22 (m, 2H), 0.82-0.91 (m, 2H)
, 0.41-0.72 (m, 4H). LC-MS: m / z 506.7
(M + H) +

(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (
Compound 390)

7-1 (410 mg, 1.01 mmol), 2-chloropyridin-4-ylboronic acid (
237 mg, 0.95 mmol), K ₂ CO ₃ (414 mg, 3.03 mmol) and Pd (PPh ₃ ) ₄ (40 mg, 0.035 mmol) in DMF (2 mL)
Stir in a microwave reactor at 150 ° C. for 1 hour. The resulting mixture was partitioned between EtOAc and water, the organic phase was washed with water, brine, concentrated and preparative TLC (PE: E
375 mg of (R) -2′-chloro-2-cyclopropyl-
6- (4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) -3,4
'-Bipyridine-5-carbonitrile was obtained. 1H NMR (chloroform-d) δ
8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39
(D, J = 1.0 Hz, 1H), 4.90 (br.s., 0.5H
), 4.52 (d, J = 11.8 Hz, 0.5H), 4.21-4
. 41 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.
54 (d, J = 4.0 Hz, 1H), 3.25-3.45 (m,
4H), 2.95-3.25 (m, 1H), 2.63-2.92 (m
, 1H), 2.42-2.63 (m, 1H), 1.87-2.07
(M, 1H), 1.36 (d, J = 6.5 Hz, 1.5H), 1.1
1-1.31 (m, 3.5H), 0.81-1.11 (m, 2H).
LC-MS: m / z 440.1 (M + H) +

(R) -2′-chloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,4′-bipyridine-5-carbonitrile (
40 mg, 0.09 mmol), vinyltributylstannane (30 mg, 0.09 mm)
ol), KOAc (10 mg) and Pd (PPh ₃ ) ₄ (5 mg) in DMF (2 mL).
The medium mixture was stirred for 20 minutes at 120 ° C. in a microwave reactor. The resulting mixture was concentrated and purified by preparative TLC (PE: EA = 1: 1) to give 25 mg of the title product. 1H NMR (chloroform-d) δ 8.64 (d, J = 5.0 H
z, 1H), 7.63 (s, 1H), 7.31-7.45 (m, 1H)
), 7.22 (dd, J = 5.0, 1.8 Hz, 1H), 6.87
(Dd, J = 17.6, 10.8 Hz, 1H), 6.27 (dd, J
= 17.6, 1.0 Hz, 1H), 5.41-5.71 (m, 1H
), 4.90 (m, 0.5H), 5.51 (m, 0.5H), 4.16
-4.44 (m, 3H), 3.74 (t, J = 6.1 Hz, 3H)
, 3.38 (s, 4H), 3.31 (d, J = 4.0 Hz, 1H)
, 3.14 (br. S., 2H), 2.59 (t, J = 6.0 Hz)
, 2H), 1.86-2.06 (m, 1H), 1.38 (d, J =
6.3 Hz, 1.5H), 1.24-1.33 (m, 1.5H), 1
. 10-1.24 (m, 2H), 0.83-1.10 (m, 2H).
LC-MS: m / z 432.6 (M + H) +

(R) -2′-chloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,4′-bipyridine-5-carbonitrile (
Compound 401): 1H NMR (chloroform-d) [delta] 8.34-8.61
(M, 1H), 7.60 (s, 1H), 7.39 (d, J = 1.0
Hz, 1H), 4.90 (br. S., 0.5H), 4.52 (d,
J = 11.8 Hz, 0.5H), 4.21-4.41 (m, 2.5H)
), 3.68-3.91 (m, 2.5H), 3.54 (d, J = 4
. 0 Hz, 1H), 3.25-3.45 (m, 4H), 2.95-
3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42
-2.63 (m, 1H), 1.87-2.07 (m, 1H), 1.3
6 (d, J = 6.5 Hz, 1.5H), 1.11-1.31 (m,
3.5H), 0.81-1.11 (m, 2H). LC-MS: m / z 4
40.1 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (
Compound 391; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
9.41 (s, 1H), 8.54 (d, J = 5.3 Hz, 1H),
8.11 (d, J = 8.0 Hz, 1H), 7.68-7.81 (
m, 2H), 7.61-7.67 (m, 1H), 7.45-7.56.
(M, 1H), 4.58 (d, J = 11.5 Hz, 1H), 4.4
6 (d, J = 13.1 Hz, 1H), 3.49-4.23 (m,
2.5H), 3.16-3.33 (m, 2.5H), 1.58-1.6
9 (m, 1H), 1.42-1.54 (m, 1H), 1.17 (t,
J = 4.9 Hz, 2H), 1.00-1.10 (m, 3H), 0
. 76-0.87 (m, 4H), 0.69 (br.s., 1H), 0
. 41-0.62 (m, 3H); LC-MS: m / z 464.2 (M +
H)

(R) -1- (4- (6-Cyclopropyl-5- (4-fluorophenyl) -3- (1
, 3,4-oxadiazol-2-yl) pyridin-2-yl) -2-methylpiperazin-1-yl) -3-methoxypropan-1-one (compound 392)

Step 1: (R) -5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) nicotinonitrile (2 g, 6.3 mmol) was added to MeOH (5 mL) and N
Dissolved in aOH (20 wt%, aqueous, 10 mL) and the reaction solution was heated to reflux overnight. The resulting solution was concentrated and then dissolved in MeOH (10 mL) and SOCl ₂ (0.1 m
1) and then heated to reflux for 2 hours. The resulting solution was concentrated, washed with brine and extracted with EA (50 mL). The organic phase was dried, concentrated and purified by flash column (EA: PE = 1: 3) to give (R) -methyl 5-bromo-6-cyclopropyl-2- (3-methylpiperazin-1-yl) Nicotinate as a white solid (804 mg, 5
0% yield).

  Step 2: The same procedure as General Procedure 1, Step F, Method 1 was followed.

  Step 3: The same procedure as General Procedure 1, Step H was followed.

Step 4: (R) -Methyl 6-cyclopropyl-5- (4-fluorophenyl) -2
-(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinate (500 mg, 1.1 mmol) and 2 mL hydrazine hydrate were dissolved in 10 mL ethanol. The reaction mixture was heated to reflux overnight and cooled to room temperature. The mixture was filtered and the residue was washed with cold ethanol. 200 mg of the title compound was obtained without further purification.

Step 5: (R) -6-cyclopropyl-5- (4-fluorophenyl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotine-hydrazide (200 mg, 0.44 mmol) was dissolved in trimethoxymethane (25 mL). The reaction mixture was heated to reflux overnight. The remainder of trimethoxymethane was removed under reduced pressure and purified by preparative TLC to give 50 mg of the title compound. 1H NMR (chloroform-d
) Δ 9.33 (s, 1H), 8.51 (d, J = 6.0 Hz, 1
H), 8.10 (s, 1H), 8.02 (d, J = 7.8 Hz, 1
H), 7.62-7.89 (m, 2H), 7.27 (s, 1H), 4
. 63-4.78 (m, 2H), 4.47-4.63 (m, 1H),
3.55-3.84 (m, 3H), 3.39 (s, 4H), 3.19
(Dd, J = 13.3, 3.5 Hz, 1H), 2.91-3.12.
(M, 2H), 2.66-2.88 (m, 3H), 2.44-2.
66 (m, 2H), 1.28-1.43 (m, 1.5H), 1.15
-1.28 (m, 3.5H), 1.12 (br. S., 1H), 0.8
0-1.06 (m, 2H); LC-MS: m / z 466.2 (M + H)
.

2- (4- (Cyclopropanecarbonyl) -3- (trifluoromethyl) piperazine-
1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (
Compound 397; General Procedure 4, Steps R and S): 1H NMR (chloroform-
d) δ 9.35 (s, 1H), 8.54 (t, J = 6.4 Hz,
1H), 8.07 (d, J = 8.0 Hz, 1H), 7.60-7.
76 (m, 3H), 7.35-7.49 (m, 1H), 5.39 (b
r. s. , 0.5H), 4.28-4.86 (m, 3.5H), 3.7
0-3.97 (m, 1H), 3.44 (d, J = 14.3 Hz,
1H), 3.23-3.39 (m, 1H), 1.68-1.91 (m
, 1H), 1.53 (td, J = 7.8, 3.5 Hz, 1H), 1
. 08-1.23 (m, 3H), 0.77-1.07 (m, 5H).
LC-MS: m / z 492.2 (M + H) +

6-cyclopropyl-5- (isoquinolin-5-yl) -2- (4- (3-methoxypropanoyl) -3- (trifluoromethyl) piperazin-1-yl) nicotinonitrile (
Compound 398; General Procedure 4, Steps R and S): 1H NMR (chloroform-
d) δ 9.35 (br. s., 1H), 8.55 (t, J = 6.0)
Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.60
-7.80 (m, 3H), 7.42 (dd, J = 19.3, 5.5)
Hz, 1H), 5.29-5.48 (m, 0.5H), 4.71-
4.92 (m, 1.5H), 4.44-4.62 (m, 1H), 4.0
2 (d, J = 13.3 Hz, 0.5H), 3.63-3.86 (m
, 2.5H), 3.33-3.51 (m, 3.5H), 3.19-3
. 32 (m, 2H), 2.75-2.94 (m, 1H), 2.52-
2.75 (m, 1H), 2.06 (br. S., 1H), 1.52 (
tq, J = 8.0, 4.1 Hz, 1H), 1.10-1.22 (m
, 2H), 0.76-0.93 (m, 2H). LC-MS: m / z
510.4 (M + H) +

6-cyclopropyl-5- (isoquinolin-5-yl) -2- (3- (trifluoromethyl) -4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) nicotinonitrile ( Compound 399; General Procedure 4, Steps R and S): 1H NMR (chloroform-d) δ 9.35 (s, 1H), 8.54 (t, J = 6.
5 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.5
5-7.80 (m, 3H), 7.32-7.45 (m, 1H), 5
. 26-5.49 (m, 0.5H), 4.45-5.03 (m, 2.
5H), 3.72-3.95 (m, 2H), 3.22-3.52 (m
, 5H), 1.54 (tq, J = 8.0, 4.2 Hz, 1H), 1
. 10-1.22 (m, 2H), 0.78-0.94 (m, 3H).
LC-MS: m / z 534.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (Compound 402; Procedure 1, Step H): 1H NMR (chloroform-d) δ 9
. 36 (br. S., 1H), 8.55 (d, J = 5.8 Hz, 1
H), 8.08 (d, J = 8.0 Hz, 1H), 7.52-7.7.
7 (m, 3H), 7.44 (t, J = 6.0 Hz, 1H), 4.9
3 (br. S., 0.5H), 4.25-4.48 (m, 2.5H),
4.21 (br. S., 0.5H), 3.95 (br. S., 2H),
3.66-3.86 (m, 1.5H), 3.56-3.66 (m,
1H), 3.28-3.47 (m, 1H), 2.99-3.28 (m
, 2H), 2.49-2.77 (m, 1H), 1.40-1.57.
(M, 3H), 1.11-1.40 (m, 2H), 0.75-1.0
4 (m, 2H); LC-MS: m / z 442.2 (M + H).

(R) -6-cyclopropyl-5- (3- (dimethylamino) phenyl) -2- (4-
(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (
Compound 413; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
7.61-7.69 (m, 1H), 7.29-7.34 (m, 1H
), 6.65-6.83 (m, 3H), 4.91 (br. S., 0.
5H), 4.54 (d, J = 13.3 Hz, 0.5H), 4.14 −
4.34 (m, 2.5H), 3.70-3.87 (m, 2.5H),
3.56 (t, J = 11.2 Hz, 0.5H), 3.34-3.46
(M, 3H), 3.00-3.28 (m, 8.5H), 2.54-
2.83 (m, 2H), 2.14-2.23 (m, 1H), 1.29
-1.43 (m, 3H), 1.07-1.20 (m, 2H), 0.8
4-1.01 (m, 2H). LC-MS: m / z 448.4 (M + H
) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3- (methylamino) phenyl) nicotinonitrile (Compound 414; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
7.63 (s, 1H), 7.23-7.27 (m, 1H), 6.72
(D, J = 7.8 Hz, 1H), 6.62-6.68 (m, 1H)
6.56-6.62 (m, 1H), 4.91 (br. S., 0.5
H), 4.54 (d, J = 13.6 Hz, 0.5H), 4.15 −
4.33 (m, 2.5H), 3.70-3.88 (m, 2.5H), 3
. 52-3.62 (m, 0.5H), 3.39 (s, 3H), 3.00
-3.28 (m, 2.5H), 2.89 (s, 3H), 2.65-
2.83 (m, 1H), 2.51-2.65 (m, 1H), 2.14
-2.21 (m, 1H), 1.30-1.47 (m, 3H), 1.1
0-1.19 (m, 2H), 0.89-0.98 (m, 2H). L
C-MS: m / z 434.5 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (
Compound 409; General Procedure 1, Step H): 1H NMR (chloroform-d) δ
9.36 (br.s., 1H), 8.54 (d, J = 4.5 Hz,
1H), 8.07 (d, J = 8.0 Hz, 1H), 7.60-7
. 84 (m, 3H), 7.44 (dd, J = 12.3, 6.0 Hz,
1H), 4.71-4.73 (m, 0.5H), 4.56 (d, J
= 11.8 Hz, 1H), 4.38-4.50 (m, 1H), 4.0
7-4.19 (m, 0.5H), 3.91 (d, J = 11.0 Hz)
, 0.5H), 3.69-3.83 (m, 3H), 3.51 (s, 3
H), 3.20-3.29 (m, 1.5H), 3.13 (br. S.,
1H), 2.61-2.70 (m, 2H), 1.52 (ddd, J
= 12.0, 7.9, 4.6 Hz, 1H), 1.40 (br. S.,
1H), 1.12-1.20 (m, 2H), 0.80-0.90 (m
, 2H), 0.48-0.77 (m, 4H). LC-MS: m / z 4
82.6 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (Compound 419; general Procedure 1, Step H): 1H NMR (chloroform-d)
δ 9.40 (br. s., 1H), 8.48-8.69 (m, 1H)
, 8.11 (d, J = 8.0 Hz, 1H), 7.63-7.86
(M, 3H), 7.44-7.55 (m, 1H), 4.70-4.7
3 (m, 0.5H), 4.57 (dd, J = 13.1, 2.0 Hz,
1H), 4.41-4.52 (m, 1H), 4.13 (d, J =
7.8 Hz, 0.5H), 3.94 (br.s., 2H), 3.69 −
3.82 (m, 1H), 3.13-3.26 (m, 3H), 2.50
-2.71 (m, 2H), 1.48-1.57 (m, 1H),
39-1.48 (m, 1H), 1.12-1.21 (m, 2H),
0.86-0.91 (m, 2H), 0.42-0.69 (m, 4H)
. LC-MS: m / z 468.5 (M + H) +

(R) -5- (5-Cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) isoquinoline 2-oxide (compound 420): 1H NMR (chloroform-d) δ 8.88 (br.
s. , 1H), 8.15 (d, J = 6.5 Hz, 1H), 7.81
(D, J = 8.3 Hz, 1H), 7.73 (t, J = 7.7 H
z, 1H), 7.63 (s, 1H), 7.52-7.58 (m, 1H)
), 7.44-7.52 (m, 1H), 4.94 (br. S., 0.
5H), 4.55-4.59 (m, 0.5H), 4.21-4.44
(M, 2.5H), 3.57-3.86 (m, 3H), 3.34-3
. 40 (m, 4H), 3.19-3.22 (m, 1.5H), 2.58
-2.86 (m, 2H), 1.47-1.55 (m, 1H),
30-1.38 (m, 3H), 1.09-1.21 (m, 2H),
0.78-0.95 (m, 2H). LC-MS: m / z 472.4 (
M + H) +

6-cyclopropyl-5- (isoquinolin-5-yl) -2- (4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile (compound 421; general procedure 1,
Step H): 1H NMR (chloroform-d) δ 9.35 (br. S.,
1H), 8.53 (d, J = 5.0 Hz, 1H), 8.06 (d,
J = 8.3 Hz, 1H), 7.68-7.75 (m, 1H), 7
. 60-7.67 (m, 2H), 7.42 (d, J = 5.8 Hz,
1H), 3.39-3.85 (m, 10H), 3.38 (s, 3H)
, 2.63-2.75 (m, 2H), 1.46-1.55 (m, 1
H), 1.08-1.18 (m, 2H), 0.75-0.85 (m,
2H). LC-MS: m / z 442.5 (M + H) +

2- (4- (Cyclopropanecarbonyl) -3- (difluoromethyl) piperazine-1
-Yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (Compound 422; General Procedure 4, Steps R and S): 1H NMR (chloroform-d
) Δ 9.37 (br.s., 1H), 8.56 (br.s., 1H)
, 8.09 (d, J = 8.0 Hz, 1H), 7.60-7.79
(M, 3H), 7.43 (d, J = 10.3 Hz, 1H), 6.09
(Br.s., 1H), 4.97-5.45 (m, 4H), 3.12.
-3.89 (m, 3H), 1.98-2.08 (m, 1H), 1.
80-1.87 (m, 1H), 1.00-1.21 (m, 4H),
0.83-0.92 (m, 4H). LC-MS: m / z 474.5 (
M + H) +

2- (4- (Cyclopropanecarbonyl) -3- (2,2,2-trifluoroethyl)
Piperazin-1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (Compound 423; General Procedure 4, Steps R and S): 1H NMR (chloroform-d) δ 9.36 (S, 1H), 8.55 (dd, J = 5
. 8, 3.5 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H)
), 7.59-7.81 (m, 3H), 7.33-7.50 (m,
1H), 5.24 (br.s., 0.5H), 4.34 (d, J = 1)
3.1 Hz, 1H), 4.26-4.50 (m, 2.5H), 3.69
(Br.s., 0.5H), 3.20-3.45 (m, 2H), 3.
13 (br. S., 0.51H),, 2.58-2.75 (m, 2H
), 1.77 (br. S., 1H), 1.47-1.61 (m, 1H)
), 1.09-1.24 (m, 4H), 0.77-0.93 (m,
4H). LC-MS: m / z 506.5 (M + H) +

(R) -2-cyclopropyl-2′-ethyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,4′-bipyridine-5-carbonitrile (
Compound 426)

Compound 390 (18 mg) in EtOH was treated with Pd / C and hydrogenated at room temperature and pressure to give the title compound as a white solid. 1H NMR (chloroform-d) δ 8.63 (d, J = 4.8 Hz, 1H), 7.63 (
s, 1H), 7.23 (d, J = 4.5 Hz, 2H), 4.92 (
br. s. , 1H), 4.55 (d, J = 12.8 Hz, 1H),
4.14-4.43 (m, 3H), 3.64-3.89 (m, 3H)
, 3.57 (br. S., 1H), 3.40 (s, 3H), 3.32.
(D, J = 11.8 Hz, 1H), 3.14 (d, J = 14.3)
Hz, 1H), 2.94 (q, J = 7.4 Hz, 2H), 2.65
-2.83 (m, 1H), 2.39-2.65 (m, 1H), 2.0
3 (td, J = 8.0, 3.9 Hz, 2H), 1.25-1.42
(M, 8H), 1.11-1.25 (m, 3H), 1.01 (dd,
J = 7.8, 3.0 Hz, 2H). LC-MS: m / z 434.2
(M + H) +

Compound 430 (General Procedure 1, Step I): 1H NMR (chloroform-d)
δ 8.41 (dd, J = 7.9, 1.4 Hz, 1H), 8.14 (
s, 1H), 7.72-7.84 (m, 1H), 7.57-7.71
(M, 2H), 4.93 (d, J = 13.3 Hz, 0.5H), 4
. 55 (d, J = 13.3 Hz, 0.5H), 4.14-4.43
(M, 3H), 3.69-3.90 (m, 3H), 3.53-3.6
8 (m, 1H), 3.34-3.46 (m, 3H), 3.27 (t,
J = 11.2 Hz, 1H), 2.97-3.22 (m, 2H),
2.54-2.84 (m, 2H), 1.55-1.80 (m, 2H)
, 1.43 (d, J = 6.5 Hz, 2H), 1.18-1.38
(M, 3H), 1.09 (br. S., 1H), 0.70-0.99
(M, 2H). LC-MS: m / z 473.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3-methylisoquinolin-5-yl) nicotinonitrile (Compound 433) ): 1H NMR (chloroform-d) δ 9.23 (s, 1H
), 7.93-8.03 (m, 1H), 7.50-7.66 (m,
3H), 7.21 (d, J = 6.0 Hz, 1H), 4.92 (br.
s. , 0.5H), 4.55 (d, J = 12.8 Hz, 0.5H),
4.19-4.42 (m, 2.5H), 3.83 (d, J = 12.
3 Hz, 0.5H), 3.65-3.78 (m, 2H), 3.56 (
d, J = 16.8 Hz, 0.5H), 3.37 (s, 3H), 3.3
1 (d, J = 13.1 Hz, 1H), 2.98-3.25 (m,
1.5H), 2.68-2.84 (m, 1H), 2.53-2.68.
(M, 5H), 1.47-1.57 (m, 1H), 1.43 (d, J
= 6.3 Hz, 1.5H), 1.29-1.36 (m, 1.5H),
1.13 (dd, J = 6.5, 4.0 Hz, 2H), 0.76 −
0.84 (m, 2H). LC-MS: m / z 470.2 (M + H) +

(R) -6-cyclopropyl-5- (1-methoxyisoquinolin-5-yl) -2- (
4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 434): 1H NMR (chloroform-d) δ 8.32 (dd,
J = 7.5, 1.3 Hz, 1H), 7.98 (d, J = 6.0 H
z, 1H), 7.52-7.65 (m, 3H), 6.94 (t, J
= 5.9 Hz, 1H), 4.85 (br.s., 0.5H), 4.55
(D, J = 12.8 Hz, 0.5H), 4.20-4.40 (m,
2.5H), 4.15 (s, 3H), 3.66-3.89 (m, 3H)
), 3.38 (s, 3H), 3.31 (d, J = 8.3 Hz, 1H)
), 3.17 (d, J = 13.3 Hz, 1.5H), 2.65-2.
. 84 (m, 1H), 2.51-2.65 (m, 1H), 1.48-
1.60 (m, 1H), 1.42 (m, 1.5H), 1.29-1.
36 (m, 1.5H), 1.03-1.19 (m, 2H), 0.81
(Dd, J = 8.0, 3.0 Hz, 2H). LC-MS: m / z 4
86.2 (M + H) +

(1R, 2R) -ethyl 2-((R) -4- (3-cyano-6-cyclopropyl-5-
(Isoquinolin-5-yl) pyridin-2-yl) -2-methylpiperazine-1-carbonyl) cyclopropanecarboxylate (Compound 435): 1H NMR (chloroform-d) δ 9.34 (s, 1H), 8 .53 (d, J = 5.8 H
z, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.62 −
7.80 (m, 3H), 7.42 (t, J = 5.9 Hz, 1H),
4.87 (br. S., 0.5H), 4.38-4.65 (m, 1.
5H), 4.33 (d, J = 12.0 Hz, 2H), 4.19 (q,
J = 7.0 Hz, 2H), 3.62-3.85 (m, 0.5H),
3.46 (d, J = 13.1 Hz, 0.5H), 3.10-3.4
0 (m, 2H), 2.36 (br. S., 1H), 2.17-2.3
1 (m, 1H), 2.09 (br.s., 1H), 1.38-1.4
5 (m, 2H), 1.22-1.37 (m, 6H), 1.03-1
. 22 (m, 2H), 0.69-0.94 (m, 2H). LC-MS:
m / z 461.2 (M + H) +

(R) -5- (5-Cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) isoquinoline 2-oxide (Compound 439) ): 1H NMR (chloroform-d) δ 8.87
(Br. S., 1H), 8.06-8.26 (m, 1H), 7.70.
-7.83 (m, 2H), 7.61-7.69 (m, 1H), 7.5
4 (br. S., 2H), 4.59 (d, J = 7.0 Hz, 1H)
, 4.47 (d, J = 12.5 Hz, 1H), 3.51-4.30
(M, 3H), 3.32 (br.s., 1H), 3.17 (br.s
. , 1H), 1.96-2.10 (m, 1H), 1.75 (br. S)
. , 1H), 1.43-1.54 (m, 1H), 1.14-1.23.
(M, 2H), 1.00-1.12 (m, 2H), 0.81-0.
94 (m, 4H), 0.38-0.73 (m, 4H). LC-MS:
m / z 480.2 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl)- N
-(Vinylsulfonyl) ethenesulfonamide (Compound 440; General Procedure 3, Step N, Method 1): 1H NMR (chloroform-d) [delta] 7.60-7.64
(M, 1H), 7.50-7.56 (m, 2H), 7.29-7.3
7 (m, 3H), 7.01-7.16 (m, 2H), 6.26-6
. 40 (m, 2H), 6.11-6.25 (m, 2H), 4.92 (
s, 0.5H), 4.54 (d, J = 13.3 Hz, 0.5H), 4
. 19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H
), 3.52-3.61 (m, 0.5H), 3.39 (s, 3H),
3.28 (t, J = 10.4 Hz, 1H), 3.02-3.14 (m,
1H), 2.65-2.80 (m, 1H), 2.55-2.64 (
m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H)
), 1.14-1.19 (m, 2H), 0.95-1.01 (m,
2H). LC-MS: m / z 600.2 (M + H) +

(R, E) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl )
-4- (Dimethylamino) but-2-enamide (Compound 441; General Procedure 3, Step N, Method 2): 1H NMR (chloroform-d) δ 9.22 (s, 1H)
7.68 (s, 1H), 7.53-7.60 (m, 1H), 7.4
1-7.53 (m, 1H), 7.31 (s, 1H), 7.08 (d,
J = 7.3 Hz, 1H), 6.86 (s, 1H), 6.61 (d,
J = 15.3 Hz, 1H), 4.83 (s, 0.5H), 4.46.
(D, J = 11.0 Hz, 0.5H), 4.22 (d, J = 9.8
Hz, 2.5H), 3.90 (s, 1.5H), 3.67-3.81
(M, 2.5H), 3.52 (s, 0.5H), 3.28-3.41 (
m, 3H), 3.24 (s, 1H), 3.04-3.15 (m, 1H)
), 2.94-3.04 (m, 1H), 2.88 (s, 2H), 2.
82 (s, 6H), 2.57 (d, J = 15.8 Hz, 1H), 1
. 97-2.08 (m, 1H), 1.33-1.40 (m, 2H),
1.18-1.30 (m, 2H), 1.02-1.15 (m, 2H)
), 0.89 (s, 2H). LC-MS: m / z 531.3 (M + H)
+

(R) -6-cyclopropyl-5- (2-hydroxyquinolin-5-yl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 442): 1H NMR (chloroform-d) δ 7.88 (d, J
= 9.5 Hz, 1H), 7.63-7.70 (m, 1H), 7.43
-7.63 (m, 3H), 6.80 (d, J = 9.5 Hz, 1H
), 4.92 (br. S., 0.5H), 4.57 (d, J = 13.
1 Hz, 0.5H), 4.15-4.45 (m, 3H), 3.66-
3.87 (m, 2H), 3.40 (s, 2H), 3.29 (t, J
= 9.7 Hz, 1H), 3.11-3.22 (m, 1H), 2.66.
-2.88 (m, 1H), 2.48-2.66 (m, 1H),
96-2.10 (m, 1H), 1.36-1.56 (m, 1.5H)
, 1.08-1.36 (m, 3.5H), 0.97 (dd, J = 7
. 8, 3.0 Hz, 2H). LC-MS: m / z 472.3 (M + H)
+

(R) -6- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile (
Compound 443; General Procedure 5, Step W): 1H NMR (chloroform-d) δ
8.66 (d, J = 4.3 Hz, 1H), 7.59-7.67 (
m, 1H), 7.35-7.45 (m, 1H), 7.24 (d, J
= 4.3 Hz, 1H), 6.89 (dd, J = 17.3, 10.8
Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H), 5.58
(D, J = 10.8 Hz, 1H), 4.87 (br.s., 1H)
, 4.56 (br.s., 1H), 4.30 (d, J = 13.3 H
z, 1H), 4.13 (br.s., 1H), 3.58-3.88 (
m, 1H), 3.33 (d, J = 10.0 Hz, 1H), 3.20
(Br.s., 2H), 1.91-2.09 (m, 1H), 1.38
-1.51 (m, 1.5H), 1.11-1.38 (m, 2.5H),
0.87-1.08 (m, 6H), 0.79-0.87 (m, 2H
). LC-MS: m / z 414.4 (M + H) +

(R) -2-cyclopropyl-6- (3-methyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5 -Carbonitrile (compound 444; general procedure 5, step W): 1H NMR (chloroform-d) δ 7.59-7.69 (m, 1H), 7.34-7.43
(M, 1H), 7.15-7.27 (m, 1H), 6.89 (dd,
J = 17.6, 10.8 Hz, 1H), 6.23-6.37 (m,
1H), 5.58 (d, J = 11.5 Hz, 1H), 4.94 (br
. s. , 1H), 4.20-4.48 (m, 2H), 3.51-3
. 79 (m, 1H), 3.37 (d, J = 5.5 Hz, 1H), 3
. 05-3.34 (m, 4H), 1.87-2.07 (m, 1H),
1.42-1.51 (m, 2H), 1.13-1.42 (m, 3H
), 0.95-1.08 (m, 2H). LC-MS: m / z 456.8
(M + H) +

(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile (compound 485; general procedure 5, step W): 1H NMR (chloroform-
d) δ 8.77 (br.s., 1H), 7.96 (br.s., 1H)
), 7.80-7.92 (m, 2H), 7.12-7.27 (m,
1H), 6.82 (d, J = 17.6 Hz, 1H), 6.06 (d,
J = 10.8 Hz, 1H), 4.67 (d, J = 12.3 Hz,
1H), 4.54 (d, J = 11.5 Hz, 2H), 4.24 (b
r. s. , 1H), 3.67 (br. S., 1H), 3.33 (br.
s. , 1H), 3.18 (br.s., 1H), 1.93 (br.s)
. , 1H), 1.67 (br.s., 1H), 1.25 (br.s.,
2H), 1.04-1.23 (m, 3H), 0.89-1.04 (
m, 3H), 0.47 (d, J = 4.8 Hz, 2H), 0.39 (
br. s. , 2H). LC-MS: m / z 440.2 (M + H) +

Compound 527 (General Procedure 5, Step W): 1H NMR (chloroform-d)
δ 8.65 (d, J = 4.7 Hz, 1H), 7.65 (s, 1H)
, 7.38 (s, 1H), 7.23 (d, J = 4.1 Hz, 1H)
6.87 (dd, J = 17.5, 10.7 Hz, 1H), 6.28.
(D, J = 17.6 Hz, 1H), 5.56 (d, J = 10.9)
Hz, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.4
3 (d, J = 12.6 Hz, 1H), 4.03-4.16 (m,
1H), 3.91 (br.s., 2H), 3.65-3.82 (m,
1H), 3.40-3.53 (m, 1H), 3.02-3.32 (m
3H), 2.49-2.69 (m, 2H), 1.98-2.10.
(M, 1H), 1.13-1.38 (m, 3H), 1.01 (dd,
J = 7.5, 3.4 Hz, 2H), 0.63 (br.s., 1H),
0.55 (br. S., 1H), 0.32-0.51 (m, 2H).
LC-MS: m / z 444.3 (M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-
5-carbonitrile (compound 498; general procedure 5, step W): 1H NMR (chloroform-d) δ 8.54-8.72 (m, 1H), 7.57-7
. 74 (m, 1H), 7.38 (d, J = 1.0 Hz, 1H), 7
. 23 (dd, J = 5.1, 1.6 Hz, 1H), 6.88 (dd,
J = 17.3, 10.8 Hz, 1H), 6.28 (dd, J = 1)
7.4, 1.1 Hz, 1H), 5.48-5.63 (m, 1H), 4
. 56 (dd, J = 13.2, 1.9 Hz, 1H), 4.45 (d,
J = 13.1 Hz, 1H), 4.11 (br.s., 1H),
65-3.88 (m, 2H), 3.32 (q, J = 9.6 Hz,
2H), 3.20 (d, J = 12.0 Hz, 1H), 2.98-3
. 15 (m, 1H), 2.04 (tt, J = 8.0, 4.7 Hz,
1H), 1.30-1.39 (m, 1H), 1.14-1.25 (m
, 2H), 0.96-1.07 (m, 2H), 0.65 (br. S.
, 1H), 0.56 (br. S., 1H), 0.41-0.54 (m
, 2H). LC-MS: m / z 482.5 (M + H) +

(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (
Compound 500; General Procedure 5, Step W): 1H NMR (chloroform-d) δ
8.66 (d, J = 5.0 Hz, 1H), 7.60-7.71 (
m, 1H), 7.41 (s, 1H), 7.26 (dd, J = 5.0,
1.3 Hz, 1H), 6.90 (dd, J = 17.4, 10.9 H
z, 1H), 6.31 (d, J = 17.1 Hz, 1H), 5.60.
(D, J = 11.0 Hz, 1H), 4.72-4.99 (m, 0.
5H), 4.54 (d, J = 13.1 Hz, 0.5H), 4.22-
4.49 (m, 2H), 3.74 (d, J = 13.6 Hz, 1H)
, 3.56 (br. S., 1H), 3.40 (br. S., 1H),
3.32 (td, J = 8.6, 3.9 Hz, 1H), 2.95-3
. 25 (m, 2H), 2.68 (br. S., 1H), 2.44-2
. 65 (m, 2H), 2.00-2.19 (m, 1H), 1.16-
1.45 (m, 3H), 0.95-1.12 (m, 3H), 0.90
(T, J = 6.8 Hz, 1H). LC-MS: m / z 418.6
(M + H) +

(R) -2-cyclopropyl-6- (4- (4,4-dimethoxybutanoyl) -3-methylpiperazin-1-yl) -2'-vinyl- [3,4'-bipyridine] -5 Carbonitrile (Compound 606; General Procedure 5, Step W): 1H NMR (chloroform-
d) δ 8.64 (d, J = 5.0 Hz, 1H), 7.63 (s,
1H), 7.38 (s, 1H), 7.23 (dd, J = 5.0,
5 Hz, 1H), 6.81-6.93 (m, 1H), 6.28 (d,
J = 11.0 Hz, 1H), 5.56 (d, J = 11.0 Hz,
1H), 4.88 (s, 0.5H), 4.24-4.53 (m, 1.
5H), 4.24-4.36 (m, 2.5H), 3.78 (d, 0.5
H), 3.54 (t, 0.5H), 3.27-3.37 (m, 4H),
3.02-3.18 (m, 1.5H), 2.35-2.56 (m,
2H), 1.92-2.06 (m, 4H), 1.38 (d, 1.5H)
, 1.28 (d, 1.5 H), 1.18-1.21 (m, 2H),
0.99-1.02 (m, 2H). LC-MS: m / z 476.2 (M
+ H) +

(R) -2-cyclopropyl-6- (3-methyl-4- (4-oxobutanoyl) piperazin-1-yl) -2′-vinyl- [3,4] obtained as a byproduct of compound 606 '−
Bipyridine] -5-carbonitrile (Compound 607) 1H NMR (chloroform-
d) δ 9.90 (s, 1H), 8.65 (d, J = 5.0 Hz,
1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.24 (d
, J = 5.0 Hz, 1H), 6.88 (q, 1H), 6.28 (d
, 1H), 5.56 (d, 1H), 4.85 (br.s., 0.5H)
4.48 (d, J = 12.8 Hz, 0.5H), 4.25-4.
37 (m, 2.5H), 3.80 (br. S., 0.5H), 3.60
(Br.s., 0.5H), 3.03-3.38 (m, 3H), 2.6
2-2.89 (m, 4.5H), 2.03 (m, 1H), 1.42 (d,
1.5H), 1.28 (d, 1.5H), 1.18-1.21 (m,
2H), 0.99-1.10 (m, 2H). LC-MS: m / z 430
. 2 (M + H) +

(S) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -2'-vinyl- [3,4'-bipyridine] -5-carbo Nitrile (Compound 587; General Procedure 5, Step W): 1H NMR (chloroform-d) δ 8.66 (d, J = 5.0 Hz, 1H), 7.62
-7.73 (m, 1H), 7.39 (s, 1H), 7.24 (dd,
J = 5.0, 1.5 Hz, 1H), 6.88 (dd, J = 17.6)
, 10.8 Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H
), 5.57 (d, J = 10.8 Hz, 1H), 4.56 (d, J
= 13.1 Hz, 1H), 4.43 (d, J = 11.3 Hz, 1
. 5H), 4.09 (d, J = 8.8 Hz, 0.5H), 3.93 (
d, J = 5.0 Hz, 2H), 3.75-3.82 (m, 1.5H)
), 3.43 (br. S., 1H), 3.16-3.32 (m, 1.
5H), 3.02-3.16 (m, 1H), 2.43-2.71 (m
, 2H), 2.00-2.09 (m, 1H), 1.67 (s, 1H)
, 1.16-1.25 (m, 2H), 0.95-1.08 (m, 2
H), 0.40-0.80 (m, 4H). LC-MS: m / z 444
. 2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinoxalin-6-yl) nicotinonitrile (Compound 4)
45; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 8.9
0 (d, J = 3.0 Hz, 2H), 8.05-8.34 (m, 2
H), 7.85 (d, J = 8.5 Hz, 1H), 7.74 (s, 1
H), 4.92 (br. S., 0.5H), 4.26-4.56 (m,
3H), 3.57-3.84 (m, 3H), 3.31-3.38 (
m, 4H), 3.13-3.16 (m, 1.5H), 2.27-2.
78 (m, 2H), 2.04-2.16 (m, 1H), 1.41 (d
, J = 5.8 Hz, 1.5H), 1.30 (d, J = 6.0 Hz)
1.5H), 1.22 (br. S., 2H), 0.94-1.06
(M, 2H). LC-MS: m / z 457.2 (M + H) +

Compound 446 (General Procedure 3, Step N, Method 1): 1H NMR (chloroform-d) δ 7.58-7.67 (m, 1H), 7.38-7.50 (
m, 2H), 7.32 (dd, J = 7.7, 1.6 Hz, 2H),
6.49 (dd, J = 16.6, 10.0 Hz, 1H), 6.25 (
d, J = 16.6 Hz, 1H), 6.06 (d, J = 10.0 H
z, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J
= 13.1 Hz, 0.5H), 4.13-4.41 (m, 3H), 3
. 71-3.87 (m, 2H), 3.49-3.63 (m, 1H),
3.39 (s, 3H), 3.21-3.34 (m, 4H), 2.95
-3.21 (m, 2H), 2.51-2.81 (m, 2H),
91-2.17 (m, 1H), 1.73 (br.s., 2H),
23-1.50 (m, 5H), 0.94-1.23 (m, 4H).
LC-MS: m / z 524.2 (M + H) +

(S) -2-Chloro-N- (3- (5-cyano-2-cyclopropyl-6-((R)-
4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) pyridine-3-
Yl) phenyl) propanamide (Compound 447; General Procedure 3, Step N, Method 2)
: 1H NMR (chloroform-d) δ 8.57 (s, 1H), 7.70
(S, 1H), 7.57-7.64 (m, 1H), 7.47-7.5
6 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.1
8 (d, J = 7.5 Hz, 1H), 4.90 (br. S., 0.5
H), 4.47-4.65 (m, 1.5H), 4.18-4.30 (
m, 2.5H), 3.73-3.81 (m, 2.5H), 3.48-
3.64 (m, 0.5H), 3.37 (s, 3H), 3.21-3.3
1 (m, 1H), 2.95-3.18 (m, 1.5H), 2.53-
2.79 (m, 2H), 2.04-2.12 (m, 1H), 1.83
(D, J = 7.0 Hz, 3H), 1.38 (d, J = 6.3 H
z, 1.5H), 1.28 (d, J = 6.5 Hz, 1.5H),
11-1.18 (m, 2H), 0.89-1.03 (m, 2H).
LC-MS: m / z 510.1 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) ethane Sulfonamide (Compound 448; General Procedure 3, Step N, Method 1): 1H NMR
(Chloroform-d) δ 7.60 (s, 1H), 7.38-7.49
(M, 2H), 7.30-7.34 (m, 1H), 7.26 (dd,
J = 8.0, 1.3 Hz, 1H), 7.18 (d, J = 7.8 H
z, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J
= 13.3 Hz, 0.5H), 4.13-4.40 (m, 2.5H),
3.67-3.93 (m, 2.5H), 3.51-3.66 (m,
0.5H), 3.38 (s, 3H), 3.02-3.32 (m, 4.5
H), 2.55-2.84 (m, 2H), 2.00-2.11 (m,
1H), 1.38-1.44 (m, 4H), 1.24-1.31 (
m, 2H), 1.12-1.21 (m, 2H), 0.90-1.03
(M, 2H). LC-MS: m / z 512.1 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl) methacryl Amide (Compound 449; General Procedure 3, Step N, Method 1): 1H NMR (
Chloroform-d) δ 7.83 (s, 1H), 7.72 (s, 1H),
7.60 (s, 1H), 7.51-7.57 (m, 1H), 7.40
(T, J = 7.9 Hz, 1H), 7.15 (d, J = 7.8 Hz
, 1H), 5.83 (s, 1H), 5.43-5.54 (m, 1H)
, 4.89 (br. S., 0.5H), 4.52 (d, J = 13.3)
Hz, 0.5H), 4.13-4.36 (m, 2.5H), 3.68
-3.87 (m, 2.5H), 3.55 (t, J = 11.3 Hz,
0.5H), 3.35-3.46 (m, 3H), 3.20-3.31
(M, 1H), 2.96-3.17 (m, 1.5H), 2.81 (s,
2H), 2.51-2.77 (m, 2H), 2.03-2.19 (
m, 4H), 1.38 (d, J = 6.3 Hz, 1.5H), 1.28
(D, J = 6.5 Hz, 1.5H), 1.10-1.18 (m,
2H), 0.88-1.02 (m, 2H). LC-MS: m / z 48
8.1 (M + H) +

(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) phenyl) propiol Amide (Compound 451; General Procedure 3, Step N, Method 1): 1H N
MR (chloroform-d) δ 7.60 (s, 1H), 7.35-7.
47 (m, 1H), 7.28 (s, 1H), 7.23-7.27 (m
, 1H), 7.15-7.22 (m, 2H), 6.63 (dd, J
= 16.6, 9.8 Hz, 1H), 6.26-6.39 (m, 1H)
, 6.01 (d, J = 9.8 Hz, 1H), 4.52 (d, J =
12.5 Hz, 1H), 4.40 (d, J = 12.3 Hz, 1H)
, 4.07-4.24 (m, 1H), 3.65-3.90 (m, 1H)
, 3.22-3.52 (m, 1.5H), 3.10 (s, 1.5H),
2.03-2.10 (m, 1H), 1.29-1.36 (m, 1H
), 1.14-1.21 (m, 2H), 0.93-1.12 (m,
4H), 0.85-0.92 (m, 1H), 0.76-0.85 (m
, 2H), 0.60-0.71 (m, 1H), 0.38-0.60
(M, 3H). LC-MS: m / z 518.2 (M + H) +

(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) phenyl) -N -(Vinylsulfonyl) ethenesulfonamide (compound 452; general procedure 3,
Step N, Method 1): 1H NMR (chloroform-d) δ 7.63 (s,
1H), 7.49-7.58 (m, 2H), 7.33-7.36 (
m, 1H), 7.31 (dt, J = 6.7, 2.3 Hz, 1H),
7.07 (d, J = 9.8 Hz, 1H), 7.10-7.13 (m,
1H), 6.28-6.38 (m, 2H), 6.14-6.22 (m
, 2H), 4.41-4.62 (m, 2.5H), 3.98-4.18.
(M, 1H), 3.75-3.90 (m, 1H), 3.09-3.33
(2.5, 1H), 2.00-2.07 (m, 1H), 1.15-
1.25 (m, 3H), 0.97-1.11 (m, 4H), 0.86
-0.92 (m, 1H), 0.82 (dd, J = 7.8, 2.3 H
z, 2H), 0.39-0.67 (m, 4H). LC-MS: m / z
608.2 (M + H) +

(R) -N- (3- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) phenyl)- 2
-Fluoro-N-methylacrylamide (Compound 453; General Procedure 3, Step N, Method 2): 1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.
43-7.54 (m, 1H), 7.34 (d, J = 7.8 Hz,
1H), 7.17-7.26 (m, 2H), 5.44 (d, J = 3
. 3 Hz, 1H), 5.18-5.38 (m, 1H), 4.82-
5.11 (m, 2H), 4.54 (d, J = 12.3 Hz, 1H),
4.10-4.40 (m, 3H), 3.75 (br. S., 2H),
3.57 (d, J = 7.8 Hz, 1H), 3.35-3.48 (
m, 6H), 3.28 (br.s., 1H), 3.14 (d, J =
10.5 Hz, 1H), 2.94-3.10 (m, 1H), 2.73
(Br.s., 1H), 2.60 (br.s., 1H), 2.19 (s
, 1H), 1.90-2.10 (m, 1H), 1.78 (br. S.
, 1H), 1.23-1.51 (m, 8H), 1.06-1.23
(M, 2H), 0.78-1.06 (m, 3H). LC-MS: m /
z 506.2 (M + H) +

(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) phenyl) acrylamide ( Compound 454; General Procedure 3, Step N, Method 1): 1H NM
R (chloroform-d) δ 7.73-7.80 (m, 2H), 7.63
(S, 1H), 7.51-7.59 (m, 1H), 7.42 (t, J
= 7.8 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H)
, 6.40-6.54 (m, 1H), 6.31 (dd, J = 16.
8, 10.3 Hz, 1H), 5.81 (d, J = 10.3 Hz, 1
H), 4.51 (d, J = 12.3 Hz, 1H), 4.39 (d,
J = 12.3 Hz, 1H), 3.92-4.27 (m, 1H), 3.5
1-3.94 (m, 1H), 3.25 (m, 1H), 2.85-3. 42
(M, 3H), 2.08-2.15 (m, 1H), 1.29-1.3
6 (m, 1H), 1.13-1.20 (m, 2H), 0.94-1
. 11 (m, 4H), 0.86-0.93 (m, 1H), 0.75-
0.85 (m, 2H), 0.68 (d, J = 12.5 Hz, 1H)
, 0.40-0.54 (m, 3H). LC-MS: m / z 482.2
(M + H) +

Compound 455 (General Procedure 3, Step N, Method 2): 1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.47 (d, J = 7.5 H
z, 1H), 7.31-7.36 (m, 1H), 5.87 (s, 1H)
), 4.83-5.04 (m, 1H), 4.19-4.42 (m,
3H), 3.76 (br.s., 2H), 3.56 (br.s., 1H)
), 3.36-3.49 (m, 6H), 3.30 (br. S., 1H)
), 2.91-3.20 (m, 4H), 2.74 (br.s., 1H)
), 2.68 (br. S., 1H), 2.61 (br. S., 1H),
1.93-2.02 (m, 1H), 1.15-1.45 (m, 16
H), 0.99 (dd, J = 7.8, 2.8 Hz, 2H), 0.76
-0.94 (m, 2H). LC-MS: m / z 512.2 (M + H)
+

Compound 456 (General Procedure 3, Step N, Method 2): 1H NMR (chloroform-d) δ □ 7.61 (s, 1H), 7.52 (t, J = 7.7 H
z, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.29 −
7.37 (m, 2H), 4.10-4.39 (m, 3H), 3.70
-3.90 (m, 2H), 3.66 (s, 1H), 3.49 (s,
1H), 3.38 (s, 5H), 3.30 (d, J = 14.8 Hz,
1H), 3.14 (br.s., 2H), 2.71-2.91 (m,
2H), 2.48-2.71 (m, 2H), 2.05 (dt, J =
7.8, 4.0 Hz, 2H), 1.13-1.42 (m, 8H),
0.91-1.08 (m, 2H). LC-MS: m / z 486.2 (
M + H) +

(R) -6-cyclopropyl-5- (1-hydroxyisoquinolin-5-yl) -2-
(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (Compound 457; General Procedure 1, Step I): 1H NMR (chloroform-d
) 10.93 (s, 1H), 8.51 (dd, J = 6.8), 2.
3 Hz, 1H), 7.51-7.67 (m, 3H), 6.32 (s,
1H), 4.92 (br.s., 0.5H), 4.55 (d, J =
12.8 Hz, 0.5H), 4.18-4.41 (m, 2.5H), 3.5
3-3.92 (m, 3.5H), 3.40 (s, 1H), 3.16-
3.38 (m, 2.5H), 2.51-2.83 (m, 2H),
61 (br. S., 1H), 1.39-1.49 (m, 1.5H),
1.31-1.39 (m, 1.5H), 1.14 (dd, J = 8.3)
, 4.8 Hz, 2H), 0.79-0.93 (m, 2H). LC-
MS: m / z 472.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (3-methylisoquinolin-5-yl) nicotinonitrile (Compound 458; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 9.25 ( s, 1H), 8.00 (dd, J = 7.2, 1
. 6 Hz, 1H), 7.54-7.67 (m, 3H), 7.16-
7.27 (m, 1H), 4.57 (d, J = 12.5 Hz, 1H),
4.46 (d, J = 12.5 Hz, 1H), 3.62-4.63 (m,
2H), 3.10-3.40 (m, 2.5H), 2.67 (d, J
= 4.5 Hz, 3H), 2.25-2.49 (m, 0.5H), 1.7
4 (br. S., 1H), 1.54 (dtd, J = 12.7, 3.9)
, 1.9 Hz, 2H), 1.13-1.23 (m, 2H), 0.95
-1.13 (m, 2H), 0.77-0.91 (m, 4H), 0.
70 (br. S., 1H), 0.39-0.60 (m, 3H). L
C-MS: m / z 478.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3- (2-oxo-2,5-dihydro-1H- Pyrrol-1-yl) phenyl) nicotinonitrile (compound 459)

(R) -5- (3-Aminophenyl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (300 mg)
, Pentane-2,4-dione (100 mg) and TFA (1 drop) in cyclohexane were refluxed for 3 hours. After evaporation, the residue was dissolved in CH ₃ CN and some Na ₂
It was added SO4, followed by the addition of _{select-F-TEDA-BF 4} (800mg). The mixture was refluxed overnight. After evaporation, the residue was purified by preparative TLC to give the title compound (75
mg). 1H NMR (chloroform-d) δ 7.86 (s, 1H)
, 7.58-7.75 (m, 2H), 7.47 (t, J = 8.0)
Hz, 1H), 7.10-7.26 (m, 2H), 6.33 (dt,
J = 6.0, 1.8 Hz, 1H), 4.91 (br.s., 0.5H)
), 4.42-4.63 (m, 2.5H), 4.13-4.40 (m
, 2.5H), 3.65-3.95 (m, 2.5H), 3.39 (s,
3H), 3.21-3.32 (m, 1H), 2.99-3.20 (
m, 2H), 2.52-2.81 (m, 2H), 2.00-2.29
(M, 1H), 1.35-1.53 (m, 1.5H), 1.23-
1.35 (m, 1.5H), 1.07-1.23 (m, 2H), 0.9
2-1.07 (m, 2H). LC-MS: m / z 486.2 (M + H)
+

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-methyl-1-oxoisoindoline-4-yl) nicoti Nononitrile (Compound 460; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 7.93-7.88 (m, 1H), 7.61-7.5
5 (m, 2H), 7.45 (dd, J = 7.5, 0.9 Hz, 1H
), 4.97 (ddd, J = 13.1, 10.1, 1.5 Hz, 1H
), 4.42-4.15 (m, 5H), 3.90-3.49 (m,
3H), 3.39 (d, J = 5.2 Hz, 3H), 3.32 (dd,
J = 13.1, 3.6 Hz, 1H), 3.26-3.09 (m,
4H), 2.85-2.53 (m, 2H), 2.12-1.88 (m
, 1H), 1.17 (dd, J = 7.5, 3.1 Hz, 3H), 0
. 96 (dd, J = 7.9, 3.2 Hz, 2H), 0.90 (t,
J = 6.8 Hz, 3H). LC-MS: m / z 474.6 (M + H) +

(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (2-methyl-1-oxoisoindoline-4-yl) nicotinonitrile (Compound 461; General Procedure 1, Step I): 1H NMR (400
MHz, CDCl3) δ = 7.93 (d, J = 7.5 Hz, 1H
), 7.64-7.57 (m, 2H), 7.53-7.47 (m,
1H), 7.44 (s, 1H), 4.93-4.21 (m, 6H),
4.21-2.84 (m, 6H), 1.82-1.65 (m, 2H)
, 1.55-1.29 (m, 4H), 1.17 (dd, J = 7.0
, 3.8 Hz, 2H), 1.10-0.97 (m, 2H), 0.95
(Dd, J = 7.8, 3.2 Hz, 2H), 0.84-0.75
(M, 2H). LC-MS: m / z 458.6.3 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-oxoisoindoline-4-yl) nicotinonitrile (Compound 464; General Procedure 1, Step I): 1H NMR (400 M
Hz, CDCl3) δ 7.95 (dd, J = 7.6, 0.8 Hz,
1H), 7.64-7.59 (m, 2H), 7.51 (dd, J =
5.4, 2.1 Hz, 1H), 6.76 (s, 1H), 5.07-4
. 24 (m, 6H), 3.22 (d, J = 59.5 Hz, 2H),
2.05 (dt, J = 15.3, 7.7 Hz, 1H), 1.31 (s
, 2H), 1.19 (dd, J = 4.4, 3.2 Hz, 2H), 0
. 96 (dd, J = 7.9, 3.2 Hz, 2H), 0.90 (t,
J = 6.8 Hz, 3H), 0.82 (dd, J = 7.9, 2.4)
Hz, 2H), 0.49 (ddd, J = 18.9, 9.9, 4.8 H
z, 3H). LC-MS: m / z 468.6 (M + H) +

(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (2-methyl-1-oxoisoindoline-4-yl) nicotinonitrile (Compound 465; General Procedure 1, Step I): 1H NMR (400
MHz, CDCl3) δ = 7.90 (d, J = 7.6 Hz, 1H
), 7.61-7.54 (m, 2H), 7.45 (d, J = 7.5
Hz, 1H), 5.04-3.99 (m, 6H), 3.78-3.
06 (m, 6H), 2.13-1.83 (m, 1H), 1.31 (d
, J = 5.5 Hz, 4H), 1.20-1.14 (m, 2H),
1.09−0.99 (m, 2H), 0.95 (dd, J = 7.9,
3.2 Hz, 2H), 0.83 (dd, J = 7.9, 1.3 Hz,
2H).
LC-MS: m / z 466.6 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2,3-dioxoindoline-7-yl) nicotinonitrile (Compound 513; General Procedure 1, Step I). (R) -2- (4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) nicotinonitrile (103.9 mg, 0.25 mol), 7-bromoisatin (67.
8 mg, 0.30 mmol), Pd (PPh ₃ ) ₄ (29 mg, 0.03 mmol), and K ₂ CO ₃ (86.3 mg, 0.63 mmol) suspended in 5 mL of 1,4-dioxane Was subjected to microwave reaction for 1 hour at 120 ° C. After the reaction, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title compound. Yield: 14.1 mg (11.7%). 1H NMR (400 MHz, CDC
l3) δ 7.75-7.65 (m, 2H), 7.64 (s, 1H),
7.53 (dd, J = 7.8, 1.2 Hz, 1H), 7.25 (d
, J = 7.7 Hz, 1H), 4.62 (d, J = 13.4 Hz,
1H), 4.49 (d, J = 12.2 Hz, 1H), 4.24 (m
, 1H), 3.77 (m, 1H), 3.26 (m, 2H), 1.88
-1.77 (m, 1H), 1.73 (s, 2H), 1.30-1.1
6 (m, 3H), 1.16-0.96 (m, 4H), 0.83 (dd
, J = 7.9, 2.5 Hz, 2H), 0.52 (dd, J = 17
. 5, 12.8 Hz, 3H). LC-MS: m / z 482.3 (M + H
) +

(R) -5- (Benzo [d] oxazol-6-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 466) General procedure 1, step I): 1H NMR (chloroform-d) δ: 8.18 (s, 1H), 7.88 (d, J = 8.3 H
z, 1H), 7.68 (s, 1H), 7.65 (d, J = 1.0 H)
z, 1H), 7.43 (dd, J = 8.2, 1.6 Hz, 1H),
4.55 (d, J = 12.5 Hz, 1H), 4.43 (d, J =
12.5 Hz, 1H), 4.18-4.34 (m, 1H), 3.91.
-4.18 (m, 1H), 3.73 (br.s., 1H), 3.28
(Br.s., 1H), 3.12 (br.s., 1H), 2.00 −
2.12 (m, 1H), 1.73 (br. S., 1H), 1.44 (b
r. s. , 1H), 1.18-1.24 (m, 2H), 0.94-
1.12 (m, 4H), 0.77-0.87 (m, 2H), 0.68
(Br.s., 1H), 0.40-0.61 (m, 3H). LC-M
S: m / z 454.5 (M + H) +

(R) -5- (Benzo [d] oxazol-6-yl) -2- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 467; General Procedure 1, Step I): 1H NMR (chloroform-d)
δ: 8.15-8.21 (m, 1H), 7.84-7.90 (m,
1H), 7.67 (s, 1H), 7.61-7.66 (m, 1H),
7.39-7.47 (m, 1H), 4.59 (br.s., 1H),
4.21-4.46 (m, 3H), 3.43-3.61 (m, 1H
), 3.39 (br.s., 1H), 3.18 (br.s., 1H),
2.00-2.10 (m, 1H), 1.78 (br.s., 1H),
1.25-1.32 (m, 3H), 1.16-1.24 (m, 2H
), 1.00-1.11 (m, 2H), 0.93-1.00 (m,
2H), 0.83 (dd, J = 7.8, 1.8 Hz, 2H). LC
-MS: m / z 428.5 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (3-methylisoquinolin-5-yl) Nicotinonitrile (Compound 471; General Procedure 2, Step M): 1H NMR (
Chloroform-d) δ 9.26 (s, 1H), 7.96-8.06 (m
, 1H), 7.55-7.69 (m, 3H), 7.21 (d, J =
15.1 Hz, 1H), 4.57 (dt, J = 13.1, 2.3 H
z, 1H), 4.46 (d, J = 12.3 Hz, 1H), 4.15.
(Br.s., 0.5H), 3.69-3.95 (m, 1.5H), 3
. 21-3.45 (m, 3H), 3.04-3.21 (m, 2H),
2.67 (d, J = 4.5 Hz, 3H), 1.40-1.61 (
m, 2H), 1.24-1.31 (m, 1H), 1.07-1.21.
(M, 2H), 0.77-0.91 (m, 2H), 0.70 (br.
s. , 1H), 0.43-0.56 (m, 2H). LC-MS: m /
z 520.2 (M + H) +

(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) phenyl) ethenesulfone Amides (Compound 472; General Procedure 3, Step N, Method 2): (R
) -5- (3-aminophenyl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (30 mg,
To a solution of 0.07 mmol) in DCM was added propiolic acid (5 mg, 0.07 mmol) and DCC (18 mg, 0.084 mmol). The mixture was stirred at 25 ° C. for 16 hours. TLC and LC-MS showed product and the mixture was purified by preparative TLC to give 15 mg of compound. 1H NMR (chloroform-d) δ 8.19 (s
, 1H), 7.66-7.77 (m, 1H), 7.62 (s, 1H)
7.47-7.56 (m, 1H), 7.36-7.47 (m, 1
H), 7.19 (d, J = 7.8 Hz, 1H), 4.51 (d, J
= 12.0 Hz, 1.5H), 4.29-4.45 (m, 1.5H)
, 4.08-4.29 (m, 1H), 3.42-3.87 (m, 1H
), 3.13-3.42 (m, 1H), 2.99-3.13 (m, 1
H), 2.98 (s, 1H), 2.05-2.14 (m, 1H), 1
. 68-1.77 (m, 1H), 1.11-1.21 (m, 3H),
1.04-1.11 (m, 1H), 0.93-1.04 (m, 3H
), 0.76-0.86 (m, 2H), 0.66 (s, 1H), 0.
38-0.60 (m, 3H). LC-MS: m / z 480.2 (M +
H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-hydroxyquinolin-5-yl) nicotinonitrile (compound 476; general procedure, step I): 1H NMR (chloroform-
d) δ 7.89 (d, J = 9.5 Hz, 1H), 7.67 (s,
1H), 7.52-7.64 (m, 3H), 6.81 (d, J = 9
. 5 Hz, 1H), 4.53 (d, J = 12.5 Hz, 2H), 4
. 41 (d, J = 12.3 Hz, 2H), 3.28 (br. S.,
2H), 3.11 (br.s., 1H), 1.96-2.07 (m,
2H), 1.14-1.32 (m, 2H), 0.93-1.11 (m
, 4H), 0.76-0.92 (m, 2H), 0.67 (br. S.
, 1H), 0.31-0.60 (m, 3H). LC-MS: m / z 4
90.2 (M + H)

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylquinolin-5-yl) nicotinonitrile (Compound 475)

Step 1: (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (2-hydroxyquinolin-5-yl) nicotinonitrile ( 50 mg, 0.104 mmol), Et3N (12 mg, 0.1
2 mmol) in DCM (2 mL) was added to Tf2O (30.3 mg, 0.107 mmol).
l) was added dropwise at 0 ° C. and stirred at room temperature for 3 hours. Water was added and the organic layers were combined, dried and concentrated to give 50 mg of product after preparative TLC.

Step 2: (R) -5- (5-cyano-6- (4- (cyclopropanecarbonyl)-
3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl)
Quinolin-2-yl trifluoromethanesulfonate (50 mg, 0.082 mmol)
, Tributyl (vinyl) stannane (27 mg, 0.086 mmol), LiCl (5.
2 mg, 0.123 mmol) in a solution of THF (2 mL), Pd (PPh ₃ ) ₄ (4.
7 mg, 0.0041 mmol) was added under N 2 and the reaction mixture was heated to 85 ° C. for 2 h. The mixture was cooled and the solvent was removed. The product (9 mg) was obtained by preparative TLC. 1H
NMR (chloroform-d) δ 8.16 (t, J = 9.3 Hz, 2
H), 7.72-7.86 (m, 3H), 7.68 (d, J = 8.
5 Hz, 1H), 7.04-7.14 (m, 2H), 6.34 (d,
J = 17.6 Hz, 1H), 5.73 (d, J = 11.0 Hz,
1H), 4.53 (d, J = 12.5 Hz, 2H), 4.41 (d
, J = 12.3 Hz, 2H), 3.28 (br.s., 2H), 3
. 11 (br. S., 1H), 1.67 (br. S., 2H), 0.9
5-1.16 (m, 6H), 0.77-0.95 (m, 6H). L
C-MS: m / z 490.2 (M + H).

2- (4- (Cyclopropanecarbonyl) -6-fluoro-1,4-diazepan-1-
Yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (compound 477; general procedure 4, steps R and S): 1H NMR (chloroform-d)
δ 9.36 (s, 1H), 8.48-8.65 (m, 1H), 8.
08 (d, J = 8.0 Hz, 1H), 7.69-7.77 (m,
1H), 7.62-7.69 (m, 2H), 7.42 (d, J = 6
. 0 Hz, 1H), 4.99 (br. S., 0.5H), 4.84 (b
r. s. , 0.5H), 4.72 (br. S., 1.5H), 4.60
(Br. S., 1H), 4.49 (d, J = 13.8 Hz, 1H),
4.17-4.39 (m, 2H), 3.76 (br. S., 0.5H),
3.32-3.57 (m, 2H), 3.22 (br.s., 1H),
1.70 (br.s., 1H), 1.54 (br.s., 1H),
14-1.20 (m, 2H), 1.04-1.12 (m, 2H),
0.83-0.90 (m, 4H). LC-MS: m / z 456.1 (
M + H)

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1H-pyrazol-4-yl) nicotinonitrile (Compound 479; General Procedure 1, Step H): 1H NMR (chloroform-d)
δ 7.70-7.81 (m, 2H), 7.65 (S, 1H), 4
. 49 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 1)
2.3 Hz, 1H), 4.13 (d, J = 14.8 Hz, 1H),
3.79 (s, 1H), 3.25 (s, 1.5H), 3.08 (s, 1
. 5H), 2.19-2.28 (m, 1H), 1.64-1.80 (
m, 1H), 1.15-1.22 (m, 2H), 0.95-1.11.
(M, 4H), 0.86-0.93 (m, 1H), 0.81 (dd,
J = 7.8, 2.3 Hz, 2H), 0.66 (s, 1H), 0.3
8-0.59 (m, 3H). LC-MS: m / z 442.2 (M + H)
+

6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2R) -2
-(Methoxymethyl) cyclopropanecarbonyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (compound 480): 1H NMR (chloroform-d) δ 9.35 (s, 1H), 8.54 (dd, J = 6.0,
1.5 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7
. 65-7.74 (m, 3H), 7.43 (dd, J = 6.0 Hz
, 1H), 4.58 (br. S., 0.5H), 4.46 (d, J =
11.8 Hz, 1H), 4.26 (br. S., 0.5H), 4.09
(Br.s., 0.5H), 3.83 (br.s., 0.5H), 3.6
8 (br. S., 0.5H), 3.52 (dd, J = 10.3, 5.
3 Hz, 1H), 3.29-3.41 (m, 4H), 3.23 (br
. s. , 2H), 1.67-1.75 (m, 2H), 1.39-1
. 59 (m, 2H), 1.26-1.36 (m, 3H), 1.16-
1.19 (m, 2H), 0.82-0.85 (m, 3H), 0.55
(Br.s., 2H), 0.48 (br.s., 2H). LC-MS:
m / z 508.1 (M + H) +

Compound 481: 1 H NMR (chloroform-d) δ 9.38 (br.s.
, 1H), 8.55 (d, J = 5.3 Hz, 1H), 8.08 (d
, J = 8.0 Hz, 1H), 7.66-7.75 (m, 3H),
7.44-7.47 (m, 1H), 4.45-4.59 (m, 2.5
H), 4.09-4.19 (m, 1H), 3.86 (s, 0.5H),
3.57-3.68 (m, 3.5H), 3.05-3.45 (m,
2.5H), 1.93 (br.s., 1H), 1.51-1.54 (m
, 1H), 1.18-1.25 (m, 6H), 0.83-0.91
(M, 4H), 0.49-0.68 (m, 4H). LC-MS: m / z
508.3 (M + H) +

(R) -5- (Benzo [d] oxazol-7-yl) -2- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 482; General procedure 1, step H): 1H NMR (chloroform-d)
δ 8.16 (s, 1H), 7.85 (dd, J = 7.8, 1.0
Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.42
(Dd, J = 7.5, 1.0 Hz, 1H), 4.58 (br. S.,
1H), 4.32 (d, J = 13.1 Hz, 2H), 3.49 −
3.62 (m, 1H), 3.46 (br. S., 1H), 3.21 (b
r. s. , 2H), 1.85-1.93 (m, 1H), 1.78 (b
r. s. , 1H), 1.31-1.45 (m, 3H), 1.18-1.
25 (m, 2H), 1.00-1.11 (m, 2H), 0.89-
0.99 (m, 2H), 0.84 (d, J = 6.8 Hz, 2H).
LC-MS: m / z 428.5 (M + H) +

(R) -5- (Benzo [d] oxazol-7-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 483 General procedure 1, step H): 1H NMR (chloroform-d) δ 8.16 (s, 1H), 7.82-7.87 (m, 1H)
, 7.79 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H)
, 7.42 (dd, J = 7.5, 1.0 Hz, 1H), 4.59 (
d, J = 12.8 Hz, 1H), 4.47 (d, J = 12.0 H
z, 1H), 3.95-4.20 (m, 2H), 3.79 (br. s)
. , 1H), 3.30 (br.s., 1H), 3.15 (br.s.,
1H), 1.85-1.97 (m, 1H), 1.61 (br. S.,
2H), 1.19-1.25 (m, 2H), 1.06 (d, J =
16.8 Hz, 2H), 0.91-0.98 (m, 2H), 0.82
(D, J = 6.5 Hz, 2H), 0.68 (br.s., 1H),
0.40-0.61 (m, 3H). LC-MS: m / z 454.5 (M
+ H) +

2- (4- (Cyclopropanecarbonyl) -6-fluoro-3-methyl-1,4-diazepan-1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (Compound 484) General Procedure 4, Steps R and S): 1H NMR (chloroform-d) δ 9.40 (br.s., 1H), 8.56 (br.s);
. , 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.69 −
7.81 (m, 2H), 7.68 (d, J = 1.0 Hz, 1H),
7.47-7.54 (m, 1H), 4.54-4.98 (m, 6H),
3.25-3.44 (m, 1H), 3.17 (br.s., 1H),
1.77-1.89 (m, 1H), 1.49-1.54 (m, 1H)
), 1.25-1.30 (m, 3H), 1.19-1.23 (m,
2H), 1.10 (br. S., 2H), 0.84-0.91 (m,
4H). LC-MS: m / z 470.2 (M + H)

(R) -5- (1- (Cyanomethyl) -1H-pyrazol-4-yl) -2- (4- (
Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (compound 486): (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-1 -Yl) -6-cyclopropyl-5- (1
H-pyrazol-4-yl) nicotinonitrile (60 mg, 0.149 mmol) in DM
To F in _{solution, K 2 CO 3 (42mg,} 0.298mmol) and 2-bromo-acetonitrile (27 mg, 0.224 mmol) was added. The resulting mixture was stirred for 16 hours. The mixture was then partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by preparative TLC to 2
5 mg of product was obtained. 1H NMR (chloroform-d) δ 7.72 (s,
1H), 7.69 (s, 1H), 7.61 (s, 1H), 5.17 (s
, 2H), 4.32-4.52 (m, 2.5H), 3.65-3.8
9 (m, 1H), 4.01-4.22 (m, 1H), 3.55-4.92 (m
, 1H), 2.89-3.33 (m, 2.5H), 2.10-2.23
(M, 1H), 1.72 (s, 1H), 1.31-1.47 (m, 1
H), 1.14-1.22 (m, 2H), 0.92-1.09 (m,
4H), 0.75-0.86 (m, 2H), 0.39-0.63 (
m, 4H). LC-MS: m / z 442.2 (M + H) +

2-((R) -4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1- (3-hydroxycyclopentyl) -1H
-Pyrazol-4-yl) nicotinonitrile (Compound 493)

Step 1: (R) -2- (4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (1H-pyrazol-4-yl) nicotinonitrile (100 mg , 0.248 mmol) in CH ₂ Cl ₂ was added to cyclopent-2-enone (51 mg, 0.621 mmol) and ScCl ₃ (338 mg, 2
. 24 mmol) was added. The mixture was stirred at room temperature for 16 hours. Mix the mixture with EtO
Partitioned between Ac and water. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by preparative TLC to give 50 mg of product.
LC-MS: m / z 485.3 (M + H) +

Step 2: (R) -2- (4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (1H-pyrazol-4-yl) nicotinonitrile (40 mg , 0.0825 mmol) in MeOH was added NaBH ₄ and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give the crude, which was purified by preparative TLC to give 15 mg of product. 1H NMR (chloroform-d) δ 7.56-7.70 (m, 3H), 4.85 (br.
s. , 1H), 4.25-4.70 (m, 4H), 4.00-4.25.
(M, 1H), 3.50-3.90 (m, 1H), 2.95-3.41
(M, 3H), 2.12-2.41 (m, 6H), 1.90-2.03
(M, 1H), 1.37-1.54 (m, 1H), 1.23-1.
37 (m, 1H), 1.17-1.28 (m, 2H), 0.94-1.
09 (m, 4H), 0.76-0.85 (m, 2H), 0.39-
0.64 (m, 4H). LC-MS: m / z 487.3 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1- (methylsulfonyl) -1H-pyrazol-4-yl) nicotinonitrile (Compound 502): (R) -2- (4- (cyclopropanecarbonyl) -3-Cyclopropylpiperazin-1-yl) -6-cyclopropyl-5-
To a solution of (1H-pyrazol-4-yl) nicotinonitrile (30 mg, 0.074 mmol) in DCM was added TEA (15 mg, 0.149 mmol) and methanesulfonyl chloride (9.4 mg, 0.082 mmol); The mixture was stirred at room temperature for 2 hours.
The mixture was partitioned between EtOAc and water. The organic layer is washed with H ₂ O, brine, N
Dry over a ₂ SO ₄ and concentrate to give the crude, which is purified by preparative TLC to 15 m
g of product was obtained. 1H NMR (chloroform-d) δ 8.16 (s, 1H
), 7.97 (s, 1H), 7.65 (s, 1H), 4.40-4.60.
(M, 2.5H), 4.09-4.25 (m, 1H), 3.53-3.
90 (m, 1H), 3.45 (s, 3H), 3.05-3.41 (m,
2.5H), 2.06-2.19 (m, 1H), 1.12-1.26
(M, 3H), 0.95-1.12 (m, 4H), 0.89 (t, J
= 6.8 Hz, 1H), 0.75-0.85 (m, 2H), 0.3
6-0.64 (m, 4H). LC-MS: m / z 481.2 (M + H)
+

(R) -2- (4- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) -1H
-Pyrazol-1-yl) acetamide (compound 501): (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (1H-pyrazole) -4-yl) nicotinonitrile (30 mg, 0.0745 m)
mol) in DMF was added K ₂ CO ₃ (21 mg, 0.149 mmol) and 2-bromoacetamide (12 mg, 0.082 mmol). The mixture was stirred at room temperature for 16 hours and then the mixture was partitioned between EtOAc and water. The organic layer is EtOAc
And the organic layer was washed with water, brine, dried over Na ₂ SO ₄ ,
Concentration gave 25 mg of product. 1H NMR (chloroform-d) δ 7.75
(S, 1H), 7.57-7.69 (m, 2H), 6.43 (br.
s. , 1H), 6.04 (br. S., 1H), 4.88 (s, 2H)
, 4.30-4.60 (m, 2.5H), 3.84-4.23 (m, 1H)
, 3.50-3.80 (m, 1H), 3.00-3.45 (m, 2.5H)
2.13-2.25 (m, 1H), 1.92 (s, 1H), 1.7
1 (s, 1H), 1.12-1.21 (m, 2H), 0.94-1
. 10 (m, 4H), 0.72-0.84 (m, 2H), 0.35-
0.63 (m, 4H). LC-MS: m / z 460.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-((methylthio) methyl) -1H-pyrazol-4-yl) nicotinonitrile (compound 510): (R) -2- (4- (cyclopropane) Carbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-
5- (1H-pyrazol-4-yl) nicotinonitrile (50 mg, 0.124 mmol)
) In DMF to NaH (10 mg, 0.248 mmol) and (chloromethyl)
(Methyl) sulfane (24 mg, 0.248 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and water and the organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give a crude product that was purified by preparative TLC to yield 15 mg of product. Got. 1H NMR (chloroform-d) δ 7.73
(S, 1H), 7.59-7.68 (m, 2H), 5.20 (s,
2H), 4.28-4.48 (m, 2.5H), 4.26-4.30 (m
, 1H), 3.50-3.80 (m, 1H), 2.99-3.40 (m,
2.5H), 2.22-2.28 (m, 1H), 2.21 (s, 3H)
, 1.73 (s, 1H), 1.30-1.48 (m, 1H), 1.1
4-1.23 (m, 2H), 0.94-1.10 (m, 4H), 0
. 75-0.85 (m, 2H), 0.39-0.64 (m, 4H).
LC-MS: m / z 463.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) nicotinonitrile (Compound 490): 1H NMR (chloroform-
d) δ 7.66 (s, 1H), 7.58-7.64 (m, 2H),
4.47 (d, J = 12.3 Hz, 1H), 4.25-4.41 (
m, 3H), 3.97-4.18 (m, 3H), 3.77 (s, 1H)
), 3.23 (s, 2H), 3.07 (s, 1H), 2.16-2.
30 (m, 1H), 1.23-1.35 (m, 2H), 1.12-
1.21 (m, 2H), 0.95-1.09 (m, 4H), 0.74
-0.87 (m, 2H), 0.38-0.64 (m, 4H). LC-
MS: m / z 446.2M + H) +

(R) -5- (Benzo [d] thiazol-6-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 487) General procedure 1, step I): 1H NMR (chloroform-d) δ 9.07 (s, 1H), 8.22 (d, J = 8.3 Hz,
1H), 8.00 (d, J = 1.5 Hz, 1H), 7.68-7
. 73 (m, 1H), 7.58 (dd, J = 8.4, 1.6 Hz,
1H), 4.55 (d, J = 12.3 Hz, 1H), 4.43 (d,
J = 12.3 Hz, 1H), 3.50 (d, J = 9.0 Hz,
2H), 3.29 (br.s., 2H), 3.13 (br.s., 1H)
), 2.04-2.12 (m, 1H), 1.29-1.40 (m,
2H), 1.18-1.25 (m, 2H), 0.94-1.12 (m
, 4H), 0.77-0.86 (m, 2H), 0.68 (br. S.
, 1H), 0.40-0.61 (m, 3H); LC-MS: m / z 4
70.2 (M + H).

