EA043056B1 - SUBSTITUTED NITROGEN-CONTAINING COMPOUNDS - Google Patents

Description

The present application claims priority under Indian Provisional Patent Application No. 201811004486 filed Feb. 6, 2018 and Indian Provisional Patent Application No. 201711019293 filed June 1, 2017, the contents of which are expressly incorporated herein by reference.

The present invention generally relates to substituted nitrogen-containing heterocyclic compounds useful as inhibitors of ROMK channel activity. This document provides substituted nitrogen-containing compounds, compositions containing such compounds, and methods of using them. The present invention also relates to pharmaceutical compositions containing at least one compound of the present invention, which are useful for the treatment of pathological conditions associated with the activity of the ROMK channel, including cardiovascular diseases.

Background of the Invention

The renal external medullary potassium channel (ROMK, Kir1.1) is a weak internal rectifying K+ channel that plays a key role in renal K+ recycling and secretion (Ho et al., Nature, 1993, 362, 31-38; Shuck et al., The Journal of Biological Chemistry, 1994, 269(39), 24261-24270; Lee and Hebert, American Journal of Physiology-Renal Physiology, 1995, 268(6), F1124-F1131; Lu et al., The Journal of Biological Chemistry, 2002, 277, 37881-37887; and Hebert et al., Physiological Reviews, 2005, 85:319371). In the thick ascending knee (TAL) of the nephron, ROMK channel activity provides a K+ gradient that is required for Na and Cl reabsorption via the Na ⁺ -K ⁺ -2CF co-transporter (NKCC2). In the distal convoluted tubule (DCT) and cortical collecting tubule (CCD), ROMK channels form the main secretory pathway for K ⁺ and, as a result, play an important role in K ⁺ homeostasis under physiological conditions (Welling and Ho, American Journal of Physiology-Renal Physiology, 2009, 297(4): F849-F863).

Ample evidence suggests that inhibition of ROMK channel activity results in natriuresis, diuresis, and a decrease in blood pressure. Therefore, inhibition of ROMK may offer a novel mechanism for the regulation of blood pressure and diuresis in patients suffering from hypertension, congestive heart failure, or any other edematous disease state. NKCC2 transporter activity is closely related to ROMK activity in the TAL region, and homozygous mutations with loss of ROMK function in humans lead to the development of a disease phenotype (renal salt wasting syndrome, elevated aldosterone levels, metabolic alkalosis, decreased blood pressure) that is very similar to that of homozygous NKCC2 mutations but with milder hypokalemia (Simon et al., Nature Genetics, 1996, 14: 152-156). In addition, people who were found to have heterozygous ROMK mutations in the Framingham Heart Study have been observed to have reduced blood pressure (Ji et al., Nature Genetics, 2008, 40(5): 592-599). Similar to human genetics, mouse genetics also supports a role for ROMK in kidney Na ⁺ reabsorption and regulation of total blood pressure (Lu et al., The Journal of Biological Chemistry, 2002, 277, 37881-37887; and Lorenz et al., The Journal of Biological Chemistry, 2002, 277: 37871-37880). In addition, pharmacological blockade of the ROMK channel has been shown to induce single dose natriuresis and diuresis in rats and dogs both single and long term (Tang et al., Bioorganic and Medicinal Chemistry Letter, 2013, 23:5829- 5832; Garcia et al., The Journal of Pharmacology and Experimental Therapeutics, 2014, 348: 153-164; Walsh et al., ACS Medicinal Chemistry Letters, 2015, 6: 747-752; and Dajee et al., Circulation, 2014 , 130: A12397). Since the ROMK channel is also involved in the regulation of net K ⁺ secretion in the distal nephron, inhibition of ROMK in this region is thought to reduce K ⁺ loss and hypokalemia associated with loop and thiazide diuretics. Single or prolonged (up to 122 days) antagonism of ROMK does not result in kaliuresis or hypokalemia in dogs (Garcia et al., The Journal of Pharmacology and Experimental Therapeutics, 2014, 348: 153-164; Walsh et al., ACS Medicinal Chemistry Letters, 2015, 6: 747-752; Dajee et al., Circulation, 2014, 130: A12397). Taken together, these data suggest that ROMK inhibition may result in diuretic efficacy that is equivalent to or better than currently available loop diuretics and with a potentially lower incidence of hypokalemia.

WO 2015/095097 discloses compounds useful as ROMK inhibitors. Other publications that disclose compounds useful as ROMK inhibitors include

- 1 043056

WO 2010/129379, WO 2010/136144, WO 2012/058116, WO

2012/058134, WO 2013/028474, WO 2013/039802, WO 2013/062892, WO 2013/062900, WO

2013/066714, WO 2013/066717, WO 2013/066718, WO 2013/090271, WO 2014/015495, WO

2014/018764, WO 2014/085210, WO 2014/099633, WO 2014/126944, WO 2014/150132, WO

2015/017305, WO 2015/065866, WO 2015/095097, WO 2015/100147, WO 2015/105736, WO

2016/008064, WO 2016/010801, WO 2016/010802, WO2016/060941, WO2016/065582,

WO2016/065602, WO2016/065603, WO2016/069426, WO2016/069427, WO2016/069428,

WO2016/069430, WO2016/091042, WO2016/122994, WO2016/127358, WO2016/130444, CN105693706 and WO2016/091042.

In view of the many pathological conditions that are expected to benefit from treatment involving ROMK inhibition, it is immediately apparent that new compounds capable of inhibiting ROMK and methods of using these compounds will provide significant therapeutic benefits for a wide range of patients.

The present invention relates to a new class of compounds that have proven to be effective inhibitors of ROMK.

Brief summary of the invention

The present invention relates to compounds of formula (I) which are useful as ROMK inhibitors and are useful in the treatment of cardiovascular diseases and the stimulation of diuresis or natriuresis.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and at least one of the compounds of formula (I) or stereoisomers, tautomers, salts, pharmaceutically acceptable salts, solvates or prodrugs thereof.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof.

The present invention also provides a method for inhibiting ROMK comprising administering to a recipient in need of such treatment a therapeutically effective amount of at least one of the compounds of formula (I) or stereoisomers, tautomers, salts, pharmaceutically acceptable salts, solvates or prodrugs thereof.

The present invention also relates to a method of treating cardiovascular disease comprising administering to a recipient in need of such treatment a therapeutically effective amount of at least one of the compounds of formula (I) or stereoisomers, tautomers, salts, pharmaceutically acceptable salts, solvates or prodrugs thereof.

The present invention also relates to a method of treating cardiovascular disease, comprising administering to a recipient in need of such treatment a therapeutically effective amount of at least one of the compounds of formula (I) or their stereoisomers, tautomers, salts, pharmaceutically acceptable salts, solvates or prodrugs, or alone, or in combination with other compounds of the present invention, or in combination with one or more other agents. One embodiment relates to a method for treating cardiovascular disease. In particular, cardiovascular diseases include, without limitation, arterial hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute decompensated heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, heart failure, nephrotic syndrome and acute renal failure.

One embodiment relates to a method for inducing diuresis or natriuresis.

The present invention also relates to the compounds of the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs for use in therapy.

The present invention also relates to the use of the compounds of the present invention, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, for the preparation of a medicament for the treatment of cardiovascular disease or for the induction of diuresis or natriuresis. The present invention also relates to a compound of formula (I) or a pharmaceutical composition in a kit with instructions for use of the compound or composition.

The present invention also relates to processes and intermediates for the preparation of the compounds of the present invention, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

These and other features of the present invention will be set forth below.