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (furan-3-carbonyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (Compound 488; general Procedure 4, Steps R and S): 1H NMR (chloroform-d
) Δ 9.36 (s, 1H), 8.55 (dd, J = 5.8, 2.0)
Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.64
-7.79 (m, 4H), 7.41-7.50 (m, 2H), 6.
59 (s, 1H), 4.61 (dd, J = 13.1, 2.0 Hz,
1H), 4.43 (br.s., 2H), 3.98 (br.s., 1H)
), 3.73 (br. S., 1H), 3.22-3.36 (m, 1H)
), 3.07-3.22 (m, 1H), 1.50-1.57 (m,
2H), 1.12-1.21 (m, 2H), 0.81-0.89 (m
, 2H), 0.65-0.78 (m, 1H), 0.53-0.62
(M, 1H), 0.47 (br. S., 2H). LC-MS: m / z
490.6 (M + H) +

(R) -Methyl 4- (3-cyano-6-cyclopropyl-5- (isoquinolin-5-yl) pyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (Compound 489; General Procedure) 4, Steps R and S): 1H NMR (chloroform-d
) Δ 9.37 (br.s., 1H), 8.55 (br.s., 1H)
, 8.08 (d, J = 8.0 Hz, 1H), 7.70-7.77
(M, 1H), 7.60-7.70 (m, 2H), 7.46 (dd,
J = 12.0, 5.8 Hz, 1H), 4.50-4.60 (m, 1
H), 4.37-4.47 (m, 1H), 4.17 (d, J = 12
. 5 Hz, 1H), 3.76 (s, 3H), 3.45-3.59 (m
, 2H), 3.29 (ddd, J = 12.9, 6.4, 3.8 Hz,
1H), 3.13 (tdd, J = 12.5, 7.2, 3.5 Hz,
1H), 1.47-1.57 (m, 1H), 1.34-1.47 (m,
1H), 1.18 (dd, J = 7.3, 4.0 Hz, 2H), 0.
85-0.93 (m, 2H), 0.60-0.72 (m, 1H),
0.48-0.60 (m, 2H), 0.36-0.48 (m, 1H)
. LC-MS: m / z 454.5 (M + H) +

(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl- [3,3′-bipyridine] -5,5′-dicarbonitrile (Compound 494; General Procedure 1, Step H): 1H NMR (chloroform-d
) Δ 8.92 (br. S., 2H), 7.9-8.07 (m, 1
H), 7.63 (s, 1H), 4.63 (d, J = 12.8 Hz,
1H), 4.50 (d, J = 12.3 Hz, 1H), 3.33 (br
. s. , 1H), 3.17 (m, 2H), 1.80-1.90 (m,
2H), 1.73 (m., 1H), 1.19-1.31 (m, 4H)
, 0.94-1.12 (m, 4H), 0.76-0.88 (m, 2
H), 0.36-0.60 (m, 4H). LC-MS: m / z 439
. 5 (M + H) +

(R) -5- (Cinnolin-4-yl) -2- (4- (cyclopropanecarbonyl)-
3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (compound 495; general procedure 1, step H): 1H NMR (chloroform-d) δ:
9.28 (d, J = 2.0 Hz, 1H), 8.66 (d, J =
8.5 Hz, 1H), 7.88-7.97 (m, 1H), 7.72-
7.85 (m, 2H), 7.66-7.72 (m, 2H), 4.60
-4.74 (m, 1.5H), 4.43-4.60 (m, 1.5H)
3.60-3.89 (m, 1H), 3.35 (br.s., 1H)
, 3.22 (br. S., 1H), 1.49-1.58 (m, 1H)
, 1.16-1.36 (m, 4H), 0.99-1.16 (m, 2
H), 0.78-0.99 (m, 4H), 0.63-0.78 (m,
1H), 0.42-0.63 (m, 3H). LC-MS: m / z 4
65.6 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylpyrimidin-4-yl) nicotinonitrile (Compound 496). The procedure was similar to the synthesis of compound 390. 1H NMR (
Chloroform-d) δ 8.67-8.84 (m, 1H), 8.07 (s
, 1H), 7.43 (d, J = 5.0 Hz, 1H), 6.87 −
7.03 (m, 1H), 6.74 (dd, J = 17.4, 1.6 Hz)
, 1H), 5.76-5.88 (m, 1H), 4.68 (d, J =
13.1 Hz, 1H), 4.55 (d, J = 13.3 Hz, 1H)
, 4.07 (br. S., 1H), 3.88 (s, 1H), 3.66
(Br.s., 1H), 3.33 (br.s., 1H), 3.17 (b
r. s. , 1H), 2.34-2.47 (m, 1H), 1.96-
2.08 (m, 2H), 1.30-1.42 (m, 2H), 1.00
-1.11 (m, 3H), 0.85-0.93 (m, 1H), 0.8
2 (dd, J = 8.0, 2.5 Hz, 2H), 0.65 (br. S
. , 1H), 0.39-0.59 (m, 3H). LC-MS: m / z
441.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-methylisoquinolin-5-yl) nicotinonitrile (Compound 497; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 8.40 ( dd, J = 6.0, 2.0 Hz, 1H), 8.
24 (d, J = 8.3 Hz, 1H), 7.68-7.76 (m,
1H), 7.31 (d, J = 6.5 Hz, 2H), 4.58 (d,
J = 10.5 Hz, 1H), 4.46 (d, J = 12.5 Hz,
1H), 4.23 (br.s., 1H), 3.82 (br.s., 1H)
), 3.67 (br.s., 1H), 3.32 (br.s., 1H),
3.17 (br. S., 1H), 2.93-3.12 (m, 3H),
1.74 (br.s., 1H), 1.47-1.57 (m, 2H),
1.14-1.22 (m, 2H), 1.00-1.12 (m, 2H)
), 0.83 (dd, J = 6.7, 4.6 Hz, 4H), 0.70
(Br. S., 1H), 0.41-0.63 (m, 3H). LC-M
S: m / z 478.3 (M + H) +

(R) -6 ′-(4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2′-cyclopropyl-6-vinyl-2,3′-bipyridine-5′-carbonitrile ( Compound 499; General Procedure 1, Step H). The procedure was similar to the synthesis of compound 390. 1H NMR (chloroform-d) δ 7.95 (s, 1H),
7.75 (t, J = 7.8 Hz, 1H), 7.39-7.45 (
m, 1H), 7.32-7.37 (m, 1H), 6.82-6.96.
(M, 1H), 6.31 (dd, J = 17.6, 1.3 Hz, 1H
), 5.49-5.59 (m, 1H), 4.58 (d, J = 12.
8 Hz, 1H), 4.45 (d, J = 12.5 Hz, 1H), 4.
19 (br. S., 0.5H), 4.06 (br. S., 0.5H),
3.78 (br.s., 0.5H), 3.60 (br.s., 0.5H)
3.28 (br.s., 2H), 3.11 (br.s., 1H),
2.29-2.39 (m, 1H), 1.67-1.79 (m, 1H)
, 1.32-1.45 (m, 1H), 1.18-1.25 (m, 2
H), 0.96-1.12 (m, 4H), 0.74-0.87 (m,
2H), 0.65 (br. S., 1H), 0.35-0.58 (m,
3H). LC-MS: m / z 440.6 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (imidazo [1,2-a] pyrazin-3-yl)
Nicotinonitrile (Compound 503; General Procedure 1, Step I): 1H NMR (40
0 MHz, CDCl3) δ = 9.20 (s, 1H), 7.89 (dd
, J = 25.5, 17.4 Hz, 3H), 7.73 (s, 1H),
4.66 (d, J = 12.8 Hz, 1H), 4.53 (d, J =
12.8 Hz, 1H), 3.49 (s, 4H), 3.36-3.10
(M, 2H), 2.15-1.83 (m, 3H), 1.53 (m, 1
H), 1.08-0.95 (m, 4H), 0.84 (m, 3H), 0
. 61-0.40 (m, 3H). LC-MS: m / z 454.1 (M
+ H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2,3-dioxoindoline-5-yl) nicotinonitrile (Compound 504; General Procedure 1, Step I): 1H NMR (400
MHz, CDCl3) δ = 8.38 (s, 1H), 7.68 (d, J
= 1.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.0
4 (d, J = 8.4 Hz, 1H), 5.48-5.23 (m, 1
H), 4.98 (m, 1H), 3.38-3.05 (m, 2H), 2
. 14-1.88 (m, 4H), 1.01 (dd, J = 7.9, 3
. 4 Hz, 3H), 0.90 (dd, J = 9.0, 4.7 Hz, 5
H), 0.86-0.77 (m, 3H), 0.57-0.40 (m,
3H). LC-MS: m / z 482.2 (M + H) +

5- (4-acryloylmorpholin-2-yl) -2-((R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 600). 2-((R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (morpholin-2-yl) nicotinonitrile (13 mg, 0.03 mmol), Acryloyl chloride (1 drop) and TEA (1
Drop) in 10 mL DCM was stirred at room temperature for 10 min. After the mixture was quenched and worked up, the filtrate was concentrated and the residue was purified by column chromatography (50% PE /
Purification by EA) gave 11 mg of the title compound. 1H NMR (chloroform-d
) Δ 7.86 (s, 1H), 6.48-6.69 (m, 1H), 6
. 31-6.48 (m, 1H), 5.80 (d, J = 9.3 Hz,
1H), 4.91 (d, J = 13.1 Hz, 1H), 4.71 (d
, J = 8.8 Hz, 1H), 4.44-4.63 (m, 1.5H),
4.05-4.34 (m, 4H), 3.92 (d, J = 12.5 H
z, 0.5H), 3.74 (d, J = 9.8 Hz, 1.5H), 3.3
5-3.52 (m, 1.5H), 3.04-3.29 (m, 3H),
2.62 (t, J = 11.3 Hz, 0.5H), 2.10 (br.
s. , 1H), 1.75 (br.s., 1H), 1.40 (br.s.
, 1.5H), 1.27 (br. S., 1.5H), 1.13 (br.
s. , 2H), 1.03 (br. S., 4H), 0.81 (d, J =
7.0 Hz, 2H). LC-MS: m / z 450.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (6-vinylpyridazin-4-yl) nicotinonitrile (Compound 613)

Step 1: 8-4 (50 mg, 0.11 mmol), 5-chloropyridazin-3-ol (21 mg, 0.16 mmol), CsF (33 mg, 0.22 mmol) and P
A mixture of d (dppf) Cl ₂ (5 mg) in dioxane and water at 1
Heated for hours. The reaction mixture was concentrated and the residue was purified by preparative TLC to give 35 mg of the title compound. 1H NMR (chloroform-d) δ 12.68 (br. S.
, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.02
(Br. S., 1H), 4.51-4.64 (m, 2.5H), 4.21
(Br.s., 1H), 3.56-3.84 (m, 1H), 3.17-
3.32 (m, 2.5H), 1.99 (br. S., 1H), 1.71
(Br.s., 1H), 1.24 (br.s., 3H), 1.01-1.
08 (m, 4H), 0.72-0.92 (m, 2H), 0.32-0.
64 (m, 4H). LC-MS: m / z 431.1 (M + H) +

Step 2: (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (6-hydroxypyridazine-4-
Yl) A solution of nicotinonitrile, Tf ₂ O and TEA in DCM was stirred for 1 hour. The reaction mixture was washed with water, dried and concentrated. The residue was purified by preparative TLC to give 1
50 mg of the title compound were obtained. 1H NMR (CHLOROFORM-d, 400M
Hz) δ 9.42 (br. S., 1 H), 7.72 (s, 1 H),
7.52 (s, 1 H), 4.58-4.75 (m, 2.5 H), 4.
32 (br. S., 0.5 H), 4.00 (br. S., 0.5 H)
, 3.73 (br. S., 1 H), 3.25-3.39 (m, 2.5
H), 1.89-1.94 (m, 1 H), 1.72 (br. S.,
1 H), 1.31 (br.s., 3 H), 1.00-1.18 (m
, 4 H), 0.84 (d, J = 6.3 Hz, 2 H), 0.45 −
0.66 (m, 4 H).

Step 3: (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (6-vinylpyridazin-4-yl) nicotinonitrile ( 50 mg, 0.09 mmol), potassium vinyl trifluoroborate (24 mg, 0.18 mmol), TEA (27 mg, 0.27 mmol) and P
A mixture of d (dppf) Cl ₂ (5 mg) i-PrOH and water was heated at 100 ° C. for 1 h. The reaction mixture was concentrated and the residue was purified by preparative TLC to give 11 mg of the title compound. 1H NMR (chloroform-d) δ 9.20 (br.s.
, 1H), 7.68 (br. S., 1H), 7.61 (br. S.,
1H), 7.04-7.22 (m, 1H), 6.36 (d, J = 1)
7.6 Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H),
4.53-4.58 (m, 2.5H), 4.17 (br.s., 1H),
3.72 (br. S., 1H), 3.19-3.34 (m, 1H),
94 (br. S., 1H), 1.80 (br. S., 1H), 1.26
(Br.s., 3H), 1.07 (br.s., 4H), 0.82 (
br. s. , 2H), 0.46-0.65 (m, 4H). LC-MS:
m / z 441.2 (M + H) +

(R) -5- (5-Cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) pyridazin-3-yltrifluor Lomethanesulfonate (Compound 614): 1H NMR (chloroform-d
) Δ 9.41 (s, 1H), 7.71 (s, 1H), 7.50 (d,
J = 1.3 Hz, 1H), 4.93 (br.s., 0.5H), 4
. 56 (d, J = 7.8 Hz, 0.5H), 4.47 (d, J =
7.3 Hz, 1.5H), 4.25-4.40 (m, 1H), 3.86
(D, J = 12.5 Hz, 0.5H), 3.76 (br.s., 2
H), 3.57 (br. S., 0.5H), 3.36-3.48 (m,
4H), 3.30 (br.s., 0.5H), 3.11-3.24 (m
, 1H), 2.71 (br.s., 1H), 2.61 (br.s., 1
H), 1.89-1.93 (m, 1H), 1.37 (d, J = 5.
5 Hz, 1.5H), 1.22-1.32 (m, 3.5H), 1.08
-1.22 (m, 2H). LC-MS: m / z 555.1 (M + H)
+

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (6-vinylpyridazin-4-yl) nicotinonitrile (
Compound 615). The procedure is similar to compound 613. 1H NMR (chloroform-d
) Δ 9.20 (br. S., 1H), 7.67 (s, 1H), 7.5
8-7.65 (m, 1H), 7.13 (dd, J = 17.8, 11
. 0 Hz, 1H), 6.37 (d, J = 17.8 Hz, 1H), 5
. 79 (d, J = 11.0 Hz, 1H), 4.92 (br. S.,
0.5H), 4.48-4.62 (m, 0.5H), 4.35-4.4
8 (m, 1.5H), 4.31 (d, J = 14.1 Hz, 1H),
3.83 (d, J = 13.3 Hz, 0.5H), 3.67-3.80
(M, 2H), 3.51-3.63 (m, 0.5H), 3.30-
3.45 (m, 4H), 3.13-3.28 (m, 1.5H), 2.6
5-2.82 (m, 1H), 2.51-2.65 (m, 1H), 1
. 92-1.96 (m, 1H), 1.38 (d, J = 5.5 Hz,
1.5H), 1.24-1.27 (m, 3.5H), 1.07 (d, J
= 4.8 Hz, 2H). LC-MS: m / z 433.1 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (6-hydroxypyridazin-4-yl) nicotinonitrile (Compound 616). 1H NMR (chloroform-d) δ 12.68
(Br.s., 1H), 7.97 (s, 1H), 7.65 (s, 1H)
7.02 (br. S., 1H), 4.51-4.64 (m, 2.5H)
, 4.21 (br. S., 1H), 3.56-3.84 (m, 1H)
3.17-3.32 (m, 2.5H), 1.99 (br.s., 1H)
1.71 (br.s., 1H), 1.24 (br.s., 3H),
1.01-1.08 (m, 4H), 0.72-0.92 (m, 2H),
0.32-0.64 (m, 4H). LC-MS: m / z 431.1 (M +
H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-methyl-6-oxo-1,6-dihydropyridazin-4-yl) nicotinonitrile (Compound 640). 1H NMR (chloroform-d) δ 7.85 (br.s., 1H), 7.60 (br.s.,
1H), 6.95 (br.s., 1H), 4.50-4.63 (m, 2.5
H), 4.21 (br.s., 1H), 3.84 (br.s., 3H)
3.69 (br. S., 1H), 3.17-3.30 (m, 2.5H),
1.99 (br.s., 1H), 1.76 (br.s., 1H), 1
. 22 (br. S., 3H), 1.07 (br. S., 4H), 0.8
1 (br. S., 2H), 0.51 (br. S., 4H). LC-MS
: M / z 445.2 (M + H) +

(R) -5- (5-Cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) pyridazine-
3-carbonitrile (Compound 641). 1H NMR (chloroform-d) δ 9.
51 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.3
Hz, 1H), 7.70 (s, 1H), 4.59-4.72 (m, 2.5
H), 4.09-4.26 (m, 1H), 3.75 (br.s., 1H)
, 3.23-3.39 (m, 2.5H), 1.82-1.95 (m, 1H
), 1.65 (br. S., 1H), 1.26-1.34 (m, 3H)
, 0.96-1.20 (m, 4H), 0.76-0.91 (m, 2
H), 0.38-0.75 (m, 4H). LC-MS: m / z 440.
2 (M + H) +

(R) -2- (4-acetyl-3-methylpiperazin-1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (Compound 516; General Procedure 4,
Steps R and S): 1H NMR (chloroform-d) δ 9.35 (s,
1H), 8.54 (d, J = 5.8 Hz, 1H), 8.07 (d,
J = 8.0 Hz, 1H), 7.64-7.74 (m, 3H), 7.
43 (t, J = 5.9 Hz, 1H), 4.91 (br.s., 0.
5H), 4.57-4.53 (d, 0.5H), 4.18-4.39.
(M, 2.5H), 3.6-3.77 (m, 1H), 3.34 (br.
s. , 1H), 3.05-3.25 (m, 1.5H), 1.91 (b
r. s. , 3H), 1.33-1.54 (m, 4H), 1.14-
1.17 (m, 2H), 0.82-0.85 (m, 2H). LC-MS
: M / z 412.2 (M + H) +

6-cyclopropyl-2-((R) -4-((1S, 2R) -2-ethoxycyclopropanecarbonyl) -3-methylpiperazin-1-yl) -5- (isoquinolin-5-yl) nicotino Nitrile (Compound 517; General Procedure 4, Steps R and S): 1H NM
R (chloroform-d) δ 9.35 (s, 1H), 8.54 (d, J
= 5.8 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H),
7.59-7.76 (m, 3H), 7.44 (t, J = 6.8 H
z, 1H), 4.87-5.02 (m, 0.5H), 4.61-4.
64 (m, 0.5H), 4.12-4.43 (m, 2.5), 3.0
5-3.70 (m, 5.5H), 2.0 (s, 1H), 1.76-
1.86 (m, 1H), 1.40-1.62 (m, 3H), 1.27
-1.35 (m, 2H), 1.16-1.21 (m, 4H), 0.9
2-0.99 (m, 1H), 0.81-0.84 (m, 2H).
LC-MS: m / z 482.2 (M + H) +

6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2S) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (isoquinoline-
5-yl) nicotinonitrile (compound 518; general procedure 4, steps R and S): 1
H NMR (chloroform-d) δ 9.37 (s, 1H), 8.54 (d
d, J = 6.0, 2.0 Hz, 1H), 8.08 (d, J = 8.
0 Hz, 1H), 7.73 (t, 1H), 7.64-7.69 (m,
2H), 7.46 (q, 1H), 4.73 (m, 0.5H), 4.43
-4.62 (m, 2.5H), 4.13-4.26 (m, 2H),
3.68-3.87 (m, 1.5H), 3.50-3.60 (m, 3
. 5H), 3.19-3.30 (s, 2H), 1.97-2.19 (
m, 2H), 1.50-1.54 (m, 1H), 1.16-1.23.
(M, 6H), 0.82-0.91 (m, 5H), 0.64-0.
68 (m, 2H), 0.43-0.51 (m, 2H). LC-MS:
m / z 508.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (4-oxobutanoyl) piperazin-1-yl) -5- (isoquinolin-5-yl) nicotinonitrile (Compound 519; general Procedure 4, Steps R and S): 1H NMR (chloroform-d)
δ 9.91 (s, 1H), 9.38 (s, 1H), 8.55 (br.
s. , 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.74
(T, 1H), 7.66-7.70 (m, 2H), 7.47 (q,
1H), 4.55-4.58 (d, 1H), 4.44-4.47 (d
, 1H), 4.09 (br.s., 1H), 3.90 (br.s.,
1H), 3.07-3.40 (m, 2.5H), 2.69-2.91.
(M, 3.5H), 2.05 (m, 2H), 14.53 (m, 1H),
0.83-0.92 (m, 6H), 0.44-0.71 (br. S.
, 4H). LC-MS: m / z 480.2 (M + H) +

6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2R) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (isoquinoline-
5-yl) nicotinonitrile (compound 526; general procedure 4, steps R and S): 1
H NMR (chloroform-d) δ 9.35 (br.s., 1H), 8.
53 (br. S., 1H), 8.07 (d, J = 8.0 Hz, 1H
), 7.68-7.74 (t, 1H), 7.64-7.67 (m,
2H), 7.45 (dd, J = 5.8 Hz, 1H), 4.58 (d,
J = 12.8 Hz, 1H), 4.49 (d, J = 11.3 Hz,
1H), 4.13-4.27 (m, 1.5H), 3.80 (br. S)
. , 0.5H), 3.52-3.59 (m, 3H), 3.22 (br.
s. , 2H), 1.82 (d, J = 7.5 Hz, 1H), 1.47
-1.57 (m, 2H), 1.17-1.20 (m, 6H), 0.
82-0.99 (m, 5H), 0.45-0.65 (m, 4H).
LC-MS: m / z 508.3 (M + H) +

6-cyclopropyl-2-((R) -4-((1R, 2R) -2- (hydroxymethyl) cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -5- (isoquinolin-5-yl ) Nicotinonitrile (Compound 505; General Procedure 4, Steps R and S)
: 1H NMR (chloroform-d) δ 9.39 (br.s., 1H),
8.56 (br. S., 1H), 8.08 (d, J = 8.0 Hz,
1H), 7.71-7.76 (m, 1H), 7.66-7.70 (m
, 1H), 7.64 (s, 1H), 7.47 (br.s., 1H),
4.18-4.89 (m, 4H), 3.25-3.80 (m, 5H)
, 2.01-2.08 (m, 1H), 1.46-1.57 (m, 2
H), 1.24-1.39 (m, 4H), 1.10-1.20 (m,
2H), 0.79-0.91 (m, 3H). LC-MS: m / z 4
68.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (quinoxalin-5-yl) nicotinonitrile (
Compound 531; General Procedure 1, Step I): 1H NMR (chloroform-d) δ
8.88 (d, J = 1.8 Hz, 1H), 8.91 (d, J =
1.5 Hz, 1H), 8.21 (dd, J = 8.4, 1.4 Hz,
1H), 7.88 (t, J = 8.4, 7.2 Hz, 1H), 7.79.
(Dd, J = 7.2, 1.4 Hz, 1H), 7.73 (s, 1H)
, 4.53 (d, 1H), 4.56 (d, 1H), 4.53-4.2
7 (m, 2.5H), 3.05-3.45 (m, 2.5H), 1.74
(Br.s., 1H), 1.56-1.65 (m, 1H), 0.97
-1.26 (m, 6H), 0.42-0.87 (m, 8H). L
C-MS: m / z 465.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (quinoxalin-5-yl) nicotinonitrile (Compound 532; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 8.89-8.92 (m, 2H), 8.22 (dd, J
= 8.4, 1.4 Hz, 1H), 7.89 (t, J = 8.3, 7.
3 Hz, 1H), 7.79-7.81 (dd, J = 8.3, 7.3)
Hz, 1H), 7.75 (s, 1H), 4.53 (d, J = 13
. 1 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4
. 14 (br. S., 0.5H), 3.75-3.89 (m, 1.5H
), 3.07-3.37 (m, 5H), 1.62 (m, 1H), 1.
19 (br. S., 2H), 0.48-0.84 (m, 6H). L
C-MS: m / z 507.3 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinoxalin-5-yl) nicotinonitrile (Compound 579) General procedure 1, step I): 1H NMR (chloroform-d)
δ 9.00 (s, 1H), 8.13 (dd, J = 8.5, 1.3 H
z, 1H), 7.84 (dd, J = 8.3, 7.3 Hz, 1H),
7.67-7.74 (m, 1H), 7.01-7.12 (m, 1H)
6.50 (d, J = 11.3 Hz, 1H), 5.84 (d, J
= 11.3 Hz, 1H), 4.92 (br.s., 0.5H), 4.5
7 (br. S., 0.5H), 4.19-4.40 (m, 2.5H),
3.68-3.78 (m, 2.5H), 3.58 (br. S., 0.
5H), 3.39 (s, 3H), 3.02-3.31 (m, 2.5H)
, 2.58-2.75 (m, 2H), 1.86 (br. S., 1H),
1.62 (m, 1H), 1.43 (d, J = 6.3 Hz, 1.5H)
, 1.33 (d, J = 6.3 Hz, 1.5H), 1.16 (br.
s. , 2H), 0.81 (br.s., 2H). LC-MS: m / z
485.2 (M + H) +

(R, E) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2- (2- (2-vinylquinoxaline-5- Il)
Vinyl) quinoxalin-5-yl) nicotinonitrile (compound 604). This was obtained as a byproduct of compound 579. 1H NMR (chloroform-d) δ 9.23 (s
, 1H), 9.09 (s, 1H), 8.17-8.20 (m, 2H)
, 8.08 (d, J = 8.5 Hz, 1H), 7.70-7.87
(M, 5H), 7.04-7.11 (q, 1H), 6.53 (d, J
= 11.3 Hz, 1H), 5.85 (d, J = 11.3 Hz, 1
H), 4.94 (br. S., 0.5H), 4.56 (d, J = 12
. 8 Hz, 0.5H), 4.26-4.37 (m, 2.5H), 3.7
5-3.84 (m, 2.5H), 3.59 (t, 0.5H), 3.40
(S, 3H), 3.06-3.32 (m, 2.5H), 2.59-
2.81 (m, 2H), 1.61-1.73 (m, 1H), 1.45
(D, J = 6.3 Hz, 1.5H), 1.32 (d, J = 6.3
Hz, 1.5H), 1.25-1.29 (m, 2H), 0.83-0
. 86 (m, 2H). LC-MS: m / z 637.3 (M + H) +

(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinoxalin-5-yl) nicotinonitrile (Compound 605) General procedure 1, step I): 1H NMR (chloroform-
d) δ 9.00 (s, 1H), 8.13 (d, J = 8.5 Hz,
1H), 7.83 (t, J = 7.8 Hz, 1H), 7.62-7.
77 (m, 2H), 6.97-7.13 (q, 1H), 6.50 (d
, J = 11.0 Hz, 1H), 5.84 (d, J = 11.0 Hz)
, 1H), 4.58-4.73 (m, 1.5H), 4.39-4.4
8 (m, 1.5H), 3.87 (d, J = 13.3 Hz, 0.5H)
, 3.74 (m, 2H), 3.42-3.60 (m, 1H), 3.3
9 (d, J = 3.3 Hz, 3H), 2.93-3.17 (m, 2
. 5H), 2.53-2.83 (m, 2H), 2.16-2.33 (
m, 1H), 1.62 (br.s., 1H), 1.07-1.10 (
m, 4H), 0.82-0.93 (m, 6H). LC-MS: m / z
511.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinoxalin-5-yl) nicotinonitrile (Compound 618) General procedure 1, step I): 1H NMR (chloroform-d)
δ 9.00 (s, 1H), 8.13 (dd, J = 8.5, 1.3
Hz, 1H), 7.84 (dd, J = 8.3, 7.3 Hz, 1H),
7.67-7.74 (m, 2H), 7.02-7.07 (m, 1H
), 6.50 (d, J = 11.3 Hz, 1H), 5.82 (d, J
= 11.3 Hz, 1H), 4.92 (br. S., 0.5H), 4.
57 (br. S., 0.5H), 4.19-4.33 (m, 3H),
3.93 (s, 2.5H), 3.58 (br.s., 0.5H), 3.0
1-3.48 (m, 4H), 2.48-2.75 (m, 3H), 1
. 63 (m, 1H), 1.43 (d, J = 6.3 Hz, 1.5H),
1.35 (d, J = 6.3 Hz, 1.5H), 1.16 (br. S
. , 2H), 0.82 (br. S., 2H). LC-MS: m / z 4
69.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinoxalin-5-yl) nicotinonitrile (compound 644; General Procedure 1, Step I): 1H NMR (chloroform-d) δ 9.00 (s, 1H), 8.13 (dd, J = 8.5, 1
. 3 Hz, 1H), 7.70-7.72 (m, 2H), 7.01-
7.12 (q, 1H), 6.50 (d, J = 11.3 Hz, 1H),
5.84 (d, J = 11.3 Hz, 1H), 4.71 (br.s.
, 0.5H), 4.52 (d, 1H), 4.41 (d, 1H), 4.1
2 (br. S., 0.5H), 3.89 (br. S., 0.5H), 3
. 74 (m, 2H), 3.39 (s, 3H), 3.01-3.31 (
m, 3H), 2.59-2.83 (m, 2H), 1.58-1.68.
(M, 1H), 0.97-1.32 (m, 4H), 0.46-0.89
(M, 7H). LC-MS: m / z 509.1 (M + H) +

(R) -2′-Bromo-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-3,4′-bipyridine-5-carbonitrile (Compound 508) General procedure 1, step H): 1H NMR (chloroform-
d) δ 8.46 (d, J = 5.0 Hz, 1H), 7.63 (s,
1H), 7.57-7.61 (m, 1H), 7.34 (dd, J =
5.0, 1.5 Hz, 1H), 4.61 (d, J = 12.8 Hz,
1H), 4.49 (d, J = 13.6 Hz, 1H), 4.18-4
. 38 (m, 1H), 3.76 (br. S., 2H), 3.31 (br
. s. , 1H), 3.15 (br.s., 1H), 1.93-2.0
8 (m, 1H), 1.72 (br. S., 1H), 1.33 (br.
s. , 1H), 1.17-1.26 (m, 2H), 0.95-1.1
2 (m, 4H), 0.76-0.91 (m, 2H), 0.66 (br
. s. , 1H), 0.35-0.60 (m, 3H). LC-MS:
m / z 493.4 (M + H) +

(R) -2′-Chloro-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-3′-fluoro-3,4′-bipyridine-5 Carbonitrile (Compound 509; General Procedure 1, Step H): 1H NMR
(Chloroform-d) δ 8.29 (d, J = 5.0 Hz, 1H), 7
. 59-7.75 (s, 1H), 7.11-7.41 (d, J =
5.0 Hz, 1H), 4.63 (d, J = 13.1 Hz, 1H),
4.50 (d, J = 12.5 Hz, 1H), 4.06 (br. S.,
1H), 3.75 (br.s., 1H), 3.65 (br.s., 1
H), 3.31 (br.s., 1H), 3.16 (br.s., 1H)
, 1.70-1.81 (m, 1H), 1.30-1.42 (m, 1
H), 1.13-1.25 (m, 2H), 0.94-1.13 (m,
4H), 0.75-0.87 (m, 2H), 0.66 (br. S.,
1H), 0.35-0.60 (m, 3H). LC-MS: m / z 46
6.9 (M + H) +

(R) -5- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) isoquinolin-1-carbonitrile ( Compound 511): 1H NMR (chloroform-d) δ 8
. 66 (dd, J = 5.8, 1.8 Hz, 1H), 8.45 (d,
J = 8.3 Hz, 1H), 7.87-7.97 (m, 1H), 7.
80 (ddd, J = 7.2, 2.1, 1.0 Hz, 1H), 7.70
(Ddd, J = 11.1, 5.8, 0.9 Hz, 1H), 7.64
(D, J = 0.8 Hz, 1H), 4.61 (d, J = 12.0 H
z, 1H), 4.49 (d, J = 12.8 Hz, 1H), 3.42-
4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.75 (
br. s. , 1H), 1.38-1.47 (m, 2H), 0.95-
1.12 (m, 2H), 0.75-0.93 (m, 6H), 0.70
(Br. S., 1H), 0.38-0.61 (m, 3H). LC-M
S: m / z 489.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (1-hydroxyisoquinoline-5
-Yl) nicotinonitrile (Compound 547; General Procedure 2, Step M): 1H NMR
(Chloroform-d) δ 10.95 (s, 1H), 8.53 (dd, J
= 6.4, 3.1 Hz, 1H), 7.57-7.72 (m, 3H)
, 7.17 (br. S., 1H), 6.31 (dd, J = 12.9,
7.4 Hz, 1H), 4.38-4.61 (m, 2H), 4.15.
(Br.s., 0.5H), 3.69-3.95 (m, 1.5H), 3
. 03-3.41 (m, 5H), 1.53-1.77 (m, 3H), 1
. 16 (dd, J = 8.3, 4.5 Hz, 2H), 0.81-0.
98 (m, 2H), 0.47-0.64 (m, 3H). LC-MS:
m / z 522.2 (M + H) +

(R) -5- (3-Chloroisoquinolin-5-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 555; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 9.17 (s, 1H), 8.06 (d, J = 7.5 Hz,
1H), 7.66-7.73 (m, 2H), 7.64 (d, J =
1.0 Hz, 1H), 7.49 (d, J = 14.8 Hz, 1H),
4.61 (d, J = 12.0 Hz, 1H), 4.49 (d, J =
12.8 Hz, 1H), 3.42-4.43 (m, 2H), 3.10-3
. 40 (m, 3H), 1.69 (br. S., 1H), 1.39-1
. 57 (m, 2H), 1.15-1.23 (m, 2H), 1.08 (
br. s. , 2H), 0.79-0.93 (m, 4H), 0.70 (
br. s. , 1H), 0.38-0.63 (m, 3H). LC-MS
: M / z 498.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-hydroxyisoquinolin-5-yl) nicotinonitrile (Compound 566; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 11.20 ( br.s., 1H), 8.52 (dd, J
= 7.0, 2.3 Hz, 1H), 7.51-7.76 (m, 3H),
7.12-7.24 (m, 1H), 6.33 (dd, J = 12.7
, 7.4 Hz, 1H), 4.56 (d, J = 12.5 Hz, 1H)
4.44 (d, J = 12.3 Hz, 1H), 3.52-4.35 (m
, 2H), 3.05-3.45 (m, 3H), 1.63 (td, J
= 7.8, 4.0 Hz, 1H), 1.27-1.45 (m, 2H),
0.96-1.23 (m, 4H), 0.77-0.96 (m, 4H)
), 0.70 (br. S., 1H), 0.36-0.62 (m, 3H
). LC-MS: m / z 480.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (3-vinylisoquinolin-5-yl) nicotinonitrile (Compound 565; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 9.29 ( s, 1H), 8.03 (d, J = 7.5 Hz,
1H), 7.55-7.77 (m, 3H), 7.31 (d, J =
12.5 Hz, 1H), 6.88 (ddd, J = 17.3, 10.6,
6.8 Hz, 1H), 6.38 (ddd, J = 17.2, 5.6,
1.3 Hz, 1H), 5.44-5.59 (m, 1H), 4.59 (
d, J = 11.8 Hz, 1H), 4.47 (d, J = 12.5 H
z, 1H), 3.55-4.35 (m, 2H), 3.05-3.45 (m
, 3H), 1.68-1.80 (m, 1H), 1.42-1.61 (
m, 2H), 1.22-1.34 (m, 2H), 1.00-1.14.
(M, 2H), 0.76-0.92 (m, 4H), 0.71 (br.
s. , 1H), 0.39-0.63 (m, 3H). LC-MS: m
/ Z 490.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (3-methylisoquinolin-5-yl) nicotinonitrile (Compound 588) General procedure 1, step H): 1H NMR (chloroform-d)
δ 9.23 (s, 1H), 7.9 (d, J = 7.3 Hz, 1H
), 7.53-7.67 (m, 3H), 7.21 (d, J = 6.5)
Hz, 1H), 4.91 (br. S., 0.5H), 4.54 (d,
J = 13.1 Hz, 0.5H), 4.15-4.43 (m, 2.5H)
), 3.86-4.02 (m, 2H), 3.68-3.83 (m,
0.5H), 3.51-3.68 (m, 0.5H), 3.26-3.4
2 (m, 1H), 2.97-3.24 (m, 1.5H), 2.49-
2.78 (m, 5H), 1.49-1.58 (m, 1H), 1.41
-1.49 (m, 1.5H), 1.30-1.40 (m, 1.5H)
, 1.06-1.20 (m, 2H), 0.72-0.91 (m, 2
H). LC-MS: m / z 456.2 (M + H) +

(R) -5- (5-Chloro-2-vinylpyrimidin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 533; General Procedure 1, Step H): 1H NMR (chloroform-d) δ 8.69-8.87 (m, 1H), 7.70-7
. 91 (m, 1H), 6.91 (dd, J = 17.3, 10.5 Hz
1H), 6.59-6.78 (m, 1H), 5.71-5.98.
(M, 1H), 4.66 (d, J = 12.8 Hz, 1H), 4.53
(D, J = 12.5 Hz, 1H), 3.09-4.42 (m, 5H)
, 1.76-1.85 (m, 1H), 1.39-1.46 (m, 1
H), 1.21-1.25 (m, 2H), 0.99-1.10 (m,
4H), 0.90 (t, J = 6.9 Hz, 1H), 0.78-0
. 85 (m, 2H), 0.66 (br. S., 1H), 0.41-0
. 60 (m, 3H). LC-MS: m / z 475.2 (M + H) +

Compound 541

Step 1: (R) -5- (6-Chloropyrimidin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile

4,6-Dichloropyrimidine (50 mg, 0.32 mmol) in dimethoxyethane (3
mL) and 2M aqueous sodium carbonate solution (0.6 mL) in a solution of 8-4 (1
00 mg, 0.22 mmol) and tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.1 equiv) were added under a nitrogen atmosphere and the mixture was
Heated for hours. After cooling to ambient temperature, the separated organic layer was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with 10% aqueous potassium carbonate and brine and dried over sodium sulfate. After evaporation, the residue was purified on silica gel and eluted with 5-20% ethyl acetate in petroleum ether to give 4-chloro-6-phenylpyrimidine (75 mg), 69% yield. 1H NMR (chloroform-d) δ 8.67
-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d,
J = 5.0 Hz, 1H), 4.68 (d, J = 13.1 Hz, 1
H), 4.53 (d, J = 13.3 Hz, 1H), 4.07 (br.
s. , 1H), 3.88 (s, 1H), 3.68 (br.s., 1H)
), 3.33 (br.s., 1H), 3.17 (br.s., 1H),
2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H)
), 1.30-1.42 (m, 2H), 1.00-1.11 (m,
3H), 0.85-0.93 (m, 1H), 0.82 (dd, J =
8.0, 2.5 Hz, 2H), 0.65 (br. S., 1H), 0.3
9-0.59 (m, 3H). LC-MS: m / z 449.2 (M +
H) +

Step 2: (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (6-vinylpyrimidin-4-yl) nicotinonitrile ( Compound 541)

(R) -5- (6-Chloropyrimidin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (60 mg, 0.06 mmol) (60 mg, 0.13 mmol), vinyl potassium-trifluoroborate (25 mg, 0.2 mmol), Pd (PPh3) 4 (3
mg, 0.1 eq), and 5 mL of a mixture of CsF (40 mg, 0.26 mmol)
Of dioxane and 1 mL of water and the resulting mixture was refluxed for 1 hour. After the reaction was complete, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 35 mg of the title compound as a yellow solid. 75% yield. 1H NMR (chloroform-d) δ 9.16-9.30 (m, 1H), 7.93-8.
07 (m, 1H), 7.49-7.56 (m, 1H), 6.82 (d
d, J = 17.3, 10.5 Hz, 1H), 6.57 (dd, J =
17.3, 1.0 Hz, 1H), 5.72-5.83 (m, 1H),
4.68 (d, J = 13.1 Hz, 1H), 4.55 (d, J =
12.3 Hz, 1H), 4.39-3.11 (br.s., 5H), 2
. 34-2.43 (m, 1H), 1.70 (br.s., 1H), 1
. 31-1.40 (m, 2H), 0.99-1.11 (m, 4H),
0.89-0.94 (m, 1H), 0.82 (dd, J = 7.9,
2.4 Hz, 2H), 0.64 (br. S., 1H), 0.41 −
0.58 (m, 3H). LC-MS: m / z 441.2 (M + H) +

(S) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (6-vinylpyrimidin-4-yl) nicotinonitrile (Compound 578): 1H NMR (chloroform-d) δ 9.24 (d,
J = 1.3 Hz, 1H), 7.94-8.05 (m, 1H), 7.
46-7.58 (m, 1H), 6.82 (dd, J = 17.3, 1
0.8 Hz, 1H), 6.57 (dd, J = 17.3, 1.0 Hz,
1H), 5.73-5.84 (m, 1H), 4.68 (d, J =
12.5 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H),
4.08 (br. S., 1H), 3.76 (s, 1H), 3.66 (
t, J = 6.7 Hz, 1H), 3.40-3.58 (m, 1H),
3.33 (br.s., 1H), 3.17 (br.s., 1H), 2
. 34-2.45 (m, 1H), 1.29-1.35 (m, 2H),
1.00-1.11 (m, 4H), 0.89-0.92 (m, 1H
), 0.82 (dd, J = 7.9, 2.4 Hz, 2H), 0.64
(Br.s., 1H), 0.43-0.58 (m, 3H). LC-MS
: M / z 441.2 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (6-vinylpyrimidin-4-yl) nicotinonitrile (Compound 621) ): 1H NMR (chloroform-d) δ 9.24 (d, J
= 1.3 Hz, 1H), 7.82-8.04 (m, 1H), 7.47.
-7.61 (m, 1H), 6.68-6.93 (m, 1H), 6.
42-6.62 (m, 1H), 5.64-5.88 (m, 1H),
4.88 (br. S., 1H), 4.29-4.57 (m, 3H),
4.17 (br. S., 1H), 3.93 (br. S., 2H), 3.
74 (d, J = 13.3 Hz, 1H), 3.47-3.63 (m,
1H), 3.29-3.41 (m, 1H), 3.05-3.25 (
m, 2H), 2.51-2.72 (m, 2H), 2.33-2.42.
(M, 1H), 1.32-1.44 (m, 2H), 1.22-
28 (m, 3H), 1.02-1.1.11 (m, 2H). LC-MS:
m / z 419.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-vinylpyrimidin-4-yl) nicotinonitrile (compound 638): 1H NMR (chloroform-d) δ 9.24 (s,
1H), 7.95-8.11 (m, 1H), 7.50-7.56 (
m, 1H), 6.74-6.87 (m, 1H), 6.48-6.65.
(M, 1H), 5.74-5.89 (m, 1H), 4.67 (d,
J = 12.8 Hz, 1H), 4.53 (d, J = 11.0 Hz,
1H), 4.10 (br.s., 0.5H), 3.83-3.93 (m
, 0.5H), 3.61-3.81 (m, 3H), 3.39 (s, 3
H), 3.21-3.35 (m, 2H), 3.08-3.21 (m,
1H), 2.72 (br.s., 1H), 2.65 (br.s., 1
H), 2.33-2.43 (m, 1H), 1.21-1.36 (m,
3H), 1.03-1.13 (m, 2H), 0.60 (br. S.,
2H), 0.45 (br.s., 2H). LC-MS: m / z 45
9.2 (M + H) +

(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-vinylpyrimidin-4-yl) nicotinonitrile (Compound 639) ): 1H NMR (chloroform-d) δ 9.09-9.
32 (m, 1H), 7.9 (s, 1H), 7.51 (s, 1H),
6.81 (dd, J = 17.3, 10.5 Hz, 1H), 6.56 (
d, J = 17.3 Hz, 1H), 5.78 (d, J = 11.3 H
z, 1H), 4.67-4.76 (m, 1H), 4.50 (d, J
= 14.6 Hz, 1H), 3.88 (d, J = 13.6 Hz, 1H)
), 3.68-3.79 (m, 2H), 3.60 (d, J = 10.
5 Hz, 1H), 3.39-3.55 (m, 1H), 3.02-3
. 24 (m, 2H), 2.85-3.02 (m, 1H), 2.52-
2.82 (m, 2H), 2.33-2.43 (m, 1H), 1.92
-2.05 (m, 1H), 1.23-1.31 (m, 2H),
00-1.10 (m, 5H), 0.83-0.92 (m, 3H).
LC-MS: m / z 461.3 (M + H) +

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (6-vinylpyrimidin-4-yl) nicotinonitrile (
Compound 597): 1H NMR (chloroform-d) δ 9.22 (s, 1H)
, 7.98 (s, 1H), 7.50 (s, 1H), 6.80 (dd,
J = 17.3, 10.8 Hz, 1H), 6.44-6.69 (m,
1H), 5.64-5.92 (m, 1H), 4.89 (br. S.,
0.5H), 4.52 (d, J = 9.5 Hz, 0.5H), 4.28
-4.46 (m, 2H), 3.65-3.95 (m, 3H), 3.4
4-3.65 (m, 1H), 3.27-3.44 (m, 4H), 3
. 00-3.27 (m, 2H), 2.51-2.81 (m, 2H),
2.25-2.47 (m, 1H), 1.14-1.44 (m, 5H
), 0.93-1.14 (m, 2H). LC-MS: m / z 433.2
(M + H) +

(R) -6-cyclopropyl-5- (6- (1-fluorovinyl) pyrimidin-4-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicochi Nononitrile (Compound 602)

(R) -5- (6-Chloropyrimidin-4-yl) -6-cyclopropyl-2- (4-
(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (
80 mg 0.21 mmol), CuI (10 mg, 10%), and Pd (PPh3)
To a solution of 2Cl2 (15 mg) in 5 ml of DMF was added (1-fluorovinyl) (methyl) diphenylsilane (7.6 mg, 0.41 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After removing the solvent under reduced pressure, the residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) to give 20 mg of pure product, 30% yield. 1H NMR (chloroform-d) δ 9.25 (s, 1H), 8.04
(S, 1H), 7.76 (s, 1H), 6.11 (d, J = 3.0
Hz, 1H), 5.99 (d, J = 3.0 Hz, 1H), 5.27
(Dd, J = 15.8, 3.0 Hz, 1H), 4.91 (br.s.
, 1H), 4.54 (d, J = 10.3 Hz, 1H), 4.31 −
4.49 (m, 1H), 3.71-3.78 (m, 1H), 3.49
-3.63 (m, 1H), 3.31-3.44 (m, 4H),
16-3.28 (m, 1H), 3.13 (br.s., 1H), 2.
51-2.81 (m, 2H), 2.30-2.44 (m, 1H),
1.35 (d, J = 6.5 Hz, 2H), 1.25 (dd, J =
4.3, 2.8 Hz, 3H), 1.04-1.13 (m, 2H). L
C-MS: m / z 451.2 (M + H) +

(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-2 '-(prop-1-en-2-yl) -3,4'-
Bipyridine-5-carbonitrile (Compound 544). Synthesized according to the procedure described for compound 602, except that trimethyl (prop-1-en-2-yl) silane was used in place of (1-fluorovinyl) (methyl) diphenylsilane. 1H NMR (chloroform-d) δ 8.67 (d, J = 5.0 Hz, 1H), 7.65 (
s, 1H), 7.53 (s, 1H), 7.16-7.27 (m, 1H)
), 5.92 (s, 1H), 5.38 (s, 1H), 4.57 (d,
J = 12.3 Hz, 1H), 4.45 (d, J = 12.3 Hz,
1H), 4.07 (br.s., 1H), 3.78 (br.s., 1H)
), 3.56-3.74 (m, 1H), 3.50 (s, 1H), 3.
29 (br.s., 1H), 3.14 (br.s., 1H), 2.26
(S, 3H), 1.98-2.10 (m, 1H), 1.72 (br.
s. , 1H), 1.17-1.27 (m, 2H), 0.97-1.
09 (m, 4H), 0.86-0.95 (m, 1H), 0.76-
0.84 (m, 2H), 0.66 (br. S., 1H), 0.40 −
0.59 (m, 3H). LC-MS: m / z 453.2 (M + H) +

(R) -5- (2-Aminopyrimidin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 507)

To the NH ₃ / MeOH (10 mL, 7M) solution, (R) -5- (2-chloropyrimidine-
4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (40 mg, 0.09 mmol) was added and the mixture was at 50 ° C. Stir overnight. After removing the solvent under reduced pressure, the residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to yield 21 mg of pure product,
A 51% yield was obtained. 1H NMR (chloroform-d) δ 8.36 (d, J
= 5.3 Hz, 1H), 7.97 (s, 1H), 6.90 (d, J
= 5.0 Hz, 1H), 5.25 (br. S., 2H), 4.64 (
d, J = 12.5 Hz, 1H), 4.51 (d, J = 12.3 H
z, 1H), 3.69 (br.s., 1H), 3.32 (br.s.,
1H), 3.26 (br.s., 1H), 3.15 (br.s., 2
H), 2.32-2.45 (m, 1H), 2.03-2.08 (m,
1H), 1.02-1.10 (m, 4H), 0.77-0.89 (
m, 4H), 0.63 (br. s., 2H), 0.43-0.58 (
m, 3H). LC-MS: m / z 430.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2- (dimethylamino) pyrimidin-4-yl) nicotinonitrile (Compound 506). Synthesized according to the procedure described for compound 507 except that dimethylamine was NH ₃ . Used in place of EtOH.
1H NMR (chloroform-d) δ 8.38 (d, J = 5.0 Hz,
1H), 7.90-8.06 (m, 1H), 6.72 (d, J =
5.0 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H),
4.49 (d, J = 12.5 Hz, 1H), 4.09-4.26 (
m, 1H), 3.30-3.58 (m, 2H), 3.26 (s, 6H)
, 3.16-3.24 (m, 1H), 3.11 (d, J = 18.3
Hz, 1H), 2.48-2.56 (m, 1H), 1.19-1.
24 (m, 3H), 0.98-1.08 (m, 4H), 0.86-
0.92 (m, 1H), 0.76-0.84 (m, 2H), 0.64
(Br. S., 1H), 0.40-0.58 (m, 3H). LC-M
S: m / z 458.3 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (2- (dimethylamino) pyrimidine-4 -Yl) nicotinonitrile (compound 534): 1H NMR (chloroform-d
) Δ 8.37 (d, J = 5.3 Hz, 1H), 7.97 (s, 1H)
), 6.89 (d, J = 5.0 Hz, 1H), 4.63 (d, J
= 13.1 Hz, 1H), 4.51 (d, J = 12.8 Hz, 1H)
), 4.00-4.17 (m, 1H), 3.68-3.87 (m,
1H), 3.17-3.38 (m, 3H), 3.12 (d, J = 1)
1.8 Hz, 1H), 2.82 (s, 2H), 2.33-2.45 (
m, 1H), 1.35 (br.s., 1H), 1.18-1.25 (
m, 2H), 0.98-1.10 (m, 2H), 0.64 (br. s)
. , 1H), 0.57 (br. S., 1H), 0.38-0.54 (
m, 2H). LC-MS: m / z 472.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2- (2-hydroxyethylamino) pyrimidin-4-yl) nicotinonitrile (compound 512): synthesized according to the procedure described in compound 507, provided that 2 - _NH 3 (methyl amino) ethanol. Used in place of EtOH. 1H NMR (chloroform-d) δ 8.32 (d, J = 5.
0 Hz, 1H), 7.94 (s, 1H), 6.83 (d, J = 5.
3 Hz, 1H), 5.91 (br. S., 1H), 4.63 (d, J
= 12.8 Hz, 1H), 4.50 (d, J = 12.5 Hz, 1
H), 3.96-4.33 (m, 1H), 3.82-3.92 (m,
2H), 3.63-3.72 (m, 2H), 3.29 (br. S.,
1H), 3.14 (br.s., 1H), 2.68-2.78 (m,
1H), 2.66 (br.s., 1H), 2.34-2.44 (m,
1H), 1.20-1.35 (m, 4H), 1.04 (dd, J =
7.7, 3.4 Hz, 4H), 0.77-0.90 (m, 3H),
0.64 (br. S., 1H), 0.49-0.55 (m, 1H),
0.44 (dt, J = 9.3, 4.4 Hz, 1H).
LC-MS: m / z 474.2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (2- (dimethylamino) pyrimidine-4 -Yl) nicotinonitrile (compound 521): 1H NMR (chloroform-d
) Δ 8.42 (d, J = 5.3 Hz, 1H), 8.00 (s, 1
H), 6.75 (d, J = 5.3 Hz, 1H), 4.62 (d, J
= 13.1 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1
H), 3.96-4.20 (m, 1H), 3.68-3.96 (m,
1H), 3.28-3.42 (m, 2H), 3.09-3.15 (
m, 1H), 2.42-2.54 (m, 1H), 1.39-1.56.
(M, 1H), 1.14-1.25 (m, 2H), 0.98-1.
08 (m, 2H), 0.65 (br. S., 1H), 0.56 (br.
s. , 1H), 0.43-0.53 (m, 2H). LC-MS: m /
z 500.2 (M + H) +

(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (6-vinylpyrazin-2-yl) nicotinonitrile (Compound 515)

Step 1: Add (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (4,4,5,5-tetramethyl) to the flask. -1,3,2-dioxaborolan-2-yl) nicotinonitrile (70 mg,
0.151 mmol), 2,6-dichloropyrazine (30 mg, 0.197 mmol),
Pd (PPh ₃ ) ₄ (17 mg, 0.015 mmol), K ₂ CO ₃ (63 mg, 0.4
53 mmol), and 1.5 mL of DMF were added. The mixture was stirred at 120 ° C. for 2 hours. After washing with saturated NaHCO 3, brine, the combined organic layers were washed with anhydrous Na
Dried over ₂ SO _4, and concentrated in vacuo. By preparative TLC purification (20% EtOAc / petroleum ether), 25 mg of (R) -5- (6-chloropyrazin-2-yl) -2- (
4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6
Cyclopropylnicotinonitrile was obtained.

Step 2: Place (R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (6-vinylpyrazin-2-yl) nicoti in a flask. Nononitrile (18 mg 0.04 mmol), tributyl (vinyl) stannane (17 mg, 0.052 mmol), Pd (PPh ₃ ) ₄ (5 mg, 0.004)
mmol), K2CO3 (14 mg, 0.052 mmol), and 1.5 mL of DMF.
Was added. The mixture was stirred at 120 ° C. for 2 hours. After washing with saturated NaHCO ₃ , brine, the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo.
Preparative TLC purification (20% EtOAc / petroleum ether) gave 10 mg of the title compound. 1H NMR (chloroform-d) δ 8.72 (s, 1H), 8.5
6 (s, 1H), 8.00 (s, 1H), 6.90 (dd, J = 1)
7.3, 10.8 Hz, 1H), 6.47 (dd, J = 17.6, 1
. 0 Hz, 1H), 5.70 (dd, J = 10.8, 1.0 Hz,
1H), 4.65 (d, J = 13.1 Hz, 1H), 4.52 (d,
J = 12.8 Hz, 1H), 3.99-4.29 (m, 1H),
3.52-3.91 (m, 1H), 3.32 (br.s., 1H),
3.16 (br. S., 1H), 2.22-2.35 (m, 1H),
1.23-1.38 (m, 5H), 0.97-1.14 (m, 4H)
, 0.81 (dd, J = 7.8, 2.3 Hz, 2H), 0.65 (
br. s. , 1H), 0.48-0.55 (m, 1H), 0.45 (
dt, J = 9.6, 4.6 Hz, 1H).
LC-MS: m / z 441.2 (M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile ( Compound 530; General Procedure 5, Step W): 1H NMR (chloroform-
d) δ 8.61 (d, J = 5.0 Hz, 1H), 7.55-7.
68 (m, 1H), 7.36 (s, 1H), 7.21 (dd, J =
5.0, 1.5 Hz, 1H), 6.84 (dd, J = 17.6, 10
. 8 Hz, 1H), 6.17-6.35 (m, 1H), 5.53 (d
d, J = 10.8, 0.8 Hz, 1H), 4.53 (d, J = 1)
2.5 Hz, 1H), 4.32-4.47 (m, 1H), 4.01-
4.16 (m, 0.5H), 3.86 (d, J = 12.5 Hz, 0
. 5H), 3.70 (t, J = 5.5 Hz, 3H), 3.35 (s,
3H), 3.18 (d, J = 11.3 Hz, 2H), 2.94 −
3.14 (m, 1H), 2.56-2.73 (m, 2H), 1.90
-2.10 (m, 1H), 1.22-1.34 (m, 1H), 1.1
4-1.32 (m, 2H), 0.83-1.06 (m, 2H), 0
. 58 (br.s., 1H), 0.52 (br.s., 1H), 0.2
8-0.48 (m, 2H). LC-MS: m / z 458.2 (M + H)
+

(R) -6- (4-Acetyl-3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 562)
General procedure 5, step W). 1H NMR (chloroform-d) δ 8.66
(D, J = 4.5 Hz, 1H), 7.65 (s, 1H), 7.39
(S, 1H), 7.24 (d, J = 4.0 Hz, 1H), 6.88
(Dd, J = 17.3, 10.8 Hz, 1H), 6.28 (d, J
= 17.3 Hz, 1H), 5.57 (d, J = 10.8 Hz, 1H)
), 4.65 (br. S., 0.5H), 4.55 (d, J = 12.5)
Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.0
8 (br. S., 0.5H), 3.77 (br. S., 1H), 3.2
1 (br.s., 2H), 3.11 (br.s., 1H), 2.17
(Br.s., 2H), 2.11 (br.s., 1H), 2.03 (b
r. s. , 1H), 1.28 (d, J = 12.0 Hz, 2H), 1
. 24-1.50 (br.s., 3H), 0.60 (br.s., 2H)
, 0.45 (br. S., 2H). LC-MS: m / z 414.3 (
M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-hydroxy-3)
-Methylbutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-
5-carbonitrile (Compound 561; General Procedure 5, Step W). 1H NMR (chloroform-d) δ 8.66 (d, J = 5.0 Hz, 1H), 7.6
6 (s, 1H), 7.39 (s, 1H), 7.24 (d, J = 4.
0 Hz, 1H), 6.88 (dd, J = 17.6, 10.8 Hz,
1H), 6.28 (d, J = 17.6 Hz, 1H), 5.57 (d,
J = 10.8 Hz, 1H), 5.16 (br.s., 1H), 4.
56 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 12
. 5 Hz, 1H), 4.14 (d, J = 8.8 Hz, 0.5H),
3.65-3.78 (m, 1H), 3.17-3.91 (m, 1.5
H), 3.04-3.14 (m, 1H), 2.43-2.57 (m,
2H), 2.02-2.07 (m, 1H), 1.33 (s, 6H),
1.25-1.30 (m, 2H), 1.21 (br. S., 2H),
1.02 (dd, J = 7.5, 3.3 Hz, 2H), 0.65 (d
, J = 6.5 Hz, 1H), 0.42-0.53 (m, 2H).
LC-MS: m / z 472.3 (M + H) +

(R) -2-cyclopropyl-6- (4- (2-ethoxyacetyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 573) General procedure 5, step W). 1H NMR (chloroform-d) δ 8
. 65 (d, J = 5.0 Hz, 1H), 7.64 (s, 1H), 7
. 36-7.41 (m, 1H), 7.23 (dd, J = 5.0, 1
. 8 Hz, 1H), 6.88 (dd, J = 17.6, 10.8 Hz,
1H), 6.21-6.35 (m, 1H), 5.57 (dd, J =
10.9, 0.9 Hz, 1H), 4.84 (br.s., 0.5H),
4.35 (br. S., 2H), 4.27 (br. S., 1H), 4
. 20 (br.s., 2H), 3.89 (br.s., 0.5H), 3
. 53-3.65 (m, 2.5H), 3.24-3.35 (m, 1H
), 3.17 (br. S., 1.5H), 1.98-2.08 (m,
1H), 1.29-1.41 (m, 3H), 1.23-1.28 (m
, 3H), 1.15-1.23 (m, 2H), 0.95-1.07
(M, 2H). LC-MS: m / z 432.2 (M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (compound 590; General Procedure 5, Step W). 1H NMR (chloroform-d)
δ 8.63 (d, J = 5.0 Hz, 1H), 7.53-7.75
(M, 2H), 7.37 (s, 1H), 7.22 (dd, J = 4.
8, 1.5 Hz, 1H), 6.86 (dd, J = 17.6, 10.8
Hz, 1H), 6.19-6.37 (m, 1H), 5.54 (d,
J = 11.5 Hz, 1H), 4.55 (d, J = 13.1 Hz,
1H), 4.42 (d, J = 12.8 Hz, 1H), 4.11-4
. 17 (m, 2H), 3.44 (s, 4H), 3.19-3.25 (
m, 1H), 3.04-3.11 (m, 1H), 2.80 (s, 1H)
), 1.89-2.07 (m, 2H), 1.17-1.27 (m,
4H), 0.95-1.02 (m, 2H), 0.41-0.54 (m
, 3H). LC-MS: m / z 444.2 (M + H) +

2-cyclopropyl-6- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (compound 572; general Procedure 5, Step W). 1H NMR (chloroform-d) δ 8.
66 (d, J = 5.0 Hz, 1H), 7.61-7.69 (m,
1H), 7.36-7.44 (m, 1H), 7.24 (dd, J =
5.0, 1.8 Hz, 1H), 6.89 (dd, J = 17.3, 10
. 8 Hz, 1H), 6.29 (dd, J = 17.6, 1.0 Hz,
1H), 5.58 (dd, J = 10.8, 0.8 Hz, 1H), 4.
90 (br. S., 0.5H), 4.54 (d, J = 13.3 Hz,
0.5H), 4.26-4.40 (m, 2H), 4.12-4.23
(M, 1H), 3.93 (br. S., 2H), 3.74 (d, J =
13.1 Hz, 1H), 3.29-3.34 (m, 1H), 3.06
-3.18 (m, 1H), 2.50-2.63 (m, 1H), 2.
17-2.25 (m, 1H), 2.02-2.07 (m, 1H),
1.41 (d, J = 6.8 Hz, 1H), 1.29-1.33 (m
, 2H), 1.28 (d, J = 2.8 Hz, 1H), 1.19 −
1.22 (m, 1.5H), 1.02 (dd, J = 7.9, 3.1 H
z, 1.5H). LC-MS: m / z 418.2 (M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (furan-3-carbonyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile ( Compound 546; General Procedure 5, Step W). 1H NMR (chloroform-d
) Δ 8.66 (d, J = 4.5 Hz, 1H), 7.73 (s, 1
H), 7.65 (s, 1H), 7.46 (s, 1H), 7.36-7
. 44 (m, 1H), 7.25 (d, J = 4.3 Hz, 1H), 6
. 88 (dd, J = 17.4, 10.9 Hz, 1H), 6.56 (s
, 1H), 6.26 (d, J = 17.6 Hz, 1H), 5.56 (
d, J = 10.8 Hz, 1H), 4.60 (d, J = 13.1 H
z, 1H), 4.44 (d, J = 12.8 Hz, 1H), 4.27.
(Br.s., 1H), 3.93 (br.s., 1H), 3.66 (b
r. s. , 1H), 3.19-3.38 (m, 1H), 3.09 (t
, J = 11.3 Hz, 1H), 2.03 (dd, J = 7.4, 3
. 1 Hz, 1H), 1.35-1.50 (m, 1H), 1.13-
1.35 (m, 2H), 0.90-1.08 (m, 2H), 0.59-
0.76 (m, 1H), 0.52 (t, J = 8.0 Hz, 1H),
0.42 (br.s., 2H). LC-MS: m / z 466.2 (M
+ H) +

2-Cyclopropyl-6-((R) -3-cyclopropyl-4-((S) -3-hydroxybutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5 −
Carbonitrile (Compound 595; General Procedure 5, Step W). 1H NMR (chloroform-d) δ 8.65 (d, J = 4.8 Hz, 1H), 7.65
(S, 1H), 7.39 (s, 1H), 7.24 (d, J = 4.3)
Hz, 1H), 6.88 (dd, J = 17.4, 10.9 Hz, 1H
), 6.28 (d, J = 17.3 Hz, 1H), 5.57 (d, J
= 10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.
43 (d, J = 12.5 Hz, 1H), 4.17-4.33 (m,
2H), 3.96-4.17 (m, 1H), 3.79 (br. S.,
1H), 3.71 (d, J = 11.8 Hz, 1H), 3.02-
3.31 (m, 2H), 2.53 (d, J = 9.8 Hz, 1H),
2.48 (m, 1H), 2.04 (m, 1H), 1.32 (br. S.
, 3H), 0.82-1.12 (m, 3H), 0.72 (br. S.
, 1H), 0.63 (br.s., 1H), 0.55 (br.s.,
1H), 0.22-0.51 (m, 2H). LC-MS: m / z 45
8.2 (M + H) +

(R) -2-cyclopropyl-6- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (compound) 631; General Procedure 5, Step W). 1H NMR (chloroform-d
) 1 H NMR (chloroform-d) v 8.61 (d, J = 5.0)
Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.20
(Dd, J = 5.0, 1.5 Hz, 1H), 6.84 (dd, J
= 17.3, 10.8 Hz, 1H), 6.25 (d, J = 17.6)
Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 4.50
-4.79 (m, 2H), 4.28-4.50 (m, 2H),
85 (d, J = 13.6 Hz, 1H), 3.63-3.79 (m,
2H), 3.57 (d, J = 10.0 Hz, 1H), 3.30 −
3.49 (m, 3H), 2.99-3.27 (m, 2H), 2.83
-2.98 (m, 1H), 2.49-2.79 (m, 1H), 2.1
7 (dt, J = 10.5, 6.7 Hz, 1H), 1.08-1.3
0 (m, 3H), 0.78-1.08 (m, 7H). LC-MS:
m / z 460.1 (M + H) +

(R) -2-cyclopropyl-6- (4- (2-hydroxyacetyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 632 General procedure 5, step W). 1H NMR (chloroform-d) δ
8.64 (d, J = 5.0 Hz, 1H), 7.64 (s, 1H),
7.31-7.50 (m, 1H), 7.23 (dd, J = 5.1,
1.6 Hz, 1H), 6.87 (dd, J = 17.4, 10.9 Hz)
, 1H), 6.27 (dd, J = 17.4, 0.9 Hz, 1H),
5.42-5.72 (m, 1H), 4.84 (br.s., 1H),
4.20-4.40 (m, 3H), 4.00-4.20 (m, 1H)
, 3.36-3.65 (m, 2H), 3.20-3.36 (m, 2
H), 2.97-3.20 (m, 1H), 2.70-2.96 (m,
4H), 1.86−2.06 (m, 1H), 1.40 (d, J =
6.3 Hz, 1H), 1.09-1.36 (m, 4H), 0.79-
1.09 (m, 2H). LC-MS: m / z 404.0 (M + H) +

2-cyclopropyl-6-((R) -3-cyclopropyl-4-((R) -3-hydroxybutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5 −
Carbonitrile (Compound 585; General Procedure 5, Step W). 1H NMR (chloroform-d) δ 8.65 (d, J = 4.8 Hz, 1H), 7.65
(S, 1H), 7.39 (s, 1H), 7.24 (d, J = 4.3)
Hz, 1H), 6.88 (dd, J = 17.4, 10.9 Hz, 1H
), 6.28 (d, J = 17.3 Hz, 1H), 5.57 (d, J
= 10.8 Hz, 1H), 4.49-4.79 (m, 2H), 4.
43 (d, J = 12.5 Hz, 1H), 4.17-4.33 (m,
2H), 3.96-4.17 (m, 1H), 3.79 (br. S.,
1H), 3.71 (d, J = 11.8 Hz, 1H), 3.02-
3.31 (m, 2H), 2.53 (d, J = 9.8 Hz, 1H),
2.48 (m, 1H), 2.04 (m, 1H), 1.32 (br. S.
, 3H), 0.82-1.12 (m, 3H), 0.72 (br. S.
, 1H), 0.63 (br.s., 1H), 0.55 (br.s.,
1H), 0.22-0.51 (m, 2H). LC-MS: m / z 458
. 2 (M + H) +

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (1H-pyrrolo [2,3-b ] Pyridin-5-yl) nicotinonitrile (Compound 539; General Procedure 2, Step M). 1H
NMR (chloroform-d) δ 10.76 (br.s., 1H), 8.
37 (br. S., 1H), 8.00 (s, 1H), 7.65-7.
77 (m, 1H), 7.48 (d, J = 3.3 Hz, 1H), 6.
59 (d, J = 3.3 Hz, 1H), 4.71 (br.s., 0.
5H), 4.52 (d, J = 13.1 Hz, 1H), 4.41 (d,
J = 12.5 Hz, 1H), 4.14 (d, J = 7.3 Hz,
0.5H), 3.66-3.95 (m, 1.5H), 3.15-3.4
4 (m, 4.5H), 2.40 (br. S., 1H), 2.05-2
. 15 (m, 1H), 1.39-1.48 (m, 1H), 1.17-
1.25 (m, 2H), 0.94-1.04 (m, 2H), 0.44
-0.81 (m, 4H). LC-MS: m / z 495.3 (M + H) +

6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2S) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (4-fluorophenyl) nicotinonitrile (compound 548; general procedure 3, steps R and S). 1H
NMR (chloroform-d) δ 7.58-7.63 (m, 1H), 7
. 33-7.43 (m, 2H), 7.09-7.21 (m, 2H),
4.39-4.50 (m, 2.5H), 4.05-4.13 (m,
1H), 3.82 (br.s., 0.5H), 3.50-3.72 (m
4H), 2.97-3.29 (m, 3H), 1.99-2.06.
(M, 1H), 1.84-1.96 (m, 1H), 1.14-1.2
7 (m, 7H), 0.93-1.00 (m, 2H), 0.38-0
. 72 (m, 4H). LC-MS: m / z 475.3 (M + H) +

(R) -5- (2-Chloroquinolin-5-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (Compound 549) . 1H NMR (400 MHz, CHLOROFORM-d
) Δ 8.09 (d, J = 8.5 Hz, 1 H), 7.91 (dd,
J = 11.4, 8.9 Hz, 1 H), 7.82 (t, J = 7.9 Hz,
1 H), 7.64 (s, 1 H), 7.46-7.57 (m, 1
H), 7.39 (d, J = 8.8 Hz, 1 H), 4.78 (dq,
J = 13.5, 6.8 Hz, 0.5 H), 4.57 (d, J = 11.8
Hz, 1.5 H), 4.45 (d, J = 11.0 Hz, 1 H),
3.92-4.07 (m, 0.5 H), 3.57-3.76 (m,
0.5 H), 3.40 (q, J = 7.0 Hz, 1 H), 3.18 −
3.35 (m, 2 H), 1.65-1.82 (m, 1 H), 1
. 20-1.31 (m, 4 H), 1.07-1.20 (m, 2
H), 0.64-0.91 (m, 4 H), 0.38-0.60 (m
, 4 H). LC-MS: m / z 498.2 (M + H) +

(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (4-fluorophenyl) nicotinonitrile (Compound 55)
0). 1H NMR (chloroform-d) δ 7.60 (s, 1H), 7.3
3-7.43 (m, 2H), 7.09-7.20 (m, 2H), 4
. 55 (br. S., 1H), 4.47 (br. S., 1H), 4.2
5 (d, J = 13.1 Hz, 3H), 3.40 (br.s., 1H
), 3.31 (br.s., 1H), 3.15 (br.s., 1H),
1.95-2.10 (m, 1H), 1.77 (br.s., 2H),
1.64 (br. S., 2H), 1.39-1.53 (m, 2H),
1.34 (br. S., 2H), 0.90-1.12 (m, 5H),
0.69-0.90 (m, 2H). LC-MS: m / z 405.2
(M + H) +

6-Cyclopropyl-2-((R) -3-cyclopropyl-4-((1R, 2S) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (4-fluorophenyl) nicotinonitrile (compound 564). 1H NMR (chloroform-d) δ
7.60 (s, 1H), 7.33-7.41 (m, 2H), 7.15
(T, J = 8.7 Hz, 2H), 4.69-4.72 (m, 0.
5H), 4.31-4.58 (m, 2H), 4.20 (d, J = 1)
3.8 Hz, 1H), 3.16-3.82 (m, 7.5H), 1.98
-2.09 (m, 1H), 1.77-1.90 (m, 1H), 1.
08-1.32 (m, 7H), 0.86-1.08 (m, 2H),
0.31-0.62 (m, 4H). LC-MS: m / z 475.3 (M
+ H) +

(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (isoquinolin-5-yl) nicotinonitrile (Compound 5)
56; General Procedure 2, Step M). 1H NMR (chloroform-d) δ 9.3
6 (br. S., 1H), 8.52 (br. S., 1H), 8.07
(D, J = 8.0 Hz, 1H), 7.70-7.75 (m, 1H)
, 7.65-7.69 (m, 1H), 7.63 (s, 1H), 7.4
7 (t, J = 5.6 Hz, 1H), 4.89-5.55 (m, 3
H), 4.15-4.58 (m, 4H), 1.56-1.68 (m,
1H), 1.42-1.56 (m, 1H), 1.12-1.21 (
m, 2H), 0.97-1.09 (m, 4H), 0.75-0.96.
(M, 6H). LC-MS: m / z 438.3 (M + H) +

(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -2- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6
Cyclopropylnicotinonitrile (Compound 575; General Procedure 1, Step I). 1H
NMR (chloroform-d) δ 7.49 (s, 1H), 6.47-6
. 77 (m, 1H), 6.22-6.44 (m, 1H), 5.88 (
br. s. , 1H), 5.76 (d, J = 10.0 Hz, 1H),
3.01-4.86 (m, 11H), 2.40 (br. S., 2H),
1.95-2.16 (m, 1H), 1.76 (br.s., 1H),
1.29-1.38 (m, 3H), 1.08-1.19 (m, 2H)
, 0.92-1.08 (m, 4H), 0.71-0.86 (m, 2
H). LC-MS: m / z 448.0 (M + H) +

5- (1-acryloylpiperidin-3-yl) -2-((R) -4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile (compound 576; general Procedure 1, Step I). 1H NMR (chloroform-d
) 7.51-7.57 (m, 1H), 6.53-6.73 (m,
1H), 6.25-6.41 (m, 1H), 5.65-5.80 (
m, 1H), 4.02-5.02 (m, 6H), 2.94-4.00.
(M, 5H), 2.37-2.49 (m, 1H), 2.28-2.
37 (m, 1H), 1.92-2.13 (m, 1H), 1.57-
1.80 (m, 6H), 0.96-1.22 (m, 6H), 0.69
-0.88 (m, 2H). LC-MS: m / z 448.2 (M + H) +

(R) -6- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropyl-3,3′-bipyridine-5,6′-dicarbonitrile (Compound 583; general Procedure 1, Step H). 1H NMR (chloroform-d) δ 8.
80 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 8.
0, 2.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H)
7.62 (s, 1H), 4.09-4.85 (m, 4H), 3.2
2-3.64 (m, 3H), 1.82-1.93 (m, 1H), 1
. 75 (br. S., 1H), 1.19-1.27 (m, 2H), 0
. 96-1.12 (m, 4H), 0.73-0.92 (m, 2H).
LC-MS: m / z 413.2 (M + H) +

(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -3,3'-bipyridine-5,6'-dicarbonitrile (Compound 584) General procedure 1, step I). 1H NMR (chloroform-d) δ 8.
79 (d, J = 1.5 Hz, 1H), 7.90 (dd, J = 8.
0, 2.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H)
, 7.62 (s, 1H), 4.89 (br. S., 0.5H), 4.5
2 (d, J = 9.8 Hz, 0.5H), 4.19-4.44 (m,
2.5H), 3.65-3.78 (m, 2.5H), 3.54 (t,
J = 11.0 Hz, 0.5H), 3.28-3.43 (m, 4H),
3.03-3.27 (m, 1.5H), 2.50-2.80 (m,
2H), 1.82-1.92 (m, 1H), 1.36 (d, J = 6)
. 5 Hz, 1.5H), 1.23-1.28 (m, 1.5H), 1.1
7-1.23 (m, 2H), 0.94-1.06 (m, 2H); L
C-MS: m / z 431.2 (M + H)

(R) -6- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropyl-2'-ethynyl-3,4'-bipyridine-5-carbonitrile (Compound 593; General procedure 1, step H). 1H NMR (chloroform-d)
δ 8.67 (d, J = 5.3 Hz, 1H), 7.62 (s, 1H)
, 7.46-7.59 (m, 1H), 7.35 (dd, J = 5.1
, 1.6 Hz, 1H), 4.15-4.90 (m, 4H), 3.13
-3.75 (m, 4H), 1.94-2.04 (m, 1H), 1.7
6 (br. S., 1H), 1.28-1.39 (m, 3H), 1.2
1 (dt, J = 7.0, 3.5 Hz, 2H), 0.95-1.09
(M, 4H), 0.76-0.88 (m, 2H). LC-MS: m /
z 413.9 (M + H) +

(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (1-propioroyl-1,2,5,6-tetrahydropyridine-3- Yl) nicotinonitrile (Compound 594; General Procedure 1, Step H). 1
1 H NMR (chloroform-d) δ 7.48 (d, J = 5.5 Hz,
1H), 5.90 (d, J = 11.3 Hz, 1H), 4.0 1 −
4.85 (m, 7), 3.96 (t, J = 5.9 Hz, 1H), 3
. 82 (t, J = 5.9 Hz, 1H), 3.03-3.80 (m,
4H), 2.82 (s, 1H), 2.44 (d, J = 3.5 Hz,
1H), 2.38 (d, J = 3.5 Hz, 1H), 2.06-2
. 12 (m, 1H), 1.31-1.37 (m, 3H), 0.97-
1.17 (m, 6H), 0.81 (d, J = 7.8 Hz, 2H).
LC-MS: m / z 444.1 (M + H) +

(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-3′-fluoro-2′-vinyl-3,4′-bipyridine-5-carbonitrile (compound 520; general procedure 1, step I). 1H NMR
(Chloroform-d) δ 8.46 (d, J = 4.8 Hz, 1H), 7
. 64 (s, 1H), 7.19 (t, J = 5.1 Hz, 1H), 7
. 08 (ddd, J = 17.4, 11.0, 1.3 Hz, 1H), 6
. 51 (dd, J = 17.3, 1.8 Hz, 1H), 5.66 (dd
, J = 10.9, 1.6 Hz, 1H), 4.59 (d, J = 12
. 8 Hz, 1H), 4.47 (d, J = 12.5 Hz, 1H), 4
. 22 (br. S., 0.5H), 4.05 (br. S., 0.5H),
3.76 (dt, J = 8.2, 4.0 Hz, 1H), 3.47 −
3.70 (m, 1H), 3.29 (br. S., 1H), 3.14 (b
r. s. , 1H), 1.77-1.85 (m, 1H), 1.57-
1.70 (m, 1H), 1.32-1.41 (m, 1H), 1.14
-1.24 (m, 2H), 0.88-1.11 (m, 4H), 0.7
3-0.86 (m, 2H), 0.59-0.73 (m, 1H), 0
. 36-0.59 (m, 3H). LC-MS: m / z 458.5 (M +
H) +

6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2S) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (isoquinoline-
5-yl) nicotinonitrile (Compound 514; General Procedure 2, Step M). 1H NM
R (chloroform-d) δ 9.35 (s, 1H), 8.54 (dd, J
= 5.9, 1.9 Hz, 1H), 8.07 (d, J = 8.0 Hz)
, 1H), 7.69-7.75 (m, 1H), 7.64-7.68.
(M, 2H), 7.44 (dd, J = 12.5, 6.0 Hz, 1H)
, 4.46-4.59 (m, 2.5H), 4.08-4.18 (m,
1H), 3.86 (br.s., 0.5H), 3.53-3.74 (
m, 3H), 3.21-3.32 (m, 2H), 1.87-2.06
(M, 2H), 1.49-1.58 (m, 1H), 1.33 (d,
J = 5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.
81-0.90 (m, 2H), 0.65 (br. S., 1H), 0.
36-0.59 (m, 3H). LC-MS: m / z 508.2 (M + H
) +

(R) -6- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropyl-3,4'-bipyridine-2 ', 5-dicarbonitrile (Compound 522; general Procedure 1, Step H). 1H NMR (chloroform-d) δ 8.
81 (d, J = 5.0 Hz, 1H), 7.80 (s, 1H), 7.
63 (s, 1H), 7.59 (dd, J = 5.1, 1.6 Hz, 1
H), 4.86 (br.s., 1H), 4.48 (br.s., 1H)
, 4.35 (d, J = 13.6 Hz, 2H), 3.63 (br. S)
. , 0.5H), 3.53 (br.s., 1H), 3.25 (br.s)
. , 1.5H), 1.85-1.99 (m, 1H), 1.76 (br.
s. , 1H), 1.60 (br.s., 3H), 1.17-1.34
(M, 4H), 1.07 (dd, J = 7.8, 3.0 Hz, 4H)
. LC-MS: m / z 413.5 (M + H) +

(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-2′-methyl-3,4′-bipyridine-5-carbonitrile (Compound 523; General Procedure 1, Step H). 1H NMR (chloroform-
d) δ 8.56 (d, J = 5.0 Hz, 1H), 7.62 (s,
1H), 7.21 (s, 1H), 7.17 (d, J = 5.3 Hz,
1H), 4.56 (d, J = 12.5 Hz, 1H), 4.44 (d,
J = 12.3 Hz, 1H), 4.04 (br.s., 1H), 3.
75 (br.s., 1.5H), 3.28 (br.s., 1.5H),
3.12 (br. S., 1H), 2.58-2.68 (m, 3H),
1.97-2.07 (m, 1H), 1.72 (br. S., 1H),
1.37 (br. S., 1H), 1.14-1.23 (m, 2H),
0.93-1.10 (m, 4H), 0.74-0.85 (m, 2H)
, 0.65 (br. S., 1H), 0.36-0.58 (m, 3H)
. LC-MS: m / z 428.5 (M + H) +

(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl)-[3,3′-bipyridine] -5,5 '−
Dicarbonitrile (Compound 525; General Procedure 2, Step M).
1H NMR (chloroform-d) δ 8.90 (d, 2H), 8.04 (
s, 1H), 7.64 (s, 1H), 4.63 (d, J = 13.1)
Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.13
(Br.s., 1H), 3.78 (br.s., 1H), 3.51 (
s, 1H), 3.33 (d, J = 9.0 Hz, 2H), 3.24 (
d, J = 12.5 Hz, 1H), 3.15 (d, J = 12.3 H
z, 1H), 2.03 (dt, J = 15.3, 7.4 Hz, 1H),
1.01-1.12 (m, 3H), 0.82-0.95 (m, 4H
), 0.66 (br. S., 1H), 0.45-0.53 (m, 1H
)
LC-MS: m / z 481.4 (M + H) +

Compound 540 (General Procedure 2, Step M)
(R) -5′-cyano-2′-cyclopropyl-6 ′-(3-cyclopropyl-4- (
3,3,3-trifluoropropanoyl) piperazin-1-yl)-[3,3′-bipyridine] -5-carboxamide 1H NMR (methanol-d) δ9.05 (br.s., 1H), 8 .8
1 (br. S., 1H), 8.26 (t, J = 2.1 Hz, 1H)
, 7.60-7.77 (m, 1H), 6.81 (br.s., 1H)
, 6.25 (br. S., 1H), 4.57 (d, J = 13.1 H
z, 1H), 4.46 (d, J = 12.3 Hz, 1H), 4.01.
-4.25 (m, 1H), 3.65-3.88 (m, 2H), 3.1
2-3.38 (m, 4H), 2.03-2.24 (m, 1H), 1
. 86-1.96 (m, 1H), 1.15-1.28 (m, 4H),
0.97-1.06 (m, 2H), 0.28-0.58 (m, 4H
)
LC-MS: m / z 499.5 (M + H) +

Compound 554 (General Procedure, Step I)
(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-5 ′-(1H-tetrazol-5-yl)-[3,3
'-Bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 9.47 (br. S, 1H), 8.
86 (s, 1H), 8.62 (s, 1H), 7.73 (s, 1H),
4.59-4.47 (m., 7H), 1.19-1.30 (m, 1H
), 1.14-1.05 (m, 3H), 0.84-0.98 (m, 1
0H), 0.42-0.57 (m, 4H)
LC-MS: m / z 482.5 (M + H) +

Compound 601 (General Procedure, Step I)
(R) -6-cyclopropyl-5- (5-fluoro-4-vinylpyrimidin-2-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotino Nitrile 1H NMR (chloroform-d) δ 8.62 (d, J = 1.8 Hz,
1H), 8.35-8.44 (m, 1H), 7.03 (dd, J =
17.3, 10.8 Hz, 1H), 6.70-6.82 (m, 1H),
5.81-5.92 (m, 1H), 4.90 (br. S., 0.5H
), 4.52 (m, 3.5H), 4.28-4.47 (m, 3H),
3.68-3.86 (m, 3H), 3.54 (br. S., 1H),
3.01-3.21 (m, 3H), 2.63-2.79 (m, 1H)
, 2.51-2.63 (m, 1H), 1.23-1.26 (m, 4
H), 1.18-1.23 (m, 2H), 1.04 (m, 2H)
LC-MS: m / z 451.5 (M + H) +

Compound 538 (General Procedure 1, Step I)
(R) -5- (2-Aminoquinazolin-5-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile 1H NMR (chloroform -D) δ 8.82 (d, J = 9.5 Hz,
1H), 7.70-7.84 (m, 1H), 7.55-7.70 (
m, 2H), 7.11-7.23 (m, 1H), 5.52 (br. s)
. , 2H), 4.39-4.67 (m, 2.5H), 4.16-4.32.
(M, 1H), 3.60-3.85 (m, 1H), 3.10-3.41 (m
, 2.5H), 1.73 (s, 1H), 1.53-1.65 (m, 1
H), 1.27-1.33 (m, 1H), 1.18-1.24 (m,
1H), 1.11-1.18 (m, 1H), 0.98-1.10 (
m, 2H), 0.79-0.90 (m, 4H), 0.61-0.74
(M, 1H), 0.40-0.61 (m, 3H)
LC-MS: m / z 480.2 (M + H) +

Compound 567 (General Procedure 1, Step H)
(R) -6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-6 ′-(trifluoromethyl)-[3,3′-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.83 (d, J = 1. 8 Hz,
1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H), 7.
77-7.87 (m, 1H), 7.65 (s, 1H), 4.40-4.
72 (m, 2.5H), 3.97-4.20 (m, 1H), 3.51-
3.78 (m, 1H), 3.08-3.62 (m, 2.5H), 1.86 −
1.98 (m, 1H), 1.72 (s, 1H), 1.34-1.45 (
m, 1H), 1.20-1.28 (m, 2H), 0.97-1.10
(M, 4H), 0.76-0.87 (m, 2H), 0.40-0.
67 (m, 3H)
LC-MS: m / z 482.2 (M + H) +

Compound 586 (General Procedure 1, Step H)
(R) -2 ′, 6′-Dichloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] -5 -Carbonitrile 1H NMR (chloroform-d) δ 7.61 (s, 1H), 7.34 (
s, 2H), 4.91 (s, 0.5H), 4.50-4.56 (m, 0.
5H), 4.22-4.50 (m, 2.5H), 3.68-3.89
(M, 2.5H), 3.49-3.62 (m, 0.5H), 3.28-
3.43 (m, 4H), 3.06-3.27 (m, 1.5H),
64-2.83 (m, 1H), 2.55-2.64 (m, 1H),
1.92-2.01 (m, 1H), 1.37 (d, J = 6.5 Hz)
, 2H), 1.21-1.31 (m, 3H), 1.01-1.12.
(M, 2H)
LC-MS: m / z 474.1 (M + H) +

Compound 622
(R) -2-cyclopropyl-2′-methoxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -6′-vinyl- [3,4′-bipyridine] −
5-carbonitrile

(R) -2′-Chloro-2-cyclopropyl-6′-methoxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] −
5-carbonitrile (40 mg, 0.085 mmol), potassium vinyl trifluoroborate (18 mg, 0.128 mmol), Pd (dppf) Cl ₂ (4 mg, 0.00
43 mmol), CsF (39 mg, 0.255 mmol) in dioxane / H ₂ O was stirred at 100 ° C. for 16 h, the mixture was partitioned between EtOAc and water, and the organics were washed with water, brine and concentrated. To obtain a crude product which is purified by column 15
mg product was obtained.
1H NMR (chloroform-d) δ 7.60 (s, 1H), 6.86 (
d, J = 1.0 Hz, 1H), 6.75 (dd, J = 17.1,
10.5 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H),
6.36 (dd, J = 17.2, 1.6 Hz, 1H), 5.49 (d
d, J = 10.5, 1.8 Hz, 1H), 4.90 (s, 0.5H)
, 4.53 (d, J = 13.3 Hz, 0.5H), 4.22-4.
38 (m, 2.5H), 4.02 (s, 3H), 3.78-3.84
(M, 0.5H), 3.75 (t, J = 6.1 Hz, 2H), 3.5
1-3.58 (m, 0.5H), 3.38 (s, 3H), 3.28 (
t, J = 9.9 Hz, 1H), 3.00-3.19 (m, 1.5H
), 2.65-2.79 (m, 1H), 2.54-2.64 (m,
1H) 2.03-2.10 (m, 1H), 1.38 (d, J = 6.
3 Hz, 1H), 1.28 (d, J = 6.8 Hz, 2H), 1.1
3-1.21 (m, 2H), 0.94-1.03 (m, 2H)
LC-MS: m / z 461.2 (M + H) +

Compound 623
(R) -2′-Chloro-2-cyclopropyl-6′-methoxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] −
5-carbonitrile

(R) -2 ′, 6′-Dichloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] -5 -Carbonitrile (300 mg, 0.623 mmol) in MeOH to NaOMe (69 m
g, 1.26 mmol) was added and the mixture was refluxed for 16 hours. After cooling, the mixture is
Partitioned between Ac and water. The organic layer was washed with water, brine and dried over Na ₂ SO ₄ . The organic layer was concentrated to give a crude that was purified by preparative HPLC to give 150 mg of product.
1H NMR (chloroform-d) δ 7.54-7.63 (m, 1H),
6.97 (d, J = 1.3 Hz, 1H), 6.70 (d, J =
1.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J
= 12.8 Hz, 0.5H), 4.23-4.39 (m, 2.5H),
3.96 (s, 3H), 3.79-3.85 (m, 0.5H),
68-3.78 (m, 2H), 3.49-3.60 (m, 0.5H)
, 3.39 (s, 3H), 3.26-3.36 (m, 1H), 3.0
4-3.20 (m, 1.5H), 2.64-2.82 (m, 1H),
2.50-2.63 (m, 1H), 2.00-2.04 (m, 1),
1.38 (d, J = 6.5 Hz, 1H), 1.28 (d, J = 5
. 5 Hz, 2H), 1.13-1.21 (m, 2H), 0.97-
1.06 (m, 2H)
LC-MS: m / z 470.2 (M + H) +

Compound 624
(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -2 ', 6'-divinyl- [3,4'-bipyridine] -5 -Carbonitrile

(R) -2 ′, 6′-Dichloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] -5 -Carbonitrile (50 mg, 0.105 mmol), potassium vinyl trifluoroborate (
50 mg, 0.316 mmol), Pd (dppf) Cl ₂ (4 mg, 0.0043 mm)
ol), a mixture of CsF (50 mg, 0.316 mmol) in dioxane / H ₂ O.
Stir at 00 ° C. for 16 hours. The mixture was partitioned between EtOAc and water and the organics were washed with water, brine and concentrated to give a crude that was purified by column to give 25 mg of product.
1H NMR (chloroform-d) δ 7.63 (s, 1H), 7.24 (
s, 1H), 7.28 (s, 1H), 6.77-6.98 (m, 2H)
), 6.30 (s, 1H), 6.34 (s, 1H), 5.55 (d,
J = 10.8 Hz, 2H), 4.09 (s, 0.5H), 4.53 (
d, J = 12.3 Hz, 0.5H), 4.21-4.36 (m, 2
. 5H), 3.68-3.85 (m, 3H), 3.50-3.61 (
m, 0.5H), 3.38 (s, 4H), 3.03-3.15 (m,
1H), 2.70 (dd, J = 15.7, 6.4 Hz, 1H), 2.
51-2.59 (m, 1H), 1.90-2.12 (m, 1H),
36-1.42 (m, 1H), 1.22-1.30 (m, 2H),
1.18 (s, 2H), 0.94-1.05 (m, 2H)
LC-MS: m / z 458.2 (M + H) +

Compound 634 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR ( Chloroform-d) δ 9.15 (d, J = 11.3 Hz)
, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.93 (t
, J = 7.8 Hz, 1H), 7.64 (d, J = 3.3 Hz,
1H), 7.50 (dd, J = 10.3, 7.3 Hz, 1H), 7.
04 (dd, J = 17.2, 10.7 Hz, 1H), 6.78 (d,
J = 17.1 Hz, 1H), 5.85 (d, J = 10.5 Hz,
1H), 4.64-4.76 (m, 1H), 4.42-4.49 (
m, 1H), 3.88 (d, J = 13.6 Hz, 0.5H), 3.7
3 (d, J = 5.8 Hz, 2H), 3.61 (d, J = 9.8)
Hz, 0.5H), 3.39-3.50 (m, 0.5H), 3.37 (
s, 3H), 3.05-3.25 (m, 2H), 2.85-3.10.
(M, 0.5H), 2.50-2.85 (m, 2H), 2.18-2.
33 (m, 1H), 1.99-2.15 (m, 1H), 0.99-
1.22 (m, 6H), 0.82-0.94 (m, 5H)
LC-MS: m / z 511.3 (M + H) +

Compound 635 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR (Chloroform-d) δ 9.15 (d, J = 7.8 Hz,
1H), 8.04 (d, J = 8.5 Hz, 1H), 7.94 (t,
J = 7.8 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1
H), 7.43-7.56 (m, 1H), 7.04 (dd, J = 1)
7.3, 10.5 Hz, 1H), 6.78 (d, J = 17.1 Hz,
1H), 5.85 (d, J = 10.5 Hz, 1H), 4. . 33-4
. 80 (m, 2.5H), 4.07-4.22 (m, 0.5H), 2.
85-4.02 (m, 1H), 3.60-3.81 (m, 3H),
3.37 (s, 3H), 2.98-3.26 (m, 2H), 2.37
-2.76 (m, 2H), 1.98-2.28 (m, 1H), 1.5
1-1.61 (m, 1H), 1.11-1.26 (m, 2H), 0
. 86 (d, J = 7.8 Hz, 2H), 0.40-0.55 (m,
4H)
LC-MS: m / z 509.3 (M + H) +

Compound 636 (General Procedure 1, Step I)
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.16 (d, J = 8.0 Hz,
1H), 8.04 (d, J = 8.5 Hz, 1H), 7.94 (t,
J = 7.8 Hz, 1H), 7.62-7.72 (m, 1H), 7
. 44-7.56 (m, 1H), 7.05 (dd, J = 17.3,
10.5 Hz, 1H), 6.78 (d, J = 17.1 Hz, 1H),
5.75-5.95 (m, 1H), 4.49-4.66 (m, 2.5
H), 4.05-4.25 (m, 1H), 3.75-3.88 (m,
1H), 3.06-3.32 (m, 2.5H), 2.29 (s, 1H),
1.50-1.57 (m, 1H), 1.34-1.47 (m, 1H
), 1.14-1.22 (m, 2H), 0.98-1.09 (m,
2H), 0.77-0.91 (m, 4H), 0.39-0.67 (m
, 4H)
LC-MS: m / z 491.2 (M + H) +

Compound 645 (General Procedure 1, Step I) (R) -6-cyclopropyl-2- (3-
Cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2
-Vinyl-1,8-naphthyridin-4-yl) nicotinonitrile (core synthesis method 1 using 4-chloro-2-vinyl-1,8-naphthyridine as a starting material)

In a sealed tube, 120 mg 4-chloro-2-vinyl-1,8-naphthyridine, 242 m
g 8-3 (0.5 mmol), 230 mg CsF (1.5 mmol), 41 mg P
d (dppf) ₂ Cl ₂ (0.05 mmol) and 10 mL of dioxane were added, and then when LC-MS showed product formation, the mixture was placed in a microwave reactor (100 ° C., 3 ° C.
0 minutes). The resulting mixture was then filtered, the filtrate was concentrated and preparative TLC (
Purification by petroleum ether: ethyl acetate = 2: 1) gave 45 mg of the title compound.
1H NMR (chloroform-d) δ 9.17 (dd, J = 4.3, 1
. 8 Hz, 1H), 8.03 (td, J = 8.7, 1.8 Hz, 1
H), 7.68 (d, J = 1.3 Hz, 1H), 7.61 (d, J
= 3.5 Hz, 1H), 7.48 (dd, J = 8.3, 4.3 H)
z, 1H), 7.15 (dd, J = 17.7, 10.9 Hz, 1H)
6.57 (dd, J = 17.6, 1.8 Hz, 1H), 5.83
(D, J = 11.0 Hz, 1H), 4.60 (d, J = 12.3)
Hz, 2H), 4.49 (d, J = 12.8 Hz, 1H), 4.15.
(Br.s., 0.5H), 3.91 (br.s., 0.5H), 3.
65-3.85 (m, 3H), 3.40 (s, 4H), 3.27 (d
, J = 12.0 Hz, 2H), 2.67 (br.s., 2H), 1
. 20 (d, J = 4.5 Hz, 2H), 0.82-0.98 (m,
2H), 0.66 (br.s., 1H), 0.59 (br.s., 1
H), 0.49 (d, J = 5.0 Hz, 2H)
LC-MS: m / z 509.1 (M + H) +

Compound 629 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ 8.99-9.21 (m, 1H),
7.9 (dd, J = 12.4, 8.4 Hz, 1H), 7.50 −
7.72 (m, 2H), 7.45 (dt, J = 7.8, 3.7 Hz)
, 1H), 7.11 (dd, J = 17.4, 10.9 Hz, 1H),
6.53 (d, J = 17.6 Hz, 1H), 5.79 (d, J =
10.8 Hz, 1H), 4.56-4.78 (m, 1.5H), 4.
35-4.56 (m, 2H), 3.74-3.99 (m, 2.5H)
3.37-3.60 (m, 1H), 3.06-3.28 (m, 2
H), 2.92-3.06 (m, 1H), 2.53-2.83 (m,
3H), 2.12 (dt, J = 10.0, 6.5 Hz, 1H), 1
. 43-1.55 (m, 1H), 0.98-1.15 (m, 4H),
0.72-0.97 (m, 5H)
LC-MS: m / z 497.3 (M + H) +

Compound 625 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ 9.05-9.19 (m, 1H),
7.98 (ddd, J = 6.1, 4.3, 2.1 Hz, 1H), 7
. 63-7.68 (m, 1H), 7.55-7.61 (m, 1H),
7.41-7.47 (m, 1H), 7.03-7.17 (m, 1H
), 6.52 (d, J = 17.6 Hz, 1H), 5.72-5.8
4 (m, 1H), 4.89 (br. S., 0.5H), 4.54 (d,
J = 12.5 Hz, 1H), 4.39 (d, J = 13.8 Hz,
1H), 4.29 (d, J = 19.8 Hz, 2H), 4.20 (b
r. s. , 1H), 3.82-4.00 (m, 2.5H), 3.01
-3.24 (m, 2H), 2.46-2.76 (m, 3H), 1.0
6-1.19 (m, 2H), 0.75-0.94 (m, 3H)
LC-MS: m / z 469.2 (M + H) +

Compound 626 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-yl)
Nicotinonitrile 1H NMR (chloroform-d) δ 9.12 (S, 1h), 7.9 (
br. s. , 1H), 7.52-7.69 (m, 2H), 7.36-
7.50 (m, 1H), 7.00-7.19 (m, 1H), 6.53
(D, J = 17.6 Hz, 1H), 5.78 (d, J = 10.8)
Hz, 1H), 4.71 (br. S., 1.5H), 4.35-4.
52 (m, 2H), 3.58-3.81 (m, 3.5H), 3.37
(D, J = 3.0 Hz, 4H), 3.18 (dd, J = 13.6,
3.5 Hz, 2H), 2.52-2.82 (m, 2H), 1.08
(Dt, J = 12.0, 5.7 Hz, 4H), 0.87 (d, J =
(6.8 Hz, 6H)
LC-MS: m / z 511.2 (M + H) +

Compound 599 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ 9.14 (dd, J = 4.1, 1
. 9 Hz, 1H), 7.98 (br.s., 1H), 7.65 (s,
1H), 7.59 (s, 1H), 7.45 (dd, J = 8.3, 4.
3 Hz, 1H), 7.11 (d, J = 10.8 Hz, 1H), 6.
44-6.62 (m, 1H), 5.80 (d, J = 10.8 Hz,
1H), 4.94 (br. S., 0.5H), 4.55 (br. S.,
0.5H), 4.42 (br.s., 3H), 3.75 (d, J =
6.3 Hz, 3H), 3.39 (s, 4H), 3.15 (br. S.,
2H), 2.63 (br. S., 2H), 1.10-1.22 (m,
3H), 0.72-0.97 (m, 4H)
LC-MS: m / z 483.1 (M + H) +

Compound 596 (General Procedure 1, Step I)
(R) -2'-cyclopropyl-6 '-(4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-vinyl-2,3'-bipyridine-5'-carbonitrile 1H NMR (chloroform-d) δ: 8.67 (d, J = 5.3 Hz)
, 1H), 7.89 (s, 1H), 7.50 (s, 3H), 6.63
-6.82 (m, 1H), 6.04 (d, J = 17.6 Hz, 1H
), 5.57 (d, J = 11.0 Hz, 1H), 4.91 (br.
s. , 0.5H), 4.51 (br. S., 1H), 4.34 (br.
s. , 3H), 3.65-3.83 (m, 2.5H), 3.33-3
. 44 (m, 4H), 3.29 (br. S., 1H), 2.71 (br
. s. , 1H), 2.62 (br. S., 2H), 1.33-1.4
3 (m, 3H), 1.15-1.25 (m, 4H)
LC-MS: m / z 431.2 (M + H) +

Compound 612 (General Procedure 1, Step I)
(R) -5- (1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-
2- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropylnicotinonitrile 1H NMR (chloroform-d) δ 7.48-7.56 (m, 1H),
6.31-6.57 (m, 2H), 5.97 (d, J = 2.0 H
z, 1H), 5.65-5.88 (m, 1H), 4.01-4.90.
(M, 8H), 3.02-3.81 (m, 3H), 2.09-2.
34 (m, 1H), 1.75 (br.s., 2H), 1.25-1.
37 (m, 3H), 1.09-1.22 (m, 2H), 0.95-
1.09 (m, 4H), 0.67-0.94 (m, 2H)
LC-MS: m / z 432.2 (M + H) +

Compound 620 (General Procedure 1, Step I)
(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -6'-vinyl-3,3'-bipyridine-5-carbonitrile 1H NMR (Chloroform-d) δ 8.63 (d, J = 2.0 Hz,
1H), 7.66-7.74 (m, 1H), 7.58-7.65 (
m, 1H), 7.40-7.50 (m, 1H), 6.87 (dd, J
= 17.6, 10.8 Hz, 1H), 6.27 (dd, J = 17.
6, 1.0 Hz, 1H), 5.54 (dd, J = 10.8, 1.0
Hz, 1H), 4.90 (br. S., 0.5H), 4.52 (d, J
= 13.1 Hz, 0.5H), 4.17-4.41 (m, 2.5H)
3.66-3.88 (m, 2.5H), 3.54 (t, J = 11
. 2 Hz, 0.5H), 3.37 (s, 3H), 3.28 (t, J =
9.8 Hz, 1H), 2.99-3.20 (m, 1.5H), 2.5
2-2.81 (m, 2H), 1.94-2.06 (m, 1H), 1
. 33-1.41 (m, 1.5H), 1.24-1.29 (m, 1.
5H), 1.14-1.23 (m, 2H), 0.91-1.04 (m
, 2H)
LC-MS: m / z 432.1 (M + H) +

Compound 619 (General Procedure 1, Step I)
(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,3'-bipyridine-5-carbonitrile 1H NMR (Chloroform-d) δ 8.54-8.72 (m, 1H),
7.45-7.58 (m, 2H), 7.18-7.34 (m, 1H
), 6.53-6.69 (m, 1H), 6.38-6.47 (m,
1H), 5.43 (d, J = 10.8 Hz, 1H), 4.90 (br
. s. , 0.5H), 4.52 (d, J = 13.1 Hz, 0.5H)
, 4.14-4.39 (m, 2.5H), 3.68-3.88 (m,
2.5H), 3.54 (d, J = 4.8 Hz, 0.5H), 3.37
(S, 3H), 3.23-3.33 (m, 1H), 2.99-3.
21 (m, 1.5H), 2.51-2.80 (m, 2H), 1.55
-1.69 (m, 1H), 1.39 (br. S., 1.5H), 1.2
9 (br. S., 1.5H), 1.04-1.19 (m, 2H), 0
. 79-1.00 (m, 2H)
LC-MS: m / z 432.2 (M + H) +

Compound 630 (General Procedure 1, Step I)
(R) -5- (1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6
-Cyclopropylnicotinonitrile 1H NMR (chloroform-d) δ 7.45 (s, 1H), 6.64 (
td, J = 16.1, 10.7 Hz, 1H), 6.29-6.42.
(M, 1H), 5.67-5.86 (m, 2H), 4.00-5.0
0 (m, 6H), 3.85-3.93 (m, 1H), 3.79 (t,
J = 5.3 Hz, 1H), 3.00−3.63 (m, 3H), 2
. 39-2.52 (m, 2H), 1.96-2.12 (m, 1H),
1.75 (br.s., 1H), 1.28-1.51 (m, 3H),
1.08-1.17 (m, 2H), 0.94-1.08 (m, 4H
), 0.76-0.86 (m, 2H)
LC-MS: m / z 446.0 (M + H) +

Compound 557 (General Procedure 1, Step I)
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-methyl-1,8-naphthyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 0.39-0.53 (m, 1 H )
0.56 (d, J = 4.52 Hz, 3 H) 0.79-0.94 (m
, 4 H) 0.94-1.14 (m, 3 H) 1.22 (br. S.
, 2 H) 1.27 (br. S., 2 H) 1.33 (br. S.,
2 H) 3.01 (s, 3 H) 4.53 (d, J = 12.55 Hz,
2.5 H) 7.46 (s, 1 H) 7.58 (br. S., 1 H)
7.67 (s, 1 H) 8.14 (br. S., 1 H) 9.22 (b
r. s. , 1 H)
LC-MS: m / z 479.3 (M + H) +

Compound 552 (General Procedure 2, Step M)
(R) -tert-butyl 5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) pyridine-3 -Yl) -1H-indazole-1-carboxylate

70 mg (R) -6-cyclopropyl-2- (3-cyclopropylpiperazin-1-yl) -5- (1H-indazol-5-yl) nicotinonitrile (NB247-78) in 10 mL DCM ( 0.18 mmol), 83 mg HATU (0.22 mmol)
, 37 mg TEA, 23 mg 3,3,3-trifluoropropanoic acid (0.18 mm
ol) was added, then the mixture was stirred at room temperature for 2 hours, concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 1: 1) to give 31.5 mg of the title compound. 1H
NMR (chloroform-d) δ 7.98 (br.s., 1H), 7.7
7 (s, 1H), 7.42-7.62 (m, 2H), 7.15 (d,
J = 7.0 Hz, 1H), 4.56 (d, J = 13.1 Hz,
2H), 4.13 (br.s., 0.5H), 3.84 (br.s.,
1.5H), 3.35 (d, J = 10.0 Hz, 2H), 3.23 (
br. s. , 2H), 3.12 (br. S., 1H), 1.94 (s,
1H), 1.15-1.32 (m, 5H), 0.94 (dd, J =
7.8, 3.3 Hz, 2H), 0.52 (d, J = 5.3 Hz,
2H)
LC-MS: m / z 495.2 (M + H) +

Compound 537 (General Procedure 2, Step M)
(R) -5- (Benzo [d] thiazol-6-yl) -6-cyclopropyl-2- (3
-Cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.07 (s, 1H), 8.22 (
d, J = 8.5 Hz, 1H), 7.9 (d, J = 1.5 Hz,
1H), 7.71 (s, 1H), 7.57 (dd, J = 8.4, 1
. 6 Hz, 1H), 4.53 (d, J = 13.3 Hz, 1H), 4
. 42 (d, J = 12.8 Hz, 1H), 3.98-4.21 (m
, 0.5H), 3.67-3.95 (m, 1.5H), 3.26-3
. 38 (m, 2H), 3.15-3.26 (m, 2H), 3.09 (
t, J = 11.3 Hz, 1H), 2.04-2.12 (m, 1H)
, 1.42 (d, J = 14.3 Hz, 1H), 1.17-1.24
(M, 2H), 0.95-1.03 (m, 2H), 0.67 (br.
s. , 1H), 0.57 (br. S., 1H), 0.45-0.53
(M, 2H)
LC-MS: m / z 512.1 (M + H) +

Compound 536 (General Procedure 2, Step M)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (2-methyl-1-oxo-1 , 2
-Dihydroisoquinolin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.45-8.58 (m, 1H)
, 7.59-7.69 (m, 2H), 7.47-7.59 (m, 1
H), 7.23 (d, J = 8.0 Hz, 1H), 7.07 (d, J
= 1.8 Hz, 1H), 4.53 (d, J = 13.1 Hz, 1H
), 4.43 (d, J = 12.0 Hz, 1H), 4.12 (br.
s. , 0.5H), 3.78 (br. S., 1H), 3.67 (s, 3
H), 3.33 (q, J = 9.8 Hz, 2H), 3.16-3.2
6 (m, 1H), 3.03-3.16 (m, 0.5H), 1.92 (
br. s. , 1H), 1.69-1.80 (m, 1H), 1.20 −
1.28 (m, 2H), 1.07-1.19 (m, 2H), 0.81
-0.95 (m, 2H), 0.67 (br. S., 1H), 0.57
(Br.s., 1H), 0.43-0.54 (m, 2H)
LC-MS: m / z 536.2 (M + H) +

Compound 580 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) d: 9.56 (s, 1H), 8.59
(D, J = 5.8 Hz, 1H), 7.74 (s, 1H), 7.64
-7.70 (m, 1H), 7.44-7.52 (m, 1H), 7.1
1 (dd, J = 17.7, 10.9 Hz, 1H), 6.44 (dd,
J = 17.7, 1.6 Hz, 1H), 5.83 (d, J = 11.
0 Hz, 1H), 4.95 (br. S., 0.5H), 4.58 (d,
J = 11.3 Hz, 0.5H), 4.42 (d, J = 11.3 H
z, 1.5H), 4.31 (br. s., 1H), 3.86 (d, J
= 13.1 Hz, 0.5H), 3.72-3.81 (m, 2H), 3
. 55-3.68 (m, 0.5H), 3.4 (s, 3H) 3.34-
3.39 (m, 0.5H), 3.04-3.30 (m, 2H), 2.5
3-2.83 (m, 2H), 1.47-1.55 (m, 1H), 1
. 37-1.46 (m, 1.5H), 1.29-1.37 (m, 1.
5H), 1.20 (t, J = 4.9 Hz, 2H), 0.84-0.
96 (m, 2H)
LC-MS: m / z 483.2 (M + H) +

Compound 609 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ 9.50-9.65 (m, 1H),
8.60 (d, J = 6.0 Hz, 1H), 7.74-7.82 (
m, 1H), 7.62-7.72 (m, 1H), 7.48-7.57.
(M, 1H), 7.11 (dd, J = 17.7, 10.9 Hz, 1
H), 6.45 (dd, J = 17.6, 1.8 Hz, 1H), 5.8
5 (d, J = 11.0 Hz, 1H), 4.93 (br. S., 0.
5H), 4.50-4.64 (m, 0.5H), 4.40-4.49.
(M, 1H), 4.31-4.40 (m, 1H), 4.22 (br.
s. , 0.5H), 3.91-4.01 (m, 2H), 3.78 (d,
J = 11.3 Hz, 0.5H), 3.61 (d, J = 11.8 H
z, 0.5H), 3.39 (d, J = 13.6 Hz, 1H), 3.1
0-3.31 (m, 1.5H), 2.65-2.80 (m, 1H),
2.52-2.65 (m, 1H), 1.43-1.54 (m, 3H
), 1.35 (t, J = 5.6 Hz, 2H), 1.21 (dd, J
= 6.9, 3.6 Hz, 2H), 0.87-0.98 (m, 2H)
LC-MS: m / z 469.2 (M + H) +

Compound 611 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl)
Nicotinonitrile 1H NMR (chloroform-d) d: 9.57 (s, 1H), 8.60
(Dd, J = 5.6, 3.1 Hz, 1H), 7.75 (d, J =
12.0 Hz, 1H), 7.66 (dd, J = 4.8, 3.3 Hz,
1H), 7.45-7.55 (m, 1H), 7.04-7.17 (
m, 1H), 6.44 (d, J = 17.6 Hz, 1H), 5.84.
(D, J = 10.8 Hz, 1H), 4.61-4.81 (m, 1.
5H), 4.42-4.56 (m, 1.5H), 3.92 (d, J =
13.6 Hz, 0.5H), 3.70-3.83 (m, 2H), 3.
44-3.56 (m, 0.5H), 3.37-3.43 (m, 3H)
, 3.08-3.31 (m, 2H), 2.90-3.05 (m, 0.
5H), 2.55−2.85 (m, 2H), 1.49 (dd, J = 7
. 4, 4.4 Hz, 1H), 1.14-1.32 (m, 2H), 1.
11 (ddd, J = 15.2, 6.5, 4.1 Hz, 4H), 0.8
3-0.98 (m, 5H)
LC-MS: m / z 511.3 (M + H) +

Compound 542
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylquinolin-4-yl) nicotinonitrile

Step 1: 10 mg of PdCl2 (dppf) in a reaction tube under nitrogen. CH2Cl2, 5 mL dioxane, 3 mL water, 150 mg (0.98 mmol) CsF, 75 m
g (0.43 mmol) quinolin-4-ylboronic acid and 150 mg (0.36 mm)
ol) (R) -5-bromo-2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile was added. The reaction solution was heated to 100 ° C. for half an hour under microwave irradiation. The reaction was extracted with ethyl acetate, washed several times with water and purified by TLC preparation (petroleum ether: ethyl acetate = 1: 1) to give 50 mg (32% yield) of the desired compound. LC-MS: m / z 438.22
(M + H) +

Step 2: (R) -2- (4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropyl-5- (quinolin-4-yl) nicotinonitrile (50 mg, 0 .108 mmol) in 10 mL of anhydrous CH2Cl2
3-Chlorobenzoperoxoic acid (37 mg, 0.216 mmol) was added in portions over 1 minute. The resulting mixture was stirred at room temperature for 3 hours. Then saturated aqueous Na2S
O3 (10 mL) was added to the reaction. The reaction is extracted with ethyl acetate to give the desired compound (
R) -4- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) quinoline 1-oxide 48
mg (93%) was obtained. LC-MS: m / z 453.22 (M + H) +

Step 3: (R) -4- (5-cyano-6- (4- (cyclopropanecarbonyl)-
3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl)
To a solution of quinoline 1-oxide (35 mg, 0.07 mmol) in 20 mL of CHCl3, POCl3 (32 mg, 0.209) was added dropwise at room temperature. The reaction mixture was then heated at reflux for 3 hours. After LC-MS showed that the reaction was complete, the mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a brown solid 30 mg (83.3%). LC-M
S: m / z 472.18 (M + H) +

Step 4 is similar to Compound 390 Step 2: Compound 542
1H NMR (chloroform-d) d: 8.21 (d, J = 8.3 Hz)
, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.68 (d
, J = 1.0 Hz, 1H), 7.48-7.66 (m, 3H),
7.13 (dd, J = 17.4, 10.9 Hz, 1H), 6.35 (
d, J = 17.6 Hz, 1H), 5.76 (d, J = 11.0 H
z, 1H), 4.61 (d, J = 12.5 Hz, 1.5H), 4.4
9 (d, J = 12.3 Hz, 1.5H), 4.12 (br. S.,
1H), 3.67-3.82 (m, 1H), 3.34 (br. S., 1.
5H), 3.19 (br.s., 1.5H), 1.58 (ddd, J =
12.0, 7.8, 4.5 Hz, 1H), 1.14-1.35 (m,
4H), 1.00-1.13 (m, 2H), 0.76-0.93 (
m, 4H), 0.71 (br. s., 1H), 0.38-0.63 (
m, 3H)
LC-MS: m / z 490.6 (M + H) +

Compound 543
(R) -5- (2-Chloroquinolin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) d: 8.12 (d, J = 8.3 Hz)
, 1H), 7.76-7.84 (m, 1H), 7.61-7.68.
(M, 2H), 7.53-7.61 (m, 1H), 7.38 (d, J
= 1.8 Hz, 1H), 4.63 (d, J = 12.5 Hz, 1H
), 4.51 (d, J = 12.5 Hz, 1H), 3.97-4.2
0 (m, 1H), 3.82 (br. S., 1H), 3.59-3.7
8 (m, 1H), 3.34 (br. S., 1H), 3.20 (br.
s. , 1H), 1.74 (br.s., 2H), 1.50-1.59
(M, 1H), 1.14-1.26 (m, 2H), 0.97-1.1
4 (m, 2H), 0.79-0.97 (m, 4H), 0.70 (br
. s. , 1H), 0.42-0.63 (m, 3H)
LC-MS: m / z 499.0 (M + H) +

Compound 571
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-4-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) d: 8.18 (d, J = 8.5 Hz)
, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.69 (d
, J = 1.0 Hz, 1H), 7.46-7.64 (m, 3H),
7.11 (dd, J = 17.7, 10.9 Hz, 1H), 6.28 −
6.39 (m, 1H), 5.75 (d, J = 11.0 Hz, 1H)
, 4.59 (d, J = 13.1 Hz, 1H), 4.47 (d, J
= 13.1 Hz, 1H), 4.13 (d, J = 8.3 Hz, 0.5
H), 3.94 (br.s., 2H), 3.82 (br.s., 1H)
, 3.76 (br.s., 1H), 3.43 (br.s., 1H),
3.21-3.37 (m, 1.5H), 3.15 (d, J = 11.5
Hz, 1H), 2.55-2.70 (m, 2H), 1.67 (br.
s. , 1H), 1.59 (tt, J = 8.1, 4.3 Hz, 1H)
, 1.10-1.24 (m, 2H), 0.80-0.94 (m, 2
H), 0.69 (br.s., 1H), 0.58 (br.s., 1H)
, 0.51 (br.s., 2H)
LC-MS: m / z 494.2 (M + H) +

Compound 574
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-4-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) δ 8.15 (d, J = 8.5 Hz,
1H), 7.71-7.78 (m, 1H), 7.67 (d, J =
1.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.54 (
d, J = 4.5 Hz, 1H), 7.46-7.53 (m, 1H),
7.02-7.14 (m, 1H), 6.32 (dd, J = 17.6
, 1.3 Hz, 1H), 5.73 (d, J = 11.3 Hz, 1H)
, 4.71-4.74 (m, 0.5H), 4.53-4.66 (m,
1H), 4.45 (d, J = 13.1 Hz, 1H), 4.06 −
4.24 (m, 0.5H), 3.91 (d, J = 11.5 Hz, 0.
5H), 3.68-3.84 (m, 3H), 3.39 (s, 3H),
3.26 (br.s., 1.5H), 3.07-3.21 (m, 1H)
, 2.61-2.85 (m, 2H), 1.53-1.64 (m, 1
H), 1.32-1.44 (m, 1H), 1.11-1.24 (m,
2H), 0.80-0.94 (m, 2H), 0.48-0.78 (
m, 1H)
LC-MS: m / z 508.1 (M + H) +

Compound 591
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinolin-4-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) δ 8.18 (d, J = 8.3 Hz,
1H), 7.76 (ddd, J = 8.3, 6.8, 1.4 Hz, 1
H), 7.68 (s, 1H), 7.57-7.63 (m, 1H), 7
. 48-7.57 (m, 2H), 7.10 (dd, J = 17.7,
10.9 Hz, 1H), 6.34 (dd, J = 17.6, 1.8 Hz)
, 1H), 5.74 (d, J = 11.0 Hz, 1H), 4.93 (
br. s. , 0.5H), 4.48-4.68 (m, 0.5H), 4.
26-4.45 (m, 2H), 3.87-3.98 (m, 2H),
3.74-3.87 (m, 0.5H), 3.61 (t, J = 12.3
Hz, 0.5H), 3.31-3.48 (m, 2H), 3.05-
3.29 (m, 1H), 2.49-2.79 (m, 2H), 1.53
-1.63 (m, 1H), 1.46 (dd, J = 6.5, 2.5 H
z, 1.5H), 1.32-1.40 (m, 1.5H), 1.15-
1.23 (m, 2H), 0.80-0.93 (m, 2H)
LC-MS: m / z 468.2 (M + H) +

Compound 592
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinolin-4-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) δ 8.19 (d, J = 8.3 Hz,
1H), 7.76 (t, J = 7.5 Hz, 1H), 7.65-7
. 68 (m, 1H), 7.58-7.64 (m, 1H), 7.48-
7.57 (m, 2H), 7.11 (dd, J = 17.7, 10.9
Hz, 1H), 6.34 (d, J = 17.8 Hz, 1H), 5.75.
(D, J = 10.8 Hz, 1H), 4.95 (br. S., 0.5
H), 4.50-4.70 (m, 0.5H), 4.24-4.47 (
m, 2.5H), 3.71-3.89 (m, 2.5H), 3.59 (d
, J = 9.8 Hz, 0.5H), 3.31-3.45 (m, 4H)
, 3.07-3.28 (m, 1.5H), 2.67-2.85 (m,
1H), 2.54-2.67 (m, 1H), 1.52-1.62 (
m, 1H), 1.33-1.49 (m, 3H), 1.11-1.21.
(M, 2H), 0.78-0.93 (m, 2H)
LC-MS: m / z 482.2 (M + H) +

Compound 553 (General Procedure 1, Step I)
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-methyl-1,7-naphthyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) d: 9.53 (s, 1H), 59
(D, J = 5.5 Hz, 1H), 7.65 (s, 1H), 7.42
-7.50 (m, 2H), 4.63 (d, J = 9.3 Hz, 1H)
, 4.51 (d, J = 11.0 Hz, 2.5H), 3.08-3.
48 (m, 4.5H), 2.87 (s, 3H), 1.59-1.68
(M, 1H), 1.46-1.53 (m, 1H), 1.22 (d, J
= 3.0 Hz, 1H), 1.05-1.11 (m, 2H), 0.9
2-0.98 (m, 2H), 0.87-0.92 (m, 2H), 0.
84 (dd, J = 7.9, 2.6 Hz, 2H), 0.70 (br.
s. , 1H), 0.42-0.63 (m, 3H)
LC-MS: m / z 479.6 (M + H) +

Compound 551
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-5-yl)
Nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (d
, J = 8.2 Hz, 1 H), 7.91 (dd, J = 12.5, 8.8
Hz, 1 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.64
-7.71 (m, 1 H), 7.57-7.64 (m, 1 H),
7.46 (dd, J = 6.9, 2.3 Hz, 1 H), 6.97 −
7.17 (m, 1 H), 6.34 (d, J = 17.8 Hz, 1 H)
, 5.75 (d, J = 10.7 Hz, 1 H), 4.56 (dd, J =
13.0, 1.7 Hz, 1 H), 4.45 (d, J = 11.8 Hz,
1 H), 4.15 (m, 0.5 H), 3.87 (m, 1.5 H)
, 3.26-3.44 (m, 2.5 H), 3.01-3.20 (
m, 2.5 H), 1.42-1.52 (m, 1 H), 1.07-
1.21 (m, 2 H), 0.79-0.92 (m, 3 H), 0.
66-0.76 (m, 2 H), 0.46-0.56 (m, 2 H
)
LC-MS: m / z 532.2 (M + H) +

Compound 570
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-5-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.11 −
8.17 (m, 1 H), 7.85-7.95 (m, 1 H), 7
. 78 (t, J = 7.3 Hz, 1 H), 7.64-7.68 (m,
1 H), 7.60 (dd, J = 8.8, 1.5 Hz, 1 H), 7.
42-7.47 (m, 1 H), 7.00-7.13 (m, 1 H)
, 6.32 (d, J = 17.6 Hz, 1 H), 5.72 (d, J =
11.0 Hz, 1 H), 4.72 (m, 0.5 H), 4.54 (d
, J = 12.5 Hz, 1 H), 4.43 (d, J = 12.8 Hz,
1 H), 4.14 (d, J = 7.8 Hz, 0.5 H), 3.91 (
d, J = 11.8 Hz, 0.5 H), 3.75 (t, J = 5.6 Hz)
, 2.5 H), 3.40 (s, 3 H), 3.23 (d, J = 8.0
Hz, 1 H), 3.01-3.17 (m, 1 H), 2.70-
2.81 (m, 1 H), 2.67 (m, 1 H), 2.03 (d,
J = 5.5 Hz, 1 H), 1.56 (td, J = 7.8, 4.0 Hz,
1 H), 1.11-1.20 (m, 3 H), 0.78-0.86
(M, 2H), 0.58-0.66 (m, 2H), 0.42-0.
52 (m, 2 H)
LC-MS: m / z 508.2 (M + H) +

Compound 569
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-5-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.10-8
. 19 (m, 1 H), 7.90 (dd, J = 12.3, 8.8 Hz,
1 H), 7.74-7.82 (m, 1 H), 7.67 (s, 1
H), 7.58-7.63 (m, 1 H), 7.45 (ddd, J = 7
. 0, 3.0, 1.0 Hz, 1 H), 7.07 (dd, J = 17.6)
, 10.9 Hz, 1 H), 6.33 (d, J = 17.5 Hz, 1 H)
, 5.73 (d, J = 11.0 Hz, 1 H), 4.72 (d, J =
9.5 Hz, 0.5 H), 4.55 (d, J = 13.0 Hz, 1 H)
, 4.43 (d, J = 12.5 Hz, 1 H), 4.12 (d, J =
7.2 Hz, 0.5 H), 3.87-3.99 (m, 2 H), 3
. 73-3.84 (m, 1 H), 3.46 (m, 1 H), 3.2
6 (m, 1.5 H), 3.13 (d, J = 10.5 Hz, 1 H)
, 2.59-2.68 (m, 1.5 H), 2.03 (d, J = 6.0)
Hz, 1 H), 1.54-1.59 (m, 1 H), 1.11-
1.19 (m, 3 H), 0.86-0.94 (m, 2 H), 0.
80-0.86 (m, 2 H), 0.51-0.57 (m, 2 H)
LC-MS: m / z 493.3 (M + H) +

Compound 608 (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl) -5- (2-vinylquinolin-5-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ8.16-8
. 24 (m, 1 H), 7.90-7.97 (m, 1 H), 7.
76-7.83 (m, 1 H), 7.59-7.66 (m, 2 H)
7.46 (d, J = 7.0 Hz, 1 H), 7.12 (dd, J =
17.6, 10.9 Hz, 1 H), 6.35 (d, J = 17.5 Hz,
1 H), 5.76 (d, J = 11.0 Hz, 1 H), 4.95 (m
, 0.5 H), 4.58 (d, J = 12.5 Hz, 0.5 H),
19-4.44 (m, 2.5 H), 3.67-3.91 (m, 1.
5 H), 3.40 (s, 3 H), 3.15-3.26 (m, 1.5
H), 2.67-2.82 (m, 1.5 H), 2.03 (d, J =
5.7 Hz, 1 H), 1.55 (td, J = 8.0, 4.1 Hz, 1
H), 1.31-1.37 (m, 3 H), 1.11-1.18 (
m, 2 H) 0.77-0.86 (m, 2 H)
LC-MS: m / z 482.2 (M + H) +

Compound 633 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinolin-5-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (400 MHz, CHLOROFORM-d) δ 8.21 (d
, J = 8.2 Hz, 1 H), 7.87-7.99 (m, 1 H),
7.75-7.85 (m, 1 H), 7.58-7.69 (m, 2
H), 7.41-7.50 (m, 1 H), 7.12 (dd, J = 17
. 0, 11.0 Hz, 1 H), 6.35 (d, J = 17.5 Hz, 1
H), 5.76 (d, J = 11.0 Hz, 1 H), 4.93 (m,
0.5 H), 4.51-4.61 (m, 0.5 H), 4.37 (d,
J = 12.8 Hz, 1 H), 4.21-4.29 (m, 1 H),
88-3.99 (m, 2 H), 3.77 (d, J = 12.0 Hz,
0.5 H), 3.60 (t, J = 12.3 Hz, 0.5 H), 3.27
-3.44 (m, 2 H), 3.02-3.26 (m, 1 H),
2.49-2.79 (m, 2 H), 1.96-2.07 (m, 1
H), 1.51-1.60 (m, 1 H), 1.27 (s, 3 H),
1.08-1.17 (m, 2 H), 0.77-0.87 (m, 2
H)
LC-MS: m / z 468.2 (M + H) +

Compound 637
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinazolin-4-yl) nicotinonitrile

The synthesis was similar to compound 542.
1H NMR (chloroform-d) δ 8.07 (d, J = 8.3 Hz,
1H), 7.85-7.96 (m, 2H), 7.81 (d, J =
8.0 Hz, 1H), 7.57 (td, J = 7.7, 1.0 Hz,
1H), 7.08 (dd, J = 17.3, 10.5 Hz, 1H), 6
. 81 (dd, J = 17.3, 1.8 Hz, 1H), 5.79-5
. 94 (m, 1H), 4.82-4.98 (m, 0.5H), 4.54
(D, J = 12 Hz, 0.5H), 4.29-4.48 (m, 2
H), 3.93 (br. S., 2H), 3.69-3.82 (m, 0
. 5H), 3.52-3.66 (m, 0.5H), 3.43-3.52
(M, 1H), 3.31-3.43 (m, 1H), 3.01-3.
30 (m, 1.5H), 2.47-2.77 (m, 2H), 1.64
-1.79 (m, 1H), 1.42 (d, J = 6.5 Hz, 1.5
H), 1.32 (d, J = 6.5 Hz, 1.5H), 1.11-1
. 24 (m, 2H), 0.90 (d, J = 5.8 Hz, 2H)
LC-MS: m / z 469.2 (M + H) +

Compound 334 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- (2-ethyl-phenyl) -2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol- d) δ 7.59 (s, 1H), 7.33-7.
36 (d, J = 4.4 Hz, 2H), 7.24-7.27 (m, 1H),
7.12-7.13 (d, J = 7.6 Hz, 1H), 4.40-4.46 (
m, 1H), 4.14-4.23 (m, 2H), 3.92-3.96 (d,
J = 14.4 Hz, 0.5H), 3.34 (s, 3H), 3.14-3.19.
(M, 2H), 3.34 (s, 4H), 2.99-3.14 (m, 0.5
H), 2.60-2.81 (m, 2H), 2.46-2.50 (m, 2H)
), 1.64-1.69 (m, 1H), 1.37-1.41 (q, J = 7.
2Hz, 1.3H), 1.26-1.30 (t, J = 6.4Hz, 1.7H
), 1.02-1.11 (m, 5H), 0.82-0.91 (m, 2H)
LC-MS: m / z 433.6 (M + H)

Compound 357 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- (2,6-dimethyl-phenyl) -2- [4- (3
-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1HNMR (methanol-d) δ 7.48 (s, 1H), 7.11-7.
18 (m, 3H), 4.79 (s, 1H), 4.39-4.45 (m,
1H), 4.21-4.24 (d, J = 12.8 Hz, 1.5H), 4.1
3-4.17 (d, J = 13.2 Hz, 0.5H), 3.91-3.95 (d
, J = 13.6 Hz, 0.5 H), 3.66-3.69 (t, J = 5.2 Hz)
, 2H), 3.55-3.61 (t, J = 7.2 Hz, 0.5H),
34 (s, 4H), 3.10-3.21 (m, 1H), 2.96-3.0
1 (m, 0.5H), 2.69-2.80 (m, 1H), 2.60-2.65
(M, 1H), 2.01-2.02 (d, J = 2.8 Hz, 6H), 1
. 51-1.57 (m, 1H), 1.38-1.39 (d, J = 6.4 Hz,
1.3H), 1.26-1.28 (d, J = 6.8 Hz, 1.7H), 1
. 08-1.11 (m, 1H), 0.75-0.91 (m, 2H) LC-M
S: m / z 433.2 (M + H)

Compound 344 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- (2-hydroxymethyl-phenyl) -2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1HNMR (methanol-d) δ 7.63 (s, 1H), 7.58-7.
60 (d, J = 7.6 Hz, 1H), 7.40-7.44 (t, J = 7.
6Hz, 1H), 7.33-7.36 (t, J = 7.6Hz, 1H), 7
. 16-7.18 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H)
, 4.36-4.49 (m, 3H), 4.13-4.24 (m, 2H), 3
. 91-3.95 (d, J = 13.2 Hz, 0.5H), 3.66-6.69
(M, 2H), 3.54-3.61 (m, 0.5H), 3.33-3.34
(M, 4H), 3.25-3.28 (m, 0.5H), 3.13-3.15
(M, 1H), 2.96-3.02 (m, 0.5H), 2.69-2.81
(M, 1H), 2.60-2.65 (m, 1H), 1.62-1.68 (m
, 1H), 1.37-1.39 (m, 1.5H), 1.25-1.28 (m
, 1.5H), 1.11-1.12 (m, 2H), 0.83-0.92 (m,
2H); LC-MS: m / z 435.2 (M + H)

Compound 328 (General Procedure 1, Step H)
(R) -2-Cyclopropyl-2′-methoxy-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl]-[3,3 ′] bipyridyl-5-carbo Nitrile 1H NMR (methanol-d) δ 8.17-8.18 (dd, J = 4.8H
z, 1H), 7.65 (s, 1H), 7.61-7.63 (dd, J = 7
. 2Hz, 1H), 7.04-7.07 (dd, J = 7.2Hz, 1H),
4.76-4.78 (m, 0.5H), 4.38-4.44 (m, 1H),
4.13-4.25 (m, 2H), 3.90 (s, 3H), 3.66-3
. 69 (t, J = 5.6 Hz, 2H), 3.54-6.60 (m, 0.5H
), 3.33 (s, 3H), 3.15-3.19 (m, 0.5H),
3.12-3.13 (m, 1H), 2.97-3.03 (m, 0.5H),
2.69-2.80 (m, 1H), 2.59-2.65 (m, 1H), 1
. 67-1.73 (m, 1H), 1.37-1.38 (d, J = 6.4 Hz,
1H), 1.25-1.27 (d, J = 6.8 Hz, 2H), 1.10-1.1
1 (m, 2H), 0.85-0.92 (m, 2H) LC-MS: m
/ Z 436.2 (M + H)

Compound 338 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- [2- (2-methoxy-ethyl) -phenyl] -2
-[4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1HNMR (methanol-d) δ 7.63 (s, 1H), 7.51-7
. 53 (d, J = 6.4 Hz, 1H), 7.39-7.42 (m, 2H),
7.22-7.23 (dd, J = 6.8 Hz, 1H), 4.15-4.45
(M, 4H), 3.93-3.96 (m, 0.5H), 3.66-3.69
(M, 2H), 3.34 (s, 4H), 3.16-3.17 (d, J = 4
. 0 Hz, 3H), 3.13-3.14 (m, 0.5H), 3.00-3.
04 (m, 0.5H), 2.70-2.81 (m, 1H), 2.61-
2.64 (m, 1H), 1.63-1.67 (m, 1H), 1.38-1
. 40 (m, 1H), 1.26-1.29 (m, 2H), 1.12-1.2
5 (m, 2H), 0.83-0.9 4 (m, 2H) LC-MS: m / z
449.2 (M + H)

Compound 360 (General Procedure 1, Step H)
(R) -5- (2-Chloro-quinolin-3-yl) -6-cyclopropyl-2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol-d) δ 8.38 (S, 1H), 8.00-8.
02 (m, 2H), 7.85 (t, J = 7.2 Hz, 2H), 7.81
(S, 1H), 7.68 (t, J = 8.0 Hz, 1H), 4.8 (m
, 1H), 4.4-4.5 (m, 1H), 4.2-4.4 (m, 1H),
3.95 (d, J = 14.0 Hz, 0.5 H), 3.67 (t, J = 18
. 0Hz, 2h), 3.54-3.60 (m, 0.5H), 3.32-3.4
5 (m, 4.5H), 3.22-3.25 (m, 1H), 3.09-3.2
2 (m, 0.5H), 2.71-2.79 (m, 1H), 2.60-2.65
(M, 1H), 1.63-1.69 (m, 1H), 1.39-1.41 (m
, 1H), 1.30 (t, J = 6.8 Hz, 2H), 1.18-1.24 (
m, 1H), 1.12-1.17 (m, 1H), 0.95-1.15 (m,
1H), 0.85-0.95 (m, 1H). LC-MS: m / z 490.
1 (M + H) +.

Compound 371 (General Procedure 1, Step H)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- (2-methyl-2H-pyrazol-3-yl) -nicoti Nononitrile 1H NMR (methanol-d) δ 7.77 (s, 1H), 7.55 (d
, J = 2.0 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 4
. 78 (m, 0.5H), 4.21-4.44 (m, 3H), 3.94 (
d, J = 12.6 Hz, 0.5H), 3.66-3.69 (m, 4.5H),
3.54-3.62 (m, 0.5H), 3.33 (m, 3.5H),
70-2.82 (m, 1H), 2.59-2.65 (m, 1H), 1.68
-1.74 (m, 1H), 1.36 (d, J = 6.8 Hz, 1H), 1.2
7 (d, J = 11.2 Hz, 2H), 1.14-1.24 (m, 2H),
0.97-1.02 (m, 2H). LC-MS: m / z 409.2 (M + H
) +.