- 2 043056

Detailed disclosure of the invention

The first aspect of the invention relates to at least one compound of formula (I)

R

R _R 1 R ^3a R ^3b

R ² or : ^d )n where the compound of formula (I) is (3a p3b or a pharmaceutically acceptable salt thereof, where R ¹ is each R ^1a is independently -CH3;

L ¹ is -C(R)2-, -C(O)- or -C(R) ₂ -C(R) ₂ -;

where R is independently H, OH, or C _1-3 -dkyl;

where R is not -OH if it is attached to a carbon atom that is attached to a nitrogen atom;

ring B is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, oxazolyl, pyridazinyl, pyrrolidinyl or imidazolidinyl;

R ² is phenyl, pyridinyl, benzo[d]oxazol-onyl, pyrazolyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl, 1,2,3-triazolyl, imidazolyl, pyrrolo[2,3- b]pyridinyl, 1,2,4-triazolyl, pyridazinyl, pyrimidinyl, oxadiazolyl or pyrrolopyridinyl, each having 0-3 R ^2a substituents;

R ^2a is independently =O, CN, halo, C1-4alkyl, C1-4fluoroalkyl, C1-4alkoxy, C1-4deuteroalkoxy, C1-4fluoroalkoxy, C3-6cycloalkyl, C(=O )N(R ^4b R ^4b ), SO2R ^e , NR ^4b SO2R ^4b or oxazolidinyl, morpholinyl, pyrrolidinyl or dioxydoisothiazolidinyl, where oxazolidinyl, morpholinyl, pyrrolidinyl and dioxydoisothiazolidinyl optionally contain an oxo substituent and are optionally substituted with R ^2b ;

R ^2b is C _1-3 alkyl;

R ^3a is H;

R ^3b is H, or C _1-3 alkyl;

R ⁴ is H, C1-3 alkyl, CO2R ^4a , C(O)R ^4a , SO2R ^4a , or OH;

R ^4a is C _1-3 alkyl;

R ^4b is independently H or C _1-3 alkyl;

R ⁵ is independently H, F, OH, C _1-3 alkyl, NR ^5b R ^5b or OR ^5c , or 2 R ⁵ are ═O; where if one R ⁵ is F, OH or NR ^5b R ^5b then the other R ⁵ is not OH or NR ^5b R ^5b ;

- 3 043056

R ^5b is independently H, C(O)R ^a , or SO2R ^a ;

R ^5c is independently H, or C(O)NR ^b R ^b ;

R ⁶ is independently H, OH, F, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3hydroxyalkyl, C1-3hydroxydeuteroalkyl or NR ^6b R ^6b ; where if one R ⁶ on one carbon atom is F, OH or NR ^6b R ^6b , then the other R ⁶ on the same carbon atom is not OH or NR6b _R 6b _;

R ^6b is independently H, C(O)R ^a or SO2R ^a ;

R ^a is independently H, C _1-3 alkyl;

R ^b is independently H, C _1-3 alkyl;

each R ^d is independently C _1-3 alkyl, C _1-3 fluoroalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, halogen, ═O, or C(O)NR ^e R ^e ;

each R ^e is independently H or C _1-3 alkyl;

n is 0, 1, or 2.

In another aspect, disclosed herein are compounds of formula (I) wherein ring B is pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, isoxazolyl, or pyridazinyl.

In another aspect, disclosed herein are compounds of formula (I) wherein

R ² is phenyl, pyridinyl, benzo[b]oxazol-2(3H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, triazolyl, oxadiazolyl, pyrazinyl, thiophenyl, pyrazolo[1,5-a]pyrimidinyl or benzo[b]oxazole -2(3H)-onyl, each substituted with 0-3 R ^2a ; And

R ^2a is ═O, CN, halogen, SO ₂ C _1-3 -alkyl, oxazolidin-2-one, substituted with 0-1 R ^2b ;

R ^2b is C _1-3 alkyl.

In another aspect, disclosed herein are compounds of formula (I) wherein ring B is pyridinyl, triazolyl, thiazolyl, oxadiazolyl, imidazolyl, or pyrazolyl; And

R ² is phenyl, pyridinyl, pyrimidinyl, benzo[6]oxazol-2(3H)-onyl, imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each substituted with 0-3 R ^2a . In another aspect, disclosed herein are compounds of formula (I) wherein L ¹ is -C(R)2-; where R is independently hydrogen, OH or C1-3-alkyl; and R ⁶ is independently H, C1-3 alkyl, or C _1-3 fluoroalkyl. According to another aspect, disclosed herein are compounds of formula (I), wherein the compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (7?)-4-methyl-6-(4-((2-(4-methyl- 1-oxo-1,3-d-ihydroisobenzofuran-5 yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;

(7?)-4-methyl-6-(4-((3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1 H-pyrazole -1 -yl)nicotinonitrile;

(7?)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)morpholino)methyl)pyridin-2-yl)benzo[(1] oxazol-2(3N)-one;

5-(4-((4,4-d iftoro-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperide in-1 yl)methyl)-1H-pyrazole-1- yl)-3-methylbenzo[<1]oxazol-2(3H)-one;

6-(4-((4,4-d iftor-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperide in-1 yl)methyl)-1 H-pyrazole-1 -yl)-4-methylnicotinonitrile;

(7?)-6-(5-Methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazole -1 -yl)-4-methylnicotinonitrile;

(7?)-4-methyl-5-(4-((1-(2-methylthiazol-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2yl)isobenzofuran-1(3H)-one ;

(7?)-4-cyclopropyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)morpholino)methyl)-1 H-pyrazol-1-yl) nicotinonitrile;

(7?)-4-methyl-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2oxooxazolidin-3-yl)methyl)-1 H- pyrazol-1-yl)nicotinonitrile;

(7?)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5oxomorpholino)methyl)-1 H-pyrazole-1 - yl) nicotinonitrile;

- 4 043056 (K)-4-methoxy-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)morpholino)ethyl)-1 H-pyrazole-1 -yl) nicotinonitrile;

(7?)-6-(5-((2-(4-methylL-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)1,3,4-oxadiazol-2-yl)nicotinonitrile;

(7?)-4-methyl-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)-1,3, 4-oxadiazol-2-yl)nicotinonitrile;

(7?)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-imidazole -1 -yl)nicotinonitrile;

(7?)-4-methyl-6-(4-((3 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5-yl)-5 oxopiperazin-1 -yl)methyl)-1 H-pyrazol-1-yl)nicotinonitrile;

(7?)-4-methoxy-5'-((5-(4-methyl-1-oxo-1,3-d-ihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-[2 ,2'-bipyridine]-5-carbonitrile;

6-(4-(1-hydroxy-2-((7?)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1Н-pyrazole-1- yl)-4-methylnicotinonitrile (Diastereomer-I and II);

(D)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)morpholino)methyl)thiazol-2-yl)benzo[<1]oxazole -2(ZN)-he;

(7?)-3-methyl-5-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-morpholine-4carbonyl)thiazol-2-yl)benzo[с1 ]oxazol-2(3N)-one;

(R) -1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5-yl) piperazin-1 yl) methyl) thiazol-2-yl) -1 H- imidazole-4-carbonitrile;

(7?)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H-1, 2,3-triazol-2-yl)nicotinonitrile;

(7?)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 Η-1 ,2,3-triazol-1-yl)nicotinonitrile;

methyl-(7?)-4-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-2(4-methyl-1-oxo-1, 3-dihydroisobenzofuran-5-yl)piperazin-1-carboxylate;