Compound 345 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- (3,5-dimethyl-isoxazol-4-yl) -2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl]
Nicotinonitrile 1H NMR (methanol-d) δ 7.70 (s, 1H), 4.77-4.8
0 (m, 0.5H), 4.42 (d, J = 13.2 Hz, 1H), 4.1
7-4.28 (m, 2H), 3.94 (d, J = 13.2 Hz, 0.5H)
3.68 (t, J = 5.2 Hz, 2H), 3.51-3.62 (m, 1
H), 3.31-3.33 (m, 3H), 3.14-3.24 (m, 1H)
, 3.01-3.08 (m, 0.5H), 2.71-2.80 (m, 1H)
, 2.59-2.70 (m, 1H), 2.30 (s, 3H), 2.14
(S, 3H), 1.75-1.82 (m, 1H), 1.38 (d, J = 6
. 8Hz, 1H), 1.25 (d, J = 11.2Hz, 2H), 1.15
1.20 (m, 2H), 0.98-1.02 (m, 2H). LC-MS:
m / z 424.2 (M + H) +.

Compound 394 (General Procedure 1, Step H)
(R) -6-cyclopropyl-5- (1H-indol-2-yl) -2- [4- (3
-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (chloroform-d) δ 8.27 (s, 1H), 7.79 (
s, 1H0, 7.64 (d, J = 8.0 Hz, 1H), 7.23 (t,
J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.6
5 (t, J = 1.2 Hz, 1H), 4.89 (s, 0.5H), 4.52
(D, J = 13.2 Hz, 0.5H), 4.23-4.35 (m, 2.5H
), 3.72-3.77 (m, 2.5H), 3.54-3.60 (m, 0.
5H), 3.37 (s, 3H), 3.26-3.32 (m, 1H), 3.
04-3.17 (m, 1H), 2.55-2.72 (m, 2H), 2.36
-2.43 (m, 1H), 1.37 (d, J = 5.6 Hz, 1H),
26 (d, J = 6.8 Hz, 2H), 1.18-1.20 (m, 2H), 1
. 03-1.04 (m, 2H). LC-MS: m / z 444.2 (M + H)
+.

Compound 361 (General Procedure 1, Step I)
(R) -5- (1H-Benzimidazol-5-yl) -6-cyclopropyl-2- [
4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol-d) 8.226 (s, 1H), 7.764 (s
, 1H), 7.697-7.614 (m, 2H), 7.333-7.31.
3 (d, J = 8 Hz, 2H), 4.775-4.856 (m, 0.5H
), 4.459-4.389 (m, 1H), 4.268-4.147
(M, 2H), 3.968-3.929 (m, 0.5H), 3.688
− 3.567 (m, 3H), 3.342 (s, 3H), 3.193 −
3.022 (m, 2H), 2.814-2.626 (m, 2H),
125-2.076 (m, 1H), 1.402-1.274 (m, 3
H), 1.175 (s, 2H), 1.54-0.928 (m, 2H).
LC-MS: m / z 445.1 (M + H) +.

Compound 352 (General Procedure 1, Step I)
(R) -5-benzothiazol-5-yl-6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol- d) 9.301 (s, 1H), 8.163 −
8.142 (d, J = 8.4 Hz, 1H), 8.102-8.099 (d,
J = 1.2, 1H), 7.807 (s, 1H), 7.559-7.53.
5 (dd, J1 = 9.6 Hz, J2 = 1.6 Hz, 1H), 4.792
(M, 0.5H), 4.453-4.418 (m, 1H), 4.282
-4.170 (m, 2H), 3.959-3.926 (m, 0.5H)
, 3.682-3.667 (m, 2H), 3.616-3.561 (
m, 0.5H), 3.338 (s, 3H), 3.212-3.004 (
m, 2H), 2.806-2.594 (m, 2H), 2.085-2.
. 022 (m, 1H), 1.392-1.262 (m, 3H), 1.21
1-1.176 (m, 2H), 1.000-0.900 (m, 2H)
. LC-MS: m / z 462.1 (M + H) +.

Compound 364 (General Procedure 1, Step I)
(R) -5-benzothiazol-6-yl-6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol- d) 9.292 (s, 1H), 8.131 (s
, 2H), 7.806 (s, 1H), 7.624-7.606 (d, J
= 7.2 Hz, 1H), 4.775-4.856 (m, 0.5H), 4
. 412-4.172 (m, 3H), 3.960-3.931 (m,
0.5H), 3.555-3.688 (m, 3H), 3.345 (s,
3H), 3.188-3.038 (m, 2H), 2.762-2.64.
0 (m, 2H), 2.047-2.035 (m, 1H), 1.379
-1.266 (m, 3H), 1.192 (s, 2H), 0.965 (s,
2H). LC-MS: m / z 462.0 (M + H) +.

Compound 417 (General Procedure 1, Step I)
(R) -5- (2-Amino-benzothiazol-6-yl) -6-cyclopropyl-2
-[4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (chloroform-d) 7.844 (s, 1H), 7.719-
7.715 (d, J = 1.6 Hz, 1H), 7.547 (s, 2H),
7.402−7.381 (d, J = 8.4 Hz, 1H), 7.266−
7.242 (d, J = 9.6, 1H), 4.631-4.664 (m,
0.5H), 4.297-4.017 (m, 3H), 3.869-3.
838 (m, 0.5H), 3.564-3.453 (m, 3H), 3.
349-3.228 (m, 3H), 3.109-2.929 (m, 2
H), 2.669-2.500 (m, 2H), 2.081-2.058
(M, 1H), 1.236 (s, 1H), 1.135-1.079 (m
, 4H), 0.964-0.936 (m, 2H). LC-MS: m /
z 477.1 (M + H) +.

Compound 370 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5-tetrazono [1,5-a] pyridin-6-yl-nicoti Nononitrile 1H NMR (methanol-d) 9.213-9215 (d, J = 0.8 Hz,
1H), 8.131-8.154 (d, J = 9.2 Hz, 1H), 7.917-
7.947 (m, 2H), 4.784 (s, 0.5H), 4.220-4.7
82 (m, 3H), 3.973-3.939 (d, J = 13.6 Hz, 0.
5H), 3.680 (s, 0.5H), 3.051-3.40 (m, 6H)
, 2.595-2.821 (m, 2H), 1.973-2.033 (m, 1
H), 1.23-1.369 (m, 5H), 0.90-1.120 (s,
2H). LC-MS: m / z 447.1 (M + H) +.

Compound 367 (General Procedure 1, Step I)
(R) -6-cyclopropyl-5-isoquinolin-8-yl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol-d ) 9.342-9.356 (d, J = 5.6 Hz,
1H), 8.626-8.642 (d, J = 6.4 Hz, 1H), 8.530
−8.546 (d, J = 6.4 Hz 1H), 8.347-8.368 (d,
J = 8.4Hz 1H), 8.263-8.284 (d, J = 8.4Hz 1H)
, 7.976-7.994 (d, J = 7.2 Hz, 1H), 7.912 (s
, 1H), 4.814 (s, 0.5H), 4.265-4.808 (m, 3
H), 3.968-4.002 (m, 2.5H), 3.151-3.441 (m
, 5H), 2.622-2.804 (m, 2H), 1.182-1.696 (m
, 5H), 0.801-0.981 (m, 2H). LC-MS: m / z 456
. 1 (M + H) +.

Compound 373 (General Procedure 1, Step I)
(R) -6-Cyclopropyl-5- (1H-indol-7-yl) -2- [4- (3
-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol-d) 7.759 (s, 1H), 7.579-7.5
99 (d, J = 8 Hz, 1H), 7.218 (s, 1H), 7.080-7.
099 (d, J = 7.6 Hz 1H), 7.0000-7.018 (d, J = 7.2
Hz 1H), 6.506-6.513 (d, J = 7.2 Hz, 1H), 4.
417-4.466 (dd, J = 8 Hz, 1H), 4.191-4.261 (m
3940), 3.940-3.976 (d, J = 1.44 Hz, 0.5H),
603-3.642 (m, 3H), 2.617-3.3346 (m, 7H), 1.
717-1.828 (m, 1H), 1.155-1.421 (m, 5H), 0
. 832-0.851 (dd, J = 4.4HZ, 2H). LC-MS: m / z 4
44.2 (M + H) +.

Compound 353 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5-quinolin-6-yl-nicotinonitrile 1H NMR (methanol-d ) 9.170-9.183 (d, J = 5.2 Hz,
1H), 9.076-9.097 (d, J = 8.4 Hz, 1H), 8.304.
−8.333 (t, 2H), 8.194-8.216 (d, J = 8.8 Hz)
1H), 8017-8.050 (m, 1H), 7.918 (s, 1H),
4.787 (s, 0.5H), 4.214-4.447 (m, 3H),
974-4.214 (d, J = 96 Hz, 0.5 H), 3.336-3.397 (
m, 3H), 3.076-3.3.250 (m, 5H), 2.599-2.81.
1 (m, 2H), 2.023-2.043 (m, 1H), 1.363-1.3
79 (d, J = 6.4 Hz 1H), 1.244-1.263 (d, J = 7.
6Hz 4H), 0.99-1.026 (m, 2H). LC-MS: m / z 456
. 1 (M + H) +.

Compound 374 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- (1H-pyrrolo [2,3-b] pyridine-5- Il)
-Nicotinonitrile 1H NMR (methanol-d) 8.313 (s, 1H), 8.280 (s, 1
H), 7.831 (s, 1H), 7.563-7.572 (d, J = 3.6H)
z 1H), 6.682-6.690 (d, J = 3.2 Hz 1H), 4.79.
5 (s, 0.5H), 4.183-4.455 (m, 3H), 3.929-3
. 969 (m, 0.5H), 3.568-3.687 (m, 3H), 3.179
-3.342 (m, 4H), 3.046-3.078 (m, 1H), 2.609
-2.810 (m, 2H), 2.020 (s, 1H), 1.194-1.39
2 (m, 5H), 0.964-0.991 (m, 2H). LC-MS: m /
z 445.2 (M + H) +.

Compound 395 (General Procedure 1, Step I)
(R)-(4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -pyridin-3-yl} -thiazole- 2-yl) -carbamic acid tert-butyl ester 1H NMR (chloroform-d) 8.282 (s, 1H), 7.884-7
. 889 (d, J = 2 Hz, 1H), 6.947-6.951 (d, J = 1
. 6Hz, 1H), 4.888 (s, 0.5H), 4.493-4.524 (
d, J = 12.4 Hz, 0.5H), 4.205-4.371 (m, J =
44.8 Hz, 2.5 H), 3.719-3.790 (m, J = 28.4 Hz,
2.5H), 3.499-3.550 (m, J = 20.4, 0.5H), 3.36
7-3.372 (d, J = 2Hz, 3H), 3.218-3.246 (t,
J = 11.2 Hz, 1H), 3.006-3.118 (m, J = 44.8 Hz,
1.5H), 2.544-2.745 (m, J = 80.4 Hz, 2H), 2.
404-2.465 (m, J = 24.4 Hz, 1H), 1.532 (s, 9
H), 1.243-1.355 (q, J = 44.8 Hz, 3H), 1.153-
1.158 (d, J = 2 Hz, 2H), 0.969-0.985 (t, J = 6
. 4Hz, 2H). LC-MS: m / z 527.2 (M + H) +.

Compound 418 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- (2-methyl-1-oxo-1,2-dihydro- Isoquinolin-4-yl) -nicotinonitrile 1H NMR (chloroform-d) 8.506-8.526 (d, J = 8.
0 Hz, 1H), 7.617-7.658 (t, J = 16.4 Hz,
1H), 7.596 (s, 1H), 7.529-7.569 (t, J
= 16 Hz, 1H), 7.209-7.240 (t, J = 12.4 H
z, 1H), 7.036 (s, 1H), 4.916 (s, 0.5H),
4.534−4.642 (m, J = 43.2 Hz, 3H), 4.20
8-4.351 (m, J = 57.2 Hz, 3H), 3.836-3
. 869 (m, J = 13.2 Jz, 0.5H), 3.681-3.73
9 (t, J = 23.2 Hz, 2H), 3.589 (s, 3H),
287-3.371 (m, J = 33.6 Hz, 1 H), 3.155-
3.192 (m, 1.5H), 2.594-2.773 (m, 2H),
1.678-1.740 (m, J = 24.8 Hz, 1H), 1.3
01-1.423 (d, J = 48.8 Hz, 3H), 1.089-
1.143 (m, 2H), 0.809-0.909 (m, 2H).
LC-MS: m / z 486.2 (M + H) +.

Compound 354 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- (4-morpholin-4-yl-phenyl) -nicotinonitrile 1H NMR (chloroform-d) 7.665 (s, 1H), 7.348 −
7.327 (d, J = 8.4 Hz, 2H), 7.129-7.107
(D, J = 8.8 Hz, 2H), 4.824-4.780 (m, 1H
), 4.440-4.408 (m, 1H), 4.220-4.109.
(M, 2H), 3.884-3.860 (m, 4H), 3.693-
3.520 (m, 3H), 3.361-3.4 (s, 3H), 3.230
-3.298 (m, 4.5H), 3.183-2.988 (m, 1.5H)
), 2.798-2.600 (m, 2H), 2.115-2.076.
(M, 1H), 1.382-1.253 (m, 3H), 1.162-
1.128 (m, 2H), 0.986-0.957 (m, 2H). L
C-MS: m / z 490.2 (M + H) +.

Compound 396 (General Procedure 1, Step I)
(R) -2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -6′-piperazin-1-yl- [3,3 ′] bipyridyl -5-carbonitrile 1H NMR (chloroform-d) 8.201-8.207 (d, J = 2.
4Hz, 1H), 7.531 (s, 2H), 6.718-6.739 (d,
J = 8.4 Hz, 1H), 4.867 (m, 1H), 4.477-4.5
07 (m, 4H), 4.149-4.302 (m, 3H), 4.17-4
. 39 (m, 3H), 3.601-3.807 (m, 6H), 3.494-3
. 549 (m, 1H), 3.349 (s, 3H), 2.992-3.213.
(M, 6H), 2.531-2.734 (m, 2H), 1.974-2.03
0 (m, 1H), 1.352-1.367 (d, J = 6 Hz, 1H),
1.235-1.265 (t, 2H), 0.967-0.992 (m, 2H).
LC-MS: m / z 490.2 (M + H) +.

Compound 406 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- [3- (1H-pyrazol-4-yl) -phenyl]
-Nicotinonitrile 1H NMR (chloroform-d) 8.030 (s, 2H), 7.735 (
s, 1H), 7.589-7.613 (m, 2H), 7.423-7.462
(M, 1H), 7.242-7.269 (m, 1H), 4.781 (m, 0.
5H), 4.376-4.441 (m, 1H), 4.131-4.243 (m
, 2H), 3.908-3.940 (d, J = 12.8 Hz, 1H), 3
. 660-3.675 (m, 2H), 3.540-3.602 (m, 0.5H
), 3.334 (s, 3H), 3.253-3.262 (d, J = 3.6)
Hz, 0.5H), 3.122-3.183 (t, 1H), 2.966-3.0
22 (t, 0.5H), 2.631-2.810 (m, 1H), 2.586
-2.615 (m, 1H), 2.061-2.124 (m, 1H), 1.3
62-1.379 (d, J = 6.8 Hz, 1H), 1.249-1.266 (
d, J = 6.8 Hz, 2H), 1.165-1.182 (m, 2H), 0.
900-0.970 (m, 2H) 137. LC-MS: m / z 471.2 (M
+ H) +.

Compound 363 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- [3- (1H-pyrazol-3-yl) -phenyl]
Nicotinonitrile 1H NMR (chloroform-d) 7.820-7.824 (d, J = 1.6H
z, 1H), 7.767-7.795 (t, 2H), 7.686-7.69.
2 (d, J = 2.4 Hz, 1H), 7.490-7.528 (t, 1H),
7.374-7.393 (d, J = 7.6 Hz, 1H), 6.720-6.7
25 (d, J = 2 Hz, 1H), 4.790 (m, 0.5H), 4.39
6-4.452 (m, 1H), 4.153-4.264 (m, 2H), 2.
920-3.953 (d, J = 13.2 Hz, 0.5H), 3.608-3.6
80 (m, 2H), 3.554-3.582 (t, 0.5H), 3.337
(S, 3H), 3.220 (m, 0.5H), 3.140-3.197 (
t, 1H), 2.986-3.043 (t, 0.5H), 2.751-2.8
03 (m, 1H), 2.591-2.729 (m, 1H), 2.069-2.
120 (m, 1H), 1.372-1.388 (d, J = 6.4 Hz, 1H)
, 1.259-1.276 (d, J = 6.8 Hz, 2H), 1.156-1.1
91 (m, 2H), 0.982 (m, 2H). LC-MS: m / z 471
. 4 (M + H) +.

Compound 436 (General Procedure 1, Step I)
(R) -6-cyclopropyl-5-imidazo [1,2-a] pyridin-6-yl-2-
[4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (chloroform-d) 8.126 (s, 1H), 7.952 (
bs, 1H), 7.681-1.684 (d, J = 1.2 Hz, 1H)
7.621 (s, 1H), 7.547 (s, 1H), 7.257-7.
280 (d, J = 13.6 Hz, 1H), 4.823 (br, 0.5
H), 4.436-4.467 (d, J = 12.4 Hz, 0.5H), 4
. 149-4.278 (m, 3H)), 3.649-3.717 (m, 2
. 5H), 3.446-3.501 (m, 0.5H), 3.299 (s,
3H), 3.219-3.254 (m, 1H), 3.019-3.12.
1 (m, 2H), 2.628- 2.646 (m, 1H), 2.501-
2.531 (m, 1H), 1.842-1.897 (m, 1H), 1
. 293-1.308 (d, J = 6 Hz, 1.5H), 1.183-1.
204 (d, J = 8.4 Hz, 1.5H), 1.097-1.115
(M, 2H), 0.902-0.933 (m, 2H). LC-MS:
m / z 445.1 (M + H) +.

Compound 437 (General Procedure 1, Step I)
(R) -5-Benzo [1,2,5] oxadiazol-4-yl-6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] −
Nicotinonitrile 1H NMR (chloroform-d) 7.785-7.808 (d, J = 9.
2 Hz, 1H), 7.646 (s, 1H), 7.433-7.473 (d
, J = 16 Hz, 1H), 7.335-7.353 (dd, J = 7
. 2 Hz, 1H), 4.835 (m, 0.5H), 4.441 (m, 0
. 5H), 4.201-4.320 (m, 3H)), 3.669-3.72.
5 (m, 2.5H), 3.478-3.487 (m, 0.5H), 3.
312 (s, 3H), 3.103-3.106 (m, 1H), 3.40
2- 3.705 (m, 2H), 2.596-2.654 (m, 1H), 2
. 484-2.537 (m, 1H), 1.769-1.800 (m,
1H), 1.308 (m, 1.5H), 1.204-1.219 (d, J
= 6 Hz, 1.5H), 1.127-1.145 (m, 2H), 0.
870-0.889 (m, 2H). LC-MS: m / z 447.1 (M
+ H) +.

Compound 438 (General Procedure 1, Step I)
(R) -6-cyclopropyl-5- (1H-indazol-4-yl) -2- [4- (
3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (chloroform-d) 7.887 (bs, 1H), 7.646
(S, 1H), 7.462-7.483 (d, J = 8.4 Hz, 1H)
, 7.391-7.429 (t, J = 15.2 Hz, 1H), 7.05
5-7.071 (d, J = 6.4 Hz, 1H), 4.859 (m, 0
. 5H), 4.465-4.500 (d, J = 14 Hz, 0.5H),
4.166-4.281 (m, 3H)), 3.671-3.733 (m,
2.5H), 3.486-3.510 (m, 0.5H), 3.312 (s
, 3H), 3.200-3.252 (m, 1H), 2.992- 3.1.
03 (m, 2H), 2.614-2.670 (m, 1H), 2.527
-2.557 (m, 1H), 1.819-1.840 (m, 1H),
1.340-1.355 (d, J = 6 Hz, 1.5H), 1.238-1
. 253 (d, J = 6 Hz, 1.5H), 1.101-1.117
(M, 2H), 0.819-0.846 (m, 2H). LC-MS: m
/ Z 445.1 (M + H) +.

Compound 473 (General Procedure 1, Step I)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -5- (2-oxo-2,3-dihydro-benzoxazole-5 -Yl) -nicotinonitrile 1H NMR (chloroform-d) 8.492 (s, 1H), 7.568-7
. 569 (d, J = 0.4 Hz, 1H), 7.277 (s, 1H), 7.1
21-7.125 (t, 1H), 7.064-7.068 (d, J = 1.6H
z, 1H), 6.720-6.725 (d, J = 2 Hz, 1H), 4.89.
7 (m, 0.5H), 4.510-4.549 (m, 0.5H), 4.17
5 (m, 2.5H), 3.780 (m, 2.5H), 3.543 (t,
0.5H), 3.369 (s, 3H), 3.246-3.273 (m, 1H
), 3.113-3.119 (m, 1H), 3.019-3.048 (t, 0
. 5H), 2.649-2.759 (m, 1H), 2.556-2.609 (
m, 1H), 1.998-2.006 (m, 1H), 1.268-1.387
(M, 3H), 1.129-1.155 (m, 2H), 0.928-0.9
55 (m, 2H). LC-MS: m / z 462.1 (M + H) +.

Compound 474 (General Procedure 1, Step I)
(R) -6-Cyclopropyl-5- (1-methoxy-isoquinolin-4-yl) -2-
[4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (chloroform-d) 8.350-8.325 (d, J = 10
Hz, 1H), 7.913 (s, 1H), 7.660-7.415 (
m, 4H), 4.915 (s, 0.5H), 4.562-4.530 (m,
0.5H), 4.278-4.228 (m, 2.5H), 4.261 (s
, 3H), 3.797-3.553 (m, 3H), 3.797 (s, 3
H), 3.577-3.044 (m, 2.5H), 2.750-2.5
68 (m, 2H), 1.633-1.625 (m, 1H), 1.429
-1.322 (m, 3H), 1.137-1.093 (m, 2H),
0.842-0.765 (m, 2H). LC-MS: m / z 486.
1 (M + H) +.

Compound 299
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (4-fluorophenyl) -4-methylnicotinonitrile 1H NMR (Chloroform-d) δ 7.10-7.16 (m, 4H),
4.62-4.65 (m, 0.5H), 4.23 (d, J = 12.
8 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 4.
04 (d, J = 8.3 Hz, 0.5H), 3.61-3.88 (m
, 3.5H), 3.31-3.38 (m, 3H), 3.25 (br.
s. , 0.5H), 3.02-3.17 (m, 1H), 2.89-3
. 02 (m, 1H), 2.51-2.73 (m, 2H), 2.09-
2.18 (m, 3H), 1.53-1.59 (m, 1H), 1.33
-1.44 (m, 1H), 0.99-1.08 (m, 2H), 0.
75-0.86 (m, 2H), 0.29-0.63 (m, 4H)
LC-MS: m / z 463.4 (M + H) ⁺

Compound 300
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (4-fluorophenyl) -4-methyl Nicotinonitrile 1H NMR (chloroform-d) δ 7.19 (d, J = 7.3 Hz,
4H), 4.70 (br. S., 0.5H), 4.30 (d, J =
13.1 Hz, 1H), 4.18-4.27 (m, 1H), 4.12
(D, J = 8.3 Hz, 0.5H), 3.81-3.94 (m, 1
H), 3.66-3.78 (m, 1H), 3.32 (q, J = 9.
8 Hz, 2H), 3.08-3.21 (m, 1H), 2.97-3
. 08 (m, 1H), 2.14-2.25 (m, 3H), 1.58-
1.67 (m, 1H), 1.50 (br. S., 1H), 1.04 −
1.14 (m, 2H), 0.81-0.89 (m, 2H), 0.65
(Br.s., 1H), 0.56 (br.s., 1H), 0.37 −
0.52 (m, 2H)
LC-MS: m / z 487.2 (M + H) +

Compound 627 (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl) -4-methyl-5- (6-vinylpyrimidine-4-
Yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.30 (d, J = 1.1 Hz,
1H), 9.30 (d, J = 1.1 Hz, 1H), 7.32 (t,
J = 4.5 Hz, 1H), 6.82 (dd, J = 17.4, 10
. 7 Hz, 1H), 6.64-6.49 (m, 1H), 5.81 (d
d, J = 14.9, 4.1 Hz, 1H), 4.93 (d, J = 1)
7.7 Hz, 1H), 4.53 (d, J = 13.3 Hz, 1H),
4.20 (dd, J = 33.1, 13.9 Hz, 2H), 3.77 (
dd, J = 18.0, 11.5 Hz, 2H), 3.57 (dd, J
= 12.8, 9.6 Hz, 1H), 3.39 (s, 3H), 3.34
-2.95 (m, 3H), 2.82-2.49 (m, 2H), 2.2
6 (s, 3H), 2.88-1.49 (m, 8H), 1.57 (dd
d, J = 12.5, 8.0, 4.5 Hz, 1H), 1.45-1.
37 (m, 2H), 1.33-1.28 (m, 2H), 1.14 (d
t, J = 7.4, 3.5 Hz, 2H), 0.96-0.81 (m,
3H).
LC-MS: m / z 447.2 (M + H) +

Compound 628 (R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl)
-3-methylpiperazin-1-yl) -4-methyl-2'-vinyl- [3,4'-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.70 (d, J = 4 .9 Hz,
1H), 7.23 (s, 1H), 7.08 (d, J = 4.1 Hz,
1H), 6.88 (dd, J = 17.4, 10.8 Hz, 1H),
6.30 (d, J = 17.4 Hz, 1H), 5.58 (d, J =
10.9 Hz, 1H), 4.92 (s, 1H), 4.53 (t, J =
14.2 Hz, 1H), 4.29-4.08 (m, 3H), 3.76.
(T, J = 6.3 Hz, 2H), 3.57 (dd, J = 23.8)
, 17.1 Hz, 1H), 3.40 (s, 3H), 3.31-2.9
5 (m, 3H), 2.68 (ddd, J = 33.7, 17.4, 11
. 1 Hz, 2H), 2.20 (d, J = 8.0 Hz, 3H),
57 (ddd, J = 12.5, 8.1, 4.6 Hz, 1H), 1.4
1 (d, J = 6.3 Hz, 2H), 1.36-1.25 (m, 4
H), 1.10 (s, 2H), 0.94-0.74 (m, 3H).
LC-MS: m / z 446.2 (M + H) +

Compound 411 (R) -5- (4-aminophenyl) -6-cyclopropyl-2- (4-
(3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) d: 6.97-7.10 (m, 2H)
6.87-6.97 (m, J = 8.0 Hz, 2H), 4.92.
(Br. S., 0.5H), 4.54 (d, J = 13.3 Hz, 0.
5H), 4.23 (br. S., 0.5H), 3.95-4.18 (m
, 2H), 3.71-3.83 (m, 2.5H), 3.58 (m, 0
. 5H) 3.40 (s, 3H), 3.11-3.27 (m, 1.5H)
, 2.88-3.10 (m, 1H), 2.53-2.82 (m, 2
H), 2.16-2.28 (m, 3H), 1.68-1.78 (m,
1H), 1.38-1.47 (m, 1.5H), 1.33 (d, J
= 6.5 Hz, 1.5H), 0.98-1.13 (m, 2H), 0.
75-0.93 (m, 2H)
LC-MS: m / z 433.5 (M + H) +

Compound 278 (R) -6-cyclopropyl-5- (6-methoxynaphthalen-2-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4
-Methylnicotinonitrile 1H NMR (chloroform-d) δ 7.83 (d, J = 8.3 Hz,
1H), 7.71-7.78 (m, 1H), 7.60 (s, 1H),
7.25-7.32 (m, 1H), 7.17-7.24 (m, 2H
), 4.92 (br. S., 0.5H), 4.55 (d, J = 13.
3 Hz, 0.5H), 4.05-4.21 (m, 2.5H), 3.91
-4.00 (m, 3H), 3.69-3.87 (m, 2.5H),
3.52-3.69 (m, 0.5H), 3.33-3.46 (m, 3
H), 3.13-3.29 (m, 1.5H), 2.97-3.11.
m, 1H), 2.65-2.83 (m, 1H), 2.60 (dd, J
= 13.1, 6.5 Hz, 1H), 2.17-2.28 (m, 3H
), 1.61-1.74 (m, 1H), 1.39-1.49 (m,
1.5H), 1.33 (d, J = 6.5 Hz, 1.5H), 0.99
-1.17 (m, 2H), 0.69-0.84 (m, 2H)
LC-MS: m / z 499.1 (M + H) +

Compound 282 (R) -6-cyclopropyl-5- (2-fluorobiphenyl-4-yl)
-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-
Methylnicotinonitrile 1H NMR (chloroform-d) δ 7.61 (d, J = 8.0 Hz,
2H), 7.44-7.57 (m, 3H), 7.37-7.44 (
m, 1H), 7.00-7.10 (m, 2H), 4.91 (br. s)
. , 0.5H), 4.54 (d, J = 13.1 Hz, 0.5H), 4
. 04-4.32 (m, 2.5H), 3.69-3.89 (m, 2.
5H), 3.58 (t, J = 10.8 Hz, 0.5H), 3.34 −
3.42 (m, 3H), 3.12-3.30 (m, 1.5H),
93-3.12 (m, 1H), 2.64-2.82 (m, 1H),
2.59 (dd, J = 13.3, 6.5 Hz, 1H), 2.25 (s
, 3H), 1.66-1.76 (m, 1H), 1.41 (d, J =
6.3 Hz, 1.5H), 1.32 (d, J = 6.8 Hz, 1.5
H), 1.04-1.15 (m, 2H), 0.87 (dt, J = 7
. 5, 3.7 Hz, 2H)
LC-MS: m / z 513.1 (M + H) +

Compound 318 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3-methyl-pyridyl-5-yl) -2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -nicotinonitrile 1H NMR (methanol-d) δ 8.79 (s, 1H), 8.70 (s
, 1H), 8.40 (d, J = 0.4 Hz, 1H), 4.77-4.79.
(M, 0.5H), 4.42 (d, J = 14.4 Hz, 1H), 4.22-
4.24 (m, 1.5H), 4.14 (d, J = 13.2 Hz, 0.5H)
3.94 (d, J = 13.2 Hz, 0.5H), 3.68 (t, J = 6)
. 0 Hz, 2H), 3.55-3.62 (m, 0.5H), 3.31-3.3
3 (m, 3H), 3.13-3.22 (m, 1H), 3.00-3.06
(M, 0.5H), 2.68-2.82 (m, 1H), 2.58-2.63 (
m, 4H), 2.22 (s, 3H), 1.47-1.54 (m, 1H),
1.37 (d, J = 6.8 Hz, 1H), 1.26 (d, J = 11.2H
z, 2H), 1.13-1.17 (m, 2H), 0.91-0.94 (m,
2H)
LC-MS: m / z 434.2 (M + H) +.

Compound 319 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (4-methanesulfonyl-phenyl) -2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-
Nicotinonitrile 1H NMR (methanol-d) d 8.07 (d, J = 8.4 Hz,
2H), 7.52 (d, J = 8.4 Hz, 2H), 4.75-4.
. 85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5
H), 3.43 (s, 3H), 3.34 (s, 3H), 3.03-3
. 25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68
-2.85 (m, 1H), 2.57-2.63 (m, 1H),
18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-
1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78
-0.85 (m, 2H)
LC-MS: m / z 497.2 (M + H) +

Compound 320 (General Procedure 6, Step G ′)
(R) -2-cyclopropyl-2′-methoxy-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl- [3,3 ′] bipyridyl -5-carbonitrile 1H NMR (methanol-d) δ 8.22 (dd, J1 = 2.0 Hz,
J2 = 4.8 Hz, 1H), 7.54 (dd, J1 = 2.0 Hz, J2
= 7.2 Hz, 1H), 7.07-7.10 (m, 1H), 4.78 (s
, 0.5H), 4.38-4.45 (m, 1H), 4.01-4.13 (m
, 2H), 3.88-3.94 (m, 3.5H), 3.66-3.69 (m
, 2H), 3.55-3.61 (m, 0.5H), 3.33 (s, 3H)
, 3.09-3.25 (m, 2H), 2.91-2.97 (m, 0.5H)
, 2.69-2.78 (m, 1H), 2.60-2.64 (m, 1H),
2.12 (s, 3H), 1.49-1.52 (m, 1H), 1.40 (d
, J = 6.4 Hz, 1.3H), 1.28 (dd, J1 = 2.4 Hz
, J2 = 6.4 Hz, 1.7H), 0.99-1.10 (m, 2H), 0
. 80-0.83 (m, 2H)
LC-MS: m / z 450.2 (M + H) +

Compound 321 (General Procedure 6, Step G ′)
(R) -5- (3-Cyano-4-fluoro-phenyl) -6-cyclopropyl-2- [
4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.71 (dd, J1 = 2.0 Hz
, J2 = 6.4 Hz, 1H), 7.60-7.64 (m, 1H), 7.5
0 (t, J = 9.2 Hz, 1H), 4.77-4.79 (m, 0.5
H), 4.38-4.44 (m, 1H), 4.05-4.16 (m, 2H)
3.93 (d, J = 13.6 Hz, 0.5H), 3.67-369.
(M, 2H), 3.57-3.58 (m, 0.5H), 3.33 (s, 3
H), 3.21-3.28 (m, 1H), 3.11-3.15 (m, 1H)
, 2.96-2.97 (m, 0.5H), 2.69-2.77 (m, 1H)
, 2.59-2.65 (m, 1H), 2.17 (s, 3H), 1.50-
1.54 (m, 1H), 1.38 (d, J = 6.4 Hz, 1.3H),
1.26 (d, J = 6.8 Hz, 1.7H), 1.09-1.10 (m,
2H), 0.84-0.89 (m, 2H)
LC-MS: m / z 462.1 (M + H) +

Compound 322 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3-methoxymethyl-phenyl) -2- [4- (
3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.47 (t, J = 7.6 Hz,
1H), 7.38 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H)
), 7.15 (d, J = 7.6 Hz, 1H), 4.79 (s, 0.5H)
), 4.50 (s, 2H), 4.37-4.45 (m, 1H), 4.01
-4.12 (m, 2H), 3.93 (d, J = 13.6 Hz, 0.5H)
3.66-3.69 (m, 2H), 3.55-3.62 (m, 0.6H)
, 3.39 (s, 3H), 3.33 (s, 3H), 3.04-3.29
(M, 2H), 2.90-2.97 (m, 0.5H), 2.59-2.81
(M, 2H), 2.15 (s, 3H), 1.62-1.66 (m, 1H)
, 1.42 (d, J = 6.4 Hz, 1.4H), 1.31 (d, J = 6
. 4 Hz, 1.6 H), 1.02-1.09 (m, 2H), 0.77-0
. 84 (m, 2H)
LC-MS: m / z 463.2 (M + H) +

Compound 323 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3-fluoro-4-methoxy-phenyl) -2-
[4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.19 (t, J = 8.4 Hz,
1H), 6.95-6.99 (m, 2H), 4.75-4.85 (m
, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.1
2 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-
3.72 (m, 2H), 3.52-3.62 (m, 0.5H),
34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-
2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.5
7-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1
. 69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-
1.09 (m, 2H), 0.78-0.85 (m, 2H)
LC-MS: m / z 467.2 (M + H) +

Compound 324 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (2-fluoro-3-methoxy-phenyl) -2-
[4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.25-7.34 (m, 2H),
6.75-6.79 (m, 1H), 4.75-4.85 (m, 0.5
H), 4.35-4.48 (m, 1H), 4.05-4.12 (m,
2H), 3.88-3.97 (m, 3.5H), 3.65-3.72.
(M, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s,
3H), 3.03-3.25 (m, 2H), 2.87-2.98 (
m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.
63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m
, 1H), 1.34-1.41 (m, 3H), 1.05-1.09
(M, 2H), 0.78-0.85 (m, 2H)
LC-MS: m / z 467.2 (M + H) ^<+> .

Compound 325 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- (1-methyl-1H-indole-5
Yl) -nicotinonitrile 1H NMR (methanol-d) δ 7.45 (d, J = 8.4 Hz,
1H), 7.35 (s, 1H), 7.21 (s, 1H), 6.96 (d
, J = 8.4 Hz, 1H), 4.75-4.85 (m, 0.5H)
, 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2
H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (
m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s,
3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m
, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.6
3 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m,
1H), 1.34-1.41 (m, 3H), 1.05-1.09 (
m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m / z 472.2 (M + H) +.

Compound 326 (General Procedure 6, Step G ′)
(R) -N- (4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -phenyl) -acetamide 1H NMR (methanol-d) δ 7.66 (d, J = 8.8 Hz,
2H), 7.16 (d, J = 8.8 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H
), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.
87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H)
2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.1
5 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1
. 41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-
0.85 (m, 2H).
LC-MS: m / z 476.2 (M + H) +.

Compound 327 (General Procedure 6, Step G ′)
(R) -3- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} −
N-methyl-benzamide 1H NMR (methanol-d) δ 7.87 (d, J = 8.0 Hz,
1H), 7.69 (s, 1H), 7.56-7.62 (m, 1H),
7.41 (d, J = 8.0 Hz, 1H) 4.75−4.85 (m
, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.1
2 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-
3.72 (m, 2H), 3.52-3.62 (m, 0.5H),
34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-
2.98 (m, 3.5H), 2.68-2.85 (m, 1H), 2.5
7-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1
. 69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-
1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m / z 476.2 (M + H) +.

Compound 329 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3-methanesulfonyl-phenyl) -2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-
Nicotinonitrile 1H NMR (methanol-d) δ 8.02 (d, J = 7.6 Hz,
1H), 7.85 (s, 1H), 7.75-7.79 (m, 1H),
7.61 (d, J = 7.6 Hz, 1H) 4.75−4.85 (m
, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.1
2 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-
3.72 (m, 2H), 3.52-3.62 (m, 0.5H),
34 (s, 3H), 3.03-3.25 (m, 5H), 2.87-
2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.5
7-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1
. 69 (m, 1H), 1.34-1.41 (m, 3H), 1.05
-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m / z 497.1 (M + H) +.

Compound 330 (General Procedure 6, Step G ′)
(R) -N- (4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -benzyl) -methanesulfonamide 1H NMR (methanol-d) δ 7.51 (d, J = 8.0 Hz,
2H), 7.22 (d, J = 8.0 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H
), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.
87-2.98 (m, 3.5H), 2.68-2.85 (m, 1H)
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.6
2-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1
. 05-1.09 (m, 2H), 0.78-0.85 (m, 2H).

LC-MS: m / z 526.2 (M + H) +.

Compound 331 (General Procedure 6, Step G ′)
(R) -4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} −
N-methyl-benzenesulfonamide 1H NMR (methanol-d) δ 7.95 (d, J = 8.4 Hz,
2H), 7.47 (d, J = 8.4 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H
), 3.43 (s, 3H), 3.16-3.25 (m, 1.5H),
2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1
H), 2.57-2.63 (m, 4H), 2.18 (s, 3H), 1
. 62-1.69 (m, 1H), 1.34-1.41 (m, 3H),
1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)
.
LC-MS: m / z 512.2 (M + H) +.

Compound 332 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- [3- (pyrrolidine-1-carbonyl)
-Phenyl] -nicotinonitrile 1H NMR (methanol-d) δ 7.57-7.59 (m, 2H),
7.40 (s, 1H), 7.34-7.37 (m, 2H), 4.75
-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4
. 05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H)
3.65-3.72 (m, 2H), 3.45-3.62 (m, 4
. 5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H),
2.87-2.98 (m, 0.5H), 2.68-2.85 (m,
1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H)
, 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2
H), 0.78-0.85 (m, 2H). LC-MS: m / z 51
6.2 (M + H) +.

Compound 333 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- [4- (pyrrolidine-1-carbonyl)
-Phenyl] -nicotinonitrile 1H NMR (methanol-d) δ 7.65 (d, J = 8.4 Hz,
2H), 7.33 (d, J = 8.4 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 4.5H
), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.
87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H)
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.8
8-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1
. 34-1.41 (m, 3H), 1.05-1.09 (m, 2H),
0.78-0.85 (m, 2H).
LC-MS: m / z 516.2 (M + H) +.

Compound 335 (General Procedure 6, Step G ′)
(R) -N- (3- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -benzyl) -methanesulfonamide 1H NMR (methanol-d) δ 7.42-7.50 (m, 2H ),
7.26 (s, 1H), 7.22 (d, J = 7.2 Hz, 1H),
4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1
H), 4.31 (s, 2H), 4.05-4.12 (m, 2H), 3
. 88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H
), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H),
3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5
H), 2.87 (s, 3H), 2.68-2.85 (m, 1H), 2
. 57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-
1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05
-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m / z 526.2 (M + H) +.

Compound 336 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (4-cyclopropylmethoxy-phenyl) -2-
[4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.11 (d, J = 8.4 Hz,
2H), 7.01 (d, J = 8.4 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.88
-4.12 (m, 5H), 3.65-3.72 (m, 2H), 3.5
2-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-
3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.
68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.21
-1.41 (m, 4H), 1.05-1.09 (m, 2H), 0.7
8-0.85 (m, 2H), 0.61-0.69 (m, 2H), 0.
35-0.41 (m, 2H).
LC-MS: m / z 489.2 (M + H) +.

Compound 337 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- (4-propoxy-phenyl) -nicotinonitrile 1H NMR (methanol-d) δ 7.10 (d, J = 8.8 Hz,
2H), 7.01 (d, J = 8.8 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.98
-4.12 (m, 4H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H
), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.
87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.78
-1.89 (m, 2H), 1.62-1.69 (m, 1H),
34-1.41 (m, 3H), 1.05-1.09 (m, 5H),
0.78-0.85 (m, 2H).
LC-MS: m / z 477.2 (M + H) +.

Compound 340 (General Procedure 6, Step G ′)
(R) -N- (4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -benzyl) -acetamide 1H NMR (methanol-d) δ 7.41 (d, J = 8.0 Hz,
2H), 7.19 (d, J = 8.0 Hz, 2H), 4.75-4.
85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3
. 65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H
), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.
87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H)
, 2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.0
1 (s, 3H), 1.62-1.69 (m, 1H), 1.34-
1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78
-0.85 (m, 2H).
LC-MS: m / z 490.1 (M + H) +.

Compound 346 (General Procedure 6, Step G ′)
(R) -5- (4-Fluoro-pyridyl-3-yl) -6-cyclopropyl-2- [4
-(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 8.10-8.09 (d, J = 2
. 4 Hz, 1H), 7.89-7.85 (m, 1H), 7.23-7
. 20 (m, 1H), 4.79-4.78 (d, J = 1.2 Hz,
0.5H), 4.44-4.41 (d, J = 14 Hz, 1H),
4.18-4.01 (m, 2H), 3.95-3.92 (d, J =
13.6 Hz, 0.5H), 3.68-3.67 (d, J = 5.6)
Hz, 2H), 3.62-3.56 (t, J = 11.6 Hz, 0.5
H), 3.33 (s, 3H), 3.26-3.24 (m, 1H),
3.20-3.11 (m, 1H), 3.01-2.98 (m, 0.5
H), 2.80-2.69 (m, 1H), 2.64-2.59 (m,
1H), 2.19 (s, 3H), 1.56-1.54 (m, 1H),
1.39-1.37 (d, J = 6.4 Hz, 1H), 1.27-
1.26 (d, J = 6.8 Hz, 1H), 1.11-1.09 (t
, J = 3.6 Hz, 2H), 0.89-0.87 (m, 2H). L
C-MS: m / z 438.1 (M + H) +.

Compound 347 (General Procedure 6, Step G ′)
(R) -5- (4-Cyano-phenyl) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.87-7.85 (d, J = 8
. 4 Hz, 2H), 7.47-7.45 (d, J = 8 Hz, 2H)
), 4.79 (s, 1H), 4.45-4.39 (m, 1H), 4.
16-4.05 (m, 2H), 3.95-3.92 (d, J = 1)
3.2 Hz, 0.5H), 3.69-3.66 (t, J = 11.6)
Hz, 2H), 3.62-3.55 (m, 0.5H), 3.33 (s
, 3H), 3.27-3.08 (m, 2H), 2.99-2.94.
(M, 0.5H), 2.81-2.69 (m, 1H), 2.64-2
. 59 (m, 1H), 2.16 (s, 3H), 1.55-1.49 (m
, 1H), 1.39-1.28 (m, 3H), 1.12-1.09
(M, 1H), 0.89-0.86 (m, 2H). LC-MS: m /
z 444.1 (M + H) +.

Compound 348 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (2-methoxymethyl-phenyl) -2- [4- (
6. 3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.53-7.55 (m, 1H),
40-7.45 (m, 2H), 7.11-7.14 (m, 1H), 4.79
(S, 0.5H), 4.42 (t, J = 14.4 Hz, 1H), 4
. 04-4.15 (m, 4H), 3.93 (d, J = 12.8 Hz,
0.5H), 3.59-3.69 (m, 2.5H), 3.33 (s, 3H)
, 3.20 (d, J = 4.8 Hz, 4H), 2.95-3.18 (m,
1H), 2.71-2.76 (m, 1H), 2.60-2.65 (m, 1H)
), 2.08 (s, 3H), 1.40-1.5 (m, 2.3H), 1.2
7-1.38 (m, 1.7H), 1.02-1.09 (m, 2H), 0.75
-0.82 (m, 2H). LC-MS: m / z 463.2 (M + H) +.

Compound 349 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- (2-methyl-2H-pyrazole-3-
Yl) -nicotinonitrile 1H NMR (methanol-d) d 7.60 (s, 1H), 6.33 (
s, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.
48 (m, 1H), 4.21-4.38 (m, 2H), 3.88-
3.95 (m, 0.5H), 3.65-3.72 (m, 2H), 3.6
3 (s, 3H), 3.52-3.62 (m, 0.5H), 3.34 (
s, 3H), 3.03-3.25 (m, 1H), 2.97-3.08
(M, 0.5H), 2.68-2.85 (m, 1H), 2.57-
2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69
(M, 1H), 1.34-1.41 (m, 3H), 1.05-1.1
9 (m, 2H), 0.78-0.95 (m, 2H). LC-MS: m
/ Z 423.2 (M + H) +.

Compound 350 (General Procedure 6, Step G ′)
(R) -N- (3- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -phenyl) -methanesulfonamide 1H NMR (methanol-d) d 7.45-7.48 (m, 1H ),
7.30 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H),
7.02 (d, J = 7.6 Hz, 1H), 4.75-4.85 (
m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.
12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65
-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3
. 34 (s, 3H), 3.03-3.25 (m, 2H), 2.98 (
s, 3H), 2.87-2.98 (m, 0.5H), 2.68-2.
85 (m, 1H), 2.57-2.63 (m, 1H), 2.16 (s
3H), 1.62-1.69 (m, 1H), 1.34-1.41.
(M, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(M, 2H). LC-MS: m / z 512.1 (M + H) +.

Compound 351 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3,5-dimethyl-isoxazol-4-yl) -2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl]
-4-methyl-nicotinonitrile 1H NMR (methanol-d) d 4.75-4.85 (m, 0.5H
), 4.35-4.48 (m, 1H), 4.05-4.12 (m,
2H), 3.88-3.97 (m, 0.5H), 3.65-3.72.
(M, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s,
3H), 3.03-3.25 (m, 2H), 2.87-2.98 (
m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.
63 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H),
2.08 (s, 3H), 1.62-1.69 (m, 1H), 1.34
-1.41 (m, 3H), 1.05-1.12 (m, 2H), 0.8
5-0.95 (m, 2H). LC-MS: m / z 438.2 (M + H
) +.

Compound 358 (General Procedure 6, Step G ′)
(R) -5- (1-Benzyl-1H-pyrazol-4-yl) -6-cyclopropyl-
2- [4- (3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4
-Methyl-nicotinonitrile 1H NMR (methanol-d) 7.742 (s, 1H), 7.499 (s
, 1H), 4.365-7.255 (m, 5H), 5.410 (s, 2H)
), 4.773 (s, 0.5H), 4.429-4.359 (m, 1H)
), 4.109-4.004 (m, 2H), 3.924-3.891.
(M, 0.5H), 3.683-3.655 (m, 2H), 3.592
-3.535 (m, 0.5H), 3.328 (s, 3H), 3.255
-3.041 (m, 2H), 2.954-2.898 (m, 0.5H)
, 2.801-2.588 (m, 2H), 2.260 (s, 3H),
1.909-1.869 (m, 1H), 1.375-1.246 (m,
3H), 1.071 (s, 2H), 0.90-0.80 (m, 2H).
LC-MS: m / z 499.2 (M + H) +.

Compound 359 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (2-ethyl-phenyl) -2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.40-7.37 (m, 2H),
7.35-7.27 (m, 1H), 7.07-7.04 (m, 1H)
, 4.80-4.79 (d, J = 2.4 Hz, 0.5H), 4.4
6-4.38 (m, 1H), 4.14-4.04 (m, 2H), 3
. 95-3.92 (d, J = 12.8 Hz, 0.5H), 3.68
-3.63 (m, 2H), 3.60 (m, 0.5H), 3.34 (s
3H), 3.26-3.06 (m, 2H), 2.97-2.94.
(D, J = 12 Hz, 0.5H), 2.80-2.60 (m, 2H
), 2.42-2.30 (m, 2H), 2.09 (s, 3H), 1.
55-1.50 (m, 1H), 1.43-1.39 (m, 1H), 1
. 32-1.27 (m, 1H), 1.08-1.03 (m, 5.5H
) 0.82-0.80 (m, 2H). LC-MS: m / z 447.2
(M + H) +.

Compound 362 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (3-dimethylamino-phenyl) -2- [4- (
3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) δ 7.53 (t, J = 8.0 Hz,
1H), 7.27 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H)
), 7.02 (d, J = 7.2 Hz, 1H), 4.78 (s, 1H),
4.38-4.45 (m, 1H), 4.03-4.14 (m, 2H), 3
. 91-3.95 (m, 0.5H), 3.65-3.70 (m, 2H), 3
. 53-3.62 (m, 0.5H), 3.34 (s, 4H), 3.21-3
. 31 (m, 1.5H), 3.16 (s, 7H), 2.96-2.98 (
m, 0.5H), 2.61-2.79 (m, 1H), 2.62-2.65 (
m, 1H), 2.19 (s, 3H), 1.61-1.67 (m, 1H),
1.38-1.40 (d, J = 6.4 Hz, 1.3H), 1.27-1.2
8 (d, J = 6.4 Hz, 1.7H), 1.07-1.09 (m, 2H)
, 0.81-0.84 (m, 2H). LC-MS: m / z 462.1 (
M + H) +.

Compound 365 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-2- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-5- (1-methyl-1H-pyrazole-4-
Yl) -nicotinonitrile 1H NMR (methanol-d) d 7.64 (s, 1H), 7.44 (
s, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.
48 (m, 1H), 3.88-4.12 (m, 5.5H), 3.65
-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3
. 34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-
2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.
57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-
1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05
-1.09 (m, 2H), 0.78-0.85 (m, 2H). L
C-MS: m / z 423.1 (M + H) +.

Compound 366 (General Procedure 6, Step G ′)
(R) -3- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} −
Benzoic acid methyl ester 1H NMR (methanol-d) d 8.06 (d, J = 8.0 Hz,
1H), 7.87 (s, 1H), 7.58-7.63 (m, 1H)
, 7.48 (d, J = 8.0 Hz, 1H), 4.75-4.85
(M, 0.5H), 4.35-4.48 (m, 1H), 4.05-4
. 12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65
-3.72 (m, 2H), 3.52-3.62 (m, 0.5H),
3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87
-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2
. 57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-
1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05
-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m / z 477.1 (M + H) +.

Compound 369 (General Procedure 6, Step G ′)
(R) -2-cyclopropyl-2′-fluoro-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl- [3,3 ′] bipyridyl -5-carbonitrile 1H NMR (methanol-d) δ 8.31-8.30 (d, J = 4
. 4 Hz, 1H), 7.90-7.86 (t, J = 8.4 Hz,
1H), 7.48-7.45 (m, 1H), 4.82-4.79 (m,
0.5H), 4.45-4.37 (m, 0.5H), 4.20-4.
10 (m, 2H), 3.95-3.92 (d, J = 12.8 Hz,
0.5H), 3.68-3.67 (m, 2H), 3.62-3.56
(T, J = 12 Hz, 0.5H), 3.34-3.33 (m, 3.5
H), 3.18-3.16 (d, J = 10.8 Hz, 1H),
01 (m, 1H), 2.80-2.71 (m, 1H), 2.65-
2.61 (m, 1H), 2.2 (s, 3H), 1.52-1.49 (m
, 1H), 1.39-1.38 (d, J = 2.8 Hz, 1H),
1.28-1.27 (d, J = 6.4 Hz, 1H), 1.13-
0.90 (m, 1H), 0.90-0.88 (m, 1H). LC-MS:
m / z 438.2 (M + H) +.

Compound 372 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (2-hydroxymethyl-phenyl) -2- [4-
(3-Methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-
Nicotinonitrile 1H NMR (chloroform-d) δ 7.61-7.59 (d, J =
7.6 Hz, 1H), 7.46-7.37 (m, 2H), 7.10
-7.08 (d, J = 7.2 Hz, 1H), 4.90 (s, 0.5
H), 4.53-4.34 (M, 2.5H), 4.22-4.05 (
m, 2.5H), 3.79-3.71 (m, 2.5H), 3.60-
3.54 (M, 0.5H), 3.48 (S, 1H), 3.37 (S, 3
H), 3.19-3.14 (M, 1.5H), 3.03-2.98.
(M, 1H), 2.75-2.66 (M, 1H), 2.60-2.5
5 (m, 1H), 2.11 (s, 3H), 1.48-1.44 (m,
2H), 1.31-1.30 (d, J = 4.8 Hz, 1.5H),
1.10-1.07 (m, 2H). LC-MS: m / z 449.1 (
M + H) +.

Compound 380 (General Procedure 6, Step G ′)
(R) -N- (4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-
Propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} -phenyl) -methanesulfonamide 1H NMR (methanol-d) d 7.36 (d, J = 8.4 Hz,
2H), 7.21 (d, J = 8.4 Hz, 2H), 4.75-4.
. 85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5
H), 3.43 (s, 3H), 3.16-3.25 (m, 1.5H),
3.03 (s, 3H), 2.87-2.98 (m, 0.5H),
68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34
-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.7
8-0.85 (m, 2H). LC-MS: m / z 512.2 (M
+ H) +.

Compound 393 (General Procedure 6, Step G ′)
(R) -4- {5-cyano-2-cyclopropyl-6- [4- (3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-pyridin-3-yl} −
Benzenesulfonamide 1H NMR (methanol-d) d 8.02 (d, J = 8.4 Hz,
2H), 7.43 (d, J = 8.4 Hz, 2H), 4.75-4.
. 85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05
-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5
H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2
. 87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H
), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.
62-1.69 (m, 1H), 1.34-1.41 (m, 3H),
1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H
). LC-MS: m / z 498.1 (M + H) +.

Compound 405 (General Procedure 6, Step G ′)
(R) -6-cyclopropyl-5- (2,3-difluoro-phenyl) -2- [4- (
6. 3-methoxy-propionyl) -3-methyl-piperazin-1-yl] -4-methyl-nicotinonitrile 1H NMR (methanol-d) [delta] 7.26-7.39 (m, 2H),
07 (t, J = 6.8 Hz, 1H), 4.72 (s, 0.5H), 4.4
1-4.45 (m, 1H), 4.07-4.19 (m, 2H), 3.93
(D, J = 13.6 Hz, 0.5H), 3.66-3.69 (m, 2H),
3.56-3.62 (m, 0.5H), 3.33 (s, 3H), 3.20
-3.28 (m, 1H), 3.14-3.17 (m, 1H), 2.96-3
. 02 (m, 0.5H), 2.60-2.81 (m, 2H), 2.18 (
s, 3H), 1.55-1.61 (m, 1H), 1.38 (d, J =
6.4 Hz, 1.3H), 1.27 (d, J = 6.8 Hz, 1.7H)
), 1.06-1.1 (m, 2H), 0.82-0.89 (m, 2H).
LC-MS: m / z 455.1 (M + H) +.

Compound 589
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-5 -Carbonitrile

This was obtained by the same procedure as compound 527.
1H NMR (chloroform-d) δ 8.70 (d, J = 5.0 Hz,
1H), 7.26 (s, 1H), 7.10 (d, J = 3.8 Hz,
1H), 6.90 (dd, J = 17.4, 10.9 Hz, 1H),
6.32 (d, J = 17.3 Hz, 1H), 5.61 (d, J =
11.3 Hz, 1H), 4.60-4.76 (m, 0.5H), 4.3
4 (d, J = 12.8 Hz, 1H), 4.26 (d, J = 12.
8 Hz, 1H), 4.08 (d, J = 9.0 Hz, 0.5H), 3
. 92 (br.s., 2H), 3.78 (br.s., 1H), 3.3
9-3.56 (m, 1H), 3.23 (br.s., 1H), 3.1
5 (d, J = 11.8 Hz, 1H), 3.05 (br.s., 1H
), 2.61 (br. S., 2H), 2.17-2.29 (m, 3H)
), 1.55-1.60 (m, 1H), 1.38-1.47 (m,
1H), 1.27-1.33 (br.s., 1H), 1.12 (br.s.
, 2H), 0.64 (br. S., 2H), 0.33-0.54 (m
, 2H)
LC-MS: m / z 458.3 (M + H) +

Compound 674
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-vinylpyridazin-4-yl) nicotinonitrile

Step 1 (R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-hydroxypyridazin-4-yl) nicotinonitrile

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3 , 2-
Dioxaborolan-2-yl) nicotinonitrile (200 mg, 0.42 mmol), 5
-Chloropyridazin-3-ol (109 mg, 0.625 mmol), CsF (127
mg, 0.84 mmol) and Pd (dppf) Cl ₂ (17 mg) in dioxane and water were heated at 100 ° C. for 2 h. The reaction mixture was concentrated and the residue was purified by preparative TLC to give 120 mg of the title compound.
LC-MS: m / z 449.2 (M + H) ⁺

Step 2 (R) -5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) pyridin-3-yl) pyridazine-3 -Il trifluoromethanesulfonate

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-hydroxypyridazin-4-yl) nicotinonitrile (120 mg 0.27 mmol), Tf ₂ O (100 mg, 0.48 mmol)
l) and TEA (0.1 mL) in DCM were stirred for 1 hour. The reaction mixture was washed with water, dried and concentrated. The residue was purified by preparative TLC to give 60 mg of the title compound.
1H NMR (chloroform-d) δ: 9.41 (d, J = 1.5 Hz,
1H), 7.71 (s, 1H), 7.51 (d, J = 1.8 Hz,
1H), 4.71 (d, J = 12.8 Hz, 1.5H), 4.58
(D, J = 11.5 Hz, 1H), 4.14 (brs, 0.5H),
3.93 (br.s., 0.5H), 3.75 (br.s., 2.5H)
, 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.5
4-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1
. 08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
LC-MS: m / z 580.7 (M + H) +

Step 3 (R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (6-vinylpyridazin-4-yl)
Nicotinonitrile (Compound 674)

(R) -5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (
3-methoxypropanoyl) piperazin-1-yl) pyridin-3-yl) pyridazine-
3-yl trifluoromethanesulfonate (25 mg, 0.043 mmol), potassium vinyl trifluoroborate (12 mg, 0.083 mmol), TEA (20 mg, 0
. 215 mmol) and Pd (dppf) Cl ₂ (3.5 mg) in i-PrOH and water were heated at 100 ° C. for 2 h. The reaction mixture is concentrated and the residue is preparative T
Purification by LC gave 11 mg of the title compound.
1H NMR (chloroform-d) δ9.21 (br.s., 1H), 7.
68 (s, 1H), 7.61 (s, 1H), 7.13 (dd, J = 1)
7.6, 11.0 Hz, 1H), 6.37 (d, J = 17.6 Hz,
1H), 5.79 (d, J = 11.0 Hz, 1H), 4.63 (d
, J = 12.8 Hz, 1.5H), 4.50 (d, J = 12.3)
Hz, 1H), 4.05-4.18 (m, 0.5H), 3.90 (d,
J = 11.0 Hz, 0.5H), 3.63-3.83 (m, 2.5
H), 3.38 (s, 3H), 3.18-3.33 (m, 2H), 3
. 15 (br. S., 1H), 2.71 -2.64 (m, 2H), 1.
89-1.99 (m, 1H), 1.29-1.40 (m, 3H),
1.07 (dd, J = 7.4, 2.9 Hz, 2H), 0.61-0.
44 (m, 4H).
LC-MS: m / z 459.0 (M + H) +

Compound 675
(R) -5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (
3-methoxypropanoyl) piperazin-1-yl) pyridin-3-yl) pyridazine-
3-yl trifluoromethanesulfonate 1H NMR (chloroform-d) δ: 9.41 (d, J = 1.5 Hz,
1H), 7.71 (s, 1H), 7.51 (d, J = 1.8 Hz,
1H), 4.71 (d, J = 12.8 Hz, 1.5H), 4.58
(D, J = 11.5 Hz, 1H), 4.14 (brs, 0.5H),
3.93 (br.s., 0.5H), 3.75 (br.s., 2.5H)
, 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.5
4-2.83 (m, 2H), 1.86-1.96 (m, 1H), 1
. 08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
LC-MS: m / z 580.7 (M + H) +

Compound 687
(R) -5- (5-Cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) pyridazine-
3-yltrifluoromethanesulfonate 1H NMR (chloroform-d) δ: 9.42 (br.s., 1H), 7
. 72 (s, 1H), 7.52 (s, 1H), 4.73 (d, J =
12.8 Hz, 1.5H), 4.60 (d, J = 12.0 Hz, 1H
), 4.33 (brs, 0.5H), 4.05 (brs, 0.5H), 3.
76 (br. S., 1H), 3.24-3.40 (m, 2.5H), 1.
89-1.97 (m, 1H), 1.72 (br. S., 1H),
29-1.34 (m, 3H), 0.99-1.20 (m, 4H),
0.78-0.90 (m, 2H), 0.41-0.66 (m, 4H)
.
LC-MS: m / z 563.0 (M + H) +

Compound 766
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -5- (5-vinylpyridazine-
3-yl) nicotinonitrile

Step 1 (R) -6-cyclopropyl-2- (3-cyclopropylpiperazine-1-
Yl) -5- (5-vinylpyridazin-3-yl) nicotinonitrile

(R) -tert-Butyl 4- (3-cyano-6-cyclopropyl-5- (5-vinylpyridazin-3-yl) pyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (100 mg , 0.2 mmol) in TFA (2 mL) was stirred overnight at room temperature. When LC-MS showed that the reaction was complete, the mixture was evaporated under reduced pressure and the residue was dissolved in DCM and washed with saturated NaHCO 3 and brine.
The organic layer was evaporated under reduced pressure to give the crude product, which was used without further purification (70
mg).