(5)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-d-ihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl ) nicotinonitrile;

(7?)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl) benzo[c1]oxazol-2(3H)-one;

(7?)-6-(5-methoxy-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-pyrazol-1 -yl )-4-methylnicotinonitrile;

(7?)-4-methoxy-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-imidazol-1 -yl ) nicotinonitrile;

(7?)-6-(4-((2-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)morpholino)methyl)-1H

- 5 043056

-imidazol-1-yl)nicotinonitrile;

(7?)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1-yl) benzo[c1]oxazol-2(3H)-one;

(7?)-4-methyl-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol- 2-yl)nicotinonitrile;

(7?)-4-methyl-6-(4-(2-(2-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)morpholino)ethyl)-1 H-pyrazol- 1 -yl) nicotinonitrile;

(7?)-4-methoxy-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)morpholino)methyl)thiazol-2-yl)nicotinonitrile;

(7?)-4-methyl-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-morpholine-4carbonyl)thiazol-2-yl)nicotinonitrile;

(7?)-4-methoxy-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholin-4-carbonyl)thiazol-2-yl)nicotinonitrile;

(7?)-4-methoxy-5'-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-[2,2'-bipyridine]-5 -carbonitrile;

(7?)-4-methyl-5-(4-((2-(4-methyl-1H-imidazol-1-yl)thiazol-5-yl)methyl)morpholin-2yl)isobenzofuran-1(3H)- He;

(7?)-1-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl)-1H-imidazol-4 -carbonitrile;

(7?)-4-methyl-5-(4-((1-(thiophen-3-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)- He;

(7?)-4-methyl-5-(4-((1-(pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)- He;

(7?)-4-(4-((2-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;

(7?)-4-methyl-5-(4-((1-(6-methylpyrazin-2-yl)-1H-pyrazol-4-yl)methyl)morpholin-2yl)isobenzofuran-1(3H)-one ;

(/?)-5-(4-((2-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)nicotinonitrile;

(7?)-3-(4-((2-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzonitrile;

(7?)-4-methyl-5-(4-((1-(pyridin-4-yl)-1Н-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3Н)- He;

(7?)-4-methyl-5-(4-((1 -(4-(methylsulfonyl)phenyl)- 1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)- He;

- 6 043056 (7?) -2-methyl-4- (4- ((2- (4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) morpholino) methyl) -1 H-pyrazol- 1-yl)benzonitrile;

(7?)-3-methyl-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-pyrazol-1 -yl )benzonitrile;

(7?)-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) morpholino)methyl)-1H-pyrazol-1-yl)picolinonitrile;

(7?)-2-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-pyrazol-1 -yl )benzonitrile;

(7?)-4-methyl-5-(4-((1-(pyrazolo[1,5-a]pyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl) isobenzofuran-1(3N)-one;

(7?)-3-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-pyrazol-1 -yl )benzonitrile;

(7?)-4-methyl-6-(3-methyl-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)morpholino)methyl)-1Н-pyrazole-1 -yl) nicotinonitrile;

(7?)-4-methyl-6-(3-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1 H-pyrazol-1 -yl ) nicotinonitrile;

(5)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1 H-pyrazol- 1 -yl) nicotinonitrile;

(7?)-5-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol- 1-yl)-3-methylbenzo[(1]oxazol-2(3H)-one;

(7?)-7-fluoro-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)- 1 H-pyrazol-1-yl)benzo[<1]oxazol-2(3H)-one;

(7?)-7-methoxy-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl) -1H-pyrazol-1-yl)benzo[<1]oxazol-2(3H)-one;

(7?)-3,7-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)-1 H -pyrazol-1-yl)benzo[<1]oxazol-2(3H)-one;

(7?)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazole -1-yl)benzo[<1]oxazol-2(3H)-one;

(7?)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazole -1 -yl)nicotinonitrile;

(7?)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-1, 2,3-triazol-1-yl)benzo[<1]oxazol-2(3H)-one;

(//)-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxad iazole -2-yl)nicotinonitrile;

(7?)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)- 7 043056 piperazin-1-yl)methyl)-[2, 2'-bipyridine]-5-carbonitrile;

(R)-1 -(5-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H- pyrazole-4-carbonitrile;

(R)-1 -(5-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)-1H- imidazole-4-carbonitrile;

(7?)-4-methyl-5-(4-((6-(4-methyl-1 H-imide azol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran- 1(ZN)-he;

(7?)-4-methyl-5-(4-((6-(3-methyl-1 Η-1,2,4-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2 -yl)isobenzofuran-1(3H)-one;

(7?)-6-(4-((4-Acetyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazole -1 -yl)-4-methylnicotinonitrile;

(7?)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4(methylsulfonyl)piperazin-1-yl)methyl )-1 H-pyrazol-1 -yl) nicotinonitrile;

(7?)-4-methyl-6-(4-((4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)- 1 H-pyrazol-1 -yl)nicotinonitrile;

(7?)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H -pyrazol-1-yl)benzo[(1]oxazol-2(3H)-one;

(7?)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1 -yl)methyl)-1 Η-1,2,3-triazol-1-yl)benzo[<1]oxazol-2(3H)-one;

(7?)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)pyridin-2-yl) -1 Η-1,2,4-triazole-3-carbonitrile;

(7?)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-[2, 2'-bipyridine]-5-carbonitrile;

(7?)-6-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5-yl)-4-((6-(3-methyl-1 Η-1,2,4triazol- 1 - yl)pyridin-3-yl)methyl)piperazin-2-one;

(7?)-6-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5-yl)-4-((6-(4-methyl-1-nimidazol-1-yl)pyridin-3-yl )methyl)piperazin-2-one;

(7?)-4-methyl-6-(4-((4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)5-oxopiperazin-1 -yl)methyl )-1 H-pyrazol-1 -yl) nicotinonitrile;

(7?)-4-methoxy-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolide in-3-yl)methyl)- 1 H-imide azol-1-yl)nicotinonitrile;

(7?)-6-(5-methoxy-4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolid in-3-yl)methyl)- 1 H-pyrazol-1-yl)-4-methylnicotinonitrile;

(7?)-3-methyl-5-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolid in-3-yl)methyl)- 1 H-pyrazol-1-yl)benzo[<1]oxazol-2(3H)-one;

- 8 043056

6-(4-(((37?, 5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5yl)piperazin-1-yl)methyl) -1 H-pyrazol-1 -yl)-4-methylnicotinonitrile;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 1 Η-1,2,3-triazol-1-yl)-4-methylnicotinonitrile;

2,4-dimethyl-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl) methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile;

4-Methoxy-2-methyl-6-(4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1-yl )methyl)-1 Η-1,2,3-triazol-1 yl)nicotinonitrile;

6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl )-4-methylnicotinonitrile, (Enantiomer-III);

6-(4-((3 -(hydroxymethyl)-5 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 Η-1,2,3 -triazol-1 -yl)-4-methylnicotinonitrile, (Enantiomersh);

6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl )-4-methoxynicotinonitrile, (Enantiomer-III);

6-(4-((3 -(hydroxymethyl-b2)-5 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 H-pyrazol- 1 -yl)-4-methylnicotinonitrile, (Enantiomer-1);

- (5 - (((37?, 5R) -3 - (hydroxymethyl) -5 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) pyridine -2-yl)-3-methyl-1 H-pyrazole-4-carbonitrile;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 1 H-pyrazol-1-yl)-2,4-dimethylnicotinonitrile;

2-methoxy-6-(4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 1 H-pyrazol-1 -yl)nicotinonitrile;

-((27?, 65)-4-((2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran -1 (ZN) -one;

4,6-dimethyl-2-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl) methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile;

4-methyl-2-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -1 H-pyrazol-1 -yl)pyrimidine-5-carbonitrile;

4-methoxy-6-(4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 1 H-imidazol-1 -yl)nicotinonitrile;

4-methyl-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -1 H-imidazol-1 -yl)nicotinonitrile;

4-methyl-2-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 - 9 043056 yl) piperazin-1 -yl )methyl)-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;

2-methoxy-4-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -1 H-imidazol-1 -yl)benzonitrile;

4-methyl-5 -((27?, 65)-6-methyl-4-((1 -(2-methylpyride in-4-yl)-1 H-pyrazol-4yl)methyl)piperazin-2-yl) isobenzofuran-1(3N)-one;

4-methoxy-2-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -1 H-imidazol-1 -yl)pyrimidine-5-carbonitrile;

2-(4-(((37?, 57?)-3 -(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl) -2H-1,2,3-triazol-2-yl)-4-methylpyrimidine-5-carbonitrile;

4-methyl-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -1 H-pyrazol-1 -yl)nicotinonitrile;

4-methyl-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) - 1H-1,2,3-triazol-1-yl)nicotinonitrile;

4-methoxy-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -2H-1,2,3-triazol-2-yl)nicotinonitrile;

-methyl-1 -(5-(((35.57?)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) pyrimide in-2-yl)-1 H-pyrazole-4-carbonitrile;

-(4-(((37?, 57?)-3 -(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)- 2H-1,2,3-triazol-2-yl)-3-methylbenzo[<1]oxazol-2(3H)-one;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 2H-1,2,3-triazol-2-yl)-4-methoxynicotinonitrile;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 1 H-pyrazol-1 -yl)-4-methoxynicotinonitrile;

4,4-methyl-6-(5-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)thiazol-2-yl)nicotinonitrile;

6-(4-((4-hydroxy-4-methyl-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)-1 H-pyrazol- 1 -yl)-4-methylnicotinonitrile;

4-methyl-6-(4-((2-methyl-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 H-pyrazol- 1 -yl) nicotinonitrile;

6-(4-((4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)-1 H -pyrazol-1 -yl)-4-methylnicotinonitrile;

4-methyl-6-(5 -(((35.57?)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl )-2-oxooxazol-3(2H)-yl)nicotinonitrile;

(7?)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)-2oxoimidazolidin-1-yl)methyl)- 177- pyrazol-1-yl)nicotinonitrile;

- 10 043056 (7?) -4-methyl-6- (4- ((4- (4-methyl-1 -oxo-1,3 - dihydroisobenzofuran-5 -yl) -1,1 dioxydo-1,2,5 -thiadiazolidin-2-yl)methyl)-17/-pyrazol-1-yl)nicotinonitrile;

2-methyl-6-(5 -(((3 S, 5R)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) pyridin-2-yl)pyridazin-3(2H)-one;

4-methyl-6-(4-(1 -((7?)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)ethyl)-2H-1, 2,3-triazol-2-yl)nicotinonitrile (Diastereomer-1:Enantiomer-1);

4-methyl-6-(4-(1 -((7?)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)ethyl)-2H-1, 2,3-triazol-2-yl)nicotinonitrile (Diastereomer-P:Enantiomer-1);

4-methyl-6-(3-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 1 Η-1,2,4-triazol-1-yl)nicotinonitrile;

6-(4-((2-(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl )-4-methylnicotinonitrile (DiastereomerGEnantiomer-!);

6-(4-((2-(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl )-4-methylnicotinonitrile (Diastereomer 1:Enantiomer-P);

6-(5-(((37?,47?)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperidin-1-yl)methyl)thiazol-2- yl)-4-methylnicotinonitrile;

-((27?, 65)-4-((1-(2-methoxypyridin-4-yl)-\H-imide azol-4-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran- 1 (377) - he;

5-((27?,65)-4-((1-(2-(difluoromethyl)pyridin-4-yl)-17/-pyrazol-4-yl)methyl)-6methylpiperazin-2-yl)-4- methylisobenzofuran-1 (377) -one;

4-methyl-5 -((27?, 65)-6-methyl-4-(( 1 -(2-(trifluoromethyl)pyridin-4-yl)- 17/-pyrazol-4yl)methyl)piperazin-2- yl)isobenzofuran-1(377)-one;

-(difluoromethyl)-4-(4-(((3 S, 5R)-3 -methyl-5 -(4-methyl-1 -oxo-1,3dihydroisobenzofuran-5 -yl)piperazin-1 -yl)methyl) -1 H-pyrazol-1 -yl)pyridin-2( 1 H)-one;

- (5 - (((37?, 57?) -3 - (hydroxymethyl) -5 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) pyridin-2-yl)-3-methyl-1 H-pyrazole-4-carbonitrile;

-(difluoromethyl)-4-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1 -oxo-1,3d ihydroisobenzofuran-5 -yl)piperazin-1 -yl) methyl)-1H-imide azol-1-yl)pyridin-2( 177)-one;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperidin-1 -yl)methyl)oxazol- 2-yl)-4-methylnicotinonitrile;

4-methyl-6-(5 -(((35.57?)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl )oxazol-2-yl)nicotinonitrile;

5-((27?,65)-4-((1-(6-(difluoromethyl)pyridin-3-yl)-17/-imidazol-4-yl)methyl)-6- 11 043056 methylpiperazin-2-yl )-4-methylisobenzofuran-1 (3 D)-one;

(7?)-3,4-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 1//- pyrazol-1-yl)benzo[c!]oxazol-2(3D)-one;

(R) -1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyride in-2-yl) -\H -pyrazole-3-carbonitrile;

(7?)-4-ethoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1//-pyrazole -1 -yl)nicotinonitrile;

(R)-1 -(5-((3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 -yl)piperazin-1 yl)methyl)pyridin-2-yl)-1// -pyrazole-4-carboxamide;

(7?)-5-(4-((2-(2,4-dimethyl-1//-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2yl)-4-methylisobenzofuran-1 ( ZYA) - he;

(7?)-4-isopropoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)- 1//-pyrazole -1 -yl)nicotinonitrile;

(7?) -4-methyl-5 - (4- ((4-methyl-6- (4-methyl-1 H-imidazol-1 -yl) pyride in-3 yl) methyl) piperazin-2-yl) isobenzofuran-1(3N)-one;

(7?) -4-methyl-5 - (4- ((2-methyl-6- (4-methyl-1 H-imidazol-1 -yl) pyride in-3 yl) methyl) piperazin-2-yl) isobenzofuran-1(3N)-one;

(7?)-4,6'-dimethoxy-5'-((3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)-[2,2' -bipyridine]-5-carbonitrile;

(7?)-5 - (4- ((5 -fluoro-6- (4-methyl-1 H-imidazol-1 -yl) pyridin-3 -yl) methyl) piperazin-2yl) -4-methylisobenzofuran- 1 (ZN) -on;

(7?)-4-methyl-6-(3-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl)nicotinonitrile;

(7?)-4-methyl-6-(5-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol-1-yl)nicotinonitrile;

(7?)-4-methyl-5 - (4- ((6- (4-methyl-1 H-imidazol-1 -yl) -4- (trifluoromethyl) pyridin-3 yl) methyl) piperazin-2- yl)isobenzofuran-1(3H)-one;