Step 2. Compound 766
Stirred 2- (oxetan-2-yl) acetic acid (20 mg) in CH ₂ Cl ₂ was added to HAT.
U (72 mg, 0.19 mmol) is added, then DIPEA is added and the mixture is stirred at room temperature for 1 hour, then (R) -6-cyclopropyl-2- (3-cyclopropylpiperazin-1-yl) -5- (5-vinylpyridazin-3-yl) nicotinonitrile (
70 mg) was added. The mixture was stirred overnight at room temperature. This was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer is washed with saturated NaHCO 3, brine and N
Dried over a2SO4, evaporated and purified by preparative TLC to give the product.
1H NMR (chloroform-d) δ: 9.23 (br.s., 1H),
7.97 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H),
6.74 (dd, J = 17.8, 11.0 Hz, 1H), 6.20 (
d, J = 17.6 Hz, 1H), 5.76 (d, J = 10.9 H)
z, 1H), 5.11-5.36 (m, 1H), 4.48-4.77.
(M, 4H), 4.08 (d, J = 8.5 Hz, 0.5H), 2.
95 (d, J = 13.2 Hz, 0.5H), 3.75 (d, J =
11.2 Hz, 0.5H), 3.32 (br.s., 1H), 3.05
-3.27 (m, 2H), 2.98 (dd, J = 14.8, 6.0
Hz, 1.5H), 2.79-2.90 (m, 2H), 2.54 (d,
J = 7.9 Hz, 1H), 2.12-2.26 (m, 1H), 1
. 25 (dd, J = 6.6, 3.7 Hz, 3H), 0.94-1.
12 (m, 2H), 0.51-0.72 (m, 2H), 0.35-
0.49 (m, 2H)
LC-MS: m / z 471.6 (M + H) +

Compound 769
(R, E) -6-cyclopropyl-2- (3-cyclopropyl-4- (5-hydroxypent-2-enoyl) piperazin-1-yl) -4-methyl-5- (5-vinylpyridazine- 3-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 9.27 (d, J = 2.1 Hz
, 1H), 7.43 (d, J = 2.1 Hz, 1H), 6.87 (d
t, J = 14.8, 7.3 Hz, 1H), 6.73 (dd, J =
17.8, 11.0 Hz, 1H), 6.26-6.48 (m, 1H),
6.21 (d, J = 17.6 Hz, 1H), 5.77 (d, J =
10.9 Hz, 1H), 4.42 (d, J = 12.9 Hz, 1H)
, 4.33 (d, J = 12.6 Hz, 1H), 3.89-4.21.
(M, 1H), 3.79 (t, J = 6.0 Hz, 2H), 3.38
(Br. S., 1H), 3.23 (d, J = 10.0 Hz, 1H)
, 3.08 (td, J = 12.5, 2.9 Hz, 1H), 2.50
(Q, J = 6.2 Hz, 2H), 2.18-2.29 (m, 3H)
, 1.36-1.50 (m, 2H), 1.15 (br. S., 2H)
, 0.88 (dd, J = 7.6, 3.2 Hz, 2H), 0.65 (
br. s. , 1H), 0.51 (br. S., 1H), 0.44 (br
. s. , 2H)
LC-MS: m / z 485.6 (M + H) +

Compound 768
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-5- (5 -Vinylpyridazin-3-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 9.28 (d, J = 2.1 Hz,
1H), 7.43 (d, J = 2.1 Hz, 1H), 6.74 (dd
, J = 17.6, 10.9 Hz, 1H), 6.21 (d, J = 1)
7.9 Hz, 1H), 5.71-5.86 (m, 1H), 5.27 (
quin, J = 6.7 Hz, 1H), 4.64-4.76 (m, 1
H), 4.49-4.63 (m, 1H), 4.41 (d, J = 12
. 6 Hz, 1H), 4.23-4.37 (m, 1H), 4.07 (d
, J = 8.2 Hz, 1H), 3.92 (d, J = 12.6 Hz,
1H), 3.69-3.86 (m, 1H), 3.20-3.36 (
m, 1H), 2.93-3.20 (m, 3H), 2.74-2.93.
(M, 2H), 2.46-2.66 (m, 1H), 2.18-2.
30 (m, 3H), 1.78 (br. S., 1H), 1.41-1.
51 (m, 2H), 1.33-1.41 (m, 1H), 1.10-
1.20 (m, 2H), 0.89 (dd, J = 7.8, 3.1 Hz,
2H), 0.58-0.72 (m, 1H), 0.53 (br. S.,
1H), 0.45 (d, J = 5.6 Hz, 2H)
LC-MS: m / z 485.6 (M + H) +

Compound 767
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-5- (5-vinylpyridazin-3-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ: 9.28 (s, 1H), 7.44 (
d, J = 2.1 Hz, 1H), 7.28 (s, 1H), 6.74 (
dd, J = 17.6, 10.9 Hz, 1H), 6.21 (d, J =
17.6 Hz, 1H), 5.78 (d, J = 10.9 Hz, 1H)
, 4.37-4.47 (m, 1H), 4.26-4.36 (m, 1
H), 4.01-4.13 (m, 1H), 3.83-3.98 (m,
2H), 3.65-3.83 (m, 1H), 3.13-3.29 (
m, 2H), 2.98-3.13 (m, 1H), 2.46-2.68.
(M, 2H), 2.19-2.29 (m, 3H), 1.84-2.
10 (m, 1H), 1.42-1.55 (m, 1H), 1.15 (b
r. s. , 1H), 0.81-0.95 (m, 3H), 0.63 (b
r. s. , 1H), 0.53 (br. S., 1H), 0.32-0.
48 (m, 2H)
LC-MS: m / z 459.6 (M + H) +

Compound 749
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -4-methyl-5- (6-vinylpyridazin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ: 9.21 (d, J = 2.1 Hz,
1H), 7.70 (s, 1H), 7.64 (d, J = 2.1 Hz,
1H), 7.15 (dd, J = 17.8, 11.0 Hz, 1H),
6.39 (d, J = 17.9 Hz, 1H), 5.81 (d, J =
10.9 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H),
4.52 (d, J = 12.9 Hz, 1H), 4.10 (d, J =
9.7 Hz, 1H), 3.85-3.99 (m, 2H), 3.71-
3.83 (m, 1H), 3.07-3.36 (m, 3H), 2.42
-2.71 (m, 2H), 1.88-2.02 (m, 1H),
20-1.40 (m, 3H), 1.01-1.12 (m, 2H),
0.45-0.78 (m, 4H)
LC-MS: m / z 473.3 (M + H) +

Compound 724
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5- (5-vinylpyridazin-3-yl) nicotinonitrile 1H NMR ( Chloroform-d) δ: 9.22 (s, 1H), 7.93 −
8.03 (m, 1H), 7.61 (d, J = 1.8 Hz, 1H),
6.74 (dd, J = 17.8, 11.0 Hz, 1H), 6.20
(D, J = 17.6 Hz, 1H), 5.76 (d, J = 10.9)
Hz, 1H), 4.65 (d, J = 13.2 Hz, 1H), 4.52
(D, J = 12.6 Hz, 1H), 4.16 (m, 1H), 3.8
0-4.02 (m, 2H), 3.58-3.74 (m, 1H), 3.4
5 (s, 3H), 3.26 (d, J = 10.3 Hz, 2H), 3.
12 (t, J = 10.6 Hz, 1H), 2.11-2.32 (m,
1H), 1.23-1.30 (m, 3H), 0.98-1.08 (
m, 2H), 0.41-0.72 (m, 4H)
LC-MS: m / z 445.2 (M + H) +

Compound 723
(R) -tert-butyl (6- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) pyridine-3
-Yl) pyridazin-4-yl) carbamate

((R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (4,4,5,5-tetramethyl-1, 3,
2-Dioxaborolan-2-yl) nicotinonitrile (67 mg, 0.157 mmol)
, Tert-butyl (6-chloropyridazin-4-yl) carbamate (30 mg,.
131 mmol), Pd (dppf) Cl ₂ (5 mg, 0.007 mmol) and Cs
A mixture of F (40 mg, 0.216 mmol) in dioxane / H ₂ O was stirred at 100 ° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was water (10 mL),
Wash with brine, dry over Na ₂ SO ₄ and concentrate to give the crude, which is preparative T
Purification by LC gave 20 mg of product.
1H NMR (chloroform-d) δ: 9.08 (s, 1H), 8.29 (
s, 1H), 7.98 (s, 1H), 7.60 (br.s., 1H),
4.64 (d, J = 12.9 Hz, 1H), 4.52 (d, J =
12.3 Hz, 1H), 4.08 (d, J = 8.5 Hz, 1H),
3.93 (s, 2H), 3.66-3.84 (m, 1H), 3.25
(M, 3H), 2.50-2.61 (m, 2H), 1.56 (s, 9H
), 1.21-1.28 (m, 3H), 1.07 (s, 2H), 0.41
-0.80 (m, 4H)
LC-MS: m / z 534.3 (M + H) +

Compound 716
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (5-vinylpyridazin-3-yl) nicotinonitrile 1H NMR (Chloroform-d) δ9.23 (s, 1H), 7.98 (s
, 1H), 7.61 (d, J = 2.1 Hz, 1H), 6.74 (d
d, J = 17.8, 11.0 Hz, 1H), 6.20 (d, J =
17.6 Hz, 1H), 5.71-5.84 (m, 1H), 4.64.
(D, J = 12.9 Hz, 1H), 4.51 (d, J = 12.6)
Hz, 1H), 4.01-4.16 (m, 1H), 3.92 (s, 2
H), 3.65-3.83 (m, 1H), 3.05-3.25 (d, J
= 11.2 Hz, 2H), 2.50-2.68 (m, 2H),
12-2.30 (m, 1H), 1.19-1.27 (m, 3H),
1.00-1.11 (m, 2H), 0.39-0.62 (m, 1H)
LC-MS: m / z 445.2 (M + H) +

Compound 715
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5- (6-vinylpyridazin-4-yl) nicotinonitrile 1H NMR ( Chloroform-d) δ 9.20 (s, 1H), 7.68 (s
, 1H), 7. 61 (s, 1H), 7.11 (dd, J = 17.8)
, 11.0 Hz, 1H), 6.36 (d, J = 17.9 Hz, 1H
), 5.77 (d, J = 11.2 Hz, 1H), 4.64 (d, J
= 12.9 Hz, 1H), 4.50 (d, J = 12.6 Hz, 1
H), 4.15 (s, 2H), 3.80-4.12 (m, 1H), 3.6
0-3.66 (m, 1H), 3.44 (s, 3H), 3.26 (dd,
J = 13.2, 3.5 Hz, 1H), 3.07-3.18 (m, 1
H), 1.87-2.04 (m, 1H), 1.19-1.29 (m,
3H), 1.06 (dd, J = 7.9, 2.9 Hz, 2H), 0.
47-0.65 (m, 4H)
LC-MS: m / z 445.2 (M + H) +

Compound 696
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (5-vinylpyridazin-3-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 9.23 (d, J = 2.1 Hz,
1H), 7.98 (s, 1H), 7.63 (d, J = 2.1 Hz,
1H), 6.75 (dd, J = 17.6, 10.9 Hz, 1H),
6.21 (d, J = 17.6 Hz, 1H), 5.78 (d, J =
10.9 Hz, 1H), 4.66 (d, J = 12.9 Hz, 2.5H
), 3.98-4.54 (m, 1H), 3.51-3.88 (m, 1H),
3.00-3.45 (m, 1H), 2.16-2.28 (m, 1H),
1.72 (s, 1H), 1.17-1.30 (m, 3H), 0.95
-1.11 (m, 4H), 0.77-0.87 (m, 2H), 0.
39-0.64 (m, 1H)
LC-MS: m / z 441.2 (M + H) +

Compound 686
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (6-vinylpyridazin-4-yl) nicotinonitrile

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3 , 2
-Dioxaborolan-2-yl) nicotinonitrile (100 mg, 0.235 mmol)
, 5-chloro-3-vinylpyridazine (30 mg, 0.213 mmol), Pd (dpp
f) Cl ₂ (8 mg, 0.011 mmol) and CsF (98 mg, 0.640 mmol)
l) The mixture in dioxane / H ₂ O was stirred at 100 ° C. for 16 hours. E mixture
Dilute with tOAc (30 mL) and filter. The filtrate was partitioned between EtOAc (30 mL) and water (10 mL) and the organic layer was washed with water (10 mL), brine, and Na ₂ SO
Dried over ₄ and concentrated to give the crude, which was purified by preparative TLC to give 25 mg of product.
1H NMR (chloroform-d) δ: 9.21 (d, J = 2.1 Hz,
1H), 7.70 (s, 1H), 7.64 (d, J = 2.1 Hz,
1H), 7.15 (dd, J = 17.8, 11.0 Hz, 1H),
6.39 (d, J = 17.9 Hz, 1H), 5.81 (d, J =
10.9 Hz, 1H), 4.64 (d, J = 13.2 Hz, 1H),
4.52 (d, J = 12.9 Hz, 1H), 4.10 (d, J =
9.7 Hz, 1H), 3.87-4.01 (m, 2H), 3.71
-3.87 (m, 1H), 3.07-3.36 (m, 3H), 2.4
6-2.70 (m, 2H), 1.81-2.03 (m, 1H), 1
. 20-1.34 (m, 3H), 1.03-1.13 (m, 2H),
0.60-0.69 (m, 1H), 0.46-0.57 (m, 4H)
LC-MS: m / z 445.2 (M + H) +

Compound 671
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (6-hydroxypyridazin-4-yl) nicotinonitrile 1H NMR (Chloroform-d) δ: 12.36 (br. S., 1H),
7.95 (d, J = 2.0 Hz, 1H), 7.65 (s, 1H),
7.00 (d, J = 2.0 Hz, 1H), 4.63 (d, J = 1)
3.1 Hz, 1H), 4.50 (d, J = 12.8 Hz, 1H),
4.01-4.19 (m, 1H), 3.89-3.98 (m, 2H)
, 3.60-3.85 (m, 1H), 3.01-3.29 (m, 3H)
, 2.60 (dd, J = 11.8, 6.0 Hz, 2H), 1.87
-2.05 (m, 1H), 1.14-1.26 (m, 3H), 0.3
1-1.14 (m, 4H).
LC-MS: m / z 435.2 (M + H) +

Compound 673
(R) -6'-Chloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4'-bipyridine] -2 ', 5 -Dicarbonitrile

(R) -2 ′, 6′-Dichloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] -5 -Carbonitrile (40 mg, 0.084 mmol), CuCN (15 mg, 0.169 mmol)
l) A mixture of CuI (1 mg) in NMP (2 mL) was stirred at 230 ° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (30 mL) and water (10 mL) and the organic layer was washed with water (10 mL), brine, dried over Na 2 SO 4 and concentrated to give the crude Was purified by preparative TLC to give 20 mg of product.
1H NMR (chloroform-d) δ: 7.72 (d, J = 1.0 Hz,
1H), 7.59-7.66 (m, 2H), 4.91 (s, 0.5H)
), 4.54 (d, J = 10.3 Hz, 0.5H), 4.24-4
. 48 (m, 2.5H), 3.69-3.79 (m, 2H), 3.51
-3.62 (m, 0.5H), 3.33-3.44 (m, 4H),
3.18-3.29 (m, 1.5H), 3.10-3.25 (m, 1.5
H), 2.63−2.82 (m, 1H), 2.52−2.63 (m,
1H), 1.82-1.95 (m, 1H), 1.36 (d, J =
6.5 Hz, 1H), 1.23-1.28 (m, 4H), 1.04-
1.15 (m, 2H)
LC-MS: m / z 465.2 (M + H) +

Compound 672
(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -6'-vinyl- [3,4'-bipyridine] -2 ', 5 -Dicarbonitrile

(R) -6'-Chloro-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4'-bipyridine] -2 ', 5 Dicarbonitrile (10 mg, 0.0215 mmol), potassium vinyl trifluoroborate (5 mg, 0.032 mmol), Pd (dppf) Cl ₂ (1 mg, 0.001 mmol)
l) and CsF (10 mg, 0.064 mmol) in dioxane / H ₂ O
Stir at 100 ° C. for 16 hours. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was partitioned between EtOAc (30 mL) and water (10 mL) and the organic layer was washed with water (10 mL), brine, dried over Na ₂ SO ₄ and concentrated to give the crude which was separated by Purification by TLC yielded 5 mg of product.
1H NMR (chloroform-d) δ: 7.63 (s, 2H), 7.52 −
7.59 (m, 1H), 6.86 (dd, J = 17.4, 10.7
Hz, 1H), 6.42 (d, J = 17.6 Hz, 1H), 5.71
(D, J = 10.8 Hz, 1H), 4.92 (s, 0.5H), 4
. 54 (d, J = 9.5 Hz, 0.5H), 4.25-4.46 (
m, 2.5H), 3.71-3.86 (m, 3.5H), 3.35-
3.42 (m, 3.5H), 3.03-3.29 (m, 1.5H), 2
. 63-2.82 (m, 1H), 2.53-2.62 (m, 1H),
1.83-1.96 (m, 1H), 1.34-1.40 (m, 2H)
), 1.20-1.26 (m, 3H), 1.00-1.11 (m,
2H).
LC-MS: m / z 457.2 (M + H) +

Compound 653
(R) -2-cyclopropyl-2 '-(3-hydroxyprop-1-en-2-yl)
-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3
, 4′-bipyridine] -5-carbonitrile

Step 1 (R) -2-cyclopropyl-2′-hydroxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4′-bipyridine] -5
-Carbonitrile

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3 2-Dioxaborolan-2-yl) nicotinonitrile (100 mg, 0.22 mmol), 4-bromopyridin-2-ol (38 mg, 0.22 mmol), CsF (66 mg, 0.44 m)
mol) and Pd (dppf) Cl ₂ (5 mg) in dioxane and water
Heated at 00 ° C. for 0.5 hour. The reaction mixture was concentrated and the residue was purified by preparative TLC to give 52 mg of the title compound.
LC-MS: m / z 422.1 (M + H) ⁺

Step 2 (R) -5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4'-bipyridine] -2'- Iltrifluoromethanesulfonate

(R) -2-cyclopropyl-2'-hydroxy-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4'-bipyridine] -5-carbonitrile (100 mg, 0.24 mmol), Tf ₂ O (40 mg) and TEA (1 drop)
Of DCM in 5 ml was stirred for 1 hour. The reaction mixture was washed with water, dried and concentrated. The residue was purified by preparative TLC to give 60 mg of the title compound.
LC-MS: m / z 554.1 (M + H) ⁺

Step 3 (R) -2-cyclopropyl-2 ′-(3-hydroxyprop-1-ene-
2-yl) -6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)-[3,4'-bipyridine] -5-carbonitrile compound 653

(R) -5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl)-[3,4'-bipyridin] -2'-yl trifluoromethanesulfonate (150 mg, 0.27 mmol), prop-2-en-1-ol (31 mg, 0.54 mmol) ), TEA (30 mg, 0.30 mmol), Pd (
OAc) ₂ (15 mg, 0.0675 mmol), and Dppf (72 mg, 0.13
mmol) in DMF (10 mL) was heated at 100 ° C. for 2 h. The reaction mixture was diluted with DCM, washed with water and brine, dried and concentrated, and the residue was purified by preparative TLC and preparative HPLC to give 16 mg of the title compound.
1H NMR (chloroform-d) δ 8.62 (d, J = 5.3 Hz,
1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.31 (d
d, J = 5.0, 1.3 Hz, 1H), 5.87 (s, 1H), 5
. 60 (s, 1H), 4.92 (brs, 0.5H), 4.65 (s, 2H)
, 4.54 (d, J = 12.5 Hz, 0.5H), 4.20-4.
46 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.4
9-3.65 (m, 0.5H), 3.39 (s, 3H), 3.33 (
d, J = 13.3 Hz, 1H), 3.01-3.27 (m, 1.5
H), 2.64-2.85 (m, 1H), 2.51-2.64 (m,
1H), 1.96-2.08 (m, 1H), 1.39 (d, J =
6.5 Hz, 1.5H), 1.25-1.36 (m, 1.5H),
17-1.25 (m, 2H), 0.95-1.09 (m, 2H).
LC-MS: m / z 462.1 (M + H) +

Compound 765
6-Cyclopropyl-2-((R) -3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -4-methyl-5- (2-vinylquinoxalin-5-yl) nicotino Nitrile 1H NMR (chloroform-d) δ: 9.00 (s, 1H), 8.09
-8.21 (m, 1H), 7.80-7.91 (m, 1H), 7.5
3-7.66 (m, 1H), 7.00-7.13 (m, 1H), 6
. 51 (d, J = 17.6 Hz, 1H), 5.85 (d, J = 1)
1.2 Hz, 1H), 4.71 (d, J = 10.0 Hz, 0.5H),
4.47 (d, J = 10.3 Hz, 0.5H), 4.40 (d, J
= 13.5 Hz, 1H), 4.23-4.35 (m, 1H),
85 (d, J = 13.5 Hz, 0.5H), 3.71-3.81 (
m, 2H), 3.59 (d, J = 10.3 Hz, 0.5H), 3.4
6-3.55 (m, 0.5H), 3.40 (d, J = 5.0 Hz,
3H), 3.05-3.14 (m, 2H), 3.02 (d, J =
9.7 Hz, 1H), 2.55-2.83 (m, 3H), 2.28-
2.44 (m, 1H), 2.15-2.28 (m, 1H), 2.04
-2.10 (m, 3H), 1.02-1.12 (m, 6H), 0.
84-0.95 (m, 2H), 0.72-0.81 (m, 1H),
0.59-0.70 (m, 1H)
LC-MS: m / z 525.6 (M + H) +

Compound 760
2-cyclopropyl-6-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-2'-vinyl -3
, 4′-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.70 (d, J = 4.4 Hz)
, 1H), 7.25 (s, 1H), 7.09 (d, J = 3.5 Hz
, 1H), 6.90 (dd, J = 17.5, 10.7 Hz, 1H),
6.32 (d, J = 17.3 Hz, 1H), 5.60 (d, J =
10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65
-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.
22-4.41 (m, 2H), 4.09 (d, J = 8.2 Hz,
1H), 3.91 (br. S., 1H), 3.38 (s, 1H), 3.
14 (br. S., 1H), 2.94-3.09 (m, 2H), 2.
68-2.94 (m, 3H), 2.49-2.63 (m, 1H),
2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12.
(Br. S., 2H), 0.88 (dd, J = 7.6, 2.9 Hz,
2H), 0.62 (br.s., 1H), 0.55 (br.s., 1
H), 0.34-0.51 (m, 2H)
LC-MS: m / z 484.7 (M + H) +

Compound 761
2-cyclopropyl-6-((R) -3-cyclopropyl-4- (2-((S) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-2'-vinyl -3
, 4′-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.70 (d, J = 4.4 Hz)
, 1H), 7.25 (s, 1H), 7.09 (d, J = 3.5 Hz
, 1H), 6.90 (dd, J = 17.5, 10.7 Hz, 1H),
6.32 (d, J = 17.3 Hz, 1H), 5.60 (d, J =
10.9 Hz, 1H), 5.22-5.34 (m, 1H), 4.65
-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.
22-4.41 (m, 2H), 4.09 (d, J = 8.2 Hz,
1H), 3.91 (br. S., 1H), 3.38 (s, 1H), 3.
14 (br. S., 1H), 2.94-3.09 (m, 2H), 2.
68-2.94 (m, 3H), 2.49-2.63 (m, 1H),
2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12.
(Br. S., 2H), 0.88 (dd, J = 7.6, 2.9 Hz,
2H), 0.62 (br.s., 1H), 0.55 (br.s., 1
H), 0.34-0.51 (m, 2H)
LC-MS: m / z 484.7 (M + H) +

Compound 664
(R) -2-cyclopropyl-6- (4- (1-hydroxycyclopropanecarbonyl) -3-methylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.64 (d, J = 5.0 Hz,
1H), 7.64 (s, 1H), 7.40 (s, 1H), 7.24 (
dd, J = 5.0, 1.5 Hz, 1H), 6.88 (dd, J =
17.6, 10.8 Hz, 1H), 6.27 (d, J = 17.6 Hz)
, 1H), 5.57 (d, J = 11.3 Hz, 1H), 4.87 (
br. s. , 1H), 4.50 (d, J = 11.8 Hz, 1H),
4.39 (d, J = 12.8 Hz, 1H), 4.32 (d, J =
11.5 Hz, 1H), 3.32 (dd, J = 13.1, 2.8 Hz)
, 1H), 3.21-3.66 (m, 2H), 1.99-2.07 (
m, 1H), 1.30-1.50 (m, 3H), 1.21 (dt, J
= 7.2, 3.5 Hz, 2H), 1.11-1.17 (m, 1H)
, 0.91-1.09 (m, 5H).
LC-MS: m / z 430.2 (M + H) +

Compound 739
(R) -methyl 4- (4- (2′-chloro-5-cyano-2-cyclopropyl-3,4)
'-Bipyridin-6-yl) -2-cyclopropylpiperazin-1-yl) -4-oxobutanoate 1H NMR (chloroform-d) δ: 8.48 (d, J = 5.0 Hz,
1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.30 (
d, J = 4.4 Hz, 1H), 4.59 (d, J = 12.3 Hz)
, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.06 (
br. s. , 1H), 3.81-3.94 (m, 1H), 3.72 (
s, 3H), 3.06-3.36 (m, 1.5H), 2.84 (br.
s. 1.5H), 2.71 (d, J = 7.9 Hz, 3H),
50-2.66 (m, 1H), 1.91-2.07 (m, 1H),
1.33 (br.s., 1H), 1.27 (br.s., 1H),
14-1.25 (m, 2H), 1.05 (dd, J = 7.5, 3.
4 Hz, 2H), 0.61 (br. S., 1H), 0.54 (br.
s. , 1H), 0.45 (d, J = 4.1 Hz, 2H).
LC-MS: m / z 494.2 (M + H) +

Compound 738
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (2-hydroxyacetyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (Chloroform-d) δ: 8.55-8.78 (m, 1H),
7.66 (s, 1H), 7.39 (br. S., 1H), 7.17 −
7.26 (m, 1H), 6.88 (dd, J = 17.3, 10.9
Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H), 5.57
(D, J = 10.9 Hz, 1H), 4.56 (d, J = 12.9)
Hz, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.2
2 (br.s., 1H), 4.18 (br.s., 1H), 4.01
(Br.s., 0.5H), 3.68 (br.s., 1.5H), 3.3
4-3.53 (m, 1H), 3.24 (d, J = 10.9 Hz,
1H), 3.09 (t, J = 11.3 Hz, 1H), 2.00-2
. 07 (m, 1H), 1.32 (br. S., 1H), 1.27 (br
. s. , 1H), 1.21 (br. S., 2H), 1.02 (br.
s. , 2H), 0.66 (br. S., 1H), 0.57 (br. S.
, 1H), 0.48 (br. S., 1H).
LC-MS: m / z 430.2 (M + H) +

Compound 747
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (4-methoxybutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.67 (d, J = 4.7 Hz)
, 1H), 7.66 (s, 1H), 7.46 (br.s., 1H),
7.31 (br. S., 1H), 6.95 (dd, J = 17.3, 1
0.9 Hz, 1H), 6.38 (d, J = 17.3 Hz, 1H),
5.66 (d, J = 10.6 Hz, 1H), 4.58 (d, J =
12.9 Hz, 1H), 4.46 (d, J = 12.3 Hz, 1H),
3.70-4.12 (br.s., 2H), 3.46 (br.s., 2
H), 3.36 (s, 3H), 3.23 (br. S., 1H), 3.1
1 (br. S., 1H), 2.49 (br. S., 2H), 1.89
-2.14 (m, 4H), 1.27-1.31 (m, 1H), 1.1
8-1.25 (m, 2H), 1.00-1.08 (m, 2H), 0
. 59 (d, J = 15.6 Hz, 2H), 0.47 (d, J = 5
. 0 Hz, 2H).
LC-MS: m / z 472.5 (M + H) +

Compound 753
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (4-hydroxybutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.64 (d, J = 5.0 Hz)
, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 7.18
-7.27 (m, 1H), 6.87 (dd, J = 17.3, 10.9
Hz, 1H), 6.28 (d, J = 17.6 Hz, 1H), 5.5
7 (d, J = 10.9 Hz, 1H), 4.55 (d, J = 12.
9 Hz, 1H), 4.42 (d, J = 12.6 Hz, 1H), 4.
09 (d, J = 7.9 Hz, 0.5H), 3.86 (d, J = 1)
3.2 Hz, 0.5H), 3.73 (br.s., 2H), 3.05 −
3.32 (m, 2H), 2.97 (s, 1H), 2.89 (s, 1H)
), 2.57 (br. S., 3H), 2.00-2.08 (m, 1H
), 1.91-1.98 (m, 2H), 1.28 (d, J = 17.
3 Hz, 1H), 1.21 (br.s., 2H), 1.01 (dd,
J = 7.6, 3.2 Hz, 2H), 0.61 (br.s., 1H),
0.54 (br. S., 1H), 0.30-0.50 (m, 2H).
LC-MS: m / z 458.6 (M + H) +

Compound 726
(R) -2-cyclopropyl-6- (3-isopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR ( Chloroform-d) δ: 8.64 (d, J = 5.0 Hz)
, 1H), 7.58-7.66 (m, 1H), 7.37 (s, 1H)
, 7.22 (dd, J = 5.0, 1.5 Hz, 1H), 6.87 (
dd, J = 17.5, 10.7 Hz, 1H), 6.21-6.33.
(M, 1H), 5.50-5.60 (m, 1H), 4.54-4.7
1 (m, 1H), 4.33-4.49 (m, 1.5H), 4.02-
4.22 (m, 2H), 3.87 (d, J = 13.8 Hz, 0.5
H), 3.33-3.50 (m, 4H), 3.03-3.23 (m,
2.5H), 2.21 (d, J = 7.6 Hz, 0.5H), 1.96
-2.16 (m, 2H), 1.11-1.24 (m, 2H), 0.
94-1.11 (m, 5H), 0.84-0.92 (m, 3H).
LC-MS: m / z 446.1 (M + H) +

Compound 721
(R) -2-cyclopropyl-6- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (Chloroform-d) δ: 8.66 (d, J = 5.0 Hz
, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.40 (s
, 1H), 7.25 (dd, J = 5.1, 1.6 Hz, 1H), 6
. 89 (dd, J = 17.5, 10.7 Hz, 1H), 6.23 −
6.35 (m, 1H), 5.55-5.63 (m, 1H), 4.58
-4.74 (m, 1.5H), 4.38-4.50 (m, 1.5H),
3.87-4.00 (m, 2H), 3.78 (d, J = 13.8
Hz, 1H), 3.39-3.55 (m, 1H), 3.05-3.2
4 (m, 2H), 2.56-2.66 (m, 2H), 2.20-2
. 30 (m, 1H), 1.98-2.06 (m, 2H), 1.25-
1.33 (m, 6H), 0.84-0.95 (m, 4H)
LC-MS: m / z 446.1 (M + H) +

Compound 719
(R) -5- (2-Amino-6-vinylpyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicochi Nononitrile

Step 1 (R) -5- (2-Amino-6-chloropyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl ) Nicotinonitrile

To a solution of 4,6-dichloropyrimidin-2-amine (270 mg, 0.58 mmol) in dimethoxyethane (5 mL) and 2M aqueous sodium carbonate (0.8 mL) in a mixture of (R) -6-cyclopropyl-2 -(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3
2-Dioxaborolan-2-yl) nicotinonitrile (100 mg, 0.22 mmol)
And tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.1 equiv) were added under a nitrogen atmosphere and the mixture was heated at 100 ° C. for 2 h. After cooling to ambient temperature, the separated organic layer was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with 10% aqueous potassium carbonate and brine and dried over sodium sulfate. After evaporation, the residue is chromatographed on silica gel, 5% in petroleum ether
(R) -5- (2-amino-6-chloropyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxy) eluting with ~ 20% ethyl acetate Propanoyl) piperazin-1-yl) nicotinonitrile (140 mg crude) was obtained.
LC-MS: m / z 468.2 (M + H) +

Step 2: Compound 719
(R) -5- (2-Amino-6-vinylpyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicochi Nononitrile

(R) -5- (2-Amino-6-chloropyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine-1
-Yl) nicotinonitrile (60 mg, 0.13 mmol), potassium vinyl fluorborate (25 mg, 0.2 mm)
ol), Pd (PPh ₃ ) ₄ (3 mg, 0.1 equiv), and CsF (40 mg, 0.2
6 mmol) was suspended in 5 mL of dioxane and 1 mL of water and the resulting mixture was refluxed for 1 hour. After the reaction was complete, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give 40 mg of the title compound as a yellow solid (7
0% yield).
LC-MS: m / z 460.2 (M + H) +
1H NMR (chloroform-d) δ: 7.92 (s, 1H), 6.87 (
s, 1H), 6.65 (dd, J = 17.3, 10.6 Hz, 1H)
, 6.39 (d, J = 17.5 Hz, 1H), 5.69 (d, J
= 10.7 Hz, 1H), 5.44 (br. S., 2H), 4.61
(D, J = 13.2 Hz, 1H), 4.48 (d, J = 12.1)
Hz, 1H), 4.07 (d, J = 7.5 Hz, 1H), 3.87
-3.98 (m, 2H), 3.63-3.84 (m, 2H), 3.1
7-3.31 (m, 2H), 3.00-3.17 (m, 1H), 2
. 50-2.66 (m, 2H), 2.30-2.45 (m, 1H),
1.17-1.28 (m, 3H), 0.97-1.13 (m, 2H
), 0.61 (br.s., 1H), 0.54 (br.s., 1H),
0.46 (br.s., 2H).
LC-MS: m / z 460.2 (M + H) +

Compound 663
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (6-vinylpyrimidin-4-yl) nicotinonitrile 1H NMR (Chloroform-d) δ: 9.19-9.32 (m, 1H),
8.01 (s, 1H), 7.46-7.59 (m, 1H), 6.82
(Dd, J = 17.3, 10.8 Hz, 1H), 6.51-6.6.
3 (m, 1H), 5.80 (d, J = 11.3 Hz, 1H), 5.
32 (s, 1H), 4.66 (d, J = 13.1 Hz, 1H), 4
. 53 (d, J = 12.8 Hz, 1H), 4.08 (d, J = 9
. 8 Hz, 1H), 3.88-3.97 (m, 2H), 3.67-
3.82 (m, 2H), 3.32 (br. S., 1H), 3.20 −
3.29 (m, 2H), 3.02-3.20 (m, 2H), 2.49
-2.66 (m, 2H), 2.34-2.45 (m, 1H), 1.2
2-1.29 (m, 3H), 1.02-1.10 (m, 2H), 0
. 63 (d, J = 7.8 Hz, 1H), 0.55 (br.s., 1
H), 0.47 (br.s., 2H).
LC-MS: m / z 445.2 (M + H) +

Compound 701
(R) -5- (2-Amino-6- (2-aminoethyl) pyrimidin-4-yl) -2-
(4- (Cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6
-Cyclopropylnicotinonitrile 1H NMR (chloroform-d) δ 7.97-8.12 (m, 1H),
7.51 (br. S., 1H), 6.21 (br. S., 2H), 4
. 71 (d, J = 12.8 Hz, 1H), 4.57 (d, J = 1)
1.0 Hz, 1H), 4.06 (s, 1H), 3.52 (br.s.,
3H), 3.31 (br.s., 3H), 3.22 (br.s., 2
H), 2.38 (br.s., 1H), 1.71 (br.s., 1H)
, 1.19-1.28 (m, 3H), 0.96-1.14 (m, 4
H), 0.75-0.87 (m, 2H), 0.62 (br. S., 1
H), 0.51 (br. S., 2H), 0.38-0.48 (m, 1
H).
LC-MS: m / z 473.3 (M + H) +

Compound 759
(R) -5- (2-Amino-6-vinylpyrimidin-4-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) nicotino Nitrile 1H NMR (chloroform-d) δ: 7.95 (s, 1H), 6.88
(S, 1H), 6.66 (dd, J = 17.5, 10.7 Hz, 1H
), 6.47 (d, J = 17.6 Hz, 1H), 5.71 (d, J
= 11.2 Hz, 1H), 5.27 (br.s., 2H), 4.64.
(D, J = 13.2 Hz, 2H), 4.50 (d, J = 12.6)
Hz, 2H), 4.16 (br.s., 3H), 4.01 (br.s)
. , 1H), 3.90 (br. S., 1H), 3.65 (d, J =
17.0 Hz, 1H), 3.46 (s, 3H), 3.18-3.32.
(M, 2H), 3.02-3.18 (m, 1H), 2.32-2.4
7 (m, 1H), 1.18-1.32 (m, 3H), 1.00-1
. 11 (m, 2H), 0.63 (br. S., 2H), 0.46 (br
. s. , 2H)
LC-MS: m / z 460.2 (M + H) +

Compound 727
(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine -1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 7.51 (br.s., 1H),
6.66 (dd, J = 16.7, 10.6 Hz, 1H), 6.35 (
d, J = 16.7 Hz, 1H), 5.88 (br.s., 1H),
5.66-5.83 (m, 1H), 4.44 (d, J = 12.6 H
z, 1H), 4.25-4.38 (m, 2H), 4.19 (br. s).
. , 1H), 3.98-4.10 (m, 1H), 3.91 (br. S)
. , 2H), 3.84 (br. S., 1H), 3.60-3.79 (
m, 3H), 3.08-3.25 (m, 2H), 2.89-3.08
(M, 1H), 2.47-2.65 (m, 2H), 2.40 (br.
s. , 2H), 2.01-2.08 (m, 1H), 1.27 (br.
s. , 1H), 1.14 (br.s., 2H), 0.98-1.10.
(M, 2H), 0.62 (br. S., 1H), 0.53 (br. S
. , 1H), 0.34-0.50 (m, 2H).
LC-MS: m / z 476.6 (M + H) +

Compound 728
(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazine- 1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 7.44-7.56 (m, 1H)
, 6.49-6.74 (m, 1H), 6.35 (d, J = 16.7).
Hz, 1H), 5.88 (br. S., 1H), 5.67-5.82
(M, 1H), 4.46 (d, J = 12.9 Hz, 1H), 4.2
5-4.39 (m, 2H), 4.07-4.23 (m, 3H), 3
. 98 (d, J = 8.5 Hz, 1H), 3.84 (t, J = 5.
1 Hz, 1H), 3.73 (t, J = 5.4 Hz, 1H), 3.4
5 (s, 3H), 3.10-3.21 (m, 1H), 3.02 (t,
J = 11.9 Hz, 1H), 2.39 (br.s., 2H), 2.
00-2.16 (m, 1H), 1.69 (br.s., 1H),
30-1.37 (m, 1H), 1.14 (br. S., 2H), 0.
97-1.09 (m, 2H), 0.64 (br.s., 1H), 0.
51 (br. S., 1H), 0.45 (br. S., 1H).
LC-MS: m / z 476.6 (M + H) +

Compound 680
(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazine- 1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) δ: 6.65 (d, J = 10.0 H
z, 1H), 6.36 (d, J = 16.8 Hz, 1H), 5.65.
-5.84 (m, 2H), 4.90 (br. S., 0.5H), 4.5
2 (d, J = 13.1 Hz, 0.5H), 4.25-4.38 (m
, 0.5H), 4.01-4.25 (m, 4H), 3.87-4.0
1 (m, 1H), 3.67-3.86 (m, 4H), 3.39 (s,
3H), 3.09-3.22 (m, 1H), 2.95-3.09 (
m, 1H), 2.54-2.71 (m, 2H), 2.36-2.48.
(M, 5H), 2.03 (br.s., 1H), 1.20-1.35
(M, 4H), 0.84-1.08 (m, 4H).
LC-MS: m / z 478.6 (M + H) +

Compound 745
(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazine -1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) δ: 6.67 (dd, J = 16.3,
10.4 Hz, 1H), 6.36 (d, J = 16.1 Hz, 1H)
, 5.65-5.85 (m, 2H), 4.13-4.34 (m, 3
H), 4.03-4.11 (m, 1H), 3.95 (d, J = 18
. 8 Hz, 1H), 3.78-3.89 (m, 1H), 3.62-
3.78 (m, 4H), 3.38 (s, 3H), 3.27 (br. S.
, 1H), 3.10 (br. S., 1H), 2.98 (br. S.,
1H), 2.36-2.47 (m, 5H), 1.96-2.08 (m
, 1H), 1.23-1.39 (m, 3H), 0.81-1.07
(M, 4H), 0.60 (br. S., 1H), 0.52 (br. S.
, 1H), 0.43 (br. S., 2H).
LC-MS: m / z 504.6 (M + H) +

Compound 755
(R) -5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine -1-yl) -4-methylnicotinonitrile


1H NMR (chloroform-d) δ: 6.67 (dd, J = 16.7,
10.9 Hz, 1H), 6.36 (d, J = 16.7 Hz, 1H)
, 5.64-5.85 (m, 1H), 4.10-4.38 (m, 3
H), 4.04 (br.s., 1H), 3.98 (br.s., 1H)
, 3.91 (br. S., 2H), 3.61-3.83 (m, 3H)
, 3.04-3.34 (m, 2H), 2.59 (br. S., 1H)
, 2.52 (d, J = 10.3 Hz, 1H), 2.37-2.48
(M, 5H), 2.06 (br. S., 1H), 1.34-1.50
(M, 1H), 1.16 (br. S., 1H), 0.93-1.10
(M, 3H), 0.62 (br. S., 1H), 0.27-0.56
(M, 3H)
LC-MS: m / z 490.6 (M + H) +

Compound 762
(R) -1′-acryloyl-2-cyclopropyl-6- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -4-methyl-1 ′, 2 ′, 5 ′
, 6′-Tetrahydro- [3,3′-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ: 6.36 (d, J = 16.7 H
z, 1H), 5.68-5.98 (m, 2H), 4.33 (d, J
= 11.7 Hz, 1H), 4.22 (d, J = 13.2 Hz, 2H
), 4.04 (br.s., 1H), 3.92 (t, J = 5.0 H)
z, 3H), 3.64-3.78 (m, 2H), 3.47 (d, J
= 7.9 Hz, 1H), 2.96-3.09 (m, 2H), 2.52
-2.65 (m, 2H), 2.38-2.48 (m, 5H),
04 (br. S., 2H), 0.95-1.07 (m, 6H), 0.
83-0.95 (m, 4H)
LC-MS: m / z 492.6 (M + H) +

Compound 649
2-cyclopropyl-6-((3R) -3-methyl-4- (2- (oxetan-2-yl) acetyl) piperazin-1-yl) -2'-vinyl- [3,4'-bipyridine] -5
-Carbonitrile 1H NMR (chloroform-d) δ: 8.60 (m, 1H), 7.64
(S, 1H), 7.37 (s, 1H), 7.19-7.27 (m, 1
H), 6.88 (dd, J = 17.4, 10.9 Hz, 1H), 6.
28 (d, J = 17.6 Hz, 1H), 5.57 (d, J = 11
. 0 Hz, 1H), 5.17-5.42 (m, 1H), 4.89 (m
, 0.5H), 4.73 (q, J = 7.0 Hz, 1H), 4.46.
-4.62 (m, 1.5H), 4.34 (m, 2H), 4.28 (d,
J = 13.3 Hz, 0.5H), 3.85 (t, J = 13.3 H)
z, 0.5H), 3.50-3.67 (m, 0.5H), 3.21-
3.32 (m, 1H), 2.99-3.20 (m, 1.5H), 2.7
6-2.94 (m, 3H), 2.46-2.60 (m, 1H), 1
. 87-2.09 (m, 1H), 1.24-1.32 (m, 3H),
1.14-1.23 (m, 2H), 0.93-1.10 (m, 3H
).
LC-MS: m / z 444.0 (M + H) +

Compound 648
2-Cyclopropyl-6-((R) -3-methyl-4- (2-((R) -oxetane-
2-yl) acetyl) piperazin-1-yl) -2′-vinyl- [3,4′-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ: 8.65 (d, J = 5. 0 Hz
, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.13
-7.27 (m, 1H), 6.88 (dd, J = 17.4, 10.9
Hz, 1H), 6.13-6.40 (m, 1H), 5.56 (d,
J = 11.5 Hz, 1H), 5.18-5.34 (m, 1H), 4
. 81-5.03 (m, 0.5H), 4.65-4.79 (m, 1H
), 4.48-4.65 (m, 1.5H), 4.30-4.42 (m
, 2H), 4.26 (d, J = 12.8 Hz, 0.5H), 3.86.
(D, J = 13.3 Hz, 0.5H), 3.49-3.66 (m,
0.5H), 3.23-3.40 (m, 1H), 3.01-3.20
(M, 1.5H), 2.71-3.01 (m, 3H), 2.37-
2.64 (m, 1H), 1.90-2.10 (m, 1H), 1.24
-1.34 (m, 3H), 1.13-1.24 (m, 2H), 0.9
3-1.09 (m, 2H)
LC-MS: m / z 444.0 (M + H) +

Compound 654
(R) -2-cyclopropyl-6- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-2'-vinyl- [3,4'-bipyridine]- 5
-Carbonitrile 1H NMR (chloroform-d) δ: 8.70 (d, J = 4.8 Hz)
, 1H), 7.23 (s, 1H), 7.07 (d, J = 4.8 Hz)
, 1H), 6.88 (dd, J = 17.4, 10.9 Hz, 1H),
6.30 (d, J = 17.3 Hz, 1H), 5.58 (d, J =
11.3 Hz, 1H), 4.90 (br. S., 0.5H), 4.54
(D, J = 13.6 Hz, 0.5H), 4.07-4.26 (m,
2.5H), 3.93 (br.s., 2H), 3.66-3.79 (
m, 0.5H), 3.58 (t, J = 11.0 Hz, 0.5H), 3
. 46 (br. S., 1H), 3.13-3.29 (m, 1.5H),
2.95-3.13 (m, 1H), 2.47-2.75 (m, 2H
), 2.22 (s, 3H), 1.74 (br.s., 1H), 1.50
-1.63 (m, 1H), 1.37-1.46 (m, 1.5H),
1.33 (d, J = 6.8 Hz, 1.5H), 1.01-1.14
(M, 2H), 0.79-0.95 (m, 2H).
LC-MS: m / z 431.5 (M + H) +

Compound 655
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-yl) Nicotinonitrile 1H NMR (chloroform-d) δ: 7.94-8.05 (m, 1H)
, 7.69 (d, J = 1.3 Hz, 1H), 7.60 (d, J =
3.5 Hz, 1H), 7.43-7.48 (m, 1H), 7.14
(Dd, J = 17.6, 10.8 Hz, 1H), 6.55 (dd, J
= 17.6, 1.8 Hz, 1H), 5.81 (d, J = 11.0)
Hz, 1H), 4.60 (d, J = 13.1 Hz, 1.5H), 4.
48 (d, J = 13.1 Hz, 1H), 4.13 (d, J = 6.
0 Hz, 0.5H), 3.86-3.99 (m, 2H), 3.82 (
br. s. , 1.5H), 3.28 (br. S., 1.5H), 3.15
(Dd, J = 15.7, 8.2 Hz, 2H), 2.56-2.68
(M, 2H), 1.13-1.23 (m, 2H), 0.80-0.
97 (m, 3H), 0.68 (br. S., 1H), 0.59 (br.
s. , 1H), 0.51 (br.s., 2H).
LC-MS: m / z 495.1 (M + H) +

Compound 650
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR ( Chloroform-d) δ 9.20 (d, J = 11.0 Hz,
1H), 8.14 (d, J = 8.5 Hz, 1H), 7.96-8
. 04 (m, 1H), 7.68 (dd, J = 4.4, 2.9 Hz,
1H), 7.49-7.59 (m, 1H), 7.06-7.23 (m
, 1H), 6.86 (d, J = 17.1 Hz, 1H), 5.94 (
d, J = 10.5 Hz, 1H), 4.62-4.80 (m, 1.5
H), 4.43-4.54 (m, 1.5H), 3.87-4.03 (
m, 2H), 3.73-3.86 (m, 1H), 2.91-3.31.
(M, 3H), 2.54-2.67 (m, 2H), 2.09-2.
25 (m, 1H), 1.54 (td, J = 8.0, 4.1 Hz, 1
H), 1.11 (dd, J = 13.7, 6.4 Hz, 4H), 0.7
9-0.94 (m, 6H).
LC-MS: m / z 497.3 (M + H) +

Compound 652
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR ( Chloroform-d) δ 9.17 (d, J = 3.3 Hz,
1H), 8.08 (d, J = 8.5 Hz, 1H), 7.97 (dd,
J = 8.4, 7.2 Hz, 1H), 7.68 (s, 1H), 7.5
2 (d, J = 7.0 Hz, 1H), 7.08 (dd, J = 17.
3, 10.5 Hz, 1H), 6.74-6.90 (m, 1H), 5.
89 (dd, J = 10.5, 1.5 Hz, 1H), 4.93 (br.
s. , 0.5H), 4.57 (d, J = 12.5 Hz, 0.5H),
4.28-4.47 (m, 2H), 4.21 (br.s., 0.5H
), 3.94 (s, 2H), 3.71-3.84 (m, 0.5H),
3.50-3.68 (m, 0.5H), 3.29-3.44 (m, 1
H), 3.06-3.26 (m, 2H), 2.49-2.78 (m,
2H), 1.50-1.62 (m, 1H), 1.45 (t, J =
7.2 Hz, 1H), 1.35 (t, J = 6.4 Hz, 2H), 1
. 14-1.22 (m, 2H), 0.83-0.98 (m, 2H)
LC-MS: m / z 469.2 (M + H) +

Compound 651
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinazolin-5-yl) nicotinonitrile 1H NMR (Chloroform-d) δ: 8.08 (d, J = 8.3 Hz,
1H), 7.97 (td, J = 7.8, 1.3 Hz, 1H), 7.
69 (d, J = 1.5 Hz, 1H), 7.47-7.56 (m,
1H), 7.09 (dd, J = 17.1, 10.5 Hz, 1H), 6
. 82 (d, J = 17.1 Hz, 1H), 5.90 (dd, J =
10.7, 1.6 Hz, 1H), 4.61 (dd, J = 13.1, 7
. 3 Hz, 1H), 4.41-4.55 (m, 1H), 4.12 (d
, J = 6.5 Hz, 1H), 3.94 (s, 2H), 3.67-3.
82 (m, 1H), 3.10-3.40 (m, 3H), 2.49-2.
68 (m, 2H), 1.56 (td, J = 8.1, 4.1 Hz, 1
H), 1.32-1.41 (m, 1H), 1.14-1.24 (m,
2H), 0.84-0.95 (m, 2H), 0.51-0.69 (m,
4H)
LC-MS: m / z 495.2 (M + H) +

Compound 657
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinoxalin-5-yl) nicotinonitrile 1H NMR (Chloroform-d) δ: 9.00 (s, 1H), 8.08
-8.18 (m, 1H), 7.79-7.90 (m, 1H), 7.6
5-7.76 (m, 2H), 7.07 (dd, J = 17.8, 11
. 0 Hz, 1H), 6.51 (d, J = 17.6 Hz, 1H), 5
. 84 (d, J = 11.0 Hz, 1H), 4.51 (d, J = 1)
3.1 Hz, 1H), 4.40 (d, J = 12.8 Hz, 1H),
4.13 (q, J = 7.0 Hz, 1.5H), 3.86-3.99
(M, 2.5H), 3.76 (d, J = 19.8 Hz, 2H),
37 (d, J = 7.8 Hz, 1H), 3.22-3.33 (m,
1H), 3.17 (d, J = 12.3 Hz, 1H), 3.09 (br
. s. , 1H), 2.55-2.69 (m, 2H), 1.58-1
. 69 (m, 1H), 1.17-1.37 (m, 3H), 1.08 (
br. s. , 2H), 0.83 (br. S., 2H), 0.66 (br
. s. , 1H), 0.55 (br. S., 1H), 0.48 (d, J
= 5.8 Hz, 3H).
LC-MS: m / z 495.1 (M + H) +

Compound 740
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (6-vinyl-1H-pyrrolo [2,3-b] Pyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 10.15 (br.s., 1H),
7.69-7.87 (m, 1H), 7.36-7.45 (m, 1H)
), 7.23 (s, 1H), 6.97 (dd, J = 17.3, 11.
2 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 6.2
8 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 10.
9 Hz, 1H), 4.58 (d, J = 12.9 Hz, 1H), 4.
45 (d, J = 12.6 Hz, 1H), 4.12 (d, J = 8.
5 Hz, 1H), 3.94 (br.s., 2H), 3.63-3.8
7 (m, 2H), 3.13-3.27 (m, 2H), 2.54-2
. 69 (m, 2H), 1.95-2.02 (m, 1H), 1.54-
1.74 (m, 1H), 1.22 (br. S., 2H), 0.97 (
dd, J = 7.6, 3.5 Hz, 2H), 0.67 (br. s.,
1H), 0.57 (br.s., 1H), 0.50 (br.s., 2H)
)
LC-MS: m / z 483.6 (M + H) +

Compound 735
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-5-yl) Nicotinonitrile 1H NMR (chloroform-d) δ9.53 (s, 1H), 8.54 (d
, J = 3.2 Hz, 1H), 7.88-8.00 (m, 1H),
7.79 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H),
7.09 (dd, J = 17.8, 11.0 Hz, 1H), 6.41 (
d, J = 17.6 Hz, 1H), 5.81 (d, J = 11.2 H)
z, 1H), 4.59 (d, J = 13.2 Hz, 1H), 4.47.
(D, J = 12.6 Hz, 1H), 4.1-4.2 (m, 0.5H),
3.93 (br.s., 2H), 3.82 (m, 1.5H), 3.44
(M, 1H), 3.05-3.35 (m, 3H), 2.54-2.70
(M, 2H), 1.47-1.64 (m, 2H), 1.13-1.
23 (m, 2H), 0.90-0.96 (m, 2H), 0.68 (b
r. s. , 1H), 0.58 (br. S., 1H), 0.51 (br.
s. , 2H)
LC-MS: m / z 495.2 (M + H) +

Compound 744
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (1-methyl-6-vinyl-1H-pyrazolo [
3,4-b] pyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.90 (s, 1H), 7.77 (s
, 1H), 7.21 (s, 1H), 6.99 (dd, J = 17.5,
10.7 Hz, 1H), 6.41 (d, J = 17.3 Hz, 1H)
, 5.58-5.73 (m, 1H), 4.60 (d, J = 13.2.
Hz, 1H), 4.48 (d, J = 12.6 Hz, 1H), 4.2
0 (s, 3H), 4.11 (d, J = 8.8 Hz, 1H), 3.9
3 (br. S., 2H), 3.65-3.85 (m, 1H), 3.44
(Br.s., 1H), 3.18-3.36 (m, 2H), 3.13
(D, J = 10.0 Hz, 1H), 2.46-2.70 (m, 2H
), 1.88-2.01 (m, 1H), 1.31-1.42 (m,
1H), 1.24 (dt, J = 7.0, 3.5 Hz, 2H), 0.9
3-1.04 (m, 2H), 0.66 (br. S., 1H), 0.5
7 (br.s., 1H), 0.32-0.53 (m, 2H)
LC-MS: m / z 498.2 (M + H) +

Compound 670
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinazolin-4-yl) nicotinonitrile 1H NMR (Chloroform-d) δ 8.09 (d, J = 8.3 Hz,
1H), 7.86-7.97 (m, 2H), 7.82 (d, J =
8.0 Hz, 1H), 7.58 (td, J = 7.7, 1.0 Hz,
1H), 7.09 (dd, J = 17.2, 10.4 Hz, 1H), 6
. 82 (dd, J = 17.3, 1.8 Hz, 1H), 5.76-5
. 93 (m, 1H), 4.65 (d, J = 13.1 Hz, 1H),
4.52 (d, J = 12.8 Hz, 1H), 4.11 (d, J =
9.3 Hz, 0.5H), 3.93 (br.s., 2H), 3.7-3.
85 (m, 1.5H), 3.48 (br.s., 1H), 3.26 (d
, J = 13.1 Hz, 2H), 3.17 (m, 1H), 2.52 −
2.68 (m, 2H), 1.88 (br. S., 1H), 1.66 −
1.80 (m, 1H), 0.81-0.99 (m, 4H), 0.62
-0.79 (m, 1H), 0.57 (br. S., 1H), 0.50
(D, J = 5.8 Hz, 2H)
LC-MS: m / z 495.2 (M + H) +

Compound 669
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylquinazolin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 8.08 (d, J = 8.5 Hz,
1H), 7.87-7.97 (m, 2H), 7.83 (d, J = 8
. 3 Hz, 1H), 7.54-7.66 (m, 1H), 7.08 (d
d, J = 17.2, 10.4 Hz, 1H), 6.74-6.90 (
m, 1H), 5.78-5.94 (m, 1H), 4.66 (d, J
= 11.3 Hz, 1H), 4.46-4.62 (m, 1H), 4.1
5-4.35 (m, 1H), 3.53-3.77 (m, 1H), 3
. 48 (d, J = 4.5 Hz, 1H), 3.30 (m, 1H), 3
. 19 (m, 1H), 1.60-1.83 (m, 2H), 1.43 (
br. s. , 1H), 1.16-1.29 (m, 2H), 1.04 (
d, J = 18.8 Hz, 2H), 0.77-0.97 (m, 4H)
, 0.59-0.77 (m, 1H), 0.37-0.59 (m, 3
H)
LC-MS: m / z 491.2 (M + H) +

Compound 720
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylquinolin-7-yl) nicotinonitrile 1H NMR (Chloroform-d) δ: 8.15-8.23 (m, 1H)
, 8.08-8.15 (m, 1H), 7.88 (d, J = 8.3
Hz, 1H), 7.72-7.79 (m, 1H), 7.66 (d, J
= 8.6 Hz, 1H), 7.56 (dd, J = 8.1, 1.6 H
z, 1H), 7.07 (dd, J = 17.6, 10.9 Hz, 1H)
, 6.34 (d, J = 17.7 Hz, 1H), 5.73 (d, J
= 11.0 Hz, 1H), 4.69 (d, J = 9.4 Hz, 0.5
H), 4.54 (d, J = 13.2 Hz, 1H), 4.42 (d,
J = 12.6 Hz, 1H), 4.10 (d, J = 8.3 Hz, 0
. 5H), 3.93 (br. S., 2H), 3.69-3.86 (m,
1H), 3.16-3.36 (m, 2H), 2.99-3.16 (
m, 1H), 2.48-2.69 (m, 2H), 2.11-2.20.
(M, 1H), 1.16-1.31 (m, 3H), 0.93-1.
05 (m, 2H), 0.66 (br. S., 1H), 0.56 (br.
s. , 1H), 0.39-0.52 (m, 2H)
LC-MS: m / z 494.9 (M + H) +

Compound 709
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinylquinolin-7-yl) nicotinonitrile (exemplified by procedure of compound 720)
1H NMR (chloroform-d) δ: 8.17 (d, J = 8.5 Hz)
, 1H), 8.11 (s, 1H), 7.86 (d, J = 8.3 Hz)
, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.5 Hz)
, 1H), 7.56 (dd, J = 8.3, 1.5 Hz, 1H), 7
. 06 (dd, J = 17.7, 10.9 Hz, 1H), 6.33 (d
, J = 17.8 Hz, 1H), 5.71 (d, J = 10.8 Hz)
, 1H), 4.56 (d, J = 12.8 Hz, 1H), 4.43 (
d, J = 12.3 Hz, 1H), 4.09 (m, 1H), 3.72.
(M, 1H), 3.29 (br. S., 2H), 3.12 (br. S.,
1H), 2.10-2.20 (m, 1H), 1.73 (br.s.,
1H), 1.44 (br.s., 1H), 1.18-1.25 (m,
2H), 1.06 (t, J = 4.4 Hz, 1H), 0.94-1
. 04 (m, 3H), 0.81 (dd, J = 7.8, 2.3 Hz,
2H), 0.67 (br.s., 1H), 0.41-0.58 (m,
3H).
LC-MS: m / z 490.9 (M + H) +

Compound 746
6-Cyclopropyl-2-((R) -3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -4-methyl-5- (2-vinyl-1,7-naphthyridine- 4-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 9.58 (br.s., 1H),
8.57 (br. S., 1H), 7.67 (d, J = 7.3 Hz,
1H), 7.21-7.34 (m, 2H), 7.10 (dd, J =
17.6, 10.9 Hz, 1H), 6.42 (dd, J = 17.6,
2.6 Hz, 1H), 5.82 (d, J = 10.9 Hz, 1H),
4.38-4.49 (m, 1H), 4.34 (d, J = 12.6 H
z, 1H), 4.14 (d, J = 7.0 Hz, 1H), 3.89 (
br. s. , 1H), 3.69-3.82 (m, 2H), 3.40 (
s, 3H), 3.23 (d, J = 13.8 Hz, 2H), 3.02
-3.17 (m, 1H), 2.72 (br.s., 1H), 2.67
(Br.s., 1H), 2.11 (d, J = 1.8 Hz, 3H),
1.45 (br.s., 1H), 1.06-1.18 (m, 2H),
0.79-0.90 (m, 1H), 0.69-0.79 (m, 2H)
, 0.64 (br.s., 1H), 0.57 (br.s., 1H),
0.41-0.55 (m, 2H).
LC-MS: m / z 522.3 (M + H) +

Compound 741
(R) -6-cyclopropyl-2- (3-isopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) nicotino Nitrile 1H NMR (chloroform-d) δ: 9.58 (s, 1H), 8.60
(Br.s., 1H), 7.79 (d, J = 10.9 Hz, 1H),
7.63-7.71 (m, 1H), 7.50-7.63 (m, 1H
), 7.12 (dd, J = 17.6, 10.9 Hz, 1H), 6.4
7 (d, J = 17.6 Hz, 1H), 5.83-5.94 (m,
1H), 4.63-4.80 (m, 1.5H), 4.37-4.58
(M, 2H), 4.04-4.26 (m, 2H), 3.93 (d, J
= 13.5 Hz, 1H), 3.10-3.33 (m, 2H),
09-2.30 (m, 0.5H), 1.92-2.08 (m, 1H)
1.11 (dd, J = 16.3, 6.6 Hz, 4H), 0.85
-0.98 (m, 6H).
LC-MS: m / z 496.3 (M + H) +

Compound 717
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ: 9.56 (s, 1H), 8.59
(D, J = 5.6 Hz, 1H), 7.72 (d, J = 3.2 Hz)
, 1H), 7.68 (s, 1H), 7.45 (dd, J = 9.5,
5.7 Hz, 1H), 7.10 (dd, J = 17.8, 11.0 Hz)
, 1H), 6.42 (dd, J = 17.6, 2.1 Hz, 1H),
5.72-5.90 (m, 1H), 4.63 (d, J = 13.2 H
z, 1H), 4.45-4.55 (m, 1H), 4.18 (br. s).
. , 2H), 4.06 (br. S., 1H), 3.96 (br. S.,
1H), 3.60-3.85 (m, 1H), 3.44-3.49 (
m, 3H), 3.23-3.34 (m, 1H), 3.16 (br. s)
. , 1H), 1.97 (br. S., 1H), 1.48-1.56 (
m, 1H), 1.22 (dd, J = 7.9, 3.8 Hz, 2H),
0.86-0.94 (m, 2H), 0.70 (br. S., 1H),
0.57 (br.s., 1.5H), 0.51 (br.s., 1.5H)
.
LC-MS: m / z 494.6 (M + H) +

Compound 689
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (2-vinyl-1,7-naphthyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 9.58 (br.s., 1H) ,
8.61 (br. S., 1H), 7.77 (d, J = 3.0 Hz,
1H), 7.64-7.73 (m, 1H), 7.54 (br. S.,
1H), 7.12 (dd, J = 17.6, 10.8 Hz, 1H), 6
. 45 (dd, J = 17.7, 2.1 Hz, 1H), 5.85 (d,
J = 11.0 Hz, 1H), 4.64 (d, J = 10.0 Hz,
1H), 4.52 (d, J = 12.0 Hz, 1H), 4.25 (b
r. s. , 1H), 3.69-3.81 (br. S., 1H), 3.38
(D, J = 15.3 Hz, 1.5H), 3.21 (br.s., 1
. 5H), 1.75 (br.s., 1H), 1.50 (br.s., 1
H), 1.26-1.37 (m, 1H), 1.23 (br. S., 2
H), 0.99-1.14 (m, 2H), 0.87-0.96 (m,
2H), 0.84 (dd, J = 7.8, 2.3 Hz, 2H), 0.
71 (br. S., 1H), 0.52-0.62 (m, 2H), 0.
43-0.52 (m, 1H).
LC-MS: m / z 490.6 (M + H) +

Compound 688
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) Nicotinonitrile 1H NMR (chloroform-d) δ: 9.59 (s, 1H), 8.60
(D, J = 5.5 Hz, 1H), 7.80 (d, J = 2.8 Hz)
, 1H), 7.69 (d, J = 1.3 Hz, 1H), 7.54 −
7.63 (m, 1H), 7.12 (dd, J = 17.6, 10.8 H
z, 1H), 6.48 (dd, J = 17.7, 2.1 Hz, 1H),
5.88 (d, J = 11.0 Hz, 1H), 4.63 (d, J =
12.5 Hz, 1H), 4.52 (d, J = 7.5 Hz, 1H),
4.13 (d, J = 9.3 Hz, 1H), 3.87-3.99 (
m, 2H), 3.67-3.87 (m, 1H), 3.30 (br. s)
. , 2H), 3.18 (br. S., 1H), 2.57-2.68 (
m, 2H), 1.43-1.54 (m, 1H), 1.32-1.41.
(M, 1H), 1.19-1.26 (m, 2H), 0.87-0.
97 (m, 2H), 0.67 (br. S., 1H), 0.60 (br.
s. , 1H), 0.40-0.55 (m, 2H).
LC-MS: m / z 494.6 (M + H) +

Compound 658
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) Nicotinonitrile 1H NMR (chloroform-d) δ: 9.57 (s, 1H), 8.59
(D, J = 5.5 Hz, 1H), 7.76 (d, J = 3.5 Hz)
, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.49 −
7.60 (m, 1H), 7.11 (dd, J = 17.6, 11.0 H
z, 1H), 6.45 (dd, J = 17.6, 1.8 Hz, 1H),
5.85 (d, J = 11.3 Hz, 1H), 4.55-4.68
(M, 1H), 4.50 (dd, J = 12.8, 2.3 Hz, 1H)
4.15 (br.s., 0.5H), 3.92 (br.s., 0.5
H), 3.66-3.84 (m, 3H), 3.40 (s, 3H), 3
. 30 (br.s., 1H), 3.22 (br.s., 1H), 3.1
5 (d, J = 7.5 Hz, 1H), 2.66 (br.s., 1H)
, 2.56 (br. S., 1H), 1.46-1.54 (m, 1H)
, 1.32 (d, J = 16.1 Hz, 1H), 1.19-1.24
(M, 2H), 0.84-0.99 (m, 2H), 0.66 (br.
s. , 1H), 0.60 (br. S., 1H), 0.49 (br. S
. , 2H).
LC-MS: m / z 508.6 (M + H) +

Compound 681
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -5- (2-vinyl-1,7-naphthyridin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ: 9.55 (s, 1H), 8.59
(Dd, J = 5.3, 3.0 Hz, 1H), 7.73 (d, J =
11.5 Hz, 1H), 7.67 (dd, J = 4.5, 2.8 Hz,
1H), 7.45 (dd, J = 12.5, 5.5 Hz, 1H), 7
. 10 (ddd, J = 17.6, 10.9, 1.1 Hz, 1H), 6
. 42 (d, J = 17.6 Hz, 1H), 5.82 (d, J = 1)
0.8 Hz, 1H), 4.61-4.79 (m, 1H), 4.41-
4.60 (m, 2H), 3.86-4.01 (m, 2H), 3.82
(D, J = 13.6 Hz, 0.5H), 3.53-3.60 (m,
0.5H), 3.10-3.30 (m, 2H), 3.01 (d, J
= 12.8 Hz, 0.5H), 2.73-2.84 (m, 0.5H),
2.56-2.68 (m, 2H), 2.09-2.37 (m, 1H
), 1.47-1.55 (m, 1H), 1.05-1.17 (m,
4H), 0.80-1.01 (m, 6H).
LC-MS: m / z 496.6 (M + H) +

Compound 710
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (1-vinylisoquinolin-7-yl) nicotinonitrile 1H NMR (chloroform-d) δ 8.61 (d, J = 5.8 Hz,
1H), 8.30 (s, 1H), 7.95 (d, J = 8.3 Hz,
1H), 7.80 (d, J = 8.0 Hz, 1H), 7.74 (s,
1H), 7.65-7.72 (m, 1H), 7.58-7.65 (
m, 1H), 6.64 (d, J = 16.1 Hz, 1H), 5.84.
(D, J = 10.3 Hz, 1H), 4.58 (d, J = 11.5)
Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.01.
-4.31 (m, 1H), 3.61-3.89 (m, 1H), 3.
33 (d, J = 17.3 Hz, 1.5H), 3.15 (br. S.,
1.5H), 2.02 to 2.09 (m, 1H), 1.42 to 1.47.
(M, 1H), 1.34 (d, J = 8.5 Hz, 1H), 1.25
-1.30 (m, 3H), 1.06-1.11 (m, 1H), 0.
98-1.02 (m, 2H), 0.90 (t, J = 6.7 Hz,
1H), 0.80-0.84 (m, 2H), 0.68 (br. S.,
1H), 0.52-0.56 (m, 1H), 0.46-0.49 (m
, 1H)
LC-MS: m / z 492.0 (M + H) +

Compound 685
(R) -5-((2-Chloropyridin-4-yl) methyl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile 1H NMR (chloroform-d) δ: 8.33 (d, J = 5.0 Hz,
1H), 7.49 (s, 1H), 7.12 (s, 1H), 6.98 −
7.06 (m, 1H), 4.47 (d, J = 12.5 Hz, 1H)
, 4.30-4.50 (m, 2.5H), 4.20-4.30 (m, 1H)
, 4.04 (s, 1H), 3.60-3.90 (s, 1H), 2.90-
3.45 (m, 1H), 2.01 (s, 1H), 1.80-1.91
(M, 1H), 1.72 (s, 1H), 1.09-1.17 (m, 2
H), 0.93-1.09 (m, 4H), 0.74-0.86 (m,
2H), 0.37-0.65 (m, 4H)
LC-MS: m / z 462.2 (M + H) +

Compound 684
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5-((2-vinylpyridin-4-yl) methyl) nicotinonitrile 1H NMR (chloroform-d): 8.50 (d, J = 5.0 Hz,
1H), 7.47 (s, 1H), 7.12 (s, 1H), 6.89 −
6.99 (m, 1H), 6.80 (dd, J = 17.6, 10.8 H
z, 1H), 6.16-6.29 (m, 1H), 5.44-5.57.
(M, 1H), 4.25-4.60 (m, 2.5H), 4.12-4.20
(M, 1H), 4.03 (s, 2H), 3.49-3.90 (m,
1H), 2.95-3.29 (m, 2.5H), 1.85-1.98 (m
, 1H), 1.71 (s, 1H), 1.35-1.45 (m, 1H)
, 1.07-1.17 (m, 2H), 0.92-1.07 (m, 4
H), 0.76-0.82 (m, 2H), 0.30-0.63 (m, 4
H)
LC-MS: m / z 454.2 (M + H) +

Compound 708
(R) -5-((2-chloropyridin-4-yl) methyl) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.34 (d, J = 5.3 Hz,
1H), 7.49 (s, 1H), 7.11 (s, 1H), 7.03 (
d, J = 5.0 Hz, 1H), 4.39-4.52 (m, 2H),
4.33 (d, J = 12.3 Hz, 1H), 4.04 (s, 2H)
, 3.85-3.97 (m, 2H), 3.66-3.81 (m, 1
H), 3.01-3.22 (m, 3H), 2.51-2.65 (m, 2
H), 1.79-1.92 (m, 1H), 1.31-1.39 (m,
1H), 1.08-1.15 (m, 2H), 0.93-1.03 (
m, 2H), 0.46-0.63 (m, 4H)
LC-MS: m / z 466.2 (M + H) +

Compound 697
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5-((2-vinylpyridin-4-yl) methyl)
Nicotinonitrile

(R) -5-((2-chloropyridin-4-yl) methyl) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl)
Nicotinonitrile (80 mg, 0.172 mmol), potassium vinyl trifluoroborate (46 mg, 0.343 mmol), Pd (dppf) Cl ₂ (7 mg, 0.009
mmol) and CsF (79 mg, 0.515 mmol) in dioxane / H ₂ O were stirred at 100 ° C. for 16 h. The mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was partitioned between EtOAc (30 mL) and water (10 mL) and the organic layer was washed with water (10 mL), brine, dried over Na ₂ SO ₄ and concentrated to give the crude which was separated by Purification by TLC yielded 25 mg of product.
1H NMR (chloroform-d): 8.47 (d, J = 5.0 Hz, 1
H), 7.46 (s, 1H), 7.10 (s, 1H), 6.87-6
. 97 (m, 1H), 6.76 (dd, J = 17.3, 10.8 Hz)
, 1H), 6.18 (dd, J = 17.6, 1.0 Hz, 1H),
5.41-5.53 (m, 1H), 4.39 (d, J = 12.8 H
z, 1H), 4.27 (d, J = 12.5 Hz, 1H), 4.01.
(M, 2H), 3.80-3.92 (m, 2H), 3.51-3.7
9 (m, 2H), 2.99-3.18 (m, 3H), 2.42-2.6
6 (m, 2H), 1.85-1.97 (m, 1H), 1.30-1.4
0 (m, 1H), 1.03-1.12 (m, 2H), 0.88-1
. 00 (m, 2H), 0.30-0.59 (m, 4H)
LC-MS: m / z 458.3 (M + H) +

Compound 698 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-vinyl-1,7-naphthyridin-4-yl) Amino) nicotinonitrile 1H NMR (chloroform-d) δ: 9.48 (s, 1H), 8.59
(D, J = 5.8 Hz, 1H), 7.90 (br.s., 1H),
7.68-7.77 (m, 1H), 7.35-7.48 (m, 1H)
6.91 (dd, J = 17.4, 10.9 Hz, 1H), 6.56
(S, 1H), 6.26 (d, J = 17.6 Hz, 1H), 5.6
7 (d, J = 11.0 Hz, 1H), 4.86-4.98 (m,
0.5H), 4.51-4.62 (d, 0.5H) 4.14-4.38 (m
, 3H), 3.94 (br. S., 2H), 3.70-3.81 (m
, 0.5H), 3.59 (t, J = 10.8 Hz, 0.5H),
27-3.41 (m, 1H), 3.01-3.24 (m, 2H),
2.48-2.78 (m, 2H), 1.97-2.09 (m, 1H)
, 1.44 (d, J = 6.5 Hz, 1.5H), 1.34 (d, J
= 6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0
. 94-1.06 (m, 2H).
LC-MS: m / z 483.2 (M + H) +

Compound 679 (General Procedure 7)
(R) -5-((2-chloropyridin-4-yl) amino) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.06 (d, J = 5.4 Hz,
1H), 7.60 (s, 1H), 6.57-6.47 (m, 2H),
6.08 (s, 1H), 4.75-4.64 (m, 0.5H), 4.
49 (t, J = 11.8 Hz, 1H), 4.37 (t, J = 10
. 9 Hz, 1H), 4.14-4.09 (m, 0.5H), 3.89
(Ddd, J = 7.5, 3.5, 2.5 Hz, 0.5H), 3.81
-3.64 (m, 2.5H), 3.39 (s, 3H), 3.31-3
. 17 (m, 1.5H), 3.10 (td, J = 12.8, 3.4 H
z, 1H), 2.69 (ddd, J = 22.8, 14.8, 9.9 H
z, 2H), 2.52 (dd, J = 20.7, 9.1 Hz, 0.5H
), 2.06 (ddd, J = 7.5, 4.5, 1.6 Hz, 1H),
1.28 (m, J = 4.7 Hz, 1H), 1.15 (m, 2H),
1.08-0.99 (m, 2H), 0.72-0.52 (m, 2H
), 0.52-0.39 (m, 2H).
LC-MS: m / z NB250-076-2 481.1 (M + H) +

Compound 678 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino) nicotino Nitrile 1H NMR (chloroform-d) δ: 8.26 (d, J = 5.7 Hz,
1H), 7.62 (s, 1H), 6.72 (dd, J = 17.4,
10.8 Hz, 1H), 6.58 (s, 1H), 6.46 (d, J =
4.1 Hz, 1H), 6.20 (d, J = 17.4 Hz, 1H),
5.94 (s, 1H), 5.49 (d, J = 10.8 Hz, 1H)
4.70 (dd, J = 14.5, 4.5 Hz, 0.5H), 4.46
(T, J = 11.4 Hz, 1H), 4.33 (d, J = 10.6)
Hz, 1H), 4.13-4.07 (m, 0.5H), 3.92-
3.85 (m, 0.5H), 3.83-3.62 (m, 2.5H), 3
. 39 (s, 3H), 3.31-3.16 (m, 1.5H), 3.09
(Td, J = 13.2, 3.7 Hz, 1H), 2.82-2.58
(M, 2H), 2.58-2.45 (m, 0.5H), 2.10 (d
t, J = 4.5, 3.0 Hz, 1H), 1.28 (s, 1H), 1
. 18-1.10 (m, 2H), 1.02 (ddd, J = 9.9,
6.4, 3.2 Hz, 2H), 0.73-0.53 (m, 2H), 0
. 53-0.39 (m, 2H).
LC-MS: m / z 473.2 (M + H) +

Compound 661 (General Procedure 7)
(R) -5-((2-chloropyridin-4-yl) amino) -6-cyclopropyl-2
-(4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.06 (d, J = 5.8 Hz,
1H), 7.60 (s, 1H), 6.54 (s, 1H), 6.51 (
dd, J = 5.8, 2.0 Hz, 1H), 6.15 (s, 1H),
4.90 (s, 0.5H), 4.54 (d, J = 13.4 Hz, 0.
5H), 4.35-4.16 (m, 2.5H), 3.93 (s, 2H)
3.74 (d, J = 13.4 Hz, 0.5H), 3.58 (d,
J = 11.0 Hz, 0.5H), 3.30 (dd, J = 10.8,
6.4 Hz, 1H), 3.15 (t, J = 12.2 Hz, 1H),
3.08-3.01 (m, 0.5H), 2.74-2.51 (m, 2
H), 2.07 (ddd, J = 12.6, 8.0, 4.7 Hz, 1H
), 1.42 (d, J = 6.6 Hz, 1.5H), 1.32 (d,
J = 6.7 Hz, 1.5H), 1.13 (dt, J = 7.2, 2.
6 Hz, 2H), 1.05 (ddd, J = 10.3, 6.6, 3.5
Hz, 2H).
LC-MS: m / z 441.0 (M + H) +

Compound 677 (General Procedure 7)
(R) -5-((2-chloropyridin-4-yl) amino) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.01 (d, J = 5.7 Hz,
1H), 7.59 (s, 1H), 6.49 (d, J = 1.8 Hz,
1H), 6.46 (dd, J = 5.7, 2.0 Hz, 1H), 6.
41 (s, 1H), 4.66 (d, J = 13.6 Hz, 0.5H),
4.45 (d, J = 12.9 Hz, 1H), 4.33 (d, J =
12.7 Hz, 1H), 4.06 (d, J = 9.3 Hz, 0.5H
), 3.91 (s, 2H), 3.80 (d, J = 13.2 Hz, 0.
5H), 3.72 (d, J = 11.6 Hz, 0.5H), 3.56 (
m, 0.5H), 3.27-3.01 (m, 2.5H), 2.59 (
dd, J = 17.2, 5.2 Hz, 1.5H), 2.11-2.04.
(M, 1H), 1.98 (m, 0.5H), 1.43-1.27 (m
, 1H), 1.18-1.09 (m, 2H), 1.07-0.98.
(M, 2H), 0.63 (m, J = 7.2, 4.7 Hz, 1H),
0.58-0.28 (m, 3H).
LC-MS: m / z 467.0 (M + H) +

Compound 676 (General Procedure 6)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.20 (d, J = 6.1 Hz,
1H), 7.63 (s, 1H), 6.73 (dd, J = 17.5,
10.9 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H),
6.63 (d, J = 3.1 Hz, 1H), 6.29 (d, J = 1)
7.5 Hz, 1H), 5.57 (d, J = 10.9 Hz, 1H),
4.69 (d, J = 11.0 Hz, 0.5H), 4.46 (d, J
= 13.0 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H)
), 4.10 (d, J = 7.7 Hz, 0.5H), 3.92 (d,
J = 3.9 Hz, 2H), 3.74 (ddd, J = 21.2, 17
. 7, 8.0 Hz, 1.5H), 3.30-3.17 (m, 1.5H)
, 3.13-3.03 (m, 1H), 2.69-2.48 (m, 2
H), 2.15-2.06 (m, 1H), 1.28 (d, J = 5.
0 Hz, 1H), 1.14 (dt, J = 7.3, 3.6 Hz, 2H
), 1.08-0.98 (m, 2H), 0.76-0.62 (m,
1H), 0.62-0.32 (m, 3H).
LC-MS: m / z 459.0 (M + H) +

Compound 718 (General Procedure 7)
(R) -5-((2-chloropyridin-4-yl) amino) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.06 (d, J = 5.7 Hz,
1H), 7.60 (s, 1H), 6.50 (d, J = 2.1 Hz,
1H), 6.46 (dd, J = 5.7, 2.2 Hz, 1H), 5.
79 (s, 1H), 4.43 (dd, J = 52.6, 11.8 Hz,
2.5H), 4.16 (s, 2H), 4.00 (s, 1.5H), 2.
67 (d, J = 24.8 Hz, 1H), 3.46 (s, 3H), 3
. 21 (dd, J = 13.0, 3.4 Hz, 1H), 3.09 (t,
J = 11.3 Hz, 1H), 2.07 (ddd, J = 12.7,
8.0, 4.7 Hz, 1H), 1.38 (s, 1H), 1.15 (dt
, J = 7.5, 3.7 Hz, 2H), 1.08-1.00 (m,
2H), 0.67 (s, 1H), 0.63-0.39 (m, 3H).
LC-MS: m / z 467.2 (M + H) +

Compound 711 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.26 (d, J = 5.7 Hz,
1H), 7.62 (s, 1H), 6.71 (dd, J = 17.4,
10.8 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H),
6.45 (dd, J = 5.7, 2.3 Hz, 1H), 6.18 (dd
, J = 17.4, 1.0 Hz, 1H), 6.01 (s, 1H), 5
. 47 (dd, J = 10.8, 0.9 Hz, 1H), 4.81-4
. 26 (m, 2.6H), 4.16 (s, 2H), 3.95 (d, J
= 43.6 Hz, 1.5H), 3.70 (s, 1H), 3.46 (s,
3H), 3.20 (dd, J = 13.0, 3.4 Hz, 1H), 3
. 07 (t, J = 11.4 Hz, 1H), 2.15-2.07 (m
, 1H), 1.41 (s, 1H), 1.19-1.10 (m, 2H)
, 1.02 (ddd, J = 10.2, 6.6, 3.4 Hz, 2H),
0.67 (s, 1H), 0.61-0.37 (m, 3H).
LC-MS: m / z NB295-002-01 459.1 (M + H) +

Compound 743
(R) -6-cyclopropyl-2- (3-isopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.24 (d, J = 5.8 Hz,
1H), 7.60 (d, J = 3.1 Hz, 1H), 6.72 (dd
, J = 17.4, 10.8 Hz, 1H), 6.61 (s, 1H),
6.51 (d, J = 4.3 Hz, 1H), 6.37 (s, 1H),
6.23 (d, J = 17.5 Hz, 1H), 5.52 (d, J =
10.9 Hz, 1H), 4.68-4.47 (m, 1.5H), 4.3
7 (t, J = 12.7 Hz, 1.5H), 4.28 (d, J = 1)
3.4 Hz, 0.5H), 4.22-4.13 (m, 1H), 4.08
(D, J = 13.5 Hz, 0.5H), 3.88 (d, J = 13
. 6 Hz, 0.5H), 3.56 (d, J = 10.6 Hz, 0.5H)
3.47 (d, J = 2.5 Hz, 3H), 3.42 (dd, J
= 13.3, 2.9 Hz, 0.5H), 3.24-2.95 (m, 2
. 5H), 2.19-2.04 (m, 2H), 1.28 (d, J =
4.7 Hz, 1H), 1.19-1.11 (m, 1H), 1.07 (
d, J = 6.5 Hz, 3H), 1.05-0.97 (m, 2H),
0.91 (dd, J = 15.7, 6.8 Hz, 3H).
LC-MS: m / z NB295-018-01 461.4 (M + H) +

Compound 731
(R) -5-((2-chloropyridin-4-yl) (methyl) amino) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine-
1-yl) nicotinonitrile

Step 1: (R) -tert-butyl 4- (5- (2-chloropyridin-4-ylamino) -3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxy rate

(R) -tert-butyl 4- (5-bromo-3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (1.5 g, 3
. 363 mmol) and 2-chloropyridin-4-amine (518.6 mg, 4.03)
6 mmol) in 1,4-dioxane (20 mL) was added Pd (OAc) ₂ (76 mg).
0.34 mmol), BINAP (314.3 mg, 0.505 mmol) and Cs
₂ CO ₃ (2.2 g, 6.726 mmol) was added under N ₂ at room temperature. The resulting mixture was heated in a microwave at 155 ° C. under N ₂ for 1 hour and stirred. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether: EtOAc) to give the title compound (1.1 g, 66.2%) as a yellow solid.
LC-MS: m / z 495.0 (M + H) +

Step 2: (R) -tert-butyl 4- (5-((2-chloropyridin-4-yl) (methyl) amino) -3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclo Propyl piperazine-1-carboxylate

(R) -tert-butyl 4- (5- (2-chloropyridin-4-ylamino) -3-
Cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1
To a solution of carboxylate (550 mg, 1.1 mmol) in anhydrous THF (10 mL) was added NaH (89 mg, 2.22 mmol) and iodomethane (2 drops) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water at 0 ° C. The mixture was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (crude, 567 mg) as a yellow solid.
LC-MS: m / z 509.1 (M + H) +

Step 3: (R) -5-((2-chloropyridin-4-yl) (methyl) amino)-
6-Cyclopropyl-2- (3-cyclopropylpiperazin-1-yl) nicotinonitrile

(R) -tert-butyl 4- (5-((2-chloropyridin-4-yl) (methyl)
Amino) -3-cyano-6-cyclopropylpyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate (567 mg, 1.1 mmol) in anhydrous DCM (5 m
L) To the solution in TFA (5 mL) was added at room temperature. The reaction mixture is stirred at room temperature for 2
Stir for hours. The solvent was removed in vacuo and the residue was adjusted to pH> 7.0. The residual mixture was extracted with EtOAc (15 mL × 2). The combined organic layers are washed with brine,
Dried over Na ₂ SO ₄ . The organic phase was filtered and the filtrate was concentrated in vacuo to give the title compound (crude, 432 mg) as a yellow solid.
LC-MS: m / z 409.1 (M + H) +

Step 4: (R) -5-((2-chloropyridin-4-yl) (methyl) amino)-
6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl)
Piperazin-1-yl) nicotinonitrile

(R) -5-((2-chloropyridin-4-yl) (methyl) amino) -6-cyclopropyl-2- (3-cyclopropylpiperazin-1-yl) nicotinonitrile (410m
g, 1.0 mmol) in DMF (8 mL) was added sodium 3-hydroxypropanoate (203.5 mg, 1.5 mmol), HATU (572.3 mg, 1.5 mmol).
l) and DIPEA (194 mg, 1.5 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (270 mg, 5
6.3%) was obtained as a pale yellow solid.
1H NMR (chloroform-d) δ: 8.03 (d, J = 5.8 Hz,
1H), 7.56 (s, 1H), 6.45 (s, 1H), 6.35 (
d, J = 3.5 Hz, 1H), 4.70 (d, J = 11.2 Hz)
, 0.5H), 4.51 (d, J = 13.0 Hz, 1H), 4.39.
(D, J = 13.4 Hz, 1H), 4.10 (d, J = 9.2)
Hz, 0.5H), 3.93 (d, J = 4.5 Hz, 2H), 3.8
6-3.65 (m, 1.5H), 3.40 (s, 1H), 3.30 (s
, 3H), 3.28-3.15 (m, 1.5H), 3.15-3.0
1 (m, 1H), 2.69-2.44 (m, 2H), 1.89-1
. 78 (m, 1H), 1.28 (d, J = 5.0 Hz, 1H), 1
. 13 (s, 2H), 1.01 (d, J = 11.8 Hz, 2H),
0.82-0.65 (m, 1H), 0.64-0.32 (m, 3H)
LC-MS: m / z 481.0 (M + H) +

Step 5: Compound 731
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (methyl (2-vinylpyridin-4-yl) amino) nicoti Nononitrile

(R) -5-((2-chloropyridin-4-yl) (methyl) amino) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazine-
1-yl) nicotinonitrile (270 mg, 0.563 mmol) in isopropanol (
10 mL) and H ₂ O (3 mL) in a solution of potassium vinyl trifluoroboronate (
113.1 mg, 0.844 mmol), Pd (dppf) Cl ₂ (49.0 mg, 0.
06Mmol) and DIPEA (145.3mg, 1.126mmol) was added under _{N 2} at room temperature. The reaction mixture was heated at reflux under N ₂ overnight and stirred. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (121 mg, 45.5%) as a pale yellow solid.
1H NMR (chloroform-d) δ: 8.25 (d, J = 5.9 Hz,
1H), 7.58 (s, 1H), 6.71 (dd, J = 17.4,
10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H)
, 6.20 (d, J = 17.3 Hz, 1H), 5.45 (d, J
= 11.2 Hz, 1H), 4.69 (d, J = 13.4 Hz, 0.
4H), 4.49 (d, J = 13.0 Hz, 1H), 4.37 (d,
J = 12.7 Hz, 1H), 4.10 (d, J = 8.6 Hz,
0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5
H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m,
1.5H), 3.15-3.00 (m, 1H), 2.69-2.45.
(M, 2H), 1.88 (ddd, J = 12.7, 8.1, 4.7)
Hz, 1H), 1.40-1.31 (m, 1H), 1.12 (s, 2
H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
LC-MS: m / z 473.4 (M + H) +

Compound 699
(R) -5-((2-chloropyridin-4-yl) (methyl) amino) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)
Nicotinonitrile

(R) -5- (2-Chloropyridin-4-ylamino) -6-cyclopropyl-2- (
To a solution of 4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile (675 mg, 1.487 mmol) in anhydrous THF (15 mL) was added iodomethane (0.5 mL) and NaH (119 mg, 2.974 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water at 0 ° C. The mixture was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , the organic phase was filtered and the filtrate was concentrated in vacuo. The residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (350 mg, 50.3%) as a white solid.
1H NMR (chloroform-d) δ: 8.04 (d, J = 5.7 Hz,
1H), 7.54 (s, 1H), 6.42 (d, J = 44.6 Hz)
, 2H), 4.92 (s, 0.5H), 4.55 (d, J = 13.0
Hz, 0.5H), 4.40-4.25 (m, 2H), 4.22 (d
, J = 13.9 Hz, 0.5H), 3.83 (d, J = 13.7)
Hz, 0.5H), 3.76 (t, J = 6.3 Hz, 2H), 3.5
7 (t, J = 11.5 Hz, 0.5H), 3.39 (s, 3H),
3.37-3.33 (m, 0.5H), 3.31 (s, 3H), 3.2
8-2.97 (m, 2H), 2.85-2.65 (m, 1H), 2
. 64-2.51 (m, 1H), 1.80 (ddd, J = 12.5,
8.0, 4.6 Hz, 1H), 1.36 (dd, J = 41.2, 6
. 2 Hz, 3H), 1.12 (s, 2H), 1.07-0.93 (m
, 2H).
LC-MS: m / z 469.2 (M + H) +

Compound 690 (General Procedure 6)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (methyl (2-vinylpyridin-4-yl) amino) nicotino Nitrile

(R) -5-((2-chloropyridin-4-yl) (methyl) amino) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)
To a solution of nicotinonitrile (330 mg, 0.71 mmol) in isopropanol (30 mL) and H ₂ O (3 mL) was added vinyltrifluoroboronic acid potassium salt (142.1 m
g, 1.06 mmol), Pd (dppf) Cl ₂ (58.0 mg, 0.071 mmol).
) And DIPEA the (182 mg, 1.41 mmol) was added under _{N 2} at room temperature. The reaction mixture was heated at reflux under N ₂ overnight and stirred. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (89 mg, 27.5%) as a white solid.
1H NMR (chloroform-d) δ: 8.24 (d, J = 5.9 Hz,
1H), 7.55 (s, 1H), 6.71 (dd, J = 17.4,
10.8 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H)
, 6.20 (d, J = 17.3 Hz, 1H), 5.46 (d, J
= 11.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d,
J = 13.1 Hz, 0.5H), 4.34-4.16 (m, 2.5
H), 3.89-3.68 (m, 2.5H), 3.56 (t, J =
11.5 Hz, 0.5H), 3.39 (s, 3H), 3.31 (s, 3
H), 3.29 (s, 1H), 3.10 (m, 1.5H), 2.80 −
2.52 (m, 2H), 1.88-1.83 (m, 1H), 1.41
(D, J = 6.3 Hz, 1.5H), 1.30 (d, J = 6.6
Hz, 1.5H), 1.10 (m, 2H), 0.97 (m, 2H).
LC-MS: m / z 461.2 (M + H) +

Compound 660 (General Procedure 6)
(R) -4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-ylamino) picolinonitrile 1H NMR ( Chloroform-d) δ: 8.32 (d, J = 5.8 Hz,
1H), 7.59 (s, 1H), 7.01 (s, 1H), 6.72 (
d, J = 3.8 Hz, 1H), 6.62 (s, 1H), 4.92 (
s, 0.5H), 4.55 (d, J = 12.7 Hz, 0.5H), 4
. 30 (t, J = 11.2 Hz, 2H), 4.22 (d, J = 1)
2.7 Hz, 0.5H), 3.83 (d, J = 13.8 Hz, 0.5
H), 3.76 (t, J = 6.3 Hz, 2H), 3.57 (t, J
= 11.5 Hz, 0.5H), 3.39 (s, 3H), 3.33 (d
, J = 12.5 Hz, 1H), 3.21-3.04 (m, 1.5H)
), 2.73 (ddd, J = 22.1, 14.2, 6.5 Hz, 1H
), 2.64-2.53 (m, 1H), 2.05-1.99 (m,
1H), 1.40 (d, J = 6.3 Hz, 1.5H), 1.30 (d
, J = 6.7 Hz, 1.5H), 1.18-1.10 (m, 2H)
, 1.09-0.98 (m, 2H).
LC-MS: m / z 446.0 (M + H) +

Compound 659 (General Procedure 6)
(R) -4,4 ′-(5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-ylazanediyl) dipicolino Nitrile 1H NMR (chloroform-d) δ: 8.62 (d, J = 5.5 Hz,
2H), 7.53 (s, 1H), 7.28-7.20 (m, 4H),
4.95 (s, 0.5H), 4.58 (d, J = 10.0 Hz, 0
. 5H), 4.37 (dd, J = 42.6, 13.4 Hz, 2.5H)
, 3.89 (d, J = 13.8 Hz, 0.5H), 3.77 (t,
J = 6.3 Hz, 2H), 3.66-3.57 (m, 0.5H),
3.44 (s, 0.5H), 3.40 (s, 3H), 3.35-3.1
3 (m, 1.5H), 2.87-2.67 (m, 1H), 2.62 (
dd, J = 13.7, 7.4 Hz, 1H), 1.68 (d, J =
4.3 Hz, 1H), 1.44 (d, J = 6.6 Hz, 1.5H),
1.34 (d, J = 6.3 Hz, 1.5H), 1.11 (dt, J
= 6.9, 3.5 Hz, 2H), 0.97-0.88 (m, 2H)
.
LC-MS: m / z 548.1 (M + H) +

Compound 729 (General Procedure 6)
(R) -4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-ylamino) picolinoamide 1H NMR (chloroform- d) δ: 8.24 (d, J = 5.7 Hz,
1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.53 (
s, 1H), 6.62 (dd, J = 5.6, 2.3 Hz, 1H),
6.03 (s, 1H), 5.65 (s, 1H), 4.92 (s, 0.5
H), 4.55 (d, J = 13.9 Hz, 0.5H), 4.27 (t
, J = 11.1 Hz, 2H), 4.19 (d, J = 13.0 Hz)
, 0.5H), 3.82 (d, J = 13.0 Hz, 0.5H),
76 (t, J = 6.2 Hz, 2H), 3.57 (t, J = 11.
5 Hz, 0.5H), 3.40 (s, 3H), 3.34-3.23 (
m, 1H), 3.15 (t, J = 12.1 Hz, 1H), 3.10
-3.00 (m, 0.5H), 2.84-2.65 (m, 1H), 2
. 60 (m, 1H), 2.07 (ddd, J = 12.6, 8.0, 4
. 6 Hz, 1H), 1.41 (d, J = 6.2 Hz, 1.5H),
1.31 (d, J = 6.7 Hz, 1.5H), 1.13 (dt, J
= 7.4, 3.6 Hz, 2H), 1.00 (td, J = 6.6, 3
. 4 Hz, 2H).
LC-MS: m / z 464.1 (M + H) +

Compound 742 (General Procedure 6)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-5- (2-vinylpyridin-4-ylamino) nicoti Nononitrile 1H NMR (chloroform-d) δ: 8.24 (d, J = 5.7 Hz,
1H), 6.70 (dd, J = 17.4, 10.8 Hz, 1H),
6.49 (s, 1H), 6.35 (s, 1H), 6.19 (d, J =
17.4 Hz, 1H), 5.79 (s, 1H), 5.48 (d, J
= 10.9 Hz, 1H), 4.68 (d, J = 12.8 Hz, 0.
5H), 4.51-4.38 (m, 0.5H), 4.34 (d, J =
12.9 Hz, 1H), 4.26 (d, J = 12.6 Hz, 1H)
, 4.08 (d, J = 9.0 Hz, 0.5H), 3.93 (s, 2
H), 3.82-3.70 (m, 1H), 3.31 (dd, J = 1)
9.9, 7.5 Hz, 0.5H), 3.24-3.12 (m, 1H),
3.11-2.97 (m, 1H), 2.56 (m, 2H), 2.39
(S, 3H), 2.11 (ddd, J = 12.6, 8.0, 4.7)
Hz, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 2
H), 0.97 (dd, J = 7.9, 3.2 Hz, 2H), 0.78
-0.34 (m, 4H).
LC-MS: m / z 473.4 (M + H) +

Compound 748 (General Procedure 6)
5- (2-Chloropyridin-4-ylamino) -6-cyclopropyl-2-((R)-
3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) nicotinonitrile

(R) -5- (2-Chloropyridin-4-ylamino) -6-cyclopropyl-2- (
3-Cyclopropylpiperazin-1-yl) nicotinonitrile (300 mg, 0.761
mmol) in DMF (3 mL) to (R) -2- (oxetan-2-yl) acetic acid (
115 mg, 0.99 mmol), HATU (436.0 mg, 1.142 mmol) and DIPEA (196.4 mg, 1.53 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified via silica gel column chromatography (DCM: MeOH) to give the title compound (182 mg, 4
8.5%) was obtained as a pale yellow solid.
1H NMR (chloroform-d) δ: 8.06 (d, J = 5.7 Hz,
1H), 7.60 (s, 1H), 6.50 (d, J = 1.8 Hz,
1H), 6.47 (dd, J = 5.7, 2.0 Hz, 1H), 5.
80 (s, 1H), 5.27 (dt, J = 13.0, 6.5 Hz,
1H), 4.72 (dd, J = 14.0, 8.0 Hz, 1H), 4.
65-4.43 (m, 2H), 4.37 (d, J = 13.2 Hz,
1H), 4.09 (d, J = 7.2 Hz, 0.5H), 3.95 (
d, J = 15.5 Hz, 0.5H), 3.80-3.67 (m, 1
H), 3.28 (ddd, J = 9.8, 9.1, 5.3 Hz, 1H)
3.16 (d, J = 11.2 Hz, 0.5H), 3.13-3.
03 (m, 1H), 2.98 (dd, J = 15.2, 6.8 Hz,
1H), 2.93-2.78 (m, 2H), 2.78-2.66 (m
, 0.5H), 2.66-2.47 (m, 1H), 2.10-2.0
2 (m, 1H), 1.28 (d, J = 4.9 Hz, 1H), 1.1
5 (dt, J = 7.3, 3.5 Hz, 2H), 1.04 (dt, J
= 7.0, 3.2 Hz, 2H), 0.77-0.38 (m, 4H)
.
LC-MS: m / z 494.0 (M + H) +

Compound 662
(R) -N- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) -N- (2- Vinylpyridin-4-yl) acetamide

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylpyridin-4-ylamino) nicotinonitrile (200 mg, 0.448 mmol) in acetic anhydride (5 mL) was heated at 135 ° C. overnight and stirred. The solvent was removed in vacuo and the residue was purified via reverse phase silica gel column chromatography (MeOH: H ₂ O) to give the title compound (16 mg, 7.3%)
Was obtained as a pale yellow solid.
1H NMR (chloroform-d) δ: 8.52 (d, J = 5.5 Hz,
1H), 7.57 (s, 1H), 7.36 (d, J = 5.3 Hz,
1H), 7.03 (d, J = 5.2 Hz, 1H), 6.78 (dd
, J = 17.4, 10.8 Hz, 1H), 6.23 (d, J = 1)
7.3 Hz, 1H), 5.52 (d, J = 10.9 Hz, 1H),
4.92 (s, 1H), 4.55 (d, J = 11.4 Hz, 1H),
4.40-4.23 (m, 3H), 3.84 (d, J = 12.8)
Hz, 1H), 3.76 (t, J = 6.3 Hz, 2H), 3.57
(T, J = 11.0 Hz, 1H), 3.39 (s, 3H), 3.35
(S, 1H), 3.17 (dt, J = 24.0, 11.2 Hz, 2
H), 2.73 (ddd, J = 23.2, 13.8, 6.3 Hz, 1
H), 2.59 (dd, J = 13.3, 7.2 Hz, 1H), 2.2
0-2.06 (m, 3H), 2.01 (dt, J = 12.8, 6.
2 Hz, 1H), 1.40 (d, J = 5.9 Hz, 2H), 1.2
9 (d, J = 6.7 Hz, 2H), 1.16 (d, J = 4.3
Hz, 3H), 1.03 (d, J = 7.5 Hz, 1H).
LC-MS: m / z 489.3 (M + H) +

Compound 758 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.12 (d, J = 5.4 Hz,
1H), 7.82 (d, J = 5.7 Hz, 1H), 6.83 (d,
J = 5.4 Hz, 1H), 6.59 (dd, J = 17.6, 10
. 8 Hz, 1H), 6.40 (s, 2H), 5.90 (d, J = 1)
7.5 Hz, 1H), 5.47 (d, J = 10.9 Hz, 1H),
4.71 (d, J = 12.5 Hz, 0.5H), 4.45 (dd, J
= 16.5, 9.9 Hz, 1.5H), 4.33-4.22 (m,
1H), 3.85 (d, J = 13.3 Hz, 0.5H), 3.82 −
3.70 (m, 2H), 3.57 (d, J = 10.5 Hz, 0.5
H), 3.49-3.41 (m, 0.5H), 3.39 (d, J =
3.3 Hz, 3H), 3.05 (dddd, J = 21.0, 19.1,
13.7, 2.9 Hz, 2H), 2.82-2.54 (m, 2H),
2.27 (dd, J = 16.7, 6.8 Hz, 0.5H), 2.18
(Ddd, J = 12.8, 8.2, 4.8 Hz, 1H), 1.35
-1.27 (m, 1H), 1.18-0.97 (m, 7H), 0.9
1 (d, J = 6.8 Hz, 1.5H), 0.86 (d, J = 6.
8 Hz, 1.5 H).
LC-MS: m / z 475.6 (M + H) +

Compound 764 (General Procedure 7)
6-cyclopropyl-2-((R) -3-isopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -5-((4-vinylpyridine- 2
-Yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.10 (d, J = 5.3 Hz,
1H), 7.81 (d, J = 8.1 Hz, 1H), 6.82 (d,
J = 5.4 Hz, 1H), 6.69 (s, 1H), 6.58 (dd
, J = 17.6, 10.8 Hz, 1H), 6.39 (s, 1H),
5.89 (d, J = 17.5 Hz, 1H), 5.46 (d, J =
10.9 Hz, 1H), 5.32-5.24 (m, 1H), 4.83
-4.61 (m, 1.5H), 4.56 (dtd, J = 7.7, 5.
8, 1.8 Hz, 1H), 4.48 (d, J = 13.5 Hz, 0.
5H), 4.46-4.39 (m, 1H), 4.27 (d, J = 1)
1.9 Hz, 1H), 3.88 (d, J = 13.4 Hz, 0.5H)
, 3.56 (d, J = 10.0 Hz, 0.5H), 3.45 (dd,
J = 13.4, 3.2 Hz, 0.5H), 3.13-2.92 (m
3H), 2.92-2.75 (m, 2H), 2.65-2.44.
(M, 1H), 2.31-2.24 (m, 0.5H), 2.21-2
. 10 (m, 2H), 1.16-1.07 (m, 2H), 1.05 (
dd, J = 6.5, 3.0 Hz, 3H), 1.04-0.98 (m
, 2H), 0.92 (d, J = 6.8 Hz, 1H), 0.86 (d
, J = 6.8 Hz, 2H).
LC-MS: m / z 487.6 (M + H) +

Compound 763 (General Procedure 7)
1H NMR (chloroform-d) δ: 8.08 (d, J = 5.6 Hz,
1H), 7.81 (s, 1H), 6.87 (d, J = 5.6 Hz,
1H), 6.59 (dd, J = 17.5, 10.9 Hz, 1H),
6.43 (s, 1H), 5.94 (d, J = 17.6 Hz, 1H),
5.53 (d, J = 10.9 Hz, 1H), 5.31-5.22
(M, 1H), 4.77-4.68 (m, 1H), 4.59-4.5
1 (m, 1H), 4.41 (s, 1H), 4.29-4.31 (m, 1
H), 4.10-4.03 (m, 1 H), 3.96-3.89 (
m, 0.5 H), 3.74-3.76 (m, 1H), 3.10-3.41.
(M, 3H), 2.83-2.90 (m, 2.5H), 2.54-2.55
(M, 1H), 2.18-2.20 (m, 1H), 1.35-1.36 (m
, 1H), 1.14-1.16 (m, 2H), 1.04-1.06 (m,
2H), 0.38-0.49 (m, 4H).
LC-MS: m / z 485.6 (M + H) +

Compound 756 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino)
Nicotinonitrile

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino)
To a solution of nicotinonitrile (180 mg, 0.46 mmol) in 10 mL DMF was added sodium 3-hydroxypropanoate (104 mg, 0.92 mmol), and triethylamine (1 mL), HATU (350 mg, 0.92 mmol). . The resulting reaction mixture was stirred at room temperature overnight. After TLC showed complete conversion of starting material to product, the reaction mixture was concentrated and purified by preparative HPLC (50% EtOAc / petroleum ether) to give 100 mg of the title compound.
1H NMR (chloroform-d) δ 8.11 (d, 1H), 7.86 (s,
1H), 7.65 (s, 1H), 6.82 (dd, 1H), 6.53-
6.62 (m, 1H), 6.40 (s, 1H), 5.89 (d., 1H)
, 5.45 (s, 1H), 4.75 (m, 0.5H), 4.37-4.3.
2 (dd, 2H), 3.92 (m, 0.5H), 3.39-3.05 (m, 3
H), 2.61-2.60 (m 2, 2H), 2.20-1.69 (m 1, 1H),
1.28-1.26 (m, 1H), 1.40-1.00 (m, 4H), 0.4
7-0.45 (m, 4H).
LC-MS: m / z 4 459 (M + H) +

Compound 656
(R) -4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) -N-methoxy-N −
Methylbenzamide

(R) -4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) benzoic acid (450 mg
1 mmol) and N, O-dimethylhydroxylammonium chloride (146 mg)
, 1.5 mmol) in DCM (10 mL) to HATU (570 mg, 1.5 mm
ol) and DIPEA (516 mg, 4 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The organic phase was washed with 1N HCl (10 mL × 3), saturated NaHCO ₃ (
20 mL × 1) and brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give 390 mg of the title compound as a white solid.
1H NMR (chloroform-d) δ: 7.71-7.85 (m, J =
8.3 Hz, 2H), 7.64 (s, 1H), 7.39-7.50.
(M, J = 8.3 Hz, 2H), 4.92 (br.s., 0.5H)
4.54 (d, J = 12.3 Hz, 0.5H), 4.13-4.
39 (m, 2.5H), 3.78-3.87 (m, 0.5H), 3.7
6 (br. S., 2H), 3.63 (s, 3H), 3.58 (d, J
= 10.3 Hz, 0.5H), 3.35-3.46 (m, 6H),
3.23-3.34 (m, 1H), 3.13 (br.s., 1H),
3.06 (d, J = 12.5 Hz, 0.5H), 2.73 (br. S
. , 1H), 2.61 (br. S., 1H), 2.00-2.12 (
m, 1H), 1.35-1.47 (m, 1.5H), 1.24-1.
35 (m, 1.5H), 1.12-1.24 (m, 2H), 0.87
-1.02 (m, 2H)
LC-MS: m / z 492.6 (M + H) +

Compound 714 (General Procedure 7)
(R) -5- (Bis (4-ethynylpyridin-2-yl) amino) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotino Nitrile 1H NMR (chloroform-d) δ: 8.29 (d, J = 5.1 Hz
, 2H), 7.59 (s, 1H), 7.12 (br.s., 2H),
7.03 (dd, J = 5.1, 1.1 Hz, 2H), 4.92 (br
. s. , 0.5H), 4.54 (d, J = 13.2 Hz, 0.5H)
, 4.14-4.36 (m, 2.5H), 3.76 (t, J = 6.
2 Hz, 2.5H), 3.49-3.66 (m, 0.5H), 3.39
(S, 3H), 3.20-3.35 (m, 3H), 3.14 (d,
J = 11.3 Hz, 1H), 3.06 (d, J = 11.3 Hz, 0
. 5H), 2.65-2.84 (m, 1H), 2.52-2.65 (
m, 1H), 1.86-1.99 (m, 1H), 1.22-1.38.
(M, 3H), 0.95-1.08 (m, 2H), 0.68-0.
82 (m, 2H)
LC-MS: m / z 546.6 (M + H) +

Compound 713 (General Procedure 7)
(R) -6-cyclopropyl-5- (4-ethynylpyridin-2-ylamino) -2-
(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.12 (d, J = 5.4 Hz
, 1H), 7.78 (s, 1H), 6.82 (dd, J = 5.4,
1.1 Hz, 1H), 6.61 (br. S., 1H), 6.52 (s,
1H), 4.92 (br.s., 0.5H), 4.54 (d, J =
13.4 Hz, 0.5H), 4.07-4.32 (m, 2.5H), 3
. 68-3.87 (m, 2.5H), 3.49-3.65 (m, 0.
5H), 3.39 (s, 3H), 3.18-3.33 (m, 2H),
2.92-3.17 (m, 1.5H), 2.64-2.83 (m, 1
H), 2.53-2.64 (m, 1H), 2.08-2.22 (m,
1H), 1.41 (d, J = 6.2 Hz, 1.5H), 1.31 (
d, J = 6.4 Hz, 1.5H), 1.07-1.18 (m, 2H)
), 0.96-1.07 (m, 2H)
LC-MS: m / z 445.5 (M + H) +

Compound 750 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2-methoxyacetyl) piperazin-1-yl) -5- (4-ethynylpyridin-2-ylamino) nicotinonitrile 1H NMR ( Chloroform-d) δ: 8.00 (d, J = 5.9 Hz
, 1H), 7.71 (s, 1H), 6.88 (dd, J = 5.9,
1.2 Hz, 1H), 6.64 (s, 1H), 4.51 (d, J =
13.2 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H),
4.17 (br. S., 2H), 4.01 (br. S., 0.5H),
3.89 (br.s., 0.5H), 3.71 (br.s., 0.5H)
), 3.40-3.52 (m, 4.5H), 3.22 (d, J = 9
. 7 Hz, 1H), 3.02-3.16 (m, 1H), 2.09-
2.20 (m, 1H), 1.03-1.22 (m, 4H), 0.67
(Br.s., 2H), 0.47 (br.s., 4H)
LC-MS: m / z 457.5 (M + H) +

Compound 647 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino) nicotinonitrile

(R) -5-amino-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl) nicotinonitrile (140 mg, 0.41 mmol)
) And 2-chloro-4-vinylpyridine (57 mg, 0.41 mmol) in 1,4-dioxane (15 mL) to give Pd2 (dba) 3 (56 mg, 0.061 mmol).
And xanthophos (59 mg, 0.1 mmol) and Cs2CO3 (267 mg, 0
. 82 mmol) was added and the mixture was heated at 110 ° C. under N 2 for 16 h. TL
After C showed complete conversion to starting product, the reaction mixture was concentrated and purified by column chromatography (DCM: MeOH = 20: 1) to give 25 mg of the title compound, compound 647 and 20 mg of compound Compound 646 was obtained.
1H NMR (chloroform-d) δ: 7.94-7.93 (d, 1H), 7
. 68 (s, 1H), 6.84-6.82 (d, 1H), 6.58-6.51
(Q, 1H), 6.38 (s, 1H), 5.95-5.90 (d, 1H
), 5.55-5.52 (d, 1H), 4.87 (s, 0.5H), 4.
54-4.51 (d, 0.5H); 4.48-4.13 (m, 3H) 3.7
9-3.70 (m, 2H) 3.44-3.35 (m, 1H) 3.25 (s, 3
H), 3.11-2.98 (m, 3H), 2.77-2.56 (m, 2H),
2.17-2.12 (m, 1H), 1.38-1.13 (m, 3H), 1.09
-1.00 (m, 2H), 0.99-0.98 (m, 2H).
LC-MS: m / z 447 (M + H) +

Compound 646 (General Procedure 7)
(R) -5- (Bis (4-vinylpyridin-2-yl) amino) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotino Nitrile 1H NMR (chloroform-d) δ: 8.15-8.14 (d, 1H), 7.
58 (s, 1H), 7.26-7.23 (d, 1H), 6.97-6.94.
(Dd, 1H), 6.79-6.72 (q, 1H), 6.03-5.98 (
dd, 1H), 5.58 (s, 1H), 5.36-5.33 (dd, 1H)
), 4.88 (s, 0.5H), 4.54-4.51 (d, 0.5H);
4.20-4.09 (dd, 2H) 3.93 (s, 2H) 3.75-3.5
2 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m,
2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m, 3H),
1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H), 1.03
-1.09 (m 2, 2H).
LC-MS: m / z 433 (M + H) +

Compound 706 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino) nicotino Nitrile 1H NMR (chloroform-d) δ: 8.13 (d, 1H), 7.85
(S, 1H), 6.83 (dd, 1.2 Hz, 1H), 6.58 (dd
, 10.7 Hz, 1H), 6.41 (s, 1H), 6.33 (br.
s. , 1H), 5.90 (d, 1H), 5.46 (d, 0.5H), 4
. 36 (d, 1H), 4.26 (d, Hz, 1H), 4.00-4.
15 (m, 0.5H), 3.87 (d, 0.5H), 3.74 (t, 3
H), 3.39 (s, 3H), 3.74-3.04 (m, 3H), 2.4
8-2.77 (m, 2H), 2.14-2.25 (m, 1H), 1
. 39 (br.s., 1H), 1.14 (t, 2H), 0.98-1
. 06 (m, 2H), 0.62-0.46 (d, 4H).
LC-MS: m / z 473 (M + H) +

Compound 754 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -5- (2-vinylpyridin-4-ylamino) nicotinonitrile 1H NMR ( DMSO-d6) δ: 8.08-8.20 (m, 1H),
7.92 (d, J = 5.3 Hz, 1H), 6.67-6.84 (
m, 2H), 6.64 (br. s., 1H), 6.25 (d, J =
16.7 Hz, 1H), 5.63 (br. S., 1H), 4.56 (t
, J = 5.3 Hz, 1.5H), 4.08-4.52 (m, 4.5
H), 3.94 (d, J = 13.5 Hz, 1H), 3.59-3.
72 (m, 3.5H), 3.07-3.20 (m, 2H), 1.91
-2.11 (m, 3H), 0.91-1.06 (m, 8H), 0.7
4 (d, J = 6.7 Hz, 3H)
LC-MS: m / z 461.6 (M + H) +

Compound 707 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.11 (d, 1H), 7.84 (
s, 1H), 7.28 (s, 1H), 6.74-6.92 (m, 1H)
), 6.67 (br. S., 1H), 6.58 (dd, 10.8 Hz,
1H), 6.41 (s, 1H), 5.90 (d, 1H), 5.47 (
d, 1H), 4.89 (br. s., 0.5H), 4.53 (d, 0.
5H), 4.07-4.36 (m, 2H), 3.93 (br. S.,
2H), 3.72-3.65 (m, 1H), 2.98-3.27 (
m, 2.5H), 2.44-2.74 (m, 2.5H), 2.14-
2.44 (m, 1H), 1.83-2.11 (m, 1.5H), 1.2
1-1.50 (m, 1.5H), 0.96-1.20 (m, 2H),
0.90 (t, 2H).
LC-MS: m / z 433 (M + H) +

Compound 725 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-5-((4-vinylpyridin-2-yl) Amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.07 (d, J = 5.3 Hz)
, 1H), 6.88 (br. S., 1H), 6.79 (dd, J =
5.3, 1.2 Hz, 1H), 6.41-6.57 (m, 1H), 6
. 10 (s, 1H), 5.86 (d, J = 17.6 Hz, 1H),
5.43 (d, J = 10.9 Hz, 1H), 4.71-4.62 (m,
2-0.5H), 4.16-4.34 (m, 2H), 4.07 (d, J
= 8.8 Hz, 0.5H), 3.92 (br.s., 3H), 3.7
7 (br. S., 1H), 3.21-3.12 (d, 2H), 2.54
-2.68 (m, 2H), 2.41 (s, 3H), 2.14-2.
31 (m, 1H), 1.03-1.13 (m, 2H), 0.89-
1.01 (m, 2H), 0.32-0.57 (m, 4H).
LC-MS: m / z 473 (M + H) +

Compound 682 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-methoxypyridin-4-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.33 (s, 1H), 7.82 (s,
1H), 7.57 (s, 1H), 6.41-6.41 (d, 1H), 6.
06 (s, 1H), 5.05 (m, 0.5H), 4.51-4.58 (m
, 0.5H), 4.14 (s, 3H), 4.12 (m, 0.5H), 3.85
(M, 2H), 3.54-3.52 (m, 0.5H); 3.28 (s, 3
H) 3.12-3.03 (m, 2H), 2.72-2.70 (m, 2H), 2
. 57-2.55 (m, 1H), 1.38-1.36 (m, 1.5H),
32 (m, 1.5H), 1.26-1.25 (m, 2H), 1.09-1.05
(M, 2H).
LC-MS: m / z 451 (M + H) +

Compound 683 (General Procedure 7)
(R) -Methyl 4-((5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) amino) picolinate 1H NMR (chloroform-d) δ: 8.35 (s, 1H), 7.60 (s,
1H), 7.44 (s, 1H), 6.82 (s, 1H), 5.32-5
. 31 (m, 0.5H), 4.28-4.26 (m, 0.5H), 4.25
-4.22 (m, 3H), 3.96 (s, 3H), 4.12 (m, 3H), 3.
37 (s, 3H), 3.03-3.28 (m, 2H), 2.61-2.58
(M, 2H) 2.05-2.03 (m, 1H), 1.40-1.38 (m
, 1.5H), 1.33-1.29 (m, 1.5H), 1.27-1.25 (m
, 2H), 1.11-0.99 (m, 2H).
LC-MS: m / z 479 (M + H) +

Compound 736 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((4-vinylpyrimidin-2-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ: 8.36 (d, 1H), 8.30
(S, 1H), 7.02-7.13 (m, 1H), 6.75 (d, 1
H), 6.63 (dd, 10.6 Hz, 1H), 6.40 (d, 1H)
, 5.67 (d, 1H), 4.91 (br. S., 0.5H), 4.5
4 (d, 0.5H), 4.23 (br. S., 0.5H), 4.00 −
4.17 (m, 2H), 3.66-3.82 (m, 2H), 3.37
-3.42 (m, 4H), 2.93-3.23 (m, 2H), 2.
53-2.79 (m, 2H), 2.08-2.20 (m, 1H),
1.38-1.45 (m, 1.5H), 1.31 (d, 1.5H), 1
. 09-1.17 (m, 2H), 1.03 (dd, 2H).
LC-MS: m / z 448 (M + H) +

Compound 705 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinyl-1,8-naphthyridin-4-ylamino)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.99 (br.s., 1H),
8.55 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H),
7.39 (dd, J = 8.3, 4.3 Hz, 1H), 6.82 (dd
, J = 17.1, 10.8 Hz, 1H), 6.38 (br. S.,
1H), 6.30 (d, J = 17.6 Hz, 1H), 5.59 (d,
J = 10.8 Hz, 1H), 4.91 (br.s., 0.5H),
4.54 (d, J = 13.6 Hz, 0.5H), 4.26 (d, J
= 11.3 Hz, 2H), 4.16 (d, J = 13.3 Hz, 1H)
), 3.70-3.89 (m, 3H), 3.50-3.09 (m,
7H), 3.04 (d, J = 12.3 Hz, 1H), 2.52-2
. 82 (m, 2.5H), 1.98-2.13 (m, 1.5H), 1.
28-1.44 (m, 5H), 0.93-1.02 (m, 2H)
LC-MS: m / z 498.1 (M + H) +

Compound 702
(R) -N- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) -N- (pyridine- 4
-Yl) acrylamide

Step 1: (R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl)
-3-Methylpiperazin-1-yl) -5- (pyridin-4-ylamino) nicotinonitrile

(R) -5-Bromo-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
To a solution of -3-methylpiperazin-1-yl) nicotinonitrile (406 mg, 1 mmol) and pyridin-4-amine (94 mg, 1 mmol) in 1,4-dioxane (5 mL) was added Pd (dba) ₃ (136 mg, 0.15 mmol) and X-phos (72 m
g, was 0.15 mmol) and _{Cs 2 CO 3 (752mg, 2mmol} ) was added under _{N 2} at room temperature. The resulting mixture was heated in a microwave at 120 ° C. under N ₂ for 1.5 hours and stirred. The solvent is removed in vacuo and the residue is purified by column chromatography (Me
(OH / DCM = 1/15) to give 168 mg of the title compound as a yellow solid.
LC-MS: m / z 471.4 (M + H) +

Step 2: Compound 702
(R) -N- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) -N- (pyridine- 4
-Yl) acrylamide

(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (pyridin-4-ylamino) nicotinonitrile (41m
g, 0.1 mmol) and N, N-diisopropylethylamine (26 mg, 0.2 m
mol) in 5 mL DCM was added acryloyl chloride (10 mg, 0.1 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 3 hours. LC-MS
After completion of the reaction, the mixture was poured into water and extracted with methylene chloride. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Column chromatography (MeOH / DCM = 1/15) gave 12.6 mg of the title compound as a colorless oil.
1H NMR (chloroform-d) δ: 8.60 (d, J = 4.8 Hz)
, 2H), 7.53 (s, 1H), 7.28 (s, 2H), 6.58
(D, J = 16.7 Hz, 1H), 6.16 (d, J = 5.1 H
z, 1H), 5.82 (d, J = 10.5 Hz, 1H), 4.92.
(M, 0.5H), 4.56 (m, 0.5H), 4.20-4.42
(M, 2H), 3.69-3.91 (m, 2H), 3.58 (m, 1
H), 3.37-3.41 (m, 3H), 3.36 (br. S.,
1H), 3.14 (br.s., 2H), 2.59 (d, J = 5.9)
Hz, 2H), 1.82-1.94 (m, 1H), 1.37-1.
44 (m, 2H), 1.20-1.36 (m, 5H).
LC-MS: m / z 475.5 (M + H) +

Compound 712
(R) -N- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) -N- (quinoline- 4
-Yl) acrylamide 1H NMR (chloroform-d) δ: 8.96 (d, J = 4.5 Hz)
, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.93 −
8.03 (m, 1H), 7.84 (t, J = 7.5 Hz, 1H),
7.70 (d, J = 7.3 Hz, 1H), 7.44 (br. S.,
1H), 7.30 (br.s., 1H), 6.61 (d, J = 16.
8 Hz, 1H), 6.16 (d, J = 5.10 Hz, 1 H), 5.8
2 (d, J = 10.48 Hz, 1 H), 4.88 (m, J = 10.48)
Hz, 0.5 H), 4.52 (m, J = 6.48 Hz, 0.5 H), 4
. 27 (t, J = 12.9 Hz, 2H), 3.74 (t, J = 6
. 1 Hz, 2H), 3.52 (m, J = 9.1 Hz, 1H), 3.
37 (s, 3H), 3.29 (d, J = 10.8 Hz, 1H), 3
. 12 (br. S., 2H), 2.72 (t, J = 9.8 Hz, 1
H), 2.58 (t, J = 5.8 Hz, 1H), 2.23 (t, J
= 7.7 Hz, 1H), 1.31-1.40 (m, 2H), 1.21
-1.31 (m, 3H), 1.14 (br.s., 2H).
LC-MS: m / z 525.5 (M + H) +

Compound 732 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-vinylquinolin-7-ylamino) nicotinonitrile

(R) -5-amino-6-cyclopropyl-2- (4- (3-methoxypropanoyl)
To a solution of -3-methylpiperazin-1-yl) nicotinonitrile (34 mg, 0.1 mmol) and 7-bromo-2-vinylquinoline (23 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added Pd. (Dba) ₃ (13.6 mg, 0.015 mmol) and X-phos (7.2 mg, 0.15 mmol) and Cs ₂ CO ₃ (75.2 mg, 0
. The 2 mmol) was added under _{N 2} at room temperature. The resulting mixture was placed in the microwave for 12
Heat at 0 ° C. under N ₂ for 1.5 hours and stir. The solvent was removed in vacuo and the residue was purified by column chromatography (MeOH / DCM = 1/15) to give 17.2 mg of the title compound as a colorless oil.
1H NMR (chloroform-d) δ: 8.08 (d, J = 8.2 Hz
, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.64 (s
, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.31 (b
r. s. , 1H), 7.03-7.18 (m, 2H), 6.32 (d
, J = 17.6 Hz, 1H), 6.18 (br.s., 1H), 5
. 74 (d, J = 10.9 Hz, 1H), 4.92 (m, 0.5H)
, 4.54 (m, 0.5H), 4.09-4.33 (m, 2H), 3
. 71-3.86 (m, 2H), 3.57 (br.s., 1H), 3
. 40 (s, 3H), 3.25 (t, J = 11.4 Hz, 1H),
3.13 (br.s., 2H), 2.75 (br.s., 1H), 2.
53-2.64 (m, 1H), 2.14-2.27 (m, 1H),
1.40-1.47 (m, 1H), 1.24-1.35 (m, 2H)
, 1.12 (t, J = 3.7 Hz, 2H), 0.97 (dd, J
= 7.9, 3.5 Hz, 2H).
LC-MS: m / z 497.4 (M + H) +

Compound 665
(R) -Methyl-4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) benzoate 1H NMR ( Chloroform-d) δ 8.12 (d, J = 7.5 Hz,
2H), 7.63 (br.s., 1H), 7.48 (d, J = 7.
5 Hz, 2H), 4.47-4.61 (d, J = 12.5 Hz, 0.5
H), 4.19-4.37 (m, 2.5H), 3.96 (br. S., 3
H), 3.75 (br.s., 2H), 3.47-3.61 (m, 1
H), 3.38 (br.s., 3H), 3.28 (br.s., 1H)
, 3.01-3.18 (m, 1H), 2.65-2.79 (m, 1
H), 2.60 (br. S., 1H), 1.96-2.10 (m, 1
H), 1.72-1.91 (m, 1H), 1.38 (br. S., 1
H), 1.28 (br.s., 2H), 1.18 (br.s., 2H)
, 0.97 (br.s., 2H)
LC-MS: m / z 463.2 (M + H) +

Compound 704 (General Procedure 8)
(R) -5-((2-chloropyridin-4-yl) oxy) -6-cyclopropyl-2
-(4- (3-Hydroxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.29 (d, J = 5.7 Hz
, 1H), 7.47 (s, 1H), 6.83-6.77 (m, 2H)
, 4.90 -4.91 (m, 1H), 4.53-4.55 (m, 1H),
4.20 (t, J = 12.8 Hz, 3H), 3.92 (s, 2H),
3.79-3.70 (m, 1H), 3.55 (d, J = 10.9
Hz, 1H), 3.31-3.20 (m, 1H), 3.14-2.9
9 (m, 1H), 2.55 (s, 2H), 2.01 (t, J = 4.
6 Hz, 1H), 1.87 (d, J = 3.4 Hz, 1H), 1.4
3 (d, J = 6.4 Hz, 1H), 1.32 (d, J = 6.4)
Hz, 2H), 1.12 (dd, J = 7.9, 3.1 Hz, 2H),
1.03 (dt, J = 7.9, 3.1 Hz, 2H).
LC-MS: m / z 442.1 (M + H) +

Compound 695 (General Procedure 8)
(R) -5-((2-chloropyridin-4-yl) oxy) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.29 (d, J = 5.6 Hz
, 1H), 7.46 (s, 1H), 6.83-6.76 (m, 2H)
, 4.69-4.72 (m, 0.5H), 4.40 (d, J = 12.6)
Hz, 1H), 4.28 (d, J = 12.7 Hz, 1H), 4.1
3 (dd, J = 14.3, 7.2 Hz, 1H), 3.88 (d, J
= 12.0 Hz, 1H), 3.78-3.64 (m, 3H), 3.
38 (s, 3H), 3.18 (d, J = 13.1 Hz, 1H), 3
. 04 (d, J = 26.4 Hz, 1H), 2.74−2.57 (m
, 2H), 2.48-2.50 (m, 0.5H), 1.98-2.04 (m
, 1H), 1.35 (t, J = 10.7 Hz, 1H), 1.13 (
dd, J = 7.4, 3.1 Hz, 2H), 1.02 (dt, J =
7.9, 3.1 Hz, 2H), 0.59 (d, J = 30.2 Hz,
2H), 0.45-0.48 (m, 2H).
LC-MS: m / z 482.1 (M + H) +

Compound 694 (General Procedure 8)
(R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (
3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicotinonitrile

(R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (
3-cyclopropylpiperazin-1-yl) nicotinonitrile (3, general procedure 8 scheme) (0.35 g, 0.88 mol), sodium 3-hydroxypropanoate (0.
10 g, 0.88 mol), HATU (0.5 g, 1.32 mmol) and 0.23 g
Of DIEA (1.76 mmol) was stirred in 8 mL of DMF for 4 hours. The mixture was then quenched by the addition of 6 mL of water, extracted with EtOAc (15 mL × 2), the organic phases were combined and concentrated to give a yellow oil that was chromatographed on silica gel (DCM: MeOH = 20: 1). ) To give 0.10 g of product as a yellow solid (52% yield).
1H NMR (chloroform-d) δ: 8.30 (d, J = 5.6 Hz)
, 1H), 7.48-7.49 (m, 0.5H), 6.81 (dt, J
= 5.6, 2.0 Hz, 2H), 4.70 (s, 1H), 4.41 (
d, J = 13.0 Hz, 1H), 4.29 (d, J = 13.0 H)
z, 1H), 4.12 (dd, J = 18.6, 7.4 Hz, 1H),
3.93 (s, 2H), 3.84-3.67 (m, 1H), 3.18
(D, J = 12.8 Hz, 1H), 3.13-2.99 (m, 1
H), 2.61 (s, 2H), 2.32-2.22 (m, 0.5H),
2.02 (t, J = 4.6 Hz, 1H), 1.35 (s, 1H),
1.29 (d, J = 9.4 Hz, 3H), 1.14 (dd, J =
7.4, 3.0 Hz, 2H), 1.04 (dt, J = 7.9).
1 Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51
(M, 2H).
LC-MS: m / z 468.1 (M + H) +

Compound 692 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (2-vinylpyridin-4-yloxy) nicotinonitrile

(R) -5- (2-chloropyridin-4-yloxy) -6-cyclopropyl-2- (
3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) nicotinonitrile (4) 0.35 g, (0.75 mmol), potassium trifluoro (vinyl) borate (0.15 g, 1. 1 mmol), PdCl ₂ dppf (80 mg, 0.07
5 mmol) and DIEA (0.24 mL, 1.5 mmol) were heated in isopropanol at 85 ° C. under nitrogen for 5 hours under reflux. The mixture was then concentrated under reduced pressure to give a yellow solid which was chromatographed on silica (PE / EA / MeOH = 15
Further purification by 0/120/8) gave 0.19 g of product as a white solid (55
%yield).
1H NMR (chloroform-d) δ: 8.47 (d, J = 5.6 Hz,
1H), 7.48-7.49 (m, 0.5 H), 6.86 (d, J =
2.3 Hz, 1H), 6.77 (dd, J = 17.4, 10.8 H)
z, 1H), 6.66 (dd, J = 5.6, 2.4 Hz, 1H),
6.22 (dd, J = 17.4, 0.9 Hz, 1H), 5.53 (d
d, J = 10.8, 0.8 Hz, 1H), 4.68 (d, J = 1)
1.7 Hz, 1H), 4.38 (d, J = 12.9 Hz, 1H),
4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H)
, 3.92 (s, 2H), 3.75 (d, J = 20.7 Hz, 1H
), 3.47 (d, J = 21.7 Hz, 1H), 3.25-3.1
2 (m, 1H), 3.09-2.95 (m, 1H), 2.60 (s,
2H), 2.32-2.22 (m, 0.5 H), 2.11-2.0
5 (m, 1H), 1.37 (d, J = 20.5 Hz, 1H), 1.
27 (d, J = 2.0 Hz, 1H), 1.16-1.10 (m,
2H), 1.01 (ddd, J = 10.1, 6.7, 3.3 Hz, 2
H), 0.65 (t, J = 33.7 Hz, 2H), 0.45-0.48
(M, 2H).
LC-MS: m / z 460.1 (M + H) +

Compound 693 (General Procedure 8)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5- (2-vinylpyridin-4-yloxy) nicotinonitrile 1H NMR (Chloroform-d) δ: 8.46 (d, J = 5.6 Hz
, 1H), 7.46 (s, 1H), 6.86 (d, J = 2.3 Hz)
, 1H), 6.77 (dd, J = 17.4, 10.8 Hz, 1H),
6.66 (dd, J = 5.6, 2.4 Hz, 1H), 6.22 (d
, J = 17.4 Hz, 1H), 5.53 (d, J = 10.9 Hz)
, 1H), 4.54-4.71 (m, 0.5 H), 4.37 (d, J
= 12.4 Hz, 1H), 4.26 (d, J = 12.6 Hz, 1H)
), 4.11 (s, 1H), 3.88 (d, J = 11.9 Hz, 1
H), 3.80-3.68 (m, 3H), 3.38 (s, 3H), 3
. 20 (t, J = 23.2 Hz, 1H), 3.05 (s, 1H),
2.68 (dd, J = 15.1, 12.2 Hz, 2H), 2.47-2
. 53 (m, 0.5H), 2.06 (dd, J = 8.6, 3.9 Hz
, 1H), 1.38-1.28 (m, 1H), 1.13 (dd, J
= 7.4, 3.1 Hz, 2H), 1.01 (dt, J = 7.9, 3
. 2 Hz, 2H), 0.73-0.51 (m, 2H), 0.43-0.
46 (m, 2H).
LC-MS: m / z 476.1 (M + H) +

Compound 668 (General Procedure 8)
(R) -5-((2-chloropyridin-4-yl) oxy) -6-cyclopropyl-2
-(4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.33 (s, 1H), 7.47
(S, 1H), 6.85 (s, 2H), 4.93-5.05 (m, 0.5
H), 4.56-4.58 (m, 0.5 H), 4.33-4.09 (m
, 3H), 3.88-3.68 (m, 3H), 3.57 (s, 1H)
, 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd,
J = 36.0, 11.2 Hz, 1H), 2.82-2.48 (m,
1H), 1.42 (d, J = 6.5 Hz, 2H), 1.36-1.
29 (m, 2H), 1.14 (s, 2H), 1.03-1.05 (m,
2H).
LC-MS: m / z 456.0 (M + H) +

Compound 666 (General Procedure 8)
(R) -5-((6-Chloropyrimidin-4-yl) oxy) -6-cyclopropyl-
2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.33 (s, 1H), 7.47
(S, 1H), 6.85 (s, 2H), 4.92-4.96 (m, 0.5
H), 4.55-4.58 (m, 0.5 H), 4.33-4.09 (m
3H), 3.88-3.68 (m, 2H), 3.57 (s, 1H)
, 3.40 (s, 3H), 3.30 (s, 1H), 3.10 (dd,
J = 36.0, 11.2 Hz, 1H), 2.82-2.48 (m,
1H), 1.42 (d, J = 6.5 Hz, 2H), 1.36-1.
29 (m, 2H), 1.14 (s, 2H), 1.03 (d, J = 4
. 1 Hz, 2H).
LC-MS: m / z 449.0 (M + H) +

Compound 734 (General Procedure 8)
(R) -5-((4-chloropyridin-2-yl) oxy) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.07 (d, J = 6.0 Hz
, 1H), 7.54 (s, 1H), 7.09-7.05 (m, 2H)
, 4.60-4.68 (m, 1H), 4.31-4.35 (m, 1H),
4.21 (d, J = 13.0 Hz, 1H), 4.07 (d, J =
9.8 Hz, 1H), 3.92 (s, 2H), 3.74 (d, J =
11.5 Hz, 1H), 3.48 (d, J = 24.4 Hz, 1H),
3.21-3.07 (m, 1H), 3.03 (d, J = 10.9
Hz, 1H), 2.58 (d, J = 17.5 Hz, 2H), 2.15
-2.00 (m, 1H), 1.44 (s, 1H), 1.13 (dd,
J = 7.3, 3.6 Hz, 2H), 0.98 (dt, J = 6.8)
, 2.7 Hz, 2H), 0.65 (s, 2H), 0.45-0.48 (
m, 2H).
LC-MS: m / z 469.2 (M + H) +

Compound 733 (General Procedure 8)
(R) -5-((4-chloropyridin-2-yl) oxy) -6-cyclopropyl-2
-(3-Cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl)
Nicotinonitrile 1H NMR (chloroform-d) δ: 8.10 (d, J = 5.3 Hz)
, 1H), 7.53 (s, 1H), 7.07 (dd, J = 5.3)
1.1 Hz, 1H), 6.97 (s, 1H), 6.70 (dd, J =
17.6, 10.9 Hz, 1H), 6.01 (d, J = 17.6 H
z, 1H), 5.56 (d, J = 10.9 Hz, 1H), 4.69−
4.71 (m, 0.5 H), 4.28 (d, J = 12.4 Hz, 1
H), 4.18 (d, J = 12.5 Hz, 1H), 4.09 (d,
J = 8.0 Hz, 1H), 3.80-3.90 (m, 0.5 H), 3
. 72 (dd, J = 13.7, 7.8 Hz, 3H), 3.39 (d,
J = 5.9 Hz, 3H), 3.27 (s, 1H), 3.09 (d,
J = 12.5 Hz, 1H), 2.97 (s, 1H), 2.73 −
2.59 (m, 2H), 2.18-2.10 (m, 1H), 1.12.
(D, J = 4.0 Hz, 2H), 0.96 (ddd, J = 9.2)
8.5, 5.1 Hz, 3H), 0.89 (dd, J = 13.9, 6
. 8 Hz, 2H), 0.62 (s, 2H), 0.45-0.47 (m,
2H).
LC-MS: m / z 474.2 (M + H) +

Compound 832 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-vinylpyridin-4-yl) oxy) nicotinonitrile


1H NMR (chloroform-d) δ: 8.47 (d, J = 5.6 Hz)
, 1H), 7.44 (d, J = 3.5 Hz, 1H), 6.88 (s
, 1H), 6.84-6.74 (m, 1H), 6.69 (d, J =
3.5 Hz, 1H), 6.28 (d, J = 17.4 Hz, 1H),
5.58 (d, J = 10.7 Hz, 1H), 4.89-4.91 (m
, 0.5H), 4.50-4.54 (m, 0.5H), 4.23-4.
06 (m, 2H), 3.82-3.68 (m, 2H), 3.50-3.
53 (m, 0.5 H), 3.37 (s, 3H), 3.26 (d, J =
12.7 Hz, 1H), 3.05-3.10 (m, 1.5 H), 2.7
8-2.52 (m, 2H), 2.05-1.93 (m, 1H), 1
. 39 (d, J = 6.0 Hz, 1H), 1.32-1.25 (m,
3H), 1.14-1.08 (m, 2H), 0.99 (dt, J =
11.5, 3.3 Hz, 2H).
LC-MS: m / z 448.0 (M + H) +

Compound 703 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-vinylpyridin-4-yl) methoxy) nicotinonitrile 1H NMR (chloroform-d) δ: 8.61 (d, J = 5.0 H
z, 1H), 7.39 (s, 1H), 7.21-7.26 (m, 1H)
), 7.18 (s, 1H), 6.85 (dd, J = 17.4, 10.
9 Hz, 1H), 6.26 (dd, J = 17.4, 1.1 Hz, 1
H), 5.47-5.61 (m, 1H), 5.06 (s, 2H), 4
. 88 (br. S., 0.5H), 4.52 (d, J = 13.6 Hz)
, 0.5H), 4.21 (d, J = 6.8 Hz, 0.5H), 3.8
5-4.05 (m, 2H), 3.67-3.81 (m, 2.5H),
3.54 (d, J = 6.8 Hz, 0.5H), 3.37 (s, 3H
), 3.04-3.18 (m, 1.5H), 2.84-3.04 (m
, 1H), 2.63-2.80 (m, 1H), 2.44-2.63
(M, 2H), 1.22-1.36 (m, 3H), 1.03-1.1
7 (m, 4H)
LC-MS: m / z 461.6 (M + H) +

Compound 789
5- (1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl) -6
Cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methylnicotinonitrile 1H NMR (chloroform -D) 6.67 (dd, J = 16.7, 10
. 6 Hz, 1H), 6.35 (dd, J = 16.7, 7.0 Hz,
1H), 5.64-5.85 (m, 2H), 5.26 (m, 6.6 Hz)
, 1H), 4.66-4.79 (m, 1H), 4.56 (br. S.
, 1H), 4.23-4.39 (m, 2H), 4.18 (d, J =
12.6 Hz, 1H), 3.95-4.11 (m, 2H), 3.90
(D, J = 17.9 Hz, 1H), 3.63-3.83 (m, 2
H), 3.27 (br.s., 1H), 3.08 (br.s., 1H)
2.96 (d, J = 10.3 Hz, 2H), 2.79-2.92.
(M, 2H), 2.53 (d, J = 7.9 Hz, 1H), 2.31
-2.48 (m, 5H), 2.04 (dd, J = 13.4, 6.0
Hz, 1H), 1.44 (d, J = 8.2 Hz, 1H), 1.15
(Br. S., 1H), 0.85-1.07 (m, 3H), 0.60
(Br.s., 1H), 0.52 (br.s., 1H), 0.44 (
br. s. , 2H)
LC-MS: m / z 516.6 (M + H)

Compound 778
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -5- (1-methyl-6 -Vinyl-1H-pyrazolo [3,4-b] pyridin-4-yl) nicotinonitrile 1H NMR (chloroform-d) 7.86-7.94 (s, 1H), 7
. 71-7.81 (s, 1H), 7.22 (s, 1H), 6.99 (
dd, J = 17.6, 10.9 Hz, 1H), 6.28-6.48.
(M, 1H), 5.66 (dd, J = 10.9, 0.9 Hz, 1H)
, 5.28 (t, J = 6.7 Hz, 1H), 4.68-4.78.
(M, 1H), 4.54-4.68 (m, 2H), 4.48 (d, J
= 14.1 Hz, 1H), 4.21 (s, 3H), 3.75-4.
17 (m, 2H), 2.77-3.35 (m, 6H), 2.45-2.
65 (m, 1H), 1.85-2.01 (m, 2H), 1.18-
1.25 (m, 2H), 0.95-1.05 (m, 2H), 0.61
-0.81 (m, 1H), 0.57 (br. S., 1H), 0.48
(Br.s., 2H)
LC-MS: m / z 524.2 (M + H) +

Compound 777
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-5-((2-vinylpyridin-4-yl) Oxy) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 5
. 7 Hz, 1H), 6.93-6.75 (m, 2H), 6.65 (d,
J = 3.7 Hz, 1H), 6.30 (d, J = 17.4 Hz,
1H), 5.60 (d, J = 10.7 Hz, 1H), 4.60-4.7.
1 (m, 0.5 H), 4.27-4.28 (m, 1H), 4.23-
4.14 (m, 1H), 4.10-4.15 (m, 0.5 H), 3.92
-3.93 (m, 2H), 3.78-3.79 (m, 1H), 3.44-
3.45 (m, 1H), 3.26-3.10 (m, 1H), 3.04-3.
05 (m, 1H), 2.61-2.62 (m, 2H), 2.31 (s,
3H), 2.01-1.94 (m, 1H), 1.44-1.45 (m, 1H)
), 1.13 -1.07 (m, 2H), 1.01- 0.94 (m, 2H)
), 0.91-0.86 (m, 1H), 0.65-0.66 (m, 1H)
), 0.46-0.52 (m, 2H). MS (ES) M + H predicted value 474.
0, measured value 474.6

Compound 833
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5-((5-vinylpyridazin-3-yl) amino)
Nicotinonitrile


1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H),
7.76 (s, 1H), 6.58 (dd, J = 17.6, 11.0 H
z, 2H), 6.05 (d, J = 17.6 Hz, 1H), 5.66.
(D, J = 11.0 Hz, 1H), 4.65-4.70 (m, 0.5
H), 4.43-4.46 (m, 1H), 4.33 (d, J = 12.4
Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.8
8 (m, 0.5 H), 3.71-3.74 (m, 3H), 3.39 (s,
3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H), 2
. 65-2.66 (m, 2H), 2.55 -2.47 (m, 1H), 2.
18 (d, J = 10.1 Hz, 1H), 1.30-1.25 (m,
1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0
. 50-0.60 (m, 2H), 0.45-0.47 (m, 2H). MS
(ES) M + H predicted value 474.0, measured value 474.6

Compound 792
(R) -5- (4-Cyanopyridin-2-ylamino) -6-cyclopropyl-2- (
3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) nicotinonitrile 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.31 (
d, J = 5.0 Hz, 1 H), 7.80-7.69 (m, 1 H
), 6.94 (dd, J = 1.3, 5.1 Hz, 1 H), 6.59.
(S, 1 H), 6.51 (s, 1 H), 4.34 (d, J = 1)
2.6 Hz, 2 H), 4.14-3.65 (m, 4 H), 3.39
(S, 3 H), 2.61-3.23 (m, 5 H), 2.15-
2.05 (m, 1 H), 1.20-1.11 (m, 2 H), 1.0
4 (td, J = 3.0, 7.8 Hz, 2 H), 0.45 (d, J
= 5.3 Hz, 5 H)
LC_MS (M + 1) + 472.5

Compound 783
4- (5-cyano-2-cyclopropyl-6-((R) -3-cyclopropyl-4- (
2-((R) -Oxetan-2-yl) acetyl) piperazin-1-yl) pyridine-3
-Ilamino) picolinonitrile 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.30 (
d, J = 5.9 Hz, 1 H), 7.59 (s, 1 H), 6.92
(D, J = 2.3 Hz, 1 H), 6.77-6.62 (m, 2
H), 5.27 (t, J = 6.7 Hz, 1 H), 4.75-4.
. 65 (m, 1 H), 4.62-4.51 (m, 1 H), 4.47
(D, J = 12.6 Hz, 1 H), 4.37 (d, J = 12.
6 Hz, 1 H), 4.07 (d, J = 7.9 Hz, 1 H), 3
. 65-3.75 (m, 1 H), 3.30-3.04 (m, 2 H
), 2.98 (s, 1 H), 2.92-2.72 (m, 3 H),
2.62-2.44 (m, 1 H), 2.05-1.98 (m, 1
H), 1.08-0.99 (m, 2 H), 0.93-0.80 (m
, 4 H), 0.63 (br. S., 1 H), 0.52 (br. S.
, 1 H), 0.48-0.36 (m, 1 H)
LC_MS (M + 1) + 484.6

Compound 774
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((S) -oxetan-2-yl) acetyl) piperazin-1-yl) -5-((2-vinylpyridine −
4-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ 8.23 (d, J = 5.9 Hz,
1H), 7.62 (s, 1H), 6.72 (dd, J = 17.4,
10.9 Hz, 1H), 6.63 (s, 1H), 6.55 (s, 1H)
, 6.26 (d, J = 17.6 Hz, 1H), 5.54 (d, J
= 10.7 Hz, 1H), 5.34-5.22 (m, 1H), 4.7.
3 (dd, J = 14.6, 8.2 Hz, 1H), 4.56 (dt,
J = 9.1, 5.8 Hz, 1H), 4.47 (d, J = 12.9).
Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 4.09
(D, J = 10.0 Hz, 0.5H), 3.89 (d, J = 13
. 3 Hz, 0.5H), 3.80-3.64 (m, 1H), 3.42
-3.15 (m, 2H), 3.15-2.78 (m, 3H), 2.7
5-2.34 (m, 2H), 2.10 (ddd, J = 12.7, 8
. 1, 4.7 Hz, 1H), 1.29 (dd, J = 6.7, 4.8)
Hz, 1H), 1.18-1.10 (m, 2H), 1.03 (dd,
J = 7.7, 3.2 Hz, 2H), 0.81-0.53 (m, 2H)
), 0.52-0.38 (m, 2H).
LC-MS: m / z NB295-063-01 485.1 (M + H) +

Compound 791
(R, E) -6-cyclopropyl-2- (4- (5-hydroxypent-2-enoyl) -3-isopropylpiperazin-1-yl) -5-((4-vinylpyridin-2-yl) Amino) nicotinonitrile 1H NMR (chloroform-d) δ 8.10 (d, J = 5.3 Hz,
1H), 7.81 (s, 1H), 6.90 (tt, J = 14.6,
7.3 Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 6
. 79-6.63 (m, 1H), 6.58 (dd, J = 17.6,
10.8 Hz, 1H), 6.41 (d, J = 14.1 Hz, 2H),
5.89 (d, J = 17.5 Hz, 1H), 5.46 (d, J =
10.8 Hz, 1H), 4.76-4.64 (m, 0.5H), 4.
55-4.37 (m, 1.5H), 4.26 (t, J = 11.6 H
z, 1H), 4.18 (d, J = 5.2 Hz, 0.5H), 3.95.
(D, J = 13.7 Hz, 0.5H), 3.81 (t, J = 6.
0 Hz, 2H), 3.67 (d, J = 9.3 Hz, 0.5H), 3
. 54-3.42 (m, 0.5H), 3.29-3.16 (m, 0. 0).
5H), 3.16-2.96 (m, 2.5H), 2.52 (dd, J
= 13.0, 6.4 Hz, 2H), 2.36-2.24 (m, 0.5
H), 2.24-2.11 (m, 1.5H), 1.18-1.08 (
m, 2H), 1.07 (d, J = 6.5 Hz, 3H), 1.04 −
0.98 (m, 2H), 0.93-0.84 (m, 3H).
LC-MS: m / z NB295-055-2-02 487.7 (M + H) +

Compound 790
(R) -6-cyclopropyl-2- (4- (5-hydroxypent-2-enoyl)-
3-Isopropylpiperazin-1-yl) -5- (2-vinylquinoxalin-5-yl)
Nicotinonitrile 1H NMR (400 MHz, CHLOROFORM-d) δ: 9.02 (
s, 1 H), 8.19-8.09 (m, 1 H), 7.91-7.
80 (m, 1 H), 7.76-7.67 (m, 2 H), 7.08
(Dd, J = 11.2, 17.6 Hz, 1 H), 6.98-6.8
2 (m, 0.5 H), 6.57-6.37 (m, 1.5 H), 5.
97-5.73 (m, 2 H), 4.70-4.35 (m, 3.5
H), 4.23-4.16 (m, 1 H), 3.86-3.75 (m
, 1.5 H), 3.60-3.42 (m, 1 H), 3.32-3
. 05 (m, 4 H), 2.58-2.48 (m, 1 H), 2.37
-2.18 (m, 1 H), 1.32-1.23 (m, 2 H),
1.16-1.05 (m, 3 H), 0.98-0.72 (m, 6
H)
LC_MS (M + 1) + 523.7