(7?)-5 - (4- ((2- (4,5 -dimethyl-1 H-imidazol-1 -yl) pyrimide in-5 -yl) methyl) piperazin-2yl) -4-methylisobenzofuran-1 ( ZN) -he;

(7?)-5 - (4- ((4-methoxy-6- (4-methyl-1 H-imidazol-1 -yl) pyride in-3 -yl) methyl) piperazin2-yl) -4-methylisobenzofuran- 1 (ZN) -on;

(7?)-5 - (4- ((2- (5 - (difluoromethyl) -4-methyl-1 H-imidazol-1 -yl) pyrimide in-5 yl) methyl) piperazin-2-yl) - 4-methylisobenzofuran-1 (3N)-one;

4,6-dimethyl-2-(4-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl )-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;

- 12 043056

3-(3 -methyl-5 -(4-(((3S, 5R)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl)piperazin-1 - yl)methyl)-1H-pyrazol-1-yl)phenyl)oxazolidin-2-one;

(7?)-4-methyl-5 -(4-((6-(4-methyl-1 H-imide azol-1 -yl) pyride azin-3 -yl) methyl) piperazin2-yl) isobenzofuran-1 (ZN) -he;

4-methoxy-6-(3-(((/?)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-1);

4-methoxy-6-(3-(((7?)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)methyl)pyrrolidin-1-yl)nicotinonitrile (Diastereomer-P);

4-methyl-6-(3-(((R)-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)pyrrolidin-1-yl) nicotinonitrile (Diastereomer-1);

4-methyl-6-(3-(((/?)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)pyrrolidin-1-yl) nicotinonitrile (Diastereomer-P);

4-methyl-6-(4-(((7?)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2-oxopyrrolidin-1 -yl) nicotinonitrile (Diastereomer-P);

4-methoxy-6-(4-(((7?)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)methyl)-2-oxopyrrolidin-1 - yl) nicotinonitrile (Diastereomer-1);

4-methyl-6-(5-(((R)-3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2-oxooxazolidin-3 -yl) nicotinonitrile (Diastereomer-P);

4-methyl-5-((27?,60)-6-methyl-4-((1-(5-(methylsulfonyl)pyridin-2-yl)-1Н-pyrazol-4 yl)methyl)piperazin-2 -yl)isobenzofuran-1(3H)-one;

4-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 1 H-imide azol-1-yl)-2-methoxybenzonitrile;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 1 H-imide azol-1-yl)-4-methylnicotinonitrile;

4-methyl-2-(4-(((35.5R)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)- 1 H-imidazol-1-yl)pyrimidine-5-carbonitrile;

4-methyl-5-((27?,65)-6-methyl-4-((6'-(methylsulfonyl)-[2,3'-bipyridine]-5yl)methyl)piperazin-2-yl)isobenzofuran- 1(ZN)-he;

4-methoxy-2-(4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)- 2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile;

4-methoxy-2-(2-methyl-4-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1 H-imidazol-1 -yl) pyrimide in-5 carbonitrile;

(7?) -4-methoxy-6- (4- ((3 - (4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5-yl) piperazin1 -yl) methyl) -2H-1,2, 3-triazol-2-yl)nicotinonitrile;

- 13 043056 (7?) -4-methyl-6- (4-methyl-5 - ((3 - (4-methyl-1 -oxo-1,3 - dihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl )-2H-1,2,3-triazol-2-yl)nicotinonitrile;

4-methoxy-6-(4-(((35.57?)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl) -2-oxopyrrolidin-1 -yl)nicotinonitrile (Diastereomer-1);

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4methoxynicotinonitrile;

6-(3-isopropyl-4-(((3S, 57?)-3-methyl-5-(4-methyl-1-oxo-1,3-d-ihydroisobenzofuran5-yl)piperazin-1-yl)methyl )-2-oxo-2,3-dihydro-1 H-imidazol-1 -yl)-4-methoxynicotinonitrile;

-methyl-4-(((35.57?)-3 -methyl-5 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 -( 2-methylpyrimidin-4-yl)-1,3-d ihydro-2H-imidazol-2-one;

- (5- (((35.57?) -3 -methyl-5 - (4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl) piperazin-1-yl) methyl) - [2.4 '-bipyridine]-2'-yl)oxazolidin-2-one;

6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-5-methyl-2H-1, 2,3-triazol-2-yl)-4-methylnicotinonitrile (Enantiomer-1);

4-methyl-6-(5-methyl-4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3d ihydroisobenzofuran-5-yl)piperazin-1 - yl) methyl)-1 Η-1,2,3-triazol-1 yl) nicotinonitrile;

(7?)-4-methyl-5-(4-((1 -(1-methyl- N-pyrrolo[2,3-b]pyridin-4-yl)- N-pyrazol-4yl)methyl)morpholine- 2-yl)isobenzofuran-1 (3R)-one;

4-methyl-5-((27?, 65)-6-methyl-4-((1-(p-tolyl)- 177-imide azol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (377 )-He;

4-methyl-5-((27?, 65)-6-methyl-4-((1-(3-methylpyride in-4-yl)- 17/- and mide azol-4yl)methyl)piperazin-2 -yl)isobenzofuran-1 (ZYA) ^-one ;

4-methyl-5-((27?, 65)-6-methyl-4-((1-(6-methylpyride in-3-yl)- 17/- and mide azol-4yl)methyl)piperazin-2 -yl)isobenzofuran-1 (ZYA) ^-one ;

5-((27?,65)-4-((1-(2,6-dimethylpyridin-4-yl)-1H-imidazol-4-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran- 1 (377) - he;

-((27?, 65)-4-(( 1 -(2,2-difluorobenzo[<1] [1,3] dioxol-5-yl)- 1H-imide azol-4-yl)methyl)-6 methylpiperazin-2-yl)-4-methylisobenzofuran-1 (377)-one;

(7?)-4-methyl-6-(2-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)pyrimidin-5-yl ) nicotinonitrile;

(7?)-2,4-d imethyl-6-(4-((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) -2H -1,2,3-triazol-2-yl)nicotinonitrile;

- 14 043056 (7/)-3 -(2-(4-((3 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) -1 H -pyrazol-1 -yl)pyridin-4-yl)oxazolidin-2-one;

(7/)-2,4-dimethyl-6-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)- 1H- 1,2,3-triazol-1-yl)nicotinonitrile;

(7/)-4-methoxy-2-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)- 1H- 1,2,3-triazol-1-yl)nicotinonitrile;

(7/)-4-methoxy-2-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)-2H- 1,2,3-triazol-2-yl)nicotinonitrile;

(7/)-2-methoxy-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)- 1H- 1,2,3-triazol-1-yl)nicotinonitrile;

6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2H-1,2,3- triazol-2-yl)-4-methoxynicotinonitrile (Enantiomer-1);

4-methoxy-6-(4-(2-((35.57/)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl) piperazin-1 -yl) ethyl)-1 H-pyrazol-1 -yl) nicotinonitrile;

6-(5-(((37/,47/)-4-hydroxy-3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)isoxazole -3-yl)-4-methylnicotinonitrile;

5-((27/.65)-4-((1-(4-methoxy-1,3,5-triazin-2-yl)-1 H-pyrazol-4-yl)methyl)-6methylpiperazin-2- yl)-4-methylisobenzofuran-1 (3N)-one;

6-(4-(((37/, 57/)-3-(hydroxymethyl)-4-methyl-5-(4-methyl-1-oxo-1,3d ihydroisobenzofuran-5-yl)piperazin-1- yl) methyl)-1H-pyrazol-1-yl)-4methylnicotinonitrile;

6-(4-(((35.57/)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)-1 H-pyrazole -1 -yl)-4-(trifluoromethyl)nicotinonitrile;

4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperid in-1 yl)methyl)-1 H-pyrazole-1- yl) nicotinonitrile (Enantiomer-1);

(7/)-2-(4-((3-(4-methyl-1-oxo-1,3-d-ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1 H-pyrazol-1-yl )isonicotinonitrile;

6-(4-((3-hydroxy-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperide in-1 yl)methyl)-1 H-pyrazol-1-yl) -4-methylnicotinonitrile (Enantiomer-IV);

6-(4-((3-methoxy-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperidin-1 yl)methyl)-1 H-pyrazol-1-yl) -4-methylnicotinonitrile (Enantiomer-P);

(7/)-5-(4-((2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyrimidin-5-yl)methyl)piperazin2-yl)-4- methylisobenzofuran-1 (3N)-one;

-methyl-2-(4-(((35.57/)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)- 1 H-pyrazol-1 -yl)isonicotinonitrile;

- 15 043056

6-(4-((3-fluoro-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperid in-1 yl)methyl)-1H-1,2,3 -triazol-1-yl)-4-methylnicotinonitrile yl (Enantiomer-1);

6-(4-((3-(1-hydroxyethyl)-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol- 1 -yl)-4-methoxynicotinonitrile (Enantiomer-1);

6-(4-((3 -(difluoromethyl)-5 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 H-pyrazol-1 -yl)-4-methylnicotinonitrile (Enantiomer-1);

4-methyl-5-((27?, 65)-6-methyl-4-((1-(5-methylpyrazin-2-yl)-1 H-pyrazol-4yl)methyl)piperazin-2-yl)isobenzofuran -1(ZN)-he;

5-((27?,65)-4-((1-(6-methoxypyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran-1 ( ZN) -he;

5-((27?,65)-4-((1-(2-methoxypyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran-1 ( ZN) -he;

4-methyl-5-((27?, 65)-6-methyl-4-((1-(2-methylpyrimidin-5-yl)-1 H-pyrazol-4yl)methyl)piperazin-2-yl)isobenzofuran -1(ZN)-he;

4-methyl-6-(3-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)isoxazole -5-yl)nicotinonitrile;

6-(4-((3-hydroxy-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolide in1-yl)methyl)-1 H-pyrazol-1-yl)- 4-methylnicotinonitrile (Diastereomer-I: Enantiomer-1);

6-(4-((3-fluoro-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidin-1 yl)methyl)-1 H-pyrazol-1-yl)- 4-methylnicotinonitrile (Diastereomer-I: Enantiomer-P);

6-(4-((3 -(2-hydroxypropan-2-yl)-5 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 N-pyrazol-1 -yl)-4-methylnicotinonitrile (Enantiomer-1);

4-methyl-6-(5-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)isoxazole -3-yl)nicotinonitrile;

(7?)-4-methyl-5 -(4-((2-(4-methyl-1 H-imidazol-1 -yl)pyrimide in-5 yl)methyl)piperazin-2-yl)isobenzofuran-1( ZN) -he;

(7?) -1 - (5 - ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyrimidin-2-yl) -1 H -imide azole-4-carbonitrile;

(7?)-1 - (5 - ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyrimidin-2-yl) -1 Η -1,2,4-triazole-3-carbonitrile;

(7?)-3 -cyclopropyl-1 -(5-((3 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofu ran-5 yl)piperazin-1 -yl)methyl)pyrimide in-2- yl)-1 H-pyrazole-4-carbonitrile;

(7?)-3-(difluoromethoxy)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)pyridin-2-yl )- 1H-pyrazole-4-carbonitrile;

(7?)-6-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1

- 16 043056 yl)methyl)-1 H-pyrazol-1 -yl)-4-morpholinonicotinonitrile;

(7?)-3 -methyl-1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyrimidin-2-yl )-1H-pyrazole-4-carbonitrile;

(7?)-4-methyl-5 -(4-((6-(4-methyl-1 Η-1,2,3 -triazol-1 -yl)pyridin-3 yl)methyl)piperazin-2- yl)isobenzofuran-1(3H)-one;

(7?)-3 -methoxy-1 -(5-((3 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5-yl)piperazin1 -yl)methyl)pyridin-2-yl)- 1H-pyrazole-4-carbonitrile;

(7?)-4-methyl-5-(4-((2-(4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)morpholin2-yl)isobenzofuran-1(3N)- He;

(R) -1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyridin-2-yl) -1H-1 ,2,3-triazole-4-carbonitrile;

(R)-3 -ethyl-1 - (5 - ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyride in-2-yl )-1 H-pyrazole-4-carbonitrile;

(7?)-3-Methoxy-1 -(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin1-yl)methyl)pyrimid in-2-yl) -1 H-pyrazole-4-carbonitrile;

(R)-3 -ethyl-1 - (5 - ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyrimidin-2-yl) -1H-pyrazole-4-carbonitrile;

(7?)-3 - (d ifluoromethyl) -1 - (5- ((3 - (4-methyl-1 -oxo-1,3 - dihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) pyrimide in- 2-yl)-1 H-pyrazole-4-carbonitrile;

(7?)-4-methyl-2-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1H-pyrazol- 1-yl)pyrimidine-5-carbonitrile;

(7?)-2-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1 H-pyrazol-1-yl )-5-(pyrrolidin-1-yl)isonicotinonitrile;

4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4oxopiperide in-1-yl)methyl)-1 H-pyrazole-1 - yl) nicotinonitrile;

(//)-6-(3-(difluoromethyl)-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)-1 H-pyrazole -1 -yl)-4-methylnicotinonitrile;

(7?)-5-(4-((2-(1H-1,2,4-triazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4methylisobenzofuran-1(3N) -He;

(R)-5-(4-((6-(4 (difluoromethyl)-1 H-imidazol-1 -yl)pyridin-3-yl)methyl)piperazin-2 yl)-4-methylisobenzofuran-1 (3N )-He;

(7?)-4-methyl-5 -(4-((2-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyrimidin-5 yl)methyl)piperazin-2-yl)isobenzofuran-1 (ZN) -he;

(//)-6-(3-cyclopropyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1 H-pyrazol- 1 -yl)-4-methylnicotinonitrile;

- 17 043056

G-methyl-5-(((35, 57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)-[2, 3'-bipyridine]-6'(GN)-one;

(7?)-4-methyl-6-(4-((3 -(1-oxo-1,3-d ihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1H-pyrazol-1-yl) nicotinonitrile;

4-methyl-6-(4-(((67?)-2-methyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)morpholino)methyl)-1H-pyrazole-1 -yl) nicotinonitrile (Diastereomer-1);

(R)-3 -methyl-1 -(6-((3 -(4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl)piperazin-1 yl)methyl)pyride in-3 -yl )-1 H-pyrazole-4-carbonitrile;

(5)-4-methyl-1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyride in-2-yl )-1 H-pyrazole-3-carbonitrile;

(5)-4-methyl-1 - (5- ((3 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) pyrimidin-2-yl) -1 H-pyrazole-3-carbonitrile;

4-methyl-6-(4-((2-methyl-5 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 H-pyrazol- 1-yl)nicotinonitrile (Enantiomer-P);

6-(3-(difluoromethyl)-4-(((37?,47?)-4-hydroxy-3-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperidin-1-yl )methyl)-1H-pyrazol-1-yl)-4methylnicotinonitrile;

6-(4-(((35.57?)-4-hydroxy-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl)- 2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile;

4'-methyl-4-(((35.5R)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-2- oxo-2H-[1,2'-bipyridine]-5'-carbonitrile;

N-(1-((1-(5-cyano-4-methylpyridin-2-yl)-1 H-pyrazol-4-yl)methyl)-3-(4-methyl-1 oxo-1,3-dihydroisobenzofuran -5-yl)piperidin-4-yl)acetamide (Diastereomer-P

Enantiomer-1);

- (6- (4- (((3 S, 5R) -3 -methyl-5 - (4-methyl-1 -oxo-1,3 -d ihydroisobenzofuran-5 yl) piperazin-1 -yl) methyl) - 1 H-pyrazol-1-yl)pyridin-2-yl)oxazol idin-2-one;

6-(4-(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)- 3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylnicotinonitrile;

-(2-methyl-6-(4-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1-yl )methyl)-1H-pyrazol-1-yl)pyridin-4-yl)oxazolidin-2-one;

M-methyl-M-(6-(4-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl) methyl)-1H-pyrazol-1-yl)pyridin-2-yl)methanesulfonamide;

-((27?, 65)-4-((1-(4-(1,1-dioxyisothiazolidin-2-yl)-6-methylpyridin-2-yl)-1Hpyrazol-4-yl)methyl)-6- methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one;

- 18 043056

-(2-methoxypyridin-4-yl)-4-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)pyrrolidin-2-one (Diastereomer-1);

(7?) -4-methoxy-6- (4- ((3 - (4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5-yl) piperazin1 -yl) methyl) - 1H-1,2, 3-triazol-1-yl)nicotinonitrile;

6-(4-((2,2-dimethyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)morpholino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile ( Enantiomer-P);

N-(1-((1-(5-cyano-4-methylpyridin-2-yl)-1 H-pyrazol-4-yl)methyl)-5-(4-methyl-1 oxo-1,3-dihydroisobenzofuran -5-yl)piperidin-3-yl)acetamide (Enantiomer-1);

1-((1 -(5-cyano-4-methylpyride in-2-yl)-1 H-pyrazol-4-yl)methyl)-3 -(4-methyl-1-oxo1,3-dihydroisobenzofuran-5- yl) piperidin-4-yl methylcarbamate (Enantiomer-1);

4-methyl-6-(3-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 1,2,4-oxadiazol-5-yl)nicotinonitrile;

(R)-1 -(5-cyano-4-methoxypyride in-2-yl)-M-methyl-4-((3-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin- 1-yl)methyl)-1H-pyrazole-3-carboxamide;

6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl)piperide in-1-yl)methyl)-1 H-pyrazole-1 - yl)-4-methylnicotinonitrile (Diastereomer-P: Enantiomer-P);

(R)-1-(5-cyano-4-methoxypyride in-2-yl)-4-((3-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1H-pyrazole-3-carboxamide;

(7?)-4-(methoxy-03)-6-(4-((3 -(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5 yl)piperazin-1 -yl)methyl)-1 Η-1,2,3-triazol-1-yl)nicotinonitrile;

(7?)-4-methyl-5-(4-((6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3yl)methyl)piperazin-2-yl)isobenzofuran-1 (ZN) -he;

2-methyl-4-(5-(((35.57?)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)- 2H-tetrazol-2-yl)benzonitrile;

-methyl-4-(((35,5R)-3 -methyl-5-(4-methyl-1 -oxo-1,3 -dihydroisobenzofuran-5yl)piperazin-1 -yl)methyl)-1 -(2- methyl pyridin-4-yl)-1,3-d ihydro-2H-imidazol-2-one;

6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1,3,4-oxadiazol- 2-yl)-4-methylnicotinonitrile (Enantiomer-1);

6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)isoxazol-3-yl)-4- methylnicotinonitrile (Enantiomer-1);

4-Methoxy-6-(5-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazole -3-yl)nicotinonitrile;

-(difluoromethyl)-4-(4-(((35.5R)-3 -methyl-5 -(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)- 2/7-1,2,3-triazol-2-yl)pyridin- 19 043056

2(Sh)-one;

5-((2A65)-4-((1-(2-(difluoromethyl)pyrimidin-4-yl)-1H-imidazol-4-yl)methyl)-6methylpiperazin-2-yl)-4-methylisobenzofuran-1 ( ZN) -he;

4-(5 -(((37?,47?)-4-hydroxy-3 -(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperidin-1-yl)methyl)-2H -tetrazol-2-yl)-2-methoxybenzonitrile;

6-(5-((3-(difluoromethyl)-5-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5 yl)piperazin-1-yl)methyl)-1,3,4- oxadiazol-2-yl)-4-methylnicotinonitrile (Enantiomer I);

4-methoxy-6-(3-methyl-4-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-2-oxoimidazolidin-1 yl)nicotinonitrile (Diastereomer-1);

-(2-methoxypyride in-4-yl)-3-methyl-4-(((3S, 57?)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl )piperazin-1-yl)methyl)-1,3-d and hydro-2H-imide azol-2-one;

-(2-(d iftoromethyl)pyride in-4-yl)-3-methyl-4-(((3S, 57?)-3-methyl-5-(4-methyl-1-oxo1,3-dihydroisobenzofuran -5-yl)piperazin-1 -yl)methyl)-1,3-dihydro-2H-imidazol-2-one; And

4-Methoxy-6-(5-(((35.5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 yl-3,3-b2)piperazine-1 -yl)methyl)isoxazol-3 -yl)nicotinonitrile.

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

ABOUT

CN or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

CN

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

- 20 043056

or a pharmaceutically acceptable salt thereof.

According to another aspect, compounds are disclosed herein, the unity is the formula (I), where co-

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein are compounds of formula (I), wherein the compound is

- 21 043056

In another aspect, disclosed herein are compounds of formula (I) wherein the unity is

or a pharmaceutically acceptable salt thereof.

According to another aspect, the unity is disclosed herein compounds with formula (I), where

According to another aspect, disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

According to another aspect, disclosed herein is a method of treating one or more diseases or disorders that can be modulated by ROMK inhibition, comprising administering to a patient in need of such treatment or such prophylaxis a therapeutically effective amount of at least one of the compounds of formula (I) or compounds of formula (I) as described in any of the other embodiments or aspects or examples, wherein the disease or disorder is treated by stimulation of diuresis or natriuresis.

According to another aspect, disclosed herein is a method for treating or preventing one or more diseases or disorders that can be modulated by ROMK inhibition, wherein a compound of any embodiment is administered in combination with at least one other type of therapeutic agent.

According to another aspect, the present document discloses a method for the treatment or prevention of multiple diseases or disorders, comprising administering to a patient in need of such treatment or such prevention a therapeutically effective amount of at least one of the compounds of formula (I) or compounds of formula (I), which are described in any of the other embodiments or aspects, wherein the disease or disorder or disorders associated with ROMK are treated by stimulation of diuresis or natriuresis.

According to another aspect, disclosed herein is the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of cardiovascular disease.

According to another aspect, disclosed herein is the use of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a cardiovascular disease, wherein said disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute decompensated heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, myocardial insufficiency, nephrotic syndrome and acute renal failure.

In another aspect, disclosed herein is the use of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to induce diuresis or natriuresis.

According to another aspect, the present invention relates to a compound selected from any sub-list of compounds within the scope of the examples.

According to another aspect, the present invention relates to the treatment of hypertension or heart failure in patients requiring diuresis or natriuresis.

According to another aspect, the present invention relates to a method for the treatment of hypertension.

According to another aspect, the present invention relates to a method for the treatment of hypertension, idiopathic hypertension, refractory hypertension and/or pulmonary hypertension.

According to another aspect, the present invention relates to a method for the treatment of heart failure.

According to another aspect, the present invention relates to a method of treating edema, heart muscle failure, systolic heart failure, diastolic heart failure, diabetic heart failure and/or acute decompensated heart failure.

The present invention may be embodied in other specific forms without departing from its spirit or essential features. The present invention covers all combinations of the preferred aspects of the present invention mentioned herein. It is understood that, without exception, all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of an embodiment is its own independent embodiment. Furthermore, any element of an embodiment is intended to be combined in combination with any and all other elements from any embodiment to describe a further embodiment.

Definitions.

The features and advantages of the present invention may become more apparent to those skilled in the art upon reading the following detailed description. It should be appreciated that certain features of the present invention, which are described above and below in the context of separate embodiments for clarity, can also be combined to form a single embodiment. Conversely, various features of the present invention, which are described for brevity in the context of one embodiment, can also be combined to obtain subcombinations of them. Embodiments designated herein as illustrative or preferred are intended to be illustrative and not restrictive.

Unless otherwise noted herein, references made in the singular form may also include plural forms. For example, the singular forms can refer either to one or to one or more.

Used in the context of this document, the phrase connection refers to at least one connection. For example, a compound of formula (I) includes a compound of formula (I) and two or more compounds of formula (I).

Unless otherwise stated, any heteroatom with unsatisfied valences is assumed to have a sufficient number of hydrogen atoms to satisfy the valences.

The definitions set forth herein take precedence over the definitions set forth in any patent, patent application and/or patent publication incorporated herein by reference.

Listed below are definitions of various terms used to describe the present invention. Such definitions apply to the terms as they are used in the description (unless they are otherwise limited in particular cases) either alone or as part of a larger group.

In the present description, a person skilled in the art can select the groups and their substituents to obtain stable elements and compounds. If the definition of a substituent suggests more than one substituent, each substituent is selected independently of the other substituent(s).

In accordance with the order used in the present technical field, used in the structural formulas in this document to denote a connection, which is the point of attachment of a fragment or substituent to the central or main structure.

The terms halogen and halide used in the context of this document are F, Cl, Br and I.

The term cyano refers to the -CN group.

The term amino refers to the -NH2 group.

The term oxo refers to the =O group.

The term alkyl as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. carbon, and is meant to include C1-, C2-, C ₃ - and C ₄ -alkyl groups. Examples of alkyl groups include, without limitation, methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, sec-butyl and t-butyl) and pentyl (for example, n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl and 4-methylpentyl. When digits appear in a subscript after the symbol C, the subscript specifies, with greater precision, the number of carbon atoms that a particular group can contain. For example, _C1 . ₆ -alkyl denotes straight and branched alkyl groups with one to six carbon atoms.

The term haloalkyl as used herein is meant to include both branched and unbranched saturated aliphatic hydrocarbon groups substituted with one or more halide atoms. For example, _C1 . ₄ -haloalkyl is meant to include C1-, C2-, _C3- and _C4 -alkyl groups substituted with one or more halide atoms. Illustrative examples of haloalkyl groups include, without limitation, -CF ₃ , -CCI3, -CFCl2 and -CH2CF3.

The term fluoroalkyl as used herein is meant to include both branched and unbranched saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, C1_ ₄ -fluoroalkyl is meant to include C ₁ -, C2-, C ₃ - and C ₄ -alkyl groups substituted with one or more fluorine atoms. Illustrative examples of fluoroalkyl groups include, without limitation, -CF ₃ and -CH ₂ CF ₃ .

The term hydroxyalkyl includes both branched and straight chain saturated alkyl hydrocarbon groups substituted with one or more hydroxyl groups. For example, hydroxyalkyl includes -CH2OH, -CH2CH2OH and C _1-4 -hydroxyalkyl.

The term cycloalkyl as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one hydrogen atom from a carbon atom of a saturated ring. Illustrative examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclopentyl, and cyclohexyl. When digits appear in a subscript after the symbol C, the subscript specifies, with greater precision, the number of carbon atoms that a particular cycloalkyl group may contain. For example, C ₃ _ ₆ -cycloalkyl denotes cycloalkyl groups with three to six carbon atoms.

The term alkoxy as used herein refers to an alkyl group attached to the parent molecular element via an oxygen atom, such as a methoxy group (-OCH3). For example, _C1-3 -alkoxy refers to alkoxy groups with one to three carbon atoms.

The terms haloalkoxy and -O(haloalkyl) denote a haloalkyl group as defined above attached via an oxygen bond (-O-). For example, C1-4 haloalkoxy is meant to include C1-, C2-, C ₃ and C ₄ haloalkoxy groups.

The terms fluoroalkoxy and -O(fluoroalkyl) denote a fluoroalkyl group as defined above attached via an oxygen bond (-O-). For example, C1_ ₄ -fluoroalkoxy is meant to include C1-, C2-, C ₃ - and C ₄ -fluoroalkoxy groups.

The term aryl, as used herein, means a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen that is bonded to an aromatic ring(s) containing(s) from 4 up to 10 or from 6 to 10 carbon atoms. Aryl groups that have two or more rings must include only aromatic rings. Illustrative examples of aryl groups include, without limitation, phenyl and naphthyl. The aryl ring may be unsubstituted or may contain one or more substituents, as valency permits.

The term benzyl as used herein refers to a methyl group in which one of the hydrogen atoms has been replaced by a phenyl group.

The phenyl ring may be unsubstituted or may contain one or more substituents, as valency permits.

The term heteroatom refers to oxygen (O), sulfur (S), and nitrogen (N).

The terms heterocyclyl or heterocycle as used herein refer to substituted and unsubstituted saturated, partially saturated and aromatic 3-7 membered monocyclic groups, 7-11 membered bicyclic groups and 10-15 membered tricyclic groups in which at least one of the rings has at least one heteroatom (O, S or N), and the ring containing the specified heteroatom has 1, 2, 3 or 4 heteroatoms selected from O, S and N. Each ring of such a group containing a heteroatom may contain one or two oxygen or sulfur atoms and/or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The fused rings constituting the bicyclic and tricyclic groups may contain other heteroatoms or only carbon atoms and may be saturated, partially saturated or aromatic. The heterocyclo group may be attached to any suitable nitrogen or carbon atom in the heterocyclo group. The term heterocyclyl includes heteroaryl groups. When valency permits, if said additional ring is cycloalkyl or heterocyclo, it is optionally further substituted =O(oxo).

The term heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11-14-membered tricyclic groups that have at least one heteroatom (O, S, or N) at least at least one of the rings, wherein said heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms which are independently selected from O, S, and/or N. Each ring of a heteroaryl heteroatom-containing group may contain one or two oxygen or sulfur atoms, and /or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings that make up the bicyclic group are aromatic and may contain other heteroatoms or only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Bicyclic and tricyclic heteroaryl groups must include only aromatic rings. The heteroaryl group may be attached to any suitable nitrogen or carbon atom from any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.

Illustrative monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

Illustrative bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolinizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl and pyrrolopyridyl.

The phrase pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions and/or dosage forms that are medically suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problem. or complications and have an appropriate benefit/risk ratio.

Compounds of formula (I) may be present as amorphous substances or crystalline substances. Lyophilization can be used to obtain the compound of formula