Compound 794
2-cyclopropyl-6-((R) -3-cyclopropyl-4- (3-((R) -oxetan-2-yl) propanoyl) piperazin-1-yl) -2'-vinyl- [3 4 '
-Bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.63 (d, J = 5.3 Hz,
1H), 7.63 (s, 1H), 7.38 (s, 1H), 7.22 (
dd, J = 5.0, 1.5 Hz, 1H), 6.86 (dd, J =
17.3, 10.9 Hz, 1H), 6.26 (d, J = 17.3 Hz)
, 1H), 5.55 (d, J = 10.9 Hz, 1H), 4.86 (
s, 1H), 4.60-4.74 (m, 1H), 4.46-4.60.
(M, 2H), 4.40 (d, J = 12.9 Hz, 1H), 4.0
7 (s, 1H), 3.82 (s, 1H), 3.69 (s, 1H), 3
. 12-3.42 (m, 2H), 2.99-3.10 (m, 1H), 2
. 48-2.63 (m, 3H), 1.96-2.24 (m, 3H), 1
. 19 (m, 2H), 0.93-1.02 (m, 2H), 0.33-0
. 54 (m, 4H)
LC-MS: m / z 484.3 (M + H) +

Compound 785
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-5- (6 -Vinylpyridazin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.01 (d, J = 1.8 Hz)
, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.13 (d
d, J = 17.8, 11.0 Hz, 1H), 6.36 (d, J =
17.9 Hz, 1H), 5.79 (d, J = 11.2 Hz, 1H),
5.27 (t, J = 6.7 Hz, 1H), 4.66-4.79 (
m, 1H), 4.51-4.63 (m, 1H), 4.41 (d, J
= 12.6 Hz, 1H), 4.09 (d, J = 7.6 Hz, 1H)
3.95 (d, J = 12.6 Hz, 1H), 3.79 (d, J
= 10.9 Hz, 1H), 2.92-3.32 (m, 4H), 2.8
4-2.92 (m, 1H), 2.46-2.61 (m, 1H), 2
. 24 (s, 3H), 2.04 (dd, J = 15.1, 7.5 Hz,
1H), 1.43-1.50 (m, 1H), 1.09-1.19 (
m, 2H), 0.83-0.91 (m, 2H), 0.35-0.62
(M, 4H)
LC-MS: m / z 485.3 (M + H) +

Compound 786
6-cyclopropyl-2-((R) -3-isopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-5- (6- Vinylpyridazin-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.01 (s, 1H), 7.50
(S, 1H), 7.12 (dd, J = 17.9, 11.2 Hz, 1H
), 6.36 (d, J = 17.9 Hz, 1H), 5.78 (d, J
= 11.2 Hz, 1H), 5.23-5.31 (m, 1H), 4.
64-4.78 (m, 1H), 4.39-4.63 (m, 3H),
4.34 (d, J = 12.6 Hz, 1H), 3.91 (d, J =
13.5 Hz, 1H), 3.43-3.65 (m, 1H), 2.92
-3.17 (m, 4H), 2.82-2.91 (m, 1H), 2.4
4-2.66 (m, 1H), 2.22 (s, 3H), 2.07-2
. 17 (m, 1H), 1.91-2.04 (m, 1H), 1.38-1
. 58 (m, 1H), 1.00-1.15 (m, 3H), 0.85-0
. 94 (m, 6H)
LC-MS: m / z 487.3 (M + H) +

Compound 776
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -4-methyl-5- (6-vinylpyridazin-4-yl) nicoti Nononitrile 1H NMR (chloroform-d) δ 9.01 (d, J = 1.8 Hz
, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.13 (d
d, J = 17.8, 11.0 Hz, 1H), 6.37 (d, J =
17.6 Hz, 1H), 5.80 (d, J = 11.2 Hz, 1H),
4.41 (d, J = 13.2 Hz, 1H), 4.32 (d, J =
12.9 Hz, 1H), 4.09 (d, J = 7.0 Hz, 1H),
3.93 (s, 2H), 3.68-3.84 (m, 2H), 3.13
-3.37 (m, 2H), 3.09 (d, J = 8.5 Hz, 1H
), 2.54-2.67 (m, 2H), 2.24 (s, 3H), 1.
45-1.49 (m, 1H), 1.07-1.19 (m, 2H),
0.92 (dd, J = 12.5, 6.3 Hz, 2H), 0.47-0.
67 (m, 4H)
LC-MS: m / z 459.2 (M + H) +

Compound 793
6-cyclopropyl-2-((R) -3-isopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-5- (5- Vinylpyridazin-3-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.27 (br.s., 1 H),
7.43 (br. S., 1 H), 6.73 (dd, J = 17.6, 1
1.2 Hz, 1 H), 6.20 (d, J = 17.6 Hz, 1 H),
5.77 (d, J = 10.9 Hz, 1 H), 5.28 (m, 1 H),
4.63-4.78 (m, 1 H), 4.30-4.60 (m, 3
. 5 H), 3.87 (d, J = 13.2 Hz, 0.5 H), 3.41
-3.61 (m, 1 H), 2.88-3.18 (m, 4 H), 2
. 72-2.88 (m, 2 H), 2.41-2.65 (m, 1 H
), 2.22 (s, 3 H), 2.01-2.16 (m, 1 H),
1.38-1.51 (m, 1 H), 1.12 (d, J = 16.4 Hz)
, 2 H), 0.98-1.05 (m, 3 H), 0.75-0.9
8 (m, 6 H)
LC-MS: m / z 487.1 (M + H)

Compound 784
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -4-methyl-5- (5-vinylpyridazin-3-yl) nicotino Nitrile 1H NMR (chloroform-d) δ 9.28 (d, J = 2.1 Hz)
, 1H), 7.44 (d, J = 2.1 Hz, 1H), 6.75 (d
d, J = 17.6, 10.9 Hz, 1H), 6.21 (d, J =
17.6 Hz, 1H), 5.79 (d, J = 11.2 Hz, 1H),
4.40-4.55 (m, 1.5H), 4.35 (d, J = 11.
2 Hz, 1H), 3.94 (t, J = 4.8 Hz, 2H), 3.6
7-3.81 (m, 0.5H), 3.41-3.57 (m, 1H),
3.01-3.21 (m, 3H), 2.57-2.66 (m, 2H
), 2.28 (s, 3H), 1.63-1.67 (m, 1H), 1.12.
-1.16 (m, 2H), 1.01-1.09 (m, 3H), 0.79
-0.98 (m, 6H)
LC-MS: m / z 461.1 (M + H)

Compound 780
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((S) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-5- (5 -Vinylpyridazin-3-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.27 (d, J = 2.1 Hz)
, 1H), 7.43 (d, J = 2.3 Hz, 1H), 6.74 (d
d, J = 17.8, 11.0 Hz, 1H), 6.20 (d, J =
17.6 Hz, 1H), 5.77 (d, J = 10.9 Hz, 1H),
5.20-5.29 (m, 1H), 4.68-4.78 (m, 1H
), 4.51-4.68 (m, 1H), 4.43 (d, J = 12.
9 Hz, 1H), 4.33 (d, J = 12.0 Hz, 1H), 4.
07 (d, J = 9.1 Hz, 0.5H), 3.81-3.93 (m
, 0.5H), 3.69-3.81 (m, 0.5H), 3.09-3
. 28 (m, 3.5H), 2.81-3.01 (m, 3H), 2.55
(M, 1H), 2.30 (s, 3H), 1.82 (br.s., 1H
), 1.41-1.54 (m, 1H), 1.15 (br.s., 2H)
), 0.88 (m, 2H), 0.43-0.72 (m, 4H)
LC-MS: m / z 485.1 (M + H)

Compound 779
(R) -5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl)
-3-methylpiperazin-1-yl)-[3,4'-bipyridine] -2'-yltrifluoromethanesulfonate 1H NMR (chloroform-d) δ 8.49 (d, J = 5.0 Hz)
, 1H), 7.65 (s, 1H), 7.46 (dd, J = 5.1,
1.3 Hz, 1H), 7.23-7.28 (m, 1H), 4.92 (
br. s. , 0.5H), 4.55 (d, J = 10.3 Hz, 0.5
H), 4.23-4.47 (m, 2.5H), 3.68-3.88 (
m, 2.5H), 3.49-3.65 (m, 0.5H), 3.31-
3.45 (m, 4H), 3.05-3.29 (m, 1.5H), 2.6
4-2.80 (m, 1H), 2.53-2.64 (m, 1H), 1
. 90-2.03 (m, 1H), 1.38 (d, J = 6.2 Hz,
1.5H), 1.18-1.33 (m, 3.5H), 1.02-1.
13 (m, 2H)
LC-MS: m / z 554.1 (M + H)

Compound 773
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -4-methyl-5- (6-vinylpyridazin-4-yl) nicotino Nitrile 1H NMR (chloroform-d) δ 9.02 (s, 1H), 7.52
(S, 1H), 7.14 (dd, J = 17.6, 11.2 Hz, 1H
), 6.37 (d, J = 17.9 Hz, 1H), 5.80 (d, J
= 11.2 Hz, 1H), 4.65-4.76 (m, 0.5H),
4.40-4.55 (m, 1.5H), 4.34 (t, J = 10.4
Hz, 1H), 3.86-4.01 (m, 2H), 3.77 (d,
J = 13.5 Hz, 0.5H), 3.42-3.57 (m, 1H),
2.96-3.21 (m, 3H), 2.53-2.69 (m, 2H
), 2.20 (s, 3H), 1.42-1.50 (m, 1H), 1.
10-1.16 (m, 2H), 1.00-1.08 (m, 3H), 0.
83-1.00 (m, 6H)
LC-MS: m / z 461.1 (M + H)

Compound 771
(R) -tert-butyl 4- (3-cyano-6-cyclopropyl-4-methyl-5-
(5-vinylpyridazin-3-yl) pyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate 1H NMR (chloroform-d) δ 9.28 (d, J = 2.1 Hz,
1H), 7.44 (d, J = 2.1 Hz, 1H), 6.75 (dd
, J = 17.8, 11.0 Hz, 1H), 6.15-6.26 (m
, 1H), 5.79 (d, J = 10.9 Hz, 1H), 4.41 (
d, J = 12.9 Hz, 1H), 4.31 (d, J = 12.6 H
z, 1H), 4.08 (d, J = 14.4 Hz, 1H), 3.36.
−3.55 (m, 2H), 3.24 (dd, J = 12.9, 3.5
Hz, 1H), 3.07 (td, J = 12.5, 3.5 Hz, 1H)
, 2.24 (s, 3H), 1.54 (s, 9H), 1.41-1.4
7 (m, 1H), 1.31-1.39 (m, 1H), 1.16 (br
. s. , 2H), 0.79-0.96 (m, 2H), 0.42-0
. 66 (m, 3H), 0.28-0.42 (m, 1H)
LC-MS: m / z 487.1 (M + H)

Compound 772
(R) -tert-butyl 4- (3-cyano-6-cyclopropyl-4-methyl-5-
(6-vinylpyridazin-4-yl) pyridin-2-yl) -2-cyclopropylpiperazine-1-carboxylate 1H NMR (chloroform-d) δ 1H NMR (chloroform-d) □:
9.27 (d, J = 2.1 Hz, 1H), 7.44 (d, J =
2.1 Hz, 1H), 6.74 (dd, J = 17.8, 11.0 Hz)
, 1H), 6.21 (d, J = 17.6 Hz, 1H), 5.77 (
d, J = 10.9 Hz, 1H), 4.41 (d, J = 12.9 H
z, 1H), 4.30 (d, J = 12.6 Hz, 1H), 4.02.
-4.22 (m, 1H), 3.36-3.53 (m, 2H), 3.1
8-3.30 (m, 1H), 3.07 (td, J = 12.4, 3.
4 Hz, 1H), 2.23 (s, 3H), 1.49 (s, 9H), 1
. 42-1.48 (m, 1H), 1.31-1.38 (m, 1H),
1.09-1.21 (m, 2H), 0.87 (dd, J = 7.8,
3.1 Hz, 2H), 0.42-0.65 (m, 3H), 0.30
-0.42 (m, 1H)
LC-MS: m / z 487.1 (M + H)

Compound 769
(R, E) -6-cyclopropyl-2- (3-cyclopropyl-4- (5-hydroxypent-2-enoyl) piperazin-1-yl) -4-methyl-5- (5-vinylpyridazine- 3-yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.27 (d, J = 2.1 Hz)
, 1H), 7.43 (d, J = 2.1 Hz, 1H), 6.87 (d
t, J = 14.8, 7.3 Hz, 1H), 6.73 (dd, J =
17.8, 11.0 Hz, 1H), 6.26-6.49 (m, 1H),
6.21 (d, J = 17.6 Hz, 1H), 5.77 (d, J =
10.9 Hz, 1H), 4.42 (d, J = 12.9 Hz, 1H)
, 4.33 (d, J = 12.6 Hz, 1H), 4.04-4.21
(M, 1H), 3.79 (t, J = 6.0 Hz, 3H), 3.38
(Br. S., 1H), 3.23 (d, J = 10.0 Hz, 1H)
, 3.08 (td, J = 12.5, 2.9 Hz, 1H), 2.50
(Q, J = 6.2 Hz, 2H), 2.27 (s, 3H), 1.35
-1.52 (m, 2H), 1.15 (br. S., 2H), 0.88
(Dd, J = 7.6, 3.2 Hz, 2H), 0.65 (br. S.,
1H), 0.51 (br. S., 1H), 0.44 (br. S., 2
H)
LC-MS: m / z 485.1 (M + H)

Compound 770
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (4-hydroxybutanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-
5-carbonitrile 1H NMR (chloroform-d) 8.69 (d, J = 5.0 Hz, 1
H), 7.23 (s, 1H), 7.07 (d, J = 5.0 Hz, 1
H), 6.87 (dd, J = 17.5, 10.7 Hz, 1H), 6.
29 (d, J = 17.3 Hz, 1H), 5.57 (dd, J = 1)
0.7, 1.0 Hz, 1H), 4.33 (d, J = 12.9 Hz,
1H), 4.25 (d, J = 12.6 Hz, 1H), 4.09 (d,
J = 7.6 Hz, 0.5H), 3.79-3.92 (m, 1H),
3.65-3.79 (m, 2.5H), 3.31 (br. S., 0.
5H), 3.14 (d, J = 12.0 Hz, 1H), 2.99-3.
. 11 (m, 1.5H), 2.58 (br. S., 2H), 2.17 −
2.26 (m, 3H), 1.90-2.00 (m, 2H), 1.51
-1.62 (m, 1H), 1.43 (d, J = 10.3 Hz, 1
H), 1.02-1.16 (m, 2H), 0.87 (dd, J = 7
. 9, 2.9 Hz, 2H), 0.62 (br. S., 1H), 0.54
(Br.s., 1H), 0.31-0.50 (m, 2H)
LC-MS: m / z 472.5 (M + H) +

Compound 781
2-Cyclopropyl-6-((R) -3-isopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-methyl-2'-vinyl- 3,
4′-bipyridine-5-carbonitrile 1H NMR (chloroform-d) 8.70 (d, J = 5.0 Hz,
1H), 7.21-7.28 (m, 1H), 7.09 (br. S.,
1H), 6.89 (dd, J = 17.3, 10.9 Hz, 1H), 6
. 30 (d, J = 17.3 Hz, 1H), 5.59 (d, J = 1)
0.9 Hz, 1H), 5.26-5.33 (m, 1H), 4.67-
4.78 (m, 1.5H), 4.56 (dt, J = 9.1, 5.9)
Hz, 1H), 4.38-4.48 (m, 1.5H), 4.29 (d,
J = 12.3 Hz, 1H), 3.89 (d, J = 13.5 Hz,
0.5H), 3.45-3.61 (m, 1H), 2.92-3.15
(M, 3.5H), 2.78-2.91 (m, 2H), 2.44-
2.65 (m, 1H), 2.26 (br. S., 0.5H), 2.19
-2.23 (m, 3H), 2.11-2.18 (m, 0.5H), 1
. 56 (td, J = 8.0, 4.5 Hz, 1H), 1.12 (br.
s. , 1H), 1.04 (d, J = 6.5 Hz, 4H), 0.93
(D, J = 6.7 Hz, 1H), 0.83-0.90 (m, 4H
)
LC-MS: m / z 486.6 (M + H) +

Compound 795
(R, E) -2-cyclopropyl-6- (4- (5-hydroxypent-2-enoyl) -3-isopropylpiperazin-1-yl) -4-methyl-2'-vinyl-3,4 ' −
Bipyridine-5-carbonitrile 1H NMR (chloroform-d) 8.68 (d, J = 5.0 Hz, 1
H), 7.23 (d, J = 9.7 Hz, 1H), 7.07 (br.
s. , 1H), 6.81-6.94 (m, 2H), 6.40 (d, J
= 15.3 Hz, 1H), 6.28 (d, J = 17.6 Hz, 1
H), 5.57 (d, J = 10.9 Hz, 1H), 4.35-4.
52 (m, 1.5H), 4.28 (d, J = 9.4 Hz, 1H),
3.94 (d, J = 12.9 Hz, 0.5H), 3.80 (t, J
= 5.9 Hz, 2H), 3.68 (d, J = 9.7 Hz, 0.5H)
), 3.52 (t, J = 11.9 Hz, 0.5H), 3.05 −3
. 18 (m, 2H), 2.51 (q, J = 6.4 Hz, 2H), 2
. 25-2.32 (m, 1H), 2.20 (s, 3H), 2.05 (
d, J = 7.3 Hz, 1H), 1.51-1.61 (m, 1H),
1.10 (br. S., 1H), 1.04 (d, J = 6.5 Hz,
4H), 0.93 (d, J = 6.7 Hz, 1H), 0.76-0
. 95 (m, 4H)
LC-MS: m / z 486.6 (M + H) +

Compound 782
(R) -6- (4- (2-Cyclopentylacetyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methyl-2′-vinyl-3,4′-bipyridine-5 Carbonitrile 1H NMR (chloroform-d) 8.69 (d, J = 5.0 Hz,
1H), 7.24 (s, 1H), 7.08 (d, J = 4.4 Hz,
1H), 6.88 (dd, J = 17.3, 10.9 Hz, 1H), 6
. 29 (d, J = 17.6 Hz, 1H), 5.57 (d, J = 1)
0.9 Hz, 1H), 4.34 (d, J = 12.9 Hz, 1H),
4.26 (d, J = 12.0 Hz, 1H), 4.13 (q, J =
7.2 Hz, 1H), . 70-3.91 (br.s., 1.5H),
3.23-3.39 (m, 0.5H), 3.09-3.21 (m, 1H
), 3.03 (t, J = 10.7 Hz, 1H), 2.33-2.5
1 (m, 2H), 2.24-2.32 (m, 1H), 2.17-2
. 24 (m, 3H), 1.80-1.95 (m, 2H), 1.61-
1.72 (m, 2H), 1.50-1.61 (m, 3H), 1.43
(D, J = 12.6 Hz, 1H), 1.14-1.24 (m, 2
H), 1.11 (br.s., 2H), 0.82-0.91 (m, 2
H), 0.51-0.75 (m, 2H), 0.44 (d, J = 5.0
Hz, 2H)
LC-MS: m / z 496.7 (M + H) +

Compound 788
(R) -2-cyclopropyl-6- (3-isopropyl-4- (4-methoxybutanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-5-
Carbonitrile 1H NMR (chloroform-d) 8.68 (d, J = 5.0 Hz,
1H), 7.23 (d, J = 8.8 Hz, 1H), 7.07 (br.
s. , 1H), 6.87 (dd, J = 17.3, 10.9 Hz, 1
H), 6.23-6.33 (m, 1H), 5.48-5.66 (m,
1H), 4.69 (d, J = 10.9 Hz, 0.5H), 4.37
-4.48 (m, 1.5H), 4.23-4.31 (m, 1H), 3
. 82 (d, J = 13.8 Hz, 0.5H), 3.41-3.53
(M, 3H), 3.22-3.38 (m, 3H), 2.92-3.1
5 (m, 3H), 2.39-2.56 (m, 2H), 2.25-2
. 33 (m, 0.5H), 2.17-2.24 (m, 3H), 2.09
-2.17 (m, 0.5H), 1.90-2.00 (m, 2H),
1.52-1.60 (m, 1H), 1.09-1.15 (m, 1H)
, 1.03 (dd, J = 6.5, 2.6 Hz, 4H), 0.91 (
d, J = 6.7 Hz, 1H), 0.80-0.89 (m, 4H)
LC-MS: m / z 488.7 (M + H) +

Compound 787
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (2-cyclopropylacetyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-5 -Carbonitrile 1H NMR (chloroform-d) 8.71 (d, J = 5.0 Hz,
1H), 7.26 (br.s., 1H), 7.09 (d, J = 4.7)
Hz, 1H), 6.88 (dd, J = 17.6, 10.9 Hz, 1
H), 6.25 (d, J = 17.6 Hz, 1H), 5.57 (d,
J = 11.2 Hz, 1H), 4.34 (d, J = 12.9 Hz,
1H), 4.25 (d, J = 12.6 Hz, 1H), 4.04-4
. 16 (m, 0.5H), 3.68-3.86 (m, 1.5H), 3
. 16 (br. S., 1.5H), 3.03 (br. S., 1H), 2
. 36 (br. S., 1.5H), 2.26 (d, J = 7.3 Hz,
2H), 2.20 (s, 3H), 1.50-1.59 (m, 1H),
1.05-1.11 (m, 3H), 0.86 (dd, J = 7.9,
3.2 Hz, 2H), 0.55-0.61 (m, 4H), 0.44
(Br.s., 1H), 0.16-0.23 (m, 3H)
LC-MS: m / z 468.6 (M + H) +

Compound 408
6-cyclopropyl-5- (isoquinolin-4-yl) -2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (Chloroform-d) δ 9.36 (s, 1H), 8.41 (
br. s. , 1H), 8.07-8.19 (m, 1H), 7.65-
7.76 (m, 2H), 7.46 (t, J = 9.0 Hz, 1H),
4.96 (br.s., 0.5H), 4.58 (br.s., 0.5H)
), 4.11-4.38 (m, 2.5H), 3.73-3.89 (m
, 2.5H), 3.58-3.64 (m, 0.5H), 3.41 (s,
3H), 3.04-3.32 (m, 2.5H), 2.56-2.84
(M, 2H), 2.10 (s, 3H), 1.42-1.51 (m,
1H), 1.31-1.41 (m, 3H), 1.03-1.14 (m
, 2H), 0.63-0.83 (m, 2H)
LC-MS: m / z 470.4 (M + H) +

Compound 410
6-cyclopropyl-5- (isoquinolin-5-yl) -2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (Chloroform-d) δ 9.48 (br.s., 1H), 8
. 58 (br. S., 1H), 8.13 (d, J = 8.3 Hz, 1
H), 7.78 (t, J = 7.7 Hz, 1H), 7.64 (d, J
= 7.0 Hz, 1H), 7.32 (d, J = 10.3 Hz, 1H)
), 4.96 (br. S., 0.5H), 4.58 (d, J = 12.
3 Hz, 0.5H), 4.08-4.36 (m, 2.5H), 3.71
-3.93 (m, 2.5H), 3.56-3.70 (m, 0.5H)
, 3.41 (s, 3H), 3.19-3.36 (m, 1.5H), 3
. 01-3.14 (m, 1H), 2.56-2.78 (m, 2H),
2.02-2.10 (m, 3H), 1.81 (br. S., 1H),
1.42-1.50 (m, 3H), 1.05-1.15 (m, 2H
), 0.61-0.81 (m, 2H)
LC-MS: m / z 470.6 (M + H) +

Compound 470
(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methylpyridine-3-
Yl) phenyl) ethenesulfonamide 1H NMR (chloroform-d) δ 7.44 (t, J = 7.8 Hz,
1H), 7.13-7.23 (m, 1H), 6.96-7.12 (
m, 2H), 6.48-6.67 (m, 2H), 6.32 (d, J
= 16.3 Hz, 1H), 6.02 (d, J = 10.0 Hz, 1H)
), 4.58 (br. S., H), 4.34 (d, J = 12.5 Hz)
, 1H), 4.26 (d, J = 12.3 Hz, 1H), 3.76 (
br. s. , 2H), 3.23 (br. S., 1H), 3.07 (br
. s. , 1H), 2.19 (s, 3H), 1.73 (br.s., 1
H), 1.32 (d, J = 11.5 Hz, 2H), 0.96-1.
15 (m, 4H), 0.74-0.88 (m, 4H), 0.67 (b
r. s. , 1H), 0.37-0.60 (m, 3H)
LC-MS: m / z 532.7 (M + H) +

Compound 271
(R) -5- (3-Chloro-4-fluorophenyl) -6-cyclopropyl-2- (4
-(3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) [delta] 7.22-7.30 (m, 2H),
7.08 (ddd, J = 8.2, 4.6, 2.0 Hz, 1H), 4
. 90 (br.s., 0.5H), 4.53 (d, J = 13.6 Hz)
, 0.5H), 4.00-4.29 (m, 2.5H), 3.66-3
. 85 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.
38 (s, 3H), 3.01-3.25 (m, 2.5H), 2.63
-2.84 (m, 1H), 2.48-2.63 (m, 1H), 2.1
8 (s, 3H), 1.51-1.61 (m, 1H), 1.31-1
. 40 (m, 2H), 1.01-1.14 (m, 2H), 0.80-
0.90 (m, 2H)
LC-MS: m / z 471.2 (M + H) +

Compound 568
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (3-hydroxybutanoyl) piperazin-1-yl) -2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ 8.65 (d, J = 4.8 Hz,
1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (
d, J = 4.3 Hz, 1H), 6.88 (dd, J = 17.4,
10.9 Hz, 1H), 6.28 (d, J = 17.3 Hz, 1H),
5.57 (d, J = 10.8 Hz, 1H), 4.49-4.79
(M, 2H), 4.43 (d, J = 12.5 Hz, 1H), 4.17
-4.33 (m, 2H), 3.96-4.17 (m, 1H), 3.
79 (br.s., 1H), 3.71 (d, J = 11.8 Hz, 1
H), 3.02-3.31 (m, 2H), 2.53 (d, J = 9.
8 Hz, 1H), 2.48 (m, 1H), 2.04 (m, 1H), 1
. 32 (br. S., 3H), 0.82-1.12 (m, 3H), 0
. 72 (br. S., 1H), 0.63 (br. S., 1H), 0.5
5 (br.s., 1H), 0.22-0.51 (m, 2H)
LC-MS: m / z 458.2 (M + H) +

Compound 558
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-
5-carbonitrile 1H NMR (chloroform-d) δ 8.59 (d, J = 4.8 Hz,
1H), 7.16 (s, 1H), 7.00 (d, J = 4.8 Hz,
1H), 6.78 (dd, J = 17.3, 10.8 Hz, 1H),
6.19 (d, J = 17.6 Hz, 1H), 5.46 (dd, J =
10.8, 1.0 Hz, 1H), 4.60 (d, J = 10.5 Hz)
, 0.5H), 4.26 (d, J = 12.8 Hz, 1H), 4.17.
(D, J = 12.5 Hz, 1H), 3.96-4.06 (m, 0
. 5H), 3.80 (d, J = 12.3 Hz, 1H), 3.59 −
3.74 (m, 3H), 3.18-3.37 (m, 4H), 3.04
-3.14 (m, 1H), 2.90-3.01 (m, 1H), 2.3
7-2.67 (m, 2H), 2.08-2.18 (m, 3H), 1
. 39-1.56 (m, 1H), 0.98-1.10 (m, 2H),
0.78 (dd, J = 7.9, 3.1 Hz, 2H), 0.51 (b
r. s. , 1H), 0.44 (br. S., 1H), 0.29-0.
40 (m, 2H)
LC-MS: m / z 472.4 (M + H) +

Compound 598
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (6- (prop-1-en-2-yl) pyrimidine- 4-
Yl) nicotinonitrile 1H NMR (chloroform-d) δ 9.22 (s, 1H), 7.98 (
s, 1H), 7.61-7.76 (m, 1H), 6.18 (s, 1H)
), 5.54 (s, 1H), 4.88 (br.s., 1H), 4.51
(D, J = 9.8 Hz, 1H), 4.18-4.47 (m, 3H
), 3.63-3.93 (m, 3H), 3.41-3.63 (m,
1H), 3.36 (s, 4H), 2.97-3.24 (m, 2H),
2.49-2.79 (m, 2H), 2.28-2.47 (m, 1H)
, 2.22 (s, 3H), 1.34 (d, J = 6.3 Hz, 2H)
, 1.14-1.30 (m, 4H), 1.04 (dd, J = 7.9
, 2.9 Hz, 2H)
LC-MS: m / z 447.2 (M + H) +

Compound 478
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-4-methyl-5- (1H-pyrazol-4-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.61 (s, 2H), 4.59 (
s, 1H), 4.33 (d, J = 12.5 Hz, 1H), 4.24.
(D, J = 12.5 Hz, 1H), 3.98-4.15 (m, 1H
), 3.84 (s, 1H), 3.22 (d, J = 15.1 Hz, 1
H), 3.05 (s, 1H), 2.31 (s, 3H), 1.83-1
. 98 (m, 1H), 1.73 (s, 1H), 1.37-1.60 (
m, 1H), 0.98-1.15 (m, 4H), 0.74-0.92.
(M, 4H), 0.34-0.65 (m, 4H).
LC-MS: m / z 416.2 (M + H) +

Compound 463
(R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methylpyridine-3-
Yl) phenyl) -N- (vinylsulfonyl) ethenesulfonamide 1H NMR (chloroform-d) δ 7.47-7.60 (m, 1H),
7.31-7.40 (m, 2H), 7.00-7.14 (m, 2H)
), 6.28 (s, 1H), 6.32 (s, 1H), 6.17 (d,
J = 9.8 Hz, 2H), 4.34 (d, J = 12.8 Hz, 1
H), 4.26 (d, J = 12.5 Hz, 2H), 3.85 (s,
1H), 3.06 (br.s., 2H), 1.85 (br.s., 1H)
), 1.72 (br.s., 1H), 1.58 (td, J = 8.2)
4.1 Hz, 2H), 0.95-1.18 (m, 4H), 0.72
-0.95 (m, 5H), 0.65 (br. S., 1H), 0.32
-0.59 (m, 3H)
LC-MS: m / z 622.2 (M + H) +

Compound 535
(R) -5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (
3,3,3-trifluoropropanoyl) piperazin-1-yl) pyridin-3-yl)
Quinoline-2-carbonitrile 1H NMR (chloroform-d) δ 8.27 (d, J = 8.5 Hz,
1H), 8.11 (dd, J = 11.5, 8.8 Hz, 1H), 7
. 94 (t, J = 7.8 Hz, 1H), 7.53-7.78 (m,
3H), 4.59 (dt, J = 13.1, 2.3 Hz, 1H), 4
. 48 (d, J = 11.8 Hz, 1H), 4.04-4.34 (m
, 1H), 3.81 (br.s., 1H), 3.21-3.51 (m
, 3H), 3.15 (d, J = 11.5 Hz, 2H), 1.68 (
br. s. , 2H), 1.37-1.48 (m, 3H), 1.14-
1.36 (m, 13H), 0.77-1.04 (m, 4H), 0.7
1 (br. S., 1H), 0.60 (br. S., 1H), 0.31
-0.57 (m, 2H)
LC-MS: m / z 513.2 (M + H) +

Compound 563
(R) -5- (5-Cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridin-3-yl) quinoline-2
-Carbonitrile 1H NMR (chloroform-d) δ 8.25 (d, J = 8.8 Hz,
1H), 8.13 (dd, J = 10.3, 9.0 Hz, 1H), 7
. 85-8.04 (m, 1H), 7.56-7.76 (m, 3H),
4.59 (d, J = 12.0 Hz, 1H), 4.47 (d, J =
12.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 1H),
3.72 (br. S., 1H), 3.42 (d, J = 10.0 Hz
, 1H), 3.09-3.36 (m, 2H), 1.66-1.86
(M, 1H), 1.52-1.66 (m, 1H), 1.36-1.5
2 (m, 2H), 1.00-1.30 (m, 8H), 0.75-1
. 00 (m, 6H), 0.71 (d, J = 7.8 Hz, 1H), 0
. 34-0.63 (m, 4H)
LC-MS: m / z 489.2 (M + H) +

Compound 610
(R) -2- (4- (Cyclopropanecarbonyl) -3-methylpiperazin-1-yl) -6-cyclopropyl-5- (1-propioroyl-2,5-dihydro-1H-pyrrol-3-yl ) Nicotinonitrile 1H NMR (chloroform-d) d: 7.53 (d, J = 1.0 Hz)
, 1H), 6.00 (dt, J = 19.1, 2.0 Hz, 1H),
4.61-4.91 (m, 2H), 4.52-4.61 (m, 1H)
, 4.40-4.52 (m, 2H), 4.19-4.40 (m, 2
H), 3.50 (s, 1H), 3.43 (d, J = 6.0 Hz, 1
H), 3.02-3.32 (m, 3H), 2.09-2.31 (m,
2H), 1.75 (br.s., 2H), 1.37-1.48 (m,
1H), 1.11-1.37 (m, 7H), 0.95-1.11 (
m, 2H), 0.66-0.95 (m, 2H).
LC-MS: m / z 430.2 (M + H) +

Compound 450 (R) -N- (3- (5-cyano-6- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropylpyridine-3-
Yl) phenyl) propionamide 1H NMR (chloroform-d) d: 7.70 (d, J = 6.0 Hz)
, 2H), 7.61 (s, 1H), 7.48 (d, J = 8.0 Hz)
, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.13 (d
, J = 7.5 Hz, 1H), 4.50 (d, J = 11.8 Hz,
1H), 4.38 (d, J = 12.3 Hz, 1H), 3.73 (d
, J = 7.0 Hz, 1H), 3.25 (br.s., 1H), 3.
07 (br. S., 1H), 2.38-2.51 (m, 2H),
98-2.22 (m, 1H), 1.73 (br.s., 1H),
21-1.45 (m, 6H), 1.16 (dt, J = 7.8, 3.
6 Hz, 3H), 0.87-1.11 (m, 5H), 0.76-0
. 86 (m, 2H), 0.65 (br. S., 1H), 0.29-0
. 59 (m, 3H).
LC-MS: m / z 484.3 (M + H) +

Compound 834 (General Procedure 2, Step M)
6-cyclopropyl-2-((R) -3-cyclopropyl-4-((1S, 2S) -2
-Ethoxycyclopropanecarbonyl) piperazin-1-yl) -5- (isoquinoline-
5-yl) nicotinonitrile


1H NMR (DEUTERIUM OXIDE) δ 9.35 (s, 1H),
8.54 (dd, J = 5.9, 1.9 Hz, 1H), 8.07 (d,
J = 8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7
. 64-7.68 (m, 2H), 7.44 (dd, J = 12.5,
6.0 Hz, 1H), 4.46-4.59 (m, 2.5H), 4.08
-4.18 (m, 1H), 3.86 (br. S., 0.5H), 3.
53-3.74 (m, 3H), 3.21-3.32 (m, 2H),
1.87-2.06 (m, 2H), 1.49-1.58 (m, 1H)
, 1.33 (d, J = 5.8 Hz, 1H), 1.14-1.28
(M, 7H), 0.81-0.90 (m, 2H), 0.65 (br.
s. , 1H), 0.36-0.59 (m, 3H).
LC-MS: m / z 508.2 (M + H) +

Compound 730 (R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (methyl (2-vinylpyridine-
4-yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ 8.25 (d, J = 5.9 Hz,
1H), 7.58 (s, 1H), 6.71 (dd, J = 17.4,
10.7 Hz, 1H), 6.46 (s, 1H), 6.33 (s, 1H)
, 6.20 (d, J = 17.3 Hz, 1H), 5.45 (d, J
= 11.2 Hz, 1H), 4.69 (d, J = 13.4 Hz, 0.
4H), 4.49 (d, J = 13.0 Hz, 1H), 4.37 (d,
J = 12.7 Hz, 1H), 4.10 (d, J = 8.6 Hz,
0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5
H), 3.42 (s, 1H), 3.31 (s, 3H), 3.22 (m,
1.5H), 3.15-3.00 (m, 1H), 2.69-2.45.
(M, 2H), 1.88 (ddd, J = 12.7, 8.1, 4.7)
Hz, 1H), 1.40-1.31 (m, 1H), 1.12 (s, 2
H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
LC-MS: m / z 473.4 (M + H) +

Compound 835
(R) -4-cyclopropyl-2- (3-cyclopropyl-4- (4-methoxybutanoyl) piperazin-1-yl) -5- (2-vinylpyridin-4-yl) benzonitrile


1H NMR (chloroform-d) 8.64 (d, J = 5.0 Hz, 1
H), 7.46 (s, 1H), 7.34-7.42 (m, 1H), 7
. 21 (dd, J = 5.0, 1.5 Hz, 1H), 6.87 (dd,
J = 17.6, 10.9 Hz, 1H), 6.54 (s, 1H), 6
. 21-6.33 (m, 1H), 5.55 (dd, J = 10.9,
0.9 Hz, 1H), 4.63-4.77 (m, 0.3H), 4.01-4
. 18 (m, 0.7H), 3.80-3.94 (m, 1H), 3.41
-3.82 (m, 4H), 3.35 (s, 3H), 3.18-3.
35 (m, 1H), 2.97-3.05 (m, 1H), 2.79-
2.93 (m, 1H), 2.46 (d, J = 7.3 Hz, 2H),
1.81-1.99 (m, 4H), 0.94-1.07 (m, 2H)
, 0.72-0.83 (m, 2H), 0.36-0.56 (m, 4
H).
LC-MS: m / z 471.2 (M + H) +

Compound 775
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -5-((5-vinylpyridazin-3-yl) amino)
Nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H),
7.76 (s, 1H), 6.58 (dd, J = 17.6, 11.0 H
z, 2H), 6.05 (d, J = 17.6 Hz, 1H), 5.66.
(D, J = 11.0 Hz, 1H), 4.65-4.70 (m, 0.5
H), 4.43-4.46 (m, 1H), 4.33 (d, J = 12.4
Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.8
8 (m, 0.5 H), 3.71-3.74 (m, 3H), 3.39 (s,
3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H), 2
. 65-2.66 (m, 2H), 2.55 -2.47 (m, 1H), 2.
18 (d, J = 10.1 Hz, 1H), 1.30-1.25 (m,
1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0
. 50-0.60 (m, 2H), 0.45-0.47 (m, 2H).
LC-MS: m / z 474.6 (M + H) +

Compound 836
(R) -tert-butyl (5- (5-cyano-2-cyclopropyl-6- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) pyridine-3
-Yl) pyridazin-3-yl) carbamate

(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3 , 2
-Dioxaborolan-2-yl) nicotinonitrile (268 mg, 0.627 mmol)
, Tert-butyl (5-chloropyridazin-3-yl) carbamate (120 mg, 0
. 523 mmol), Pd (dppf) Cl ₂ (20 mg, 0.026 mmol) and CsF (159 mg, 1.045 mmol) in dioxane / H ₂ O (8 mL / 2 mL) were stirred at 100 ° C. for 16 h. The mixture was diluted with EtOAc (50 mL) and filtered. Partition the filtrate between EtOAc (50 mL) and water (30 mL),
The organic layer was washed with water (30 mL), brine, dried over Na ₂ SO ₄ and concentrated to give a crude that was purified by preparative TLC to give 150 mg of product.
1H NMR (chloroform-d) δ: 8.97 (d, J = 2.1 Hz,
1H), 8.33 (d, J = 1.8 Hz, 1H), 8.24 (br
. s. , 1H), 7.70 (s, 1H), 4.62 (d, J = 13
. 2 Hz, 1H), 4.49 (d, J = 12.9 Hz, 1H), 4
. 08 (d, J = 8.8 Hz, 1H), 3.92 (t, J = 4.
5 Hz, 2H), 3.63-3.85 (m, 1H), 3.02-3
. 23 (m, 3H), 2.41-2.67 (m, 2H), 1.91-
2.06 (m, 1H), 1.48-1.63 (m, 9H), 1.15
-1.25 (m, 3H), 1.02-1.13 (m, 2H), 0.
46-0.72 (m, 4H)
LC-MS: m / z 534.3 (M + H) +

Compound 339 (General Procedure 9)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinolin-3-ylamino) nicotinonitrile 1H NMR (MeOD): δ 8.797-8.790 (d, J = 2.8)
Hz, 1H), 8.059-8.037 (d, J = 8.8 Hz, 1H)
), 7.985-7.962 (d, J = 9.2 Hz, 1H), 7.92.
6-7.920 (d, J = 2.4 Hz, 1H), 7.861 (s, 1
H), 7.795-7.710 (m, 2H), 4.797-4.783 (m,
0.5 H), 4.451-4.416 (m, 1H), 4.227-4.112.
(M, 2H), 3.972-3.932 (m, 0.5H), 3.694-3
. 613 (m, 2H), 3.608-3.577 (m, 0.5H), 3.3
34 (s, 3H), 3.284 (m, 0.5H), 3.211-3.137
(M, 1H), 3.045-3.007 (m, 0.5H), 2.852-2
. 704 (m, 1H), 2.700-2578 (m, 1.5H), 2.2
40-2.177 (m, 1H), 1.401-1.384 (d, J = 6.
8 Hz, 1.5H), 1.284-1.267 (d, J = 6.8 Hz,
1.5H), 1.188-1.170 (m, 2H), 0.992-0.965
(M, 2H);
LC-MS: m / z 471.5 (M + H) +

Compound 355 (General Procedure 9)
(R) -6-cyclopropyl-5-((4-fluorophenyl) amino) -2- (4-
(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (MeOD): δ 7.543 (s, 1H), 6.936-6.
893 (t, J = 8.6 Hz, 2H), 6.723-6.690 (q,
J = 4.4 Hz, 2H), 4.798-4.781 (m, 0.5 H)
, 4.443-4.361 (m, 1H), 4.050-3.898 (m, 2
. 5H), 3.675-3.509 (m, 2.5H), 3.336 (s, 3
H), 3.254-2.877 (m, 2.5H), 2.792-2.588 (
m, 2H), 2.260-2.196 (m, 1H), 1.402-1.255.
(M, 3H), 1.115-1.097 (m, 2H), 0.992-0.
968 (m, 2H);
LC-MS: m / z 438.5 (M + H) +

Compound 356 (General Procedure 9)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (quinolin-4-ylamino) nicotinonitrile 1H NMR (MeOD): δ 8.593-8.572 (d, J = 8.4
Hz, 1H), 8.440-8.422 (d, J = 7.2 Hz, 1H
), 8.065-8.026 (m, 1H), 7.983-7.962 (d,
J = 8.4 Hz, 1H), 7.931 (s, 1H), 7.854-7.
813 (m, 2H), 6.552-6.535 (d, J = 6.8 Hz,
1H), 4.792-4.783 (m, 0.5 H), 4.451-4.42.
0 (m, 1H), 4.329-4.207 (m, 2H), 3.982-3.
948 (m, 0.5H), 3.414-3.3338 (m, 4H), 3.25
7-3.068 (m, 1.5H), 2.829-2.610 (m, 2H),
2.091-2.026 (m, 1H), 1.389-1.256 (m, 3H
), 1.199-1.181 (m, 2H), 1.050-0.988 (m,
2H);
LC-MS: m / z 471.5 (M + H) +

Compound 368 (General Procedure 9)
(R) -5- (4-Acetylpiperazin-1-yl) -6-cyclopropyl-2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (MeOD): [delta] 7.558 (s, 1H), 4.763-4.
752 (m, 0.5 H), 4.429-4.346 (m, 1H), 4.0
52-3.883 (m, 3H), 3.747-3.668 (m, 6H), 3
. 328 (s, 3H), 3.182-3.119 (m, 2H), 3.061
-2.886 (m, 4.5H), 2.781-2.677 (m, 1H), 2
. 623-2.562 (m, 2H), 2.142 (s, 3H), 1.375
-1.358 (m, 1.5H), 1.261-1.244 (m, 1.5H),
1.109-1.036 (m, 4H);
LC-MS: m / z 455.5 (M + H) +

Compound 375 (General Procedure 9)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-morpholinonicotinonitrile 1H NMR (MeOD): δ 7.551 (s , 1H), 4.762-4.
748 (m, 0.5 H), 4.428-4.352 (m, 1H), 4.0
39-3.975 (m, 2H), 3.941-3.827 (m, 5H), 3
. 681-3.667 (m, 2H), 3.574-3.501 (m, 1H),
3.327 (s, 3H), 3.173-3.116 (m, 2H),
046-2.911 (m, 1H), 2.940-2.882 (m, 4H),
2.744-2.522 (m, 2.5H), 1.378-1.361 (m, 1
. 5H), 1.264-1.247 (m, 1.5H), 1.097-1.012
(M, 4H);
LC-MS: m / z 414.5 (M + H) +

Compound 376 (General Procedure 9)
(R) -Ethyl 4- (5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) piperazine-1
-Carboxylate 1H NMR (MeOD): [delta] 7.549 (s, 1H), 4.763-4.
747 (m, 0.5 H), 4.426-4.343 (m, 1H), 4.17
1-4.118 (m, 2H), 4.044-3.882 (m, 1.5H),
3.666-3.639 (m, 6H), 3.573-3.501 (m, 1H)
3.327 (s, 3H), 3.176-2.988 (m, 2H), 2
. 911-2.886 (m, 4.5H), 2.781-2.546 (m, 3H
), 1.374-1.358 (m, 1.5H), 1.289-1.253 (m
, 4.5H), 1.101-1.026 (m, 4H);
LC-MS: m / z 485.6 (M + H) +

Compound 377 (General Procedure 9)
(R) -6-cyclopropyl-5- (4- (ethylsulfonyl) piperazin-1-yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (MeOD): δ 7.587 (s, 1H), 4.765-4.
749 (m, 0.5 H), 4.426-4.348 (m, 1H), 4.05
5-3.882 (m, 1.5H), 3.669-3.457 (m, 7H),
3.329 (s, 3H), 3.152-3.066 (m, 4H), 3.00
4-2.888 (m, 4.5H), 2.742-2538 (m, 3H),
1.373-1.335 (m, 4.5H), 1.261-1.245 (m, 1
. 5H), 1.094-1.036 (m, 4H);
LC-MS: m / z 505.6 (M + H) +

Compound 378 (General Procedure 9)
(R) -6-cyclopropyl-5- (4- (cyclopropylmethyl) piperazine-1-
Yl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl)
Nicotinonitrile 1H NMR (MeOD): δ 7.598 (s, 1H), 4.768-4.
752 (m, 0.5 H), 4.431-4.355 (m, 1H), 4.0
68-3.892 (m, 2.5H), 3.688-3.660 (m, 2H),
3.572-3.507 (m, 1H), 3.333 (s, 3H), 3.1
01-2.930 (m, 9H), 2.903-2.871 (m, 1H), 2
. 787-2.586 (m, 4H), 2.544-2.493 (m, 1H),
1.378-1.362 (m, 1.5H), 1.264-1.248 (m,
1.5H), 1.124-1.044 (m, 5H), 0.698-0.652
(M, 2H), 0.357-0.268 (m, 2H);
LC-MS: m / z 467.6 (M + H) +

Compound 379 (General Procedure 9)
(R) -5- (4-Benzoylpiperazin-1-yl) -6-cyclopropyl-2- (
4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (MeOD): δ 7.588 (s, 1H), 7.492-7.
451 (m, 5H), 4.780-4.768 (m, 0.5 H), 4.4
30-4.346 (m, 1H), 4.053-3.881 (m, 4.5H),
3.667-3.630 (m, 2.5H), 3.536-3.477 (m, 2
H), 3.326 (m, 4H), 3.180-3.085 (m, 1.5H)
, 3.023-2.923 (m, 5H), 2.756-2.709 (m, 1
H), 2.619-2.567 (m, 2H), 1.373-1.357 (m,
1.5H), 1.259-1.243 (m, 1.5H), 1.113-1.0
33 (m, 4H);
LC-MS: m / z 517.6 (M + H) +

Compound 265 (General Procedure 6)
(R) -6-cyclopropyl-5- (3-fluorophenyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR ( Chloroform-d) δ 7.41-7.51 (m, 1H)
, 7.12 (td, J = 8.5, 2.5 Hz, 1H), 7.01 (
d, J = 7.5 Hz, 1H), 6.95 (d, J = 9.0 Hz,
1H), 4.92 (br.s., 0.5H), 4.55 (d, J =
12.8 Hz, 0.5H), 4.02-4.22 (m, 2.5H), 3
. 70-3.92 (m, 2.5H), 3.53-3.67 (m, 0.
5H), 3.40 (s, 3H), 2.92-3.31 (m, 2.5H)
, 2.61-2.84 (m, 21H), 2.16-2.25 (m, 3
H), 1.57-1.65 (m, 1H), 1.43 (d, J = 6.
5 Hz, 1.5H), 1.33 (d, J = 6.8 Hz, 1.5H),
1.08 (t, J = 4.6 Hz, 2H), 0.79-0.90 (
m, 2H)
LC-MS: m / z 437.4 (M + H) +

Compound 264 (General Procedure 6)
6-Cyclopropyl-5- (2,4-difluorophenyl) -2-((R) -4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) [delta] 7.15-7.25 (m, 1H)
, 6.94-7.06 (m, 2H), 4.92 (br. S., 0.5
H), 4.55 (d, J = 13.3 Hz, 0.5H), 4.05 −
4.34 (m, 2.5H), 3.70-3.85 (m, 2.5H), 3
. 52-3.67 (m, 0.5H), 3.40 (s, 3H), 2.93
-3.31 (m, 2.5H), 2.73 (td, J = 15.3, 7
. 3 Hz, 1H), 2.54-2.64 (m, 1H), 2.21 (s
3H), 1.54-1.61 (m, 1H), 1.39-1.45.
(M, 1.5H), 1.32 (t, J = 5.8 Hz, 1.5H), 1
. 01-1.18 (m, 2H), 0.83-0.93 (m, 2H)
LC-MS: m / z 455.4 (M + H) +

Compound 263 (General Procedure 6)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (4- (trifluoromethoxy) phenyl)
Nicotinonitrile 1H NMR (chloroform-d) δ 7.31-7.36 (m, J =
8.0 Hz, 2H), 7.23-7.28 (m, J = 8.3 Hz)
, 2H), 4.92 (br. S., 0.5H), 4.55 (d, J =
13.8 Hz, 0.5H), 4.00-4.22 (m, 2.5H),
3.68-3.87 (m, 2.5H), 3.53-3.67 (m, 0
. 5H), 3.36-3.44 (m, 3H), 3.12-3.31 (
m, 1.5H), 2.94-3.12 (m, 1H), 2.64-2.
83 (m, 1H), 2.61 (br. S., 1H), 2.16-2.
22 (m, 3H), 1.52-1.63 (m, 1H), 1.39-
1.47 (m, 1.5H), 1.32 (d, J = 6.3 Hz, 1.5
H), 1.03-1.15 (m, 2H), 0.78-0.90 (m,
2H)
LC-MS: m / z 503.3 (M + H) +

Compound 272 (General Procedure 8)
(R) -Benzyl 2- (5-cyano-2-isopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) ethylcarbamate 1H NMR (chloroform -D) δ 7.32-7.40 (m, 5H)
7.18 (s, 1H), 4.90 (br.s., 0.5H), 4.5
3 (d, J = 12.5 Hz, 0.5H), 4.21 (br. S.,
0.5H), 4.06 (d, J = 14.1 Hz, 1H), 3.95 −
4.01 (m, 2.5H), 3.68-3.79 (m, 3H), 3.
53-3.67 (m, 2.5H), 3.30-3.44 (m, 5H)
, 3.07-3.25 (m, 2H), 2.89-3.07 (m, 1
H), 2.51-2.79 (m, 2.5H), 1.40 (d, J =
6.5 Hz, 1.5H), 1.30 (d, J = 6.8 Hz, 1.5H)
), 1.11-1.20 (m, 7H)
LC-MS: m / z 524.3 (M + H) +

Compound 270 (General Procedure 6)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (thiophen-3-yl) nicotinonitrile 1H NMR (Chloroform-d) δ 7.47 (dd, J = 5.0,
3.0 Hz, 1H), 7.17 (dd, J = 2.8, 1.3 Hz,
1H), 7.00 (dd, J = 5.0, 1.3 Hz, 1H), 4.9
1 (br. S., 0.5H), 4.55 (d, J = 10.8 Hz,
0.5H), 3.98-4.28 (m, 2.5H), 3.75 (q, J
= 6.0 Hz, 2.5H), 3.50-3.67 (m, 0.5H),
3.36-3.46 (m, 3H), 3.10-3.30 (m, 1.
5H), 2.89-3.10 (m, 1H), 2.65-2.81 (m
, 2H), 2.25 (s, 3H), 1.71-1.79 (m, 1H)
, 1.42 (d, J = 6.5 Hz, 1.5H), 1.32 (d, J
= 6.8 Hz, 1.5H), 1.05-1.12 (m, 2H), 0
. 81-0.90 (m, 2H)
LC-MS: m / z 425.3 (M + H) +

Compound 269 (General Procedure 6)
(R) -5- (Benzo [d] [1,3] dioxol-5-yl) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4
-Methylnicotinonitrile 1H NMR (chloroform-d) δ 6.91 (d, J = 8.0 Hz)
, 1H), 6.60-6.74 (m, 2H), 6.01-6.11
(M, 2H), 4.92 (br. S., 0.5H), 4.55 (d, J
= 13.6 Hz, 0.5H), 4.24 (br.s., 0.5H),
4.02-4.20 (m, 2H), 3.70-3.85 (m, 2.5
H), 3.59 (t, J = 11.7 Hz, 0.5H), 3.39 (s
, 3H), 3.19 (t, J = 13.7 Hz, 1.5H), 2.92.
-3.08 (m, 1H), 2.65-2.83 (m, 1H), 2.
55-2.64 (m, 1H), 2.19-2.27 (m, 3H),
1.67-1.76 (m, 1H), 1.42 (d, J = 6.5 Hz)
, 1.5H), 1.31-1.38 (m, 1.5H), 1.06 (t,
J = 5.3 Hz, 2H), 0.79-0.91 (m, 2H)
LC-MS: m / z 463.3 (M + H) +

Compound 268 (General Procedure 6)
(R) -2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-3,4'-bipyridine-5-carbonitrile 1H NMR ( Chloroform-d) δ 8.87 (br.s., 2H),
7.86 (br.s., 2H), 4.90-5.00 (m, 0.5H)
, 4.57 (br. S., 0.5H), 4.33 (d, J = 12.5
Hz, 2.5H), 3.71-3.82 (m, 2.5H), 3.58
(Br.s., 0.5H), 3.40 (s, 3H), 3.09-3.2
8 (m, 2.5H), 2.68 (br. S., 1H), 2.61 (br
. s. , 1H), 2.23-2.28 (m, 3H), 1.62-1
. 66 (m, 1H), 1.32-1.38 (m, 3H), 1.20 (
br. s. , 2H), 0.98 (br.s., 2H)
LC-MS: m / z 420.5 (M + H) +

Compound 267 (General Procedure 6)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methyl-5- (naphthalen-2-yl) nicotinonitrile 1H NMR (Chloroform-d) δ 7.84-8.00 (m, 3H),
7.71 (s, 1H), 7.53-7.60 (m, 2H), 7.34
(Dd, J = 8.4, 1.4 Hz, 1H), 4.94 (br. S.
, 0.5H), 4.57 (d, J = 13.3 Hz, 0.5H), 4.
06-4.34 (m, 2.5H), 3.71-3.85 (m, 2.5
H), 3.52-3.69 (m, 0.5H), 3.37-3.45 (
m, 3H), 3.14-3.30 (m, 1.5H), 2.94-3.
12 (m, 1H), 2.67-2.85 (m, 1H), 2.54-
2.66 (m, 1H), 2.19-2.28 (m, 3H), 1.62
-1.70 (m, 1H), 1.45 (d, J = 5.8 Hz, 1.5
H), 1.35 (d, J = 5.5 Hz, 1.5H), 1.03-1
. 16 (m, 2H), 0.74-0.84 (m, 2H)
LC-MS: m / z 469.4 (M + H) +

Compound 559 (General Procedure 9)
(R) -6-cyclopropyl-5- (4- (ethylsulfonyl) piperazin-1-yl) -2- (3-methyl-4- (3,3,3-trifluoropropanoyl) piperazine-1
-Yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.38 (s, 1H), 4.29
(D, J = 12.8 Hz, 1H), 4.18 (d, J = 12.5)
Hz, 1H), 4.09 (d, J = 7.5 Hz, 0.5H), 3.7
0-3.81 (m, 1.5H), 3.46-3.55 (m, 4.5H
), 3.30 (q, J = 9.8 Hz, 2H), 2.92-3.14
(M, 8.5H), 2.38-2.53 (m, 1H), 1.38-
1.49 (m, 3H), 1.29-1.36 (m, 1H), 1.02
-1.17 (m, 4H), 0.42-0.67 (m, 4H)
LC-MS: m / z 555.2 (M + H) +

Compound 529 (General Procedure 9)
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (4- (ethylsulfonyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.37 (s, 1H), 3.42
-4.57 (m, 9H), 2.90-3.22 (m, 8H), 2.4
0-2.52 (m, 1H), 1.73 (br.s., 1H), 1.3
9-1.50 (m, 4H), 1.10-1.17 (m, 2H), 0
. 95-1.09 (m, 4H), 0.76-0.85 (m, 2H),
0.35-0.58 (m, 4H)
LC-MS: m / z 513.2 (M + H) +

Compound 528 (General Procedure 9)
(R) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5- (quinolin-4-ylamino) nicotinonitrile 1H NMR (chloroform-d) δ 8.55 (d, J = 5.5 Hz)
, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.10 (d
, J = 8.3 Hz, 1H), 7.67-7.78 (m, 2H),
7.51-7.63 (m, 1H), 6.32 (d, J = 5.3 Hz)
, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.38 (
d, J = 12.3 Hz, 1H), 3.12-4.18 (m, 5H)
, 2.05-2.13 (m, 1H), 1.03-1.22 (m, 5
H), 0.95-1.01 (m, 3H), 0.83 (dd, J = 7
. 9, 2.4 Hz, 2H), 0.39-0.62 (m, 4H)
LC-MS: m / z 479.3 (M + H) +

Compound 722 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3-hydroxypropanoyl) piperazin-1-yl) -5-((2-vinyl-1,7-naphthyridine-4-
Yl) amino) nicotinonitrile 1H NMR (chloroform-d) δ 9.48 (s, 1H), 8.58 (
d, J = 5.9 Hz, 1H), 7.87 (br.s., 1H), 7
. 74 (s, 1H), 6.91 (dd, J = 17.6, 10.9 Hz
, 1H), 6.57 (s, 1H), 6.27 (d, J = 17.6 H
z, 1H), 5.69 (d, J = 10.9 Hz, 1H), 4.52
(D, J = 12.9 Hz, 1H), 4.40 (d, J = 12.3)
Hz, 1H), 4.11 (d, J = 7.9 Hz, 1H), 3.94
(Br.s., 2H), 3.64-3.88 (m, 1H), 3.33
(Br. S., 1H), 3.24 (d, J = 13.5 Hz, 1H),
3.03-3.19 (m, 1H), 2.48-2.69 (m, 2H
), 1.98-2.09 (m, 1H), 1.37 (d, J = 16.
1 Hz, 1H), 1.10-1.22 (m, 2H), 0.95-1
. 08 (m, 2H), 0.66 (br. S., 1H), 0.57 (br
. s. , 1H), 0.49 (br.s., 2H)
LC-MS: m / z 430.2 (M + H) +

Compound 819 (General Procedure 6)
(R) -6- (4- (2-cyclobutylacetyl) -3-cyclopropylpiperazine-
1-yl) -2-cyclopropyl-4-methyl-2'-vinyl-3,4'-bipyridine-
5-carbonitrile 1H NMR (chloroform-d) δ 8.69 (d, J = 4.7 Hz)
, 1H), 7.23 (br. S., 1H), 7.07 (d, J = 4
. 4 Hz, 1H), 6.87 (dd, J = 17.3, 10.9 Hz,
1H), 6.29 (d, J = 17.3 Hz, 1H), 5.57 (d
, J = 11.7 Hz, 1H), 4.34 (d, J = 12.9 Hz)
, 1H), 4.25 (d, J = 12.0 Hz, 1H), 4.09 (
br. s. , 1H), 3.80 (br.s., 1H), 3.13 (br
. s. , 2H), 3.02 (br. S., 1H), 2.73 (dt,
J = 15.6, 7.8 Hz, 1H), 2.51 (br.s., 2H)
, 2.21 (s, 3H), 2.10-2.20 (m, 2H), 1.6
7-1.97 (m, 5H), 1.50-1.66 (m, 1H), 1
. 43 (d, J = 15.8 Hz, 1H), 1.11 (br. S.,
2H), 0.83-0.93 (m, 2H), 0.61 (br. S.,
1H), 0.52 (br. S., 1H), 0.31-0.48 (m,
2H)
LC-MS: m / z 482.6 (M + H) +

Compound 820 (General Procedure 6)
(R) -6- (4- (2-Cyclobutylideneacetyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methyl-2'-vinyl-3,4'-bipyridine- 5-carbonitrile 1H NMR (chloroform-d) δ 8.70 (d, J = 5.0 Hz)
, 1H), 7.25 (s, 1H), 7.09 (d, J = 3.8 Hz
, 1H), 6.89 (dd, J = 17.6, 10.9 Hz, 1H),
6.31 (d, J = 17.3 Hz, 1H), 5.92 (br. S.
, 1H), 5.59 (d, J = 11.2 Hz, 1H), 4.35 (
d, J = 12.9 Hz, 1H), 4.27 (d, J = 12.6 H
z, 1H), 3.91-4.19 (m, 1H), 3.78 (br. s)
. , 1H), 3.10-3.31 (m, 3H), 3.04 (td, J
= 12.4, 3.4 Hz, 1H), 2.84 (t, J = 8.4 H
z, 2H), 2.43-2.55 (m, 1H), 2.22 (s, 3H)
), 1.98-2.17 (m, 2H), 1.53-1.63 (m,
1H), 1.45 (br.s., 1H), 1.04-1.18 (m,
2H), 0.82-0.96 (m, 2H), 0.64 (br. S.,
1H), 0.50 (br. S., 1H), 0.31-0.48 (m,
2H)
LC-MS: m / z 480.6 (M + H) +

Compound 266 (General Procedure 6)
(R) -6-cyclopropyl-5- (3-fluoro-4-methylphenyl) -2- (4
-(3-Methoxypropanoyl) -3-methylpiperazin-1-yl) -4-methylnicotinonitrile 1H NMR (chloroform-d) [delta] 7.25-7.31 (m, 1H)
6.85-6.92 (m, 2H), 4.91 (br. S., 0.5
H), 4.54 (d, J = 13.3 Hz, 0.5H), 4.00 −
4.23 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3
. 51-3.63 (m, 0.5H), 3.39 (s, 3H), 3.10
-3.27 (m, 1.5H), 2.94-3.09 (m, 1H),
2.64-2.82 (m, 1H), 2.55-2.64 (m, 1H)
, 2.32-2.39 (m, 3H), 2.20 (s, 3H), 1.6
0-1.70 (m, 1H), 1.39-1.47 (m, 1.5H),
1.30-1.35 (m, 1.5H), 1.07 (t, J = 4.6)
Hz, 2H), 0.83 (dt, J = 7.5, 3.5 Hz, 2H)
LC-MS: m / z 451.4 (M + H) +

Compound 277 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (1-phenylethoxy) nicotinonitrile 1H NMR (chloroform-d) δ 7.28-7.42 (m, 5H)
6.97 (d, J = 3.3 Hz, 1H), 5.15 (q, J =
6.3 Hz, 1H), 4.85 (br. S., 0.5H), 4.48 (
d, J = 13.1 Hz, 0.5H), 4.15 (br.s., 0.5
H), 3.76-3.94 (m, 2H), 3.64-3.76 (m,
2.5H), 3.41-3.57 (m, 0.5H), 3.36 (s,
3H), 2.96-3.13 (m, 1.5H), 2.77-2.96.
(M, 1H), 2.61-2.77 (m, 1H), 2.48-2.6
1 (m, 2H), 1.67 (d, J = 6.3 Hz, 3H), 1.2
6 (d, J = 5.3 Hz, 3H), 0.97-1.15 (m, 4
H)
LC-MS: m / z 449.2 (M + H) +

Compound 279 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (pyridin-2-ylmethoxy) nicotinonitrile 1H NMR (chloroform-d ) Δ 8.64 (d, J = 4.5 H)
z, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.51 −
7.62 (m, 1H), 7.29-7.39 (m, 1H), 7.23
(S, 1H), 5.22 (s, 2H), 4.88 (br. S., 0.
5H), 4.51 (d, J = 12.8 Hz, 0.5H), 4.18 (
br. s. , 0.5H), 3.82-4.03 (m, 2H), 3.63
-3.81 (m, 2.5H), 3.44-3.61 (m, 0.5H)
3.37 (s, 3H), 3.09 (t, J = 13.2 Hz,
5H), 2.82-3.01 (m, 1H), 2.62-2.79 (m
, 1H), 2.45-2.61 (m, 2H), 1.26 (d, J =
5.3 Hz, 3H), 0.99-1.16 (m, 4H)
LC-MS: m / z 436.2 (M + H) +

Compound 280 (General Procedure 8)
(R) -6-Cyclopropyl-5- (3-methoxybenzyloxy) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) [delta] 7.32 (t, J = 7.9 Hz)
, 1H), 7.18 (s, 1H), 6.93-7.05 (m, 2H)
, 6.89 (dd, J = 8.0, 2.3 Hz, 1H), 5.02 (
s, 2H), 4.87 (br. s., 0.5H), 4.51 (d, J
= 13.3 Hz, 0.5H), 4.18 (br.s., 0.5H), 3
. 92 (t, J = 12.7 Hz, 2H), 3.83 (s, 3H),
3.73 (t, J = 6.1 Hz, 2.5H), 3.53 (d, J =
8.0 Hz, 0.5H), 3.37 (s, 3H), 3.01-3.1
8 (m, 1.5H), 2.81-3.00 (m, 1H), 2.62-
2.78 (m, 1H), 2.45-2.62 (m, 2H), 1.27
-1.44 (m, 3H), 0.97-1.15 (m, 4H)
LC-MS: m / z 465.2 (M + H) +

Compound 281 (General Procedure 8)
(R) -6-Cyclopropyl-5- (4-methoxybenzyloxy) -2- (4- (3
-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.28-7.39 (m, J =
8.8 Hz, 2H), 7.20 (s, 1H), 6.88-6.97.
(M, J = 8.8 Hz, 2H), 4.96 (s, 2H), 4.88
(D, J = 7.8 Hz, 0.5H), 4.51 (d, J = 13.3
Hz, 0.5H), 4.18 (br. S., 1H), 3.92 (t,
J = 12.5 Hz, 2H), 3.83 (s, 3H), 3.67-3
. 78 (m, 2.5H), 3.46-3.60 (m, 0.5H), 3.
37 (s, 3H), 3.00-3.16 (m, 1.5H), 2.80
-2.99 (m, 1H), 2.61-2.80 (m, 1H), 2.4
2−2.61 (m, 2H), 1.39 (d, J = 6.5 Hz, 1
. 5H), 1.29 (d, J = 6.8 Hz, 1.5H), 0.92 −
1.14 (m, 4H)
LC-MS: m / z 465.2 (M + H) +

Compound 292 (General Procedure 8)
(R) -Methyl 3-((5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) methyl) benzoate 1H NMR (chloroform-d) δ 8.11 (s, 1H), 8.04
(D, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz
, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.19 (s
, 1H), 5.07 (s, 2H), 4.88 (br.s., 0.5H)
, 4.51 (d, J = 13.6 Hz, 0.5H), 4.18 (br.
s. , 0.5H), 3.94 (s, 3H), 3.83-4.02 (m
, 2H), 3.64-3.80 (m, 2.5H), 3.52 (br.
s. , 0.5H), 3.37 (s, 3H), 3.09 (t, J = 13
. 6 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62
-2.80 (m, 1H), 2.41-2.62 (m, 2H), 1.3
9 (d, J = 6.5 Hz, 1.5H), 1.29 (d, J = 6.
8 Hz, 1.5H), 0.98-1.15 (m, 4H)
LC-MS: m / z 493.2 (M + H) +

Compound 293 (General Procedure 8)
(R) -Methyl 4-((5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) methyl) benzoate 1H NMR (chloroform-d) δ 8.01-8.14 (m, 2H)
, 7.44-7.56 (m, J = 8.5 Hz, 2H), 7.18
(S, 1H), 5.10 (s, 2H), 4.88 (br. S., 0.5
H), 4.51 (d, J = 13.6 Hz, 0.5H), 4.19 (b
r. s. , 0.5H), 3.93 (s, 3H), 3.82-4.02
(M, 2H), 3.66-3.81 (m, 2.5H), 3.46-3
. 60 (m, 0.5H), 3.37 (s, 3H), 3.10 (t, J
= 13.7 Hz, 1.5H), 2.82-3.01 (m, 1H), 2
. 62-2.79 (m, 1H), 2.43-2.62 (m, 2H),
1.39 (d, J = 6.5 Hz, 1.5H), 1.27-1.34
(M, 1.5H), 0.96-1.17 (m, 4H)
LC-MS: m / z 493.2 (M + H) +

Compound 294 (General Procedure 8)
(R) -5- (3-Cyanobenzyloxy) -6-cyclopropyl-2- (4- (3-
Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.75 (s, 1H), 7.61
-7.71 (m, 2H), 7.54 (t, J = 7.9 Hz, 1H)
7.17 (s, 1H), 5.06 (s, 2H), 4.88 (br.
s. , 0.5H), 4.52 (d, J = 13.6 Hz, 0.5H),
4.21 (br. S., 0.5H), 3.85-4.06 (m, 2H)
, 3.74 (br. S., 2.5H), 3.54 (br. S., 0.5
H), 3.37 (s, 3H), 3.04-3.21 (m, 1.5H),
2.84-3.04 (m, 1H), 2.55-2.81 (m, 2H),
2.40-2.51 (m, 1H), 1.39 (d, J = 5.5 Hz
, 1.5H), 1.30 (d, J = 6.3 Hz, 1.5H), 0.9
8-1.16 (m, 4H)
LC-MS: m / z 460.2 (M + H) +

Compound 301 (General Procedure 8)
(R) -6-cyclopropyl-5- (4- (hydroxymethyl) benzyloxy) -2
-(4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.35-7.49 (m, 4H)
, 7.18 (s, 1H), 5.04 (s, 2H), 4.81-4.9
1 (m, 0.5H), 4.73 (s, 2H), 4.50 (d, J =
13.3 Hz, 0.5H), 4.18 (br.s., 0.5H), 3.8
1-4.00 (m, 2H), 3.64-3.81 (m, 2.5H),
3.45-3.60 (m, 0.5H), 3.37 (s, 3H),
00-3.17 (m, 1.5H), 2.81-2.99 (m, 1H)
, 2.61-2.79 (m, 1H), 2.43-2.61 (m, 2
H), 1.92-2.08 (m, 1H), 1.31-1.41 (m,
3H), 0.97-1.14 (m, 4H)
LC-MS: m / z 465.2 (M + H) +

Compound 302 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (2-methyl-1-phenylpropoxy) nicotinonitrile 1H NMR ( Chloroform-d) δ 7.27-7.39 (m, 5H),
6.87 (d, J = 1.5 Hz, 1H), 4.84 (br. S.,
0.5H), 4.66-4.74 (m, 1H), 4.47 (d, J
= 13.3 Hz, 0.5H), 4.14 (br.s., 0.5H), 3
. 63-3.90 (m, 4.5H), 3.40-3.57 (m, 0.
5H), 3.35 (s, 3H), 2.93-3.12 (m, 1.5H)
, 2.76-2.93 (m, 1H), 2.47-2.75 (m, 3
H), 2.18 (dq, J = 13.3, 6.6 Hz, 1H), 1.1
9-1.39 (m, 3H), 1.00-1.11 (m, 7H), 0
. 87-0.97 (m, 3H)
LC-MS: m / z 477.2 (M + H) +

Compound 303 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((S) -1-phenylethoxy) nicotinonitrile 1H NMR ( Chloroform-d) δ 7.27-7.42 (m, 5H),
6.91-7.00 (m, 1H), 5.15 (q, J = 6.5 H
z, 1H), 4.85 (br. s., 0.5H), 4.48 (d, J
= 13.6 Hz, 0.5H), 4.15 (br.s., 0.5H), 3
. 78-3.95 (m, 2H), 3.61-3.77 (m, 2.5H)
), 3.43-3.57 (m, 0.5H), 3.36 (s, 3H),
2.96-3.13 (m, 1.5H), 2.85 (td, J = 12.
4, 2.8 Hz, 1H), 2.48-2.76 (m, 3H), 1.6
7 (d, J = 6.5 Hz, 3H), 1.36 (d, J = 6.5
Hz, 1.5H), 1.21-1.28 (m, 1.5H), 0.97-
1.13 (m, 4H)
LC-MS: m / z 449.2 (M + H) +

Compound 304 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (pyridin-3-ylmethoxy) nicotinonitrile 1H NMR (chloroform-d ) Δ 8.70 (s, 1H), 8.63
(D, J = 3.8 Hz, 1H), 7.79 (dt, J = 7.8,
1.9 Hz, 1H), 7.37 (dd, J = 7.8, 4.8 Hz,
1H), 7.24 (s, 1H), 5.06 (s, 2H), 4.88 (b
r. s. , 0.5H), 4.51 (d, J = 12.5 Hz, 0.5H
), 4.20 (br. S., 0.5H), 3.83-4.04 (m,
2H), 3.63-3.83 (m, 2.5H), 3.53 (br. S.
, 0.5H), 3.37 (s, 3H), 3.03-3.17 (m, 1
. 5H), 2.84-3.02 (m, 1H), 2.62-2.78 (
m, 1H), 2.51-2.62 (m, 1H), 2.39-2.51
(M, 1H), 1.36-1.43 (m, 2H), 1.27-1.
34 (m, 2H), 0.91-1.15 (m, 4H)
LC-MS: m / z 436.2 (M + H) +

Compound 307 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((R) -1-phenylethoxy) nicotinonitrile 1H NMR ( Chloroform-d) δ 7.27-7.42 (m, 5H),
6.92-6.98 (m, 1H), 5.15 (q, J = 6.4 H
z, 1H), 4.84 (br. s., 0.5H), 4.49 (d, J
= 13.6 Hz, 0.5H), 4.15 (br.s., 0.5H), 3
. 77-3.95 (m, 2H), 3.72 (t, J = 6.3 Hz,
2.5H), 3.43-3.56 (m, 0.5H), 3.36 (s,
3H), 2.97-3.13 (m, 1.5H), 2.78-2.95.
(M, 1H), 2.48-2.78 (m, 3H), 1.67 (d, J
= 6.3 Hz, 3H), 1.36 (d, J = 6.8 Hz, 1.5
H), 1.26 (d, J = 5.5 Hz, 1.5H), 0.97-1
. 14 (m, 4H)
LC-MS: m / z 449.2 (M + H) +

Compound 308 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (1-phenylpropoxy) nicotinonitrile 1H NMR (chloroform-d) δ 7.28-7.42 (m, 5H),
6.92 (d, J = 2.3 Hz, 1H), 4.78-4.95 (
m, 1.5H), 4.48 (d, J = 13.3 Hz, 0.5H), 4
. 14 (br. S., 0.5H), 3.77-3.93 (m, 2H),
3.65-3.77 (m, 2.5H), 3.48 (br. S., 0.
5H), 3.36 (s, 3H), 2.95-3.12 (m, 1.5H)
, 2.76-2.95 (m, 1H), 2.46-2.76 (m, 3
H), 2.00-2.13 (m, 1H), 1.84-1.98 (m,
1H), 1.36 (d, J = 6.8 Hz, 1.5H), 1.25 −
1.29 (m, 1.5H), 0.92-1.12 (m, 7H)
LC-MS: m / z 463.2 (M + H) +

Compound 309 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (pyridin-4-ylmethoxy) nicotinonitrile 1H NMR (chloroform-d ) Δ 8.67 (d, J = 5.8 Hz,
2H), 7.39 (d, J = 5.8 Hz, 2H), 7.17 (s,
1H), 5.07 (s, 2H), 4.79-4.95 (m, 0.5H)
), 4.51 (d, J = 13.6 Hz, 0.5H), 4.19 (br
. s. , 0.5H), 3.86-4.04 (m, 2H), 3.62-
3.81 (m, 2.5H), 3.45-3.59 (m, 0.5H),
3.37 (s, 3H), 3.03-3.18 (m, 1.5H), 2.8
3-3.02 (m, 1H), 2.62-2.79 (m, 1H), 2
. 43-2.61 (m, 2H), 1.39 (d, J = 6.8 Hz,
1.5H), 1.27-1.31 (m, 1.5H), 0.99-1.
15 (m, 4H)
LC-MS: m / z 436.2 (M + H) +

Compound 310 (General Procedure 8)
5- (1- (3-Chlorophenyl) ethoxy) -6-cyclopropyl-2-((R)-
4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.33-7.38 (m, 1H),
7.27-7.33 (m, 3H), 7.19-7.25 (m, 1H
), 6.96 (d, J = 4.5 Hz, 1H), 5.11 (q, J
= 6.3 Hz, 1H), 4.85 (br. S., 0.5H), 4.49.
(D, J = 13.6 Hz, 0.5H), 4.16 (br.s., 0
. 5H), 3.78-3.97 (m, 2H), 3.63-3.78 (
m, 2.5H), 3.49 (br. s., 0.5H), 3.36 (s,
3H), 2.98-3.14 (m, 1.5H), 2.79-2.97.
(M, 1H), 2.60-2.77 (m, 1H), 2.46-2.6
0 (m, 2H), 1.65 (d, J = 6.3 Hz, 3H), 1.3
6 (d, J = 6.5 Hz, 1.5H), 1.26 (d, J = 7.
8 Hz, 1.5H), 0.98-1.15 (m, 4H)
LC-MS: m / z 483.2 (M + H) +

Compound 311 (General Procedure 8)
5- (1- (4-Chlorophenyl) ethoxy) -6-cyclopropyl-2-((R)-
4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.23-7.40 (m, 4H)
6.95 (d, J = 3.8 Hz, 1H), 5.13 (q, J =
6.1 Hz, 1H), 4.85 (br.s., 0.5H), 4.49.
(D, J = 13.1 Hz, 0.5H), 4.16 (br. S., 0.
5H), 3.79-3.98 (m, 2H), 3.63-3.78 (m
, 2.5H), 3.42-3.57 (m, 0.5H), 3.36 (s,
3H), 2.98-3.13 (m, 1.5H), 2.77-2.97.
(M, 1H), 2.60-2.76 (m, 1H), 2.43-2.
60 (m, 2H), 1.65 (d, J = 6.3 Hz, 3H),
33-1.39 (m, 1.5H), 1.22-1.29 (m, 1.5
H), 0.97-1.13 (m, 4H)
LC-MS: m / z 483.2 (M + H) +

Compound 312 (General Procedure 8)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (3-nitrobenzyloxy) nicotinonitrile 1H NMR (chloroform-d ) Δ 8.33 (s, 1H), 8.24
(Dd, J = 8.2, 1.2 Hz, 1H), 7.72-7.84 (
m, 1H), 7.54-7.67 (m, 1H), 7.21 (s, 1H)
), 5.13 (s, 2H), 4.88 (br. S., 0.5H), 4.
51 (d, J = 13.7 Hz, 0.5H), 4.19 (br. S.,
0.5H), 3.86-4.03 (m, 2H), 3.63-3.84
(M, 2.5H), 3.53 (br. S., 0.5H), 3.37 (s
, 3H), 3.04-3.18 (m, 1.5H), 2.84-3.0
4 (m, 1H), 2.62-2.78 (m, 1H), 2.42-2
. 61 (m, 2H), 1.39 (d, J = 6.7 Hz, 1.5H),
1.29 (d, J = 6.7 Hz, 1.5H), 0.97-1.19
(M, 4H)
LC-MS: m / z 480.2 (M + H) +

Compound 341 (General Procedure 8)
(R) -5- (3-Aminobenzyloxy) -6-cyclopropyl-2- (4- (3-
Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ 7.13-7.24 (m, 2H)
, 6.79 (d, J = 7.8 Hz, 1H), 6.74 (s, 1H)
, 6.67 (dd, J = 8.0, 1.5 Hz, 1H), 4.95 (
s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J
= 13.6 Hz, 0.5H), 4.17 (br. S., 0.5H), 3
. 81-3.98 (m, 2H), 3.73 (t, J = 6.1 Hz,
2.5H), 3.53 (d, J = 8.8 Hz, 0.5H), 3.37
(S, 3H), 3.01-3.16 (m, 1.5H), 2.81-
3.00 (m, 1H), 2.61-2.79 (m, 1H), 2.46
-2.61 (m, 2H), 1.39 (d, J = 6.5 Hz, 1.5
H), 1.29 (d, J = 6.5 Hz, 1.5H), 0.95 −1
. 14 (m, 4H)
LC-MS: m / z 450.2 (M + H) +

Compound 381 (General Procedure 8)
(R) -N- (3-((5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) methyl) Phenyl) acrylamide 1H NMR (chloroform-d) δ 8.11 (br.s., 1H), 7
. 82 (br.s., 1H), 7.52 (d, J = 8.3 Hz, 1
H), 7.35 (t, J = 7.8 Hz, 1H), 7.13-7.2.
3 (m, 2H), 6.45 (dd, J = 16.8, 1.3 Hz, 1
H), 6.31 (dd, J = 16.8, 10.0 Hz, 1H), 5.
76 (dd, J = 10.2, 1.4 Hz, 1H), 4.99 (s,
2H), 4.86 (br.s., 0.5H), 4.50 (d, J = 1)
3.6 Hz, 0.5H), 4.18 (br.s., 0.5H), 3.81
-3.99 (m, 2H), 3.72 (t, J = 6.0 Hz, 2.
5H), 3.45-3.59 (m, 0.5H), 3.35 (s, 3H)
, 3.00-3.16 (m, 1.5H), 2.81-2.99 (m,
1H), 2.62-2.79 (m, 1H), 2.41-2.62 (
m, 2H), 1.39 (d, J = 6.8 Hz, 1.5H), 1.25
-1.32 (m, 1.5H), 0.94-1.15 (m, 4H)
LC-MS: m / z 504.2 (M + H) +

Compound 382 (General Procedure 8)
(R) -2-Bromo-N- (3-((5-cyano-2-cyclopropyl-6- (4- (
3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) methyl) phenyl) acetamide 1H NMR (chloroform-d) δ 8.52 (s, 1H), 7.73 (
s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 (
t, J = 7.8 Hz, 1H), 7.12-7.26 (m, 2H),
5.02 (s, 2H), 4.87 (br. S., 0.5H), 4.50
(D, J = 13.3 Hz, 0.5H), 4.19 (d, J = 8.
5 Hz, 0.5H), 4.03 (s, 2H), 3.81-3.99 (
m, 2H), 3.64-3.81 (m, 2.5H), 3.45-3.
61 (m, 0.5H), 3.36 (s, 3H), 3.02-3.18
(M, 1.5H), 2.82-3.02 (m, 1H), 2.62-2
. 80 (m, 1H), 2.42-2.62 (m, 2H), 1.39 (
d, J = 6.5 Hz, 1.5H), 1.22-1.33 (m, 1.
5H), 0.95-1.14 (m, 4H)
LC-MS: m / z 570.1 (M + H) +

Compound 388 (General Procedure 8)
6-cyclopropyl-2-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5- (1- (pyridin-4-yl) ethoxy) nicotinonitrile 1H NMR (chloroform-d) δ 8.57-8.70 (m, 2H)
, 7.33 (d, J = 6.0 Hz, 2H), 6.96 (d, J =
3.3 Hz, 1H), 5.17 (q, J = 6.4 Hz, 1H),
4.86 (br. S., 0.5H), 4.49 (d, J = 12.8 H
z, 0.5H), 4.17 (br. s., 0.5H), 3.81-4.
05 (m, 2H), 3.63-3.81 (m, 2.5H), 3.51
(D, J = 15.3 Hz, 0.5H), 3.36 (s, 3H),
07 (t, J = 12.9 Hz, 1.5H), 2.81-3.00 (
m, 1H), 2.60-2.78 (m, 1H), 2.46-2.60.
(M, 2H), 1.67 (d, J = 6.5 Hz, 3H), 1.36
(D, J = 5.0 Hz, 1.5H), 1.24-1.28 (m,
1.5H), 0.99-1.16 (m, 4H)
LC-MS: m / z 450.2 (M + H) +

Compound 389 (General Procedure 8)
N- (4- (1- (5-cyano-2-cyclopropyl-6-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) Ethyl) phenyl) acrylamide 1H NMR (chloroform-d) δ 8.03 (br.s., 1H),
7.56-7.64 (m, 2H), 7.30 (d, J = 8.3 Hz)
, 2H), 6.90-7.05 (m, 1H), 6.43 (dd, J
= 16.8, 1.3 Hz, 1H), 6.29 (dd, J = 16.8,
10.0 Hz, 1H), 5.74 (dd, J = 10.0, 1.3 H
z, 1H), 5.05-5.19 (m, 1H), 4.85 (br. s)
. , 0.5H), 4.48 (d, J = 12.5 Hz, 0.5H), 4
. 16 (br. S., 0.5H), 3.65-3.95 (m, 5.5H)
), 3.50 (d, J = 11.3 Hz, 0.5H), 3.34 (s,
3H), 2.97-3.14 (m, 1.5H), 2.77-2.95.
(M, 1H), 2.61-2.77 (m, 1H), 2.47-2.
61 (m, 2H), 1.65 (d, J = 6.3 Hz, 3H),
36 (d, J = 6.5 Hz, 1.5H), 1.26 (d, J = 5
. 0 Hz, 1.5H), 0.97-1.15 (m, 4H)
LC-MS: m / z 518.2 (M + H) +

Compound 400 (General Procedure 8)
(R, E) -N- (3-((5-cyano-2-cyclopropyl-6- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) Methyl) phenyl) but-2-enamide 1H NMR (chloroform-d) δ 7.75 (br.s., 1H),
7.47 (d, J = 8.0 Hz, 1H), 7.30-7.40 (m
, 2H), 7.10-7.23 (m, 2H), 6.88-7.09.
(M, 1H), 5.96 (dd, J = 15.1, 1.5 Hz, 1H)
, 5.01 (s, 2H), 4.87 (br. S., 0.5H), 4.5
0 (d, J = 13.6 Hz, 0.5H), 4.18 (br. S.,
0.5H), 3.82-4.00 (m, 2H), 3.64-3.80
(M, 2.5H), 3.46-3.62 (m, 0.5H), 3.36 (
s, 3H), 3.01-3.16 (m, 1.5H), 2.83-3.
01 (m, 1H), 2.62-2.77 (m, 1H), 2.44-
2.61 (m, 2H), 1.93 (dd, J = 6.9, 1.6 Hz,
3H), 1.39 (d, J = 6.5 Hz, 1.5H), 1.29 (
d, J = 7.0 Hz, 1.5H), 0.95-1.13 (m, 4H
)
LC-MS: m / z 518.2 (M + H) +

Compound 407 (General Procedure 8)
N- (3- (1- (5-cyano-2-cyclopropyl-6-((R) -4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yloxy) Ethyl) phenyl) acrylamide 1H NMR (chloroform-d) δ 7.75 (br.s., 1H),
7.63 (br. S., 1H), 7.46 (br. S., 1H), 7.
34 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5
Hz, 1H), 6.94-7.01 (m, 1H), 6.46 (dd,
J = 16.8, 1.3 Hz, 1H), 6.28 (dd, J = 16
. 9, 10.2 Hz, 1H), 5.79 (dd, J = 10.3,
0 Hz, 1H), 5.13 (q, J = 6.1 Hz, 1H), 4.8
6 (br. S., 0.5H), 4.49 (d, J = 13.3 Hz,
0.5H), 4.17 (br.s., 0.5H), 3.78-3.95.
(M, 2H), 3.63-3.78 (m, 2.5H), 3.52 (d,
J = 14.6 Hz, 0.5H), 3.37 (s, 3H), 2.98
-3.14 (m, 1.5H), 2.79-2.97 (m, 1H), 2
. 63-2.78 (m, 1H), 2.48-2.63 (m, 2H),
1.68 (d, J = 6.3 Hz, 3H), 1.38 (d, J =
6.3 Hz, 1.5H), 1.24-1.30 (m, 1.5H), 1.
00-1.14 (m, 4H)
LC-MS: m / z 518.2 (M + H) +

Compound 827 (General Procedure 6)
(R) -2-cyclopropyl-6- (3-cyclopropyl-4-hexanoylpiperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile 1H NMR (Chloroform-d) δ 8.69 (d, J = 4.7 Hz)
, 1H), 7.23 (s, 1H), 7.07 (d, J = 4.7 Hz)
, 1H), 6.87 (dd, J = 17.6, 10.9 Hz, 1H),
6.19-6.36 (m, 1H), 5.47-5.63 (m, 1H
), 4.34 (d, J = 12.9 Hz, 1H), 4.26 (d, J
= 12.6 Hz, 1H), 4.10 (br.s., 0.65H), 3
. 64-3.91 (m, 1.35H), 2.88-3.38 (m, 2
H), 2.37 (br. S., 2H), 2.21 (s, 3H), 1.6
1-1.73 (m, 2H), 1.51-1.61 (m, 1H), 1
. 44 (br. S., 1H), 1.35 (br. S., 4H), 1.0
4-1.17 (m, 2H), 0.90-0.98 (m, 3H), 0
. 87 (dd, J = 8.1, 3.1 Hz, 2H), 0.60 (br.
s. , 1H), 0.55 (br. S., 1H), 0.23-0.50
(M, 2H)
LC-MS: m / z 484.3 (M + H) +

Compound 826 (General Procedure 6)
(R) -6- (4- (3-Cyclobutylpropanoyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methyl-2'-vinyl-3,4'-bipyridine- 5-carbonitrile 1H NMR (chloroform-d) δ 8.70 (d, J = 5.0 Hz)
, 1H), 7.25 (s, 1H), 7.09 (d, J = 4.7 Hz
, 1H), 6.88 (dd, J = 17.6, 10.9 Hz, 1H),
6.28 (d, J = 17.6 Hz, 1H), 5.51-5.64
(M, 1H), 4.34 (d, J = 12.9 Hz, 1H), 4.26.
(D, J = 12.0 Hz, 1H), 4.09 (br. S., 0.6
H), 3.63-3.92 (m, 1.4H), 3.01-3.13 (m,
2H), 2.25-2.38 (m, 2H), 2.22 (s, 3H),
2.00-2.13 (m, 4H), 1.82-1.90 (m, 2H
), 1.75 (q, J = 7.4 Hz, 2H), 1.61-1.69
(M, 2H), 1.56 (td, J = 8.3, 4.0 Hz, 1H)
, 1.12 (br. S., 2H), 0.80-0.94 (m, 2H)
, 0.61 (br. S., 1H), 0.55 (br. S., 1H),
0.44 (br.s., 2H)
LC-MS: m / z 496.3 (M + H) +

Compound 825 (General Procedure 6)
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3-cyclopropylpropanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-bipyridine- 5-carbonitrile 1H NMR (chloroform-d) δ 8.72 (d, J = 5.0 Hz)
, 1H), 7.26 (s, 1H), 7.09 (d, J = 4.7 Hz)
, 1H), 6.89 (dd, J = 17.6, 10.9 Hz, 1H),
6.27 (d, J = 17.6 Hz, 1H), 5.52-5.65
(M, 1H), 4.34 (d, J = 12.6 Hz, 1H), 4.26
(D, J = 12.6 Hz, 1H), 4.02-4.17 (m, 0
. 6H), 3.71-3.95 (m, 1.4H), 2.95-3.4 (m,
2H), 2.45-2.56 (m, 1H), 2.36 (t, J = 7
. 5 Hz, 3H), 2.22 (s, 3H), 1.63-1.70 (m
, 2H), 1.11 (br. S., 2H), 0.75-0.89 (m,
3H), 0.51-0.74 (m, 3H), 0.34-0.50 (m
, 4H), 0.10 (d, J = 4.1 Hz, 2H)
LC-MS: m / z 482.2 (M + H) +

Compound 582 (General Procedure 7)
(R) -5-((5-cyano-2-cyclopropyl-6- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) pyridin-3-yl) amino) picolinonitrile 1H NMR (400 MHz, CDCl3) δ 8.18-8.17 (d, 1
H), 7.61 (s, 1H), 7.51-7.49 (d, 1H), 6.89
-6.86 (dd, 1H), 6.38 (s, 1H), 4.87 (s, 0
. 5H), 4.53-4.50 (d, 0.5H); 4.27-4.16 (dd
, 2H) 3.92 (s, 2H) 3.75-3.10 (m, 4H) 2.69-
2.51 (m, 2H), 2.07-2.02 (m, 1H), 1.41-1.26
(M, 3H), 1.43-1.10 (m, 2H), 1.04-1.01 (m,
2H).
LC-MS: m / z 432.2 (M + H) +

Compound 577 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-((6-vinylpyridin-3-yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.15-8.14 (d, 1
H), 7.58 (s, 1H), 7.26-7.23 (d, 1H), 6.97.
-6.94 (dd, 1H), 6.79-6.72 (q, 1H), 6.03-
5.98 (dd, 1H), 5.58 (s, 1H), 5.36-5.33 (
dd, 1H), 4.88 (s, 0.5H), 4.54-4.51 (d, 0
. 5H); 4.20-4.09 (dd, 2H) 3.93 (s, 2H)
75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.5
0 (m, 2H), 2.18-2.10 (m, 1H), 1.41-1.26 (m,
3H), 1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H)
, 1.03-1.09 (m, 2H).
LC-MS: m / z 433.2 (M + H) +

Compound 298 (General Procedure 6)
(R) -6-cyclopropyl-5- (4-fluorophenyl) -4- (methoxymethyl) -2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δt: 7.21-7.27 (m, 2
H), 7.11-7.19 (m, 2H), 4.85-4.95 (s,
0.5H), 4.45-4.57 (m, 0.5H), 4.05-4.27
(M, 4H), 3.74 (t, J = 6.4 Hz, 2.5H),
57-3.63 (m, 0.5H), 3.35-3.40 (m, 3H),
3.29 (s, 3H), 3.09-3.26 (m, 2H), 2.59
(Br.s., 1H), 1.60-1.70 (m, 1H), 1.38
-1.44 (m, 1H), 1.30 (d, J = 6.8 Hz, 2H
), 1.25 (s, 1H), 1.04-1.10 (m, 2H), 0.
81-0.88 (m, 2H).
LC-MS: m / z 487.2 (M + H) +

Compound 823 (General Procedure 6)
2-cyclopropyl-6-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -4-ethyl-2'-vinyl − [
3,4'-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.57-8.87 (m, 1H)
, 7.25 (s, 1H), 7.02-7.16 (m, 1H), 6.8
9 (dd, J = 17.5, 10.7 Hz, 1H), 6.30 (d,
J = 17.3 Hz, 1H), 5.59 (d, J = 10.9 Hz,
1H), 5.27 (t, J = 6.6 Hz, 1H), 4.51-4.
78 (m, 2H), 4.30-4.42 (m, 1H), 4.26 (d
, J = 11.4 Hz, 1H), 4.09 (d, J = 9.1 Hz,
1H), 3.84-3.98 (m, 1H), 3.56-3.84 (
m, 1H), 2.95-3.45 (m, 3H), 2.68-2.92 (
m, 2H), 2.41-2.63 (m, 3H), 1.49-1.55.
(M, 1H), 1.34 (d, J = 8.2 Hz, 1H), 1.10
(T, J = 7.6 Hz, 5H), 0.80-0.94 (m, 3H
), 0.35-0.75 (m, 4H)
LC-MS: m / z 498.3 (M + H) +

Compound 805 (General Procedure 6)
2-Cyclopropyl-6-((3R) -3-cyclopropyl-4- (2- (tetrahydrofuran-2-yl) acetyl) piperazin-1-yl) -4-methyl-2'-vinyl-
[3,4'-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.69 (d, J = 5.0 Hz)
, 1H), 7.23 (s, 1H), 7.07 (d, J = 5.0 Hz)
, 1H), 6.87 (dd, J = 17.3, 10.9 Hz, 1H),
6.22-6.40 (m, 1H), 5.57 (dd, J = 10.9
, 0.9 Hz, 1H), 4.60-4.70 (m, 0.5H), 4.18
-4.41 (m, 3H), 4.02-4.15 (m, 0.5H),
89 (d, J = 7.3 Hz, 1.5H), 3.63-3.82 (m
1.5H), 2.90-3.45 (m, 3H), 2.64-2.85.
(M, 1H), 2.53 (dd, J = 14.8, 6.0 Hz, 1H)
, 2.08-2.32 (m, 4H), 1.88-2.00 (m, 2
H), 1.51-1.69 (m, 2H), 1.43 (d, J = 13
. 8 Hz, 1H), 1.11 (s, 2H), 0.87 (dd, J =
7.9, 2.9 Hz, 2H), 0.35-0.66 (m, 4H)
LC-MS: m / z 498.3 (M + H) +

Compound 806 (General Procedure 6)
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (2- (5-oxotetrahydrofuran-2-yl) acetyl) piperazin-1-yl) -4-methyl-2 '
-Vinyl- [3,4'-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.71 (d, J = 4.7 Hz
, 1H), 7.25 (s, 1H), 7.09 (d, J = 4.7 Hz
, 1H), 6.90 (dd, J = 17.3, 10.9 Hz, 1H),
6.31 (d, J = 17.3 Hz, 1H), 5.60 (d, J =
11.2 Hz, 1H), 4.94-5.08 (m, 1H), 4.17
-4.45 (m, 2H), 4.08 (s, 1H), 3.79 (s,
2H), 2.80-3.45 (m, 4H), 2.51-2.73 (m,
4H), 2.19-2.28 (m, 3H), 1.57 (td, J =
8.1, 4.0 Hz, 1H), 1.12 (s, 3H), 0.88 (dd
, J = 7.9, 3.2 Hz, 3H), 0.25-0.74 (m, 4H
)
LC-MS: m / z 512.3 (M + H) +

Compound 808 (General Procedure 7)
2- (5-cyano-2-cyclopropyl-6-((R) -3-cyclopropyl-4- (
2-((R) -Oxetan-2-yl) acetyl) piperazin-1-yl) pyridine-3
-Ylamino) pyrimidine-4-carbonitrile 1H NMR (chloroform-d) δ: 8.59 (d, J = 4.7 Hz)
, 1H), 7.87-8.13 (m, 1H), 7.00-7.17.
(M, 2H), 5.10-5.32 (m, 2H), 4.67-4.8
3 (m, 1H), 4.47-4.63 (m, 1H), 4.39 (d,
J = 11.7 Hz, 1H), 4.30 (d, J = 12.3 Hz,
1H), 4.08 (d, J = 7.3 Hz, 1H), 3.92 (d,
J = 12.9 Hz, 1H), 3.64-3.84 (m, 1H),
3.18-3.45 (m, 1H), 2.93-3.18 (m, 3H)
, 2.54 (d, J = 6.7 Hz, 1H), 1.94-2.14
(M, 2H), 1.86 (br. S., 2H), 1.46 (d, J =
8.2 Hz, 1H), 1.39 (br.s., 1H), 1.33 (b
r. s. , 1H), 1.27 (s, 1H), 0.97-1.23 (m
, 4H), 0.63 (br. S., 1H), 0.54 (br. S.,
1H), 0.27-0.50 (m, 2H).
LC-MS: m / z 485.2 (M + H) +

Compound 809 (General Procedure 7)
5- (4-Cyanopyridin-2-ylamino) -6-cyclopropyl-2-((R)-
3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) nicotinonitrile 1H NMR (chloroform-d) δ: 8.65 (d, J = 5 .3 Hz
, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24
(Dd, J = 5.0, 1.5 Hz, 1H), 6.88 (dd, J =
17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H)
5.51-5.65 (m, 1H), 4.55 (d, J = 12.9).
Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.
29 (m, 2H), 4.00 (br. S., 1H), 3.80 (br.
s. , 1H), 3.62-3.77 (m, 1H), 3.54 (br.
s. , 2H), 3.22 (d, J = 12.6 Hz, 2H), 3.0
9 (t, J = 10.9 Hz, 1H), 2.40-2.54 (m,
3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m
, 11H), 0.94-1.10 (m, 3H), 0.74-0.94
(M, 2H), 0.65 (br. S., 2H), 0.47 (br. S
. , 3H).
LC-MS: m / z 484.2 (M + H) +

Compound 803 (General Procedure 6)
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (3- (oxetan-2-yl) propanoyl) piperazin-1-yl) -4-methyl-2'-vinyl- [3
, 4′-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.69 (d, J = 5.0 Hz,
1H), 7.23 (s, 1H), 7.07 (d, J = 3.8 Hz,
1H), 6.87 (dd, J = 17.3, 10.9 Hz, 1H),
6.29 (d, J = 17.3 Hz, 1H), 5.45-5.62 (
m, 1H), 4.88 (s, 1H), 4.64-4.74 (m, 1H)
), 4.54 (dt, J = 8.8, 5.9 Hz, 1H), 4.33
(D, J = 12.6 Hz, 1H), 4.18-4.29 (m, 1H
), 4.03-4.15 (m, 1H), 3.60-3.90 (m, 1H)
), 3.09-3.39 (m, 2H), 2.94-3.09 (m,
1H), 2.66-2.78 (m, 1H), 2.25-2.60 (m,
3H), 2.21 (s, 3H), 2.01-2.14 (m, 2H),
1.51-1.68 (m, 1H), 1.43 (d, J = 12.9 H
z, 1H), 1.00-1.16 (m, 2H), 0.87 (dd, J
= 7.9, 2.9 Hz, 2H), 0.25-0.65 (m, 4H)
LC-MS: m / z 498.3 (M + H) +

Compound 802 (General Procedure 5)
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (2- (5-oxotetrahydrofuran-2-yl) acetyl) piperazin-1-yl) -2'-vinyl- [
3,4′-bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.67 (d, J = 5.0 Hz,
1H), 7.60-7.71 (m, 1H), 7.40 (s, 1H),
7.21-7.27 (m, 1H), 6.89 (dd, J = 17.5
, 10.7 Hz, 1H), 6.29 (d, J = 17.3 Hz, 1H
), 5.58 (d, J = 10.9 Hz, 1H), 4.94-5.0
6 (m, 1H), 4.35-4.75 (m, 2.5H), 4.01-4
. 09 (m, 0.5H), 3.70-3.81 (m, 1.5H), 2.90
-3.40 (m, 3.5H), 2.50-2.79 (m, 4H),
98-2.04 (m, 1H), 1.29-1.37 (m, 2H),
1.22 (dt, J = 7.0, 3.5 Hz, 2H), 0.97-1
. 06 (m, 2H), 0.26-0.70 (m, 4H)
LC-MS: m / z 498.2 (M + H) +

Compound 801 (General Procedure 5)
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (2- (tetrahydrofuran-2-yl) acetyl) piperazin-1-yl) -2'-vinyl- [3,4'-
Bipyridine] -5-carbonitrile 1H NMR (chloroform-d) δ 8.65 (d, J = 5.0 Hz)
, 1H), 7.64 (s, 1H), 7.39 (s, 1H), 7.23
(D, J = 4.7 Hz, 1H), 6.88 (dd, J = 17.6,
10.9 Hz, 1H), 6.28 (d, J = 17.6 Hz, 1H)
, 5.56 (d, J = 10.9 Hz, 1H), 4.50-4.62
(M, 1H), 4.43 (d, J = 12.9 Hz, 1H), 4.2
1-4.35 (m, 1H), 4.05-4.11 (m, 1H), 3.8
0-3.92 (m, 1.5H), 3.62-3.80 (m, 1.5H)
), 3.07-3.41 (m, 3H), 2.45-2.97 (m,
2H), 2.15-2.20 (m, 1H), 1.98-2.05 (m
, 2H), 1.92 (dt, J = 14.2, 6.9 Hz, 2H),
1.62 (d, J = 7.3 Hz, 1H), 1.16-1.24 (m
, 2H), 1.00 (dd, J = 7.5, 3.4 Hz, 2H), 0
. 34-0.71 (m, 4H)
LC-MS: m / z 484.3 (M + H) +

Compound 824 (General Procedure 7)
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -5-((2- (hydroxy Methyl) pyridin-4-yl) amino) nicotinonitrile 1H NMR (400 MHz, MeOD) δ 8.08 (d, J = 6.
5 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 6.8
1 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 6.4)
, 2.3 Hz, 1H), 6.18-6.11 (m, 1H), 5.62.
(Dd, J = 6.8, 5.5 Hz, 1H), 5.24 (s, 1H)
, 4.66 (d, J = 7.0 Hz, 3H), 4.51 (d, J =
13.1 Hz, 1H), 4.37 (s, 1H), 4.14-3.97
(M, 1H), 3.71 (dd, J = 10.8, 4.4 Hz, 2H
), 3.62 (s, 1H), 3.18-3.04 (m, 1H), 2.
84 (s, 1H), 2.49 (d, J = 6.5 Hz, 1H), 2.
17-2.09 (m, 1H), 1.96 (s, 1H), 1.53-
1.25 (m, 3H), 1.21-1.13 (m, 2H), 1.04
(Dd, J = 7.7, 3.4 Hz, 2H), 0.71-0.36 (
m, 4H).
LC-MS: m / z 489.2 (M + H) +

Compound 810 (General Procedure 5)
Sodium (R) -3- (4- (5-cyano-2-cyclopropyl-2′-vinyl- [
3,4'-bipyridin] -6-yl) -2-cyclopropylpiperazin-1-yl) -3
-Oxopropyl phosphate 1H NMR (400 MHz, D2O) δ 8.37 (d, J = 5.0)
Hz, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.
26 (s, 1H), 6.74 (dd, J = 17.5, 11.3 Hz,
1H), 6.04 (d, J = 17.8 Hz, 1H), 5.51 (d
, J = 11.2 Hz, 1H), 4.47 (s, 1H), 4.35 (
s, 2H), 3.91 (d, J = 6.7 Hz, 3H), 3.82 (
s, 1H), 3.56 (q, J = 7.1 Hz, 2H), 3.20 (
s, 1H), 2.78 (s, 1H), 2.71-2.63 (m, 1H)
), 1.92 (s, 1H), 1.55 (s, 4H), 1.18 (s,
2H), 0.89 (s, 1H), 0.45-0.46 (m, 2H), 0.
37-0.22 (m, 2H).
LC-MS: m / z 568.2 (M + H) +

Compound 828 (General Procedure 7)
1H NMR (chloroform-d) δ 8.07 (d, J = 5.3 Hz)
, 1H), 7.81 (s, 1H), 7.02 (br.s., 1H),
6.71-6.84 (m, 1H), 6.55 (dd, J = 17.6,
10.9 Hz, 1H), 6.38 (s, 1H), 5.86 (d, J
= 17.6 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H)
), 4.18-4.44 (m, 3H), 4.11 (q, J = 7.0)
Hz, 1H), 3.81-3.99 (m, 2H), 3.62-3.
81 (m, 2H), 3.11 (d, J = 12.9 Hz, 2H), 3
. 04 (m, 1H), 2.73 (d, J = 6.5 Hz, 1H),
2.08-2.28 (m, 2H), 1.82-1.97 (m, 2H)
), 1.59 (dd, J = 12.0, 7.9 Hz, 1H), 1.25
(T, J = 7.0 Hz, 1H), 1.04-1.18 (m, 2H
), 0.88-1.02 (m, 2H), 0.51-0.59 (m, 2H)
), 0.42-0.49 (m, 2H)
LC-MS: m / z 499.2 (M + H) +

Compound 829 (General Procedure 7)
1H NMR (chloroform-d) δ 7.56 (s, 1H), 7.14
(D, J = 7.3 Hz, 1H), 6.11 (br, s, 1H), 5
. 79 (dd, J = 7.3, 2.3 Hz, 1H), 5.58 (br.
s. , 1H), 5.26 (t, J = 6.6 Hz, 1H), 4.71
(Td, J = 7.9, 6.2 Hz, 1H), 4.56 (m, 1H)
, 4.43 (d, J = 12.3 Hz, 1H), 4.32 (d, J
= 12.6 Hz, 1H), 4.06 (d, J = 9.1 Hz, 0.5
H), 3.92 (d, J = 12.3 Hz, 0.5H), 3.69 −
3.82 (m, 1H), 3.47 (s, 3H), 3.08-3.34
(M, 2H), 2.92-3.08 (m, 2.5H), 2.78-2
. 90 (m, 1.5H), 2.54 (d, J = 7.3 Hz, 1H),
2.06-2.17 (m, 1H), 1.27 (s, 1H), 1.06
-1.16 (m, 2H), 0.98-1.05 (m, 2H), 0.
53- 0.63 (m, 2H), 0.30-0.49 (m, 2H)
LC-MS: m / z 489.2 (M + H) +

Compound 830 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4-hexanoylpiperazin-1-yl) -5- (4-vinylpyridin-2-ylamino) nicotinonitrile 1H NMR (chloroform-d) δ 8.02 (d, J = 4.4 Hz,
1H), 7.72 (s, 1H), 6.82 (d, J = 5.3 Hz,
1H), 6.56 (dd, J = 17.3, 10.9 Hz, 1H),
6.34 (s, 1H), 5.90 (d, J = 17.6 Hz, 1H),
5.49 (d, J = 10.9 Hz, 1H), 4.40 (d, J =
12.9 Hz, 1H), 4.29 (d, J = 12.0 Hz, 1H)
, 4.11 (br.s., 1H), 3.80 (br.s., 2H),
3.16 (br.s., 2H), 2.90-3.11 (m, 1H),
2.25-2.45 (m, 5H), 1.56-1.73 (m, 4H)
, 1.20-1.48 (m, 4H), 1.07-1.20 (m, 2
H), 0.82-1.07 (m, 2H). .
LC-MS: m / z 485.2 (M + H) +

Compound 818 (General Procedure 5)
1H NMR (chloroform-d) δ 8.66 (d, J = 4.7 Hz)
, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.22
-7.28 (m, 1H), 6.90 (dd, J = 17.3, 10.9
Hz, 1H), 6.31 (d, J = 17.3 Hz, 1H), 5.6
0 (d, J = 10.9 Hz, 1H), 4.55 (d, J = 12.
9 Hz, 1H), 4.43 (dd, J = 12.9, 2.1 Hz, 1
H), 4.14 (m, 2H), 3.72 (m, 1H), 3.43-3
. 63 (m, 2H), 3.22 (d, J = 11.4 Hz, 2H),
3.01-3.16 (m, 2H), 2.06-2.11 (m, 1H),
79-2.09 (m, 1H), 1.65 (br.s., 1H), 1.
40-1.53 (m, 1H), 1.17-1.25 (m, 2H),
0.96-1.08 (m, 2H), 0.66-0.75 (m, 2H),
0.39-0.61 (m, 2H)
LC-MS: m / z 483.7 (M + H) +

Compound 821 (General Procedure 5)
1H NMR (chloroform-d) δ 8.66 (d, J = 5.3 Hz)
, 1H), 7.65 (s, 1H), 7.33-7.46 (m, 1H)
, 7.24 (dd, J = 5.0, 1.5 Hz, 1H), 6.88 (
dd, J = 17.5, 10.7 Hz, 1H), 6.24-6.39.
(M, 1H), 5.57 (dd, J = 10.9, 1.2 Hz, 1H)
, 5.01 (t, J = 6.3 Hz, 1H), 4.56 (m, 1.5
H), 4.44 (d, J = 14.1 Hz, 1H), 3.79 (m,
1H), 3.22 (m, 1.5H), 2.70 (d, J = 6.7 Hz
, 1H), 2.49-2.65 (m, 3H), 1.90-2.14
(M, 4H), 1.35 (m, 1H), 1.21 (m, 3H), 0.9
2-1.08 (m, 2H), 0.48 (m, 4H)
LC-MS: m / z 498.7 (M + H) +

Compound 822 (General Procedure 5)
1H NMR (chloroform-d) δ 8.64 (d, J = 4.7 Hz)
, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.22
(Dd, J = 5.0, 1.5 Hz, 1H), 6.87 (dd, J =
17.6, 10.9 Hz, 1H), 6.18-6.36 (m, 1H)
, 5.49-5.62 (m, 1H), 4.67-4.71 (m, 0.5H)
, 4.54 (d, J = 12.6 Hz, 1H), 4.36-4.46.
(M, 1H), 4.28 (quin, J = 6.5 Hz, 1H), 4
. 11 (d, J = 7.9 Hz, 0.5H), 3.81-4.00 (
m, 1.5H), 3.63-3.79 (m, 1.5H), 3.08-
3.20 (m, 1H), 2.64-2.85 (m, 2H), 2.46
-2.60 (m, 1H), 2.08-2.24 (m, 1H), 1.9
7-2.08 (m, 1H), 1.82-1.97 (m, 2H), 1
. 52-1.70 (m, 1H), 1.26-1.30 (m, 2 H),
12-1.24 (m, 2H), 0.92-1.05 (m, 2H),
0.49-0.73 (m, 2H), 0.45 (m, 2H)
LC-MS: m / z 484.7 (M + H) +

Compound 811 (General Procedure 6)
1H NMR (chloroform-d) δ 7.23 (s, 1H), 7.07
(Dd, J = 5.0, 1.2 Hz, 1H), 6.87 (dd, J =
17.5, 10.7 Hz, 1H), 6.29 (d, J = 17.3 H
z, 1H), 5.57 (dd, J = 10.9, 1.2 Hz, 1H),
4.32 (d, J = 12.9 Hz, 1H), 4.23 (dd, J
= 12.6, 2.1 Hz, 1H), 4.14 (m, 1H), 3.99
(Br.s., 1H), 3.72 (br.s., 1.5H), 3.42
-3.57 (m, 2.5H), 3.10-3.25 (m, 2H), 2
. 98-3.10 (m, 3H), 2.10-2.38 (m, 4H),
1.51-1.62 (m, 1H), 1.45 (dq, J = 14.7
, 7.3 Hz, 1H), 1.07-1.17 (m, 2H), 0.88
(Dd, J = 7.9, 3.2 Hz, 2H), 0.66 (br. S.
, 1H), 0.30-0.59 (m, 3H)
LC-MS: m / z 497.7 (M + H) +

Compound 814 (General Procedure 5)
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (2- (2-oxopyrrolidin-1-yl) acetyl) piperazin-1-yl) -2'-vinyl-3,4 ' -Bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ 8.65 (d, J = 5.3 Hz,
1H), 7.65 (s, 1H), 7.39 (s, 1H), 7.24 (
dd, J = 5.0, 1.5 Hz, 1H), 6.88 (dd, J =
17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H),
5.51-5.65 (m, 1H), 4.55 (d, J = 12.9)
Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.2
9 (m, 2H), 4.00 (br. S., 1H), 3.80 (br.
s. , 1H), 3.62-3.77 (m, 1H), 3.54 (br.
s. , 2H), 3.22 (d, J = 12.6 Hz, 2H), 3.09
(T, J = 10.9 Hz, 1H), 2.40-2.54 (m, 3
H), 2.01-2.17 (m, 4H), 1.15-1.45 (m,
4H), 0.94-1.10 (m, 3H), 0.74-0.94 (
m, 2H), 0.65 (br. s., 2H), 0.47 (br. s.,
3H).
LC-MS: m / z 497.2 (M + H) +

Compound 815 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (4-hydroxybutanoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) amino) nicotino Nitrile 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 5
. 5 Hz, 1H), 7.84 (s, 1H), 6.86 (dd, J =
5.5, 1.1 Hz, 1H), 6.80 (s, 1H), 6.59 (dd
, J = 17.6, 10.9 Hz, 1H), 6.44 (s, 1H),
5.93 (d, J = 17.5 Hz, 1H), 5.51 (d, J =
10.9 Hz, 1H), 4.75-4.61 (m, 0.5H), 4.3
7 (d, J = 12.8 Hz, 1H), 4.27 (d, J = 12.
6 Hz, 1H), 4.10 (d, J = 7.2 Hz, 0.5H), 3
. 85 (d, J = 10.0 Hz, 0.5H), 3.81-3.65
(M, 2.5H), 3.30 (dd, J = 9.3, 5.7 Hz, 1H
), 3.22-3.12 (m, 1H), 3.12-2.97 (m,
1H), 2.66-2.43 (m, 2H), 2.21-2.14 (m
, 1H), 1.97 (dd, J = 12.0, 6.2 Hz, 2H),
1.46 (dd, J = 8.5, 6.8 Hz, 1H), 1.14 (dd
, J = 7.1, 4.0 Hz, 2H), 1.04 (ddd, J = 9
. 5, 6.4, 3.0 Hz, 2H), 0.77-0.38 (m, 4H
).
LC-MS: m / z 473.2 (M + H) +

Compound 816 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (2- (2-oxopyrrolidin-1-yl) acetyl) piperazin-1-yl) -5-((4-vinylpyridine- 2-yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 5
. 6 Hz, 1H), 7.83 (s, 1H), 7.19 (s, 1H),
6.87 (dd, J = 5.7, 1.3 Hz, 1H), 6.60 (dd
, J = 17.5, 10.9 Hz, 1H), 6.44 (s, 1H),
5.95 (d, J = 17.5 Hz, 1H), 5.54 (d, J =
10.9 Hz, 1H), 4.55 (s, 0.5H), 4.39 (d, J
= 12.9 Hz, 1H), 4.28 (dd, J = 12.7, 2.1
Hz, 1H), 4.19 (s, 1H), 4.00 (s, 0.5H),
3.75 (dd, J = 30.5, 3.9 Hz, 2H), 3.55 (s
, 2H), 3.33 (s, 1H), 3.18 (d, J = 11.9 H
z, 1H), 3.05 (t, J = 13.2 Hz, 1H), 2.47.
(T, J = 8.0 Hz, 2H), 2.21-2.16 (m, 1H)
, 2.12 (dt, J = 15.4, 7.6 Hz, 2H), 1.28
(D, J = 5.1 Hz, 1H), 1.19-1.10 (m, 2H)
, 1.05 (ddd, J = 9.0, 6.6, 2.5 Hz, 2H),
0.78-0.41 (m, 4H).
LC-MS: m / z 513.6 (M + H) +

Compound 817 (General Procedure 7)
(R) -2- (4- (2-cyclobutylacetyl) -3-cyclopropylpiperazine-
1-yl) -6-cyclopropyl-5-((4-vinylpyridin-2-yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl 3) δ 8.07 (d, J = 5
. 6 Hz, 1H), 7.80 (s, 1H), 6.87 (dd, J =
5.7, 1.2 Hz, 1H), 6.59 (dd, J = 17.6, 10
. 8 Hz, 1H), 6.43 (s, 1H), 5.95 (d, J = 1)
7.5 Hz, 1H), 5.54 (d, J = 10.8 Hz, 1H),
4.65 (d, J = 11.7 Hz, 0.4H), 4.41 (d, J
= 12.6 Hz, 1H), 4.30 (d, J = 12.3 Hz, 1H)
), 4.09 (d, J = 5.2 Hz, 0.6H), 3.91-3.
59 (m, 1.5H), 3.34-3.10 (m, 1.5H), 3.0
9-2.94 (m, 1H), 2.74 (dt, J = 15.5, 7.
8 Hz, 1H), 2.52 (s, 2H), 2.25-2.12 (m,
3H), 1.98-1.82 (m, 2H), 1.82-1.63 (
m, 2H), 1.28 (s, 1H), 1.19-1.09 (m, 2H)
), 1.04 (dt, J = 6.9, 3.0 Hz, 2H), 0.78
-0.34 (m, 4H).
LC-MS: m / z 483.6 (M + H) +

Compound 812 (General Procedure 7)
6-cyclopropyl-2-((3R) -3-cyclopropyl-4- (3- (oxetan-2-yl) propanoyl) piperazin-1-yl) -5-((4-vinylpyridine-2
-Yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5
. 4 Hz, 1H), 7.85 (s, 1H), 6.83 (dd, J =
5.4, 1.3 Hz, 1H), 6.59 (dd, J = 17.6, 10
. 8 Hz, 1H), 6.41 (s, 1H), 6.39 (s, 1H),
5.90 (d, J = 17.6 Hz, 1H), 5.47 (d, J =
11.0 Hz, 1H), 4.89 (s, 1H), 4.70 (dd, J
= 14.1, 7.8 Hz, 1H), 4.55 (dd, J = 14.7,
5.8 Hz, 1H), 4.36 (d, J = 12.8 Hz, 1H),
4.25 (dd, J = 12.5, 1.8 Hz, 1H), 4.09 (
dd, J = 7.2, 2.6 Hz, 1H), 3.78 (ddd, J =
23.5, 14.1, 6.1 Hz, 1.5H), 3.28 (s, 0.5
H), 3.13 (d, J = 12.4 Hz, 1H), 3.02 (dd,
J = 21.5, 9.8 Hz, 1H), 2.74 (ddd, J = 1)
4.2, 11.1, 8.0 Hz, 1H), 2.62-2.47 (m,
1H), 2.46-2.32 (m, 2H), 2.23-1.98 (m
, 3H), 1.28 (d, J = 4.8 Hz, 1H), 1.19 −
1.09 (m, 2H), 1.02 (ddd, J = 9.4, 6.4, 3
. 0 Hz, 2H), 0.75-0.35 (m, 4H).
LC-MS: m / z 499.6 (M + H) +

Compound 813 (General Procedure 7)
6-cyclopropyl-2-((3R) -3-cyclopropyl-4- (2- (tetrahydrofuran-2-yl) acetyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) ) Amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 5)
. 4 Hz, 1H), 7.84 (s, 1H), 6.84 (dd, J =
5.4, 1.2 Hz, 1H), 6.59 (dd, J = 17.5, 10
. 8 Hz, 1H), 6.46 (s, 1H), 6.41 (s, 1H),
5.91 (d, J = 17.6 Hz, 1H), 5.47 (d, J =
10.9 Hz, 1H), 4.69 (d, J = 13.9 Hz, 0.5H)
), 4.46-4.33 (m, 1H), 4.28 (dd, J = 15
. 4, 9.1 Hz, 2H), 4.11 (d, J = 5.3 Hz, 0.
5H), 3.98-3.83 (m, 1.5H), 3.75 (dt, J
= 22.2, 11.1 Hz, 1.5H), 3.40-3.09 (m,
2H), 3.09-2.93 (m, 1H), 2.83-2.47 (m
, 2H), 2.47-2.29 (m, 0.5H), 2.26-2.1
2 (m, 2H), 2.11-1.99 (m, 0.5H), 1.93 (
dt, J = 13.7, 7.0 Hz, 2H), 1.28 (d, J =
5.3 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (
ddd, J = 9.8, 6.6, 2.9 Hz, 2H), 0.77-0
. 32 (m, 4H).
LC-MS: m / z 499.3 (M + H) +

Compound 807 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-isopropyl-4- (3-methoxypropanoyl) piperazin-1-yl) -4-methyl-5-((2-vinylpyridin-4-yl)
Amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 6)
. 1 Hz, 1H), 6.69 (dd, J = 17.4, 10.9 Hz,
1H), 6.57 (s, 1H), 6.45 (s, 1H), 6.21 (
d, J = 17.6 Hz, 1H), 6.18-6.10 (m, 1H)
, 5.60 (d, J = 11.1 Hz, 1H), 4.71 (d, J
= 13.2 Hz, 0.5H), 4.50-4.37 (m, 1.5H),
4.33-4.25 (m, 1H), 3.87 (d, J = 13.1
Hz, 0.5H), 3.82-3.67 (m, 2H), 3.60 (d,
J = 10.2 Hz, 0.5H), 3.47 (dd, J = 18.2,
7.7 Hz, 0.5H), 3.38 (d, J = 4.2 Hz, 3H)
3.14 (ddd, J = 13.3, 9.5, 5.2 Hz, 1.5H
), 3.09-2.94 (m, 1H), 2.81-2.56 (m,
2H), 2.38 (s, 3H), 2.25 (dd, J = 13.6, 6
. 4 Hz, 0.5H), 2.07 (ddd, J = 15.8, 11.1,
6.8 Hz, 1.5H), 1.15-1.09 (m, 1H), 1.0
4 (dd, J = 6.5, 2.9 Hz, 4H), 0.97 (dd, J
= 7.5, 5.0 Hz, 2H), 0.93 (d, J = 6.8 Hz)
, 1.5H), 0.86 (d, J = 6.8 Hz, 1.5H).
LC-MS: m / z 489.6 (M + H) +

Compound 799 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-isopropylpiperazin-1-yl) -4-methyl-5-((2-vinylpyridin-4-yl) amino ) Nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 5)
. 7 Hz, 1H), 6.70 (dd, J = 17.4, 10.8 Hz,
1H), 6.50 (s, 1H), 6.33 (s, 1H), 6.16 (
d, J = 17.4 Hz, 1H), 5.74 (s, 1H), 5.48.
(Dd, J = 10.8, 0.9 Hz, 1H), 4.69 (d, J =
9.7 Hz, 0.5H), 4.41 (ddd, J = 6.7, 6.1,
4.4 Hz, 1.5H), 4.27 (t, J = 10.2 Hz, 1H)
), 4.00-3.86 (m, 2H), 3.76 (d, J = 13.
5 Hz, 0.5H), 3.60-3.52 (m, 1H), 3.50-
3.44 (m, 1H), 3.17-3.05 (m, 2H), 3.01
(Dd, J = 11.6, 9.4 Hz, 0.5H), 2.61 (pd,
J = 11.7, 5.1 Hz, 2H), 2.38 (s, 3H), 2.
33-2.22 (m, 0.5H), 2.11 (ddd, J = 12.7
, 9.3, 5.2 Hz, 1.5H), 1.11 (ddd, J = 8.9
, 6.6, 4.7 Hz, 1H), 1.05 (d, J = 6.5 Hz,
4H), 0.97 (dt, J = 7.8, 6.6 Hz, 2H), 0.
93 (d, J = 6.9 Hz, 1.5H), 0.86 (d, J = 6
. 8 Hz, 1.5 H).
LC-MS: m / z 475.2 (M + H) +

Compound 798 (General Procedure 7)
(R, E) -6-cyclopropyl-2- (3-cyclopropyl-4- (5-hydroxypent-2-enoyl) piperazin-1-yl) -5-((4-vinylpyridin-2-yl) ) Amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 5)
. 3 Hz, 1H), 7.83 (s, 1H), 6.89-6.77 (m
, 2H), 6.57 (dd, J = 17.6, 10.8 Hz, 1H),
6.53-6.43 (m, 1H), 6.40 (s, 1H), 6.39
-6.26 (m, 1H), 5.88 (d, J = 17.5 Hz, 1
H), 5.44 (d, J = 10.9 Hz, 1H), 4.74-4.
43 (m, 0.3H), 4.35 (t, J = 11.7 Hz, 1H),
4.26 (d, J = 12.5 Hz, 1H), 4.11-3.87
(M, 0.8H), 3.78 (dd, J = 11.6, 5.5 Hz, 2
H), 3.75-3.68 (m, 1H), 3.53 (m, 0.5H)
, 3.45 (m, 0.5H), 3.42-3.28 (m, 0.5H)
, 3.24-3.11 (m, 1.5H), 3.03 (td, J = 1)
2.6, 3.3 Hz, 1H), 2.49 (dd, J = 12.5, 6.
2 Hz, 2H), 2.22-2.15 (m, 1H), 1.45 (d,
J = 6.5 Hz, 1H), 1.17-1.08 (m, 2H), 1
. 00 (ddd, J = 9.4, 6.5, 3.0 Hz, 2H), 0.7
3-0.32 (m, 4H).
LC-MS: m / z 485.6 (M + H) +

Compound 581 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 5
. 7 Hz, 1H), 7.62 (s, 1H), 6.71 (dd, J =
17.4, 10.8 Hz, 1H), 6.58 (d, J = 2.0 Hz,
1H), 6.45 (dd, J = 5.7, 2.2 Hz, 1H), 6.
19 (d, J = 17.2 Hz, 1H), 5.90 (s, 1H), 5
. 48 (d, J = 11.2 Hz, 1H), 4.90 (s, 0.5H)
, 4.54 (d, J = 13.6 Hz, 0.5H), 4.23 (dd,
J = 31.3, 14.0 Hz, 2.5H), 3.94 (s, 2H),
3.74 (d, J = 13.6 Hz, 0.5H), 3.57 (t, J
= 11.0 Hz, 0.5H), 3.29 (dd, J = 10.5, 6
. 5 Hz, 1H), 3.15 (dd, J = 23.7, 11.6 Hz,
1H), 3.09-2.99 (m, 0.5H), 2.62 (m, J
= 34.8, 15.8 Hz, 2H), 2.12 (td, J = 8.1,
4.1 Hz, 1H), 1.43 (d, J = 6.4 Hz, 1.5H)
, 1.32 (d, J = 6.8 Hz, 1.5H), 1.13 (dd,
J = 7.2, 4.2 Hz, 2H), 1.03 (ddd, J = 10.
0, 6.4, 3.3 Hz, 2H).
LC-MS: m / z 447.6 (M + H) +

Compound 642 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-methoxypropanoyl) -3-methylpiperazin-1-yl) -5-((2-vinylpyridin-4-yl) amino) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 5
. 9 Hz, 1H), 7.61 (s, 1H), 6.72 (dd, J =
17.5, 10.9 Hz, 1H), 6.62 (s, 1H), 6.53 (
d, J = 4.4 Hz, 1H), 6.24 (d, J = 17.4 Hz)
, 1H), 5.53 (d, J = 10.9 Hz, 1H), 4.92 (
s, 1H), 4.55 (d, J = 16.6 Hz, 1H), 4.25.
(T, J = 11.9 Hz, 2H), 4.17 (d, J = 13.8)
Hz, 1H), 3.82 (d, J = 8.4 Hz, 1H), 3.76
(T, J = 6.2 Hz, 2H), 3.58 (d, J = 12.3 H
z, 1H), 3.39 (s, 3H), 3.30 (d, J = 13.0
Hz, 1H), 3.15 (t, J = 11.7 Hz, 1H), 3.06
(D, J = 12.2 Hz, 1H), 2.73 (ddd, J = 22
. 9, 14.3, 6.7 Hz, 1H), 2.64-2.53 (m, 1
H), 2.09 (td, J = 7.9, 4.1 Hz, 1H), 1.40
(D, J = 5.7 Hz, 2H), 1.30 (d, J = 7.1 H
z, 2H), 1.13 (dd, J = 6.8, 4.1 Hz, 2H),
1.02 (dd, J = 7.6, 3.3 Hz, 2H).
LC-MS: m / z 447.2 (M + H) +

Compound 643 (General Procedure 7)
(R) -5-((2-chloropyridin-4-yl) amino) -6-cyclopropyl-2
-(4- (3-Methoxypropanoyl) -3-methylpiperazin-1-yl) nicotinonitrile 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 4
. 9 Hz, 1H), 7.59 (s, 1H), 6.53 (s, 1H),
6.50 (s, 1H), 6.00 (s, 1H), 4.91 (s, 1H)
, 4.55 (d, J = 10.6 Hz, 1H), 4.29 (d, J
= 11.2 Hz, 2H), 4.20 (d, J = 12.9 Hz, 1H)
), 3.82 (d, J = 13.8 Hz, 1H), 3.73 (dt,
J = 9.5, 5.8 Hz, 2H), 3.57 (t, J = 11.0
Hz, 1H), 3.39 (s, 3H), 3.30 (d, J = 12.0
Hz, 1H), 3.15 (t, J = 11.8 Hz, 1H), 3.0
7 (d, J = 12.0 Hz, 1H), 2.83-2.65 (m,
1H), 2.60 (dd, J = 13.4, 7.5 Hz, 1H),
07 (ddd, J = 12.6, 7.0, 4.8 Hz, 1H), 1.4
0 (d, J = 6.4 Hz, 2H), 1.34-1.27 (m, 1
H), 1.13 (s, 2H), 1.09-0.99 (m, 2H).
LC-MS: m / z 455.3 (M + H) +

Compound 796 (General Procedure 6)
(R) -2-cyclopropyl-6- (3-cyclopropyl-4- (3- (furan-2-
Yl) propanoyl) piperazin-1-yl) -4-methyl-2'-vinyl-3,4'-
Bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ 8.69 (d, J = 5.0 Hz,
1H), 7.31-7.38 (m, 1H), 7.23 (s, 1H),
7.07 (d, J = 4.1 Hz, 1H), 6.88 (dd, J =
17.6, 10.9 Hz, 1H), 6.21-6.40 (m, 2H)
, 6.06 (d, J = 2.9 Hz, 1H), 5.57 (d, J =
11.4 Hz, 1H), 4.22 (d, J = 12.6 Hz, 2H)
2.93-3.18 (m, 4H), 2.72 (br. S., 2H)
, 2.21 (s, 3H), 1.33-1.62 (m, 2H), 1.0
3-1.33 (m, 3H), 0.87 (dd, J = 7.9, 3.2
Hz, 2H), 0.44 (br. S., 4H).
LC-MS: m / z 508.6 (M + H) +

Compound 797 (General Procedure 6)
(R) -6- (4- (3-Cyclopentylpropanoyl) -3-cyclopropylpiperazin-1-yl) -2-cyclopropyl-4-methyl-2'-vinyl-3,4'-bipyridine-5 -Carbonitrile 1H NMR (chloroform-d) δ 8.69 (d, J = 4.7 Hz,
1H), 7.23 (s, 1H), 7.07 (d, J = 4.4 Hz,
1H), 6.87 (dd, J = 17.5, 10.7 Hz, 1H),
6.12-6.41 (m, 1H), 5.41-5.69 (m, 1H)
, 4.19-4.48 (m, 2H), 3.96-4.19 (m, 1
H), 3.80 (br.s., 1H), 3.15 (br.s., 2H)
, 3.04 (br. S., 1H), 2.28-2.49 (m, 2H)
, 2.21 (s, 3H), 1.86 (br. S., 1H), 1.80
(Br.s., 3H), 1.47-1.72 (m, 8H), 1.11.
(Br.s., 4H), 0.73-1.00 (m, 3H), 0.60
(Br.s., 1H), 0.55 (br.s., 1H), 0.23 −
0.50 (m, 2H).
LC-MS: m / z 510.7 (M + H) +

Compound 804 (General Procedure 5)
(R) -Di-tert-butyl 4- (4- (5-cyano-2-cyclopropyl-2′-
Vinyl-3,4′-bipyridin-6-yl) -2-cyclopropylpiperazin-1-yl) -4-oxobutylphosphate 1H NMR (chloroform-d) δ 8.66 (d, J = 5.0 Hz
, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.25
(Dd, J = 5.1, 1.6 Hz, 1H), 6.89 (dd, J =
17.6, 10.9 Hz, 1H), 6.30 (d, J = 16.7 H
z, 1H), 5.58 (d, J = 11.2 Hz, 1H), 4.56
(D, J = 12.9 Hz, 1H), 4.35-4.49 (m, 1H
), 3.99-4.20 (m, 3H), 3.71-3.84 (m,
1H), 2.99-3.22 (m, 2H), 2.53 (d, J = 5
. 9 Hz, 1H), 2.00-2.07 (m, 3H), 1.66 (d
, J = 12.3 Hz, 3H), 1.52 (s, 18H), 1.18
-1.25 (m, 2H), 0.98-1.06 (m, 2H), 0.6
2 (br. S., 1H), 0.56 (br. S., 1H), 0.47
(D, J = 5.0 Hz, 2H)
LC-MS: m / z 650.3 (M + H) +

Compound 560 (General Procedure 7)
(R) -6-cyclopropyl-2- (3-cyclopropyl-4- (3,3,3-trifluoropropanoyl) piperazin-1-yl) -5- (quinolin-4-ylamino) nicotinonitrile 1H NMR (chloroform-d) δ 8.55 (d, J = 5.5 Hz)
, 1H), 8.11 (d, J = 8.3 Hz, 1H), 8.03 (d
, J = 8.3 Hz, 1H), 7.80 (t, J = 7.3 Hz,
1H), 7.71 (s, 1H), 7.63 (t, J = 7.7 Hz,
1H), 6.36 (d, J = 5.5 Hz, 1H), 4.52 (d,
J = 13.3 Hz, 1H), 4.41 (d, J = 13.8 Hz,
1H), 4.15 (br.s., 1H), 3.69-3.86 (m,
2H), 3.12-3.35 (m, 4H), 2.01-2.13 (m
, 1H), 1.33-1.35 (m, 1H), 1.12-1.21
(M, 2H), 0.95-1.07 (m, 2H), 0.45-0.7
3 (m, 4H)
LC-MS: m / z 521.2 (M + H) +

Compound 617 (General Procedure 7)
(R) -6-cyclopropyl-2- (4- (3-hydroxypropanoyl) -3-methylpiperazin-1-yl) -5- (6-vinylpyrimidin-4-ylamino) nicotinonitrile 1H NMR ( Chloroform-d) δ 8.58-8.68 (m, 1H)
, 7.72-7.80 (m, 1H), 6.90-7.01 (m, 1
H), 6.53-6.66 (m, 1H), 6.35-6.48 (m,
1H), 6.27 (s, 1H), 5.62 (dd, J = 10.5,
1.3 Hz, 1H), 4.90 (br.s., 0.5H), 4.54 (
d, J = 13.6 Hz, 0.5H), 4.11-4.34 (m, 2
. 5H), 3.93 (br.s., 2H), 3.74 (d, J = 13
. 6 Hz, 0.5H), 3.50-3.65 (m, 0.5H), 3.4
5 (br.s., 0.5H), 3.23-3.32 (m, 1H), 3
. 10-3.20 (m, 0.5H), 2.98-3.09 (m, 0. 0).
5H), 2.48-2.76 (m, 2H), 2.08-2.16 (m
, 1H), 1.42 (d, J = 6.5 Hz, 1.5H), 1.32
(D, J = 6.8 Hz, 1.5H), 1.10-1.20 (m, 2
H), 0.97-1.09 (m, 2H)
LC-MS: m / z 434.3 (M + H) +

Compound 700 (General Procedure 5)
(R) -5- (2-Amino-6-vinylpyrimidin-4-yl) -2- (4- (cyclopropanecarbonyl) -3-cyclopropylpiperazin-1-yl) -6-cyclopropylnicotinonitrile 1H NMR (chloroform-d) δ 7.97 (s, 1H), 6.89
(S, 1H), 6.66 (dd, J = 17.3, 10.5 Hz, 1H
), 6.52 (d, J = 17.8 Hz, 1H), 5.74 (d, J
= 10.5 Hz, 1H), 5.41 (br. S., 2H), 4.66.
(D, J = 12.5 Hz, 1H), 4.52 (d, J = 12.5)
Hz, 1H), 3.16-4.28 (m, 5H), 2.33-2.
49 (m, 1H), 1.72 (br.s., 2H), 1.21-
26 (m, 2H), 0.98-1.15 (m, 4H), 0.82 (d
d, J = 7.8, 2.3 Hz, 2H), 0.63 (br.s., 1
H), 0.36-0.58 (m, 3H)
LC-MS: m / z 456.4 (M + H) +

Compound 751 (General Procedure 7)
6-cyclopropyl-2-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -5- (2-vinylpyridine- 4
-Ylamino) nicotinonitrile 1H NMR (chloroform-d) δ 8.24 (d, J = 5.9 Hz)
, 1H), 7.62 (s, 1H), 6.70 (dd, J = 17.3,
10.9 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H),
6.49 (d, J = 5.9 Hz, 1H), 6.19 (d, J =
17.6 Hz, 1H), 6.04 (br.s., 1H), 5.53 (d
, J = 10.9 Hz, 1H), 5.27 (quin, J = 6.7).
Hz, 1H), 4.69-4.79 (m, 1H), 4.42-4.5
8 (m, 2H), 4.35 (d, J = 12.9 Hz, 1H), 4.
09 (d, J = 8.8 Hz, 1H), 3.95 (d, J = 13.
8 Hz, 1H), 3.67-3.82 (m, 1H), 2.75-3
. 34 (m, 5H), 2.55 (d, J = 9.1 Hz, 1H), 2
. 08 (td, J = 8.1, 4.0 Hz, 1H), 1.33 (br.
s. , 1H), 1.10-1.18 (m, 2H), 1.03 (dd,
J = 7.8, 3.4 Hz, 2H), 0.63 (br.s., 1H)
, 0.55 (br.s., 1H), 0.47 (d, J = 5.9 Hz)
, 2H)
LC-MS: m / z 485.6 (M + H) +

Compound 752 (General Procedure 5)
2-cyclopropyl-6-((R) -3-cyclopropyl-4- (2-((R) -oxetan-2-yl) acetyl) piperazin-1-yl) -2'-vinyl-3,4 '-Bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ 8.66 (d, J = 5.0 Hz,
1H), 7.65 (s, 1H), 7.35-7.46 (m, 1H),
7.23 (dd, J = 5.1, 1.6 Hz, 1H), 6.88 (d
d, J = 17.5, 10.7 Hz, 1H), 6.21-6.36 (
m, 1H), 5.49-5.61 (m, 1H), 5.27 (quin,
J = 6.6 Hz, 1H), 4.72 (td, J = 7.9, 6.2)
Hz, 1H), 4.50-4.65 (m, 2H), 4.44 (d,
J = 12.9 Hz, 1H), 4.09 (d, J = 8.2 Hz, 0
. 6H), 3.84-4.02 (m, 0.7H), 3.74 (t, J
= 12.0 Hz, 0.7H), 3.25 (br.s., 1H), 2.9
1-3.23 (m, 3.5H), 2.55-2.9 (m, 2.5H)
, 2.55 (d, J = 8.8 Hz, 1H), 1.97-2.11.
(M, 1H), 1.33 (br.s., 1H), 1.18-1.26.
(M, 2H), 0.94-1.07 (m, 2H), 0.63 (br.
s. , 1H), 0.56 (br. S., 1H), 0.47 (br. S.
, 2H)
LC-MS: m / z 470.2 (M + H) +

Compound 800 (General Procedure 5)
2-cyclopropyl-6-((3R) -3-cyclopropyl-4- (3- (tetrahydrofuran-2-yl) propanoyl) piperazin-1-yl) -2'-vinyl-3,4 '
-Bipyridine-5-carbonitrile 1H NMR (chloroform-d) δ: 8.63 (d, J = 5.3 Hz)
, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.21
(Dd, J = 5.0, 1.5 Hz, 1H), 6.86 (dd, J =
17.5, 10.7 Hz, 1H), 6.26 (d, J = 17.6 H
z, 1H), 5.54 (d, J = 10.9 Hz, 1H), 4.53
(D, J = 12.9 Hz, 1H), 4.41 (d, J = 12.6)
Hz, 1H), 4.00-4.22 (m, 1H), 3.85 (d, J
= 6.5 Hz, 3H), 3.62-3.77 (m, 2H), 3.0
8-3.29 (m, 3H), 2.31-2.60 (m, 2H), 1
. 83-2.11 (m, 5H), 1.68-1.83 (m, 1H),
1.46-1.58 (m, 1H), 1.20 (dt, J = 7.3)
3.6 Hz, 2H), 0.93-1.07 (m, 2H), 0.49
-0.76 (m, 2H), 0.43 (br. S., 2H)
LC-MS: m / z 498.7 (M + H) +

Although several aspects of several embodiments have been described in this manner, it should be appreciated that various changes, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the above detailed description and drawings are merely examples.

Claims (1)

  Invention described in the specification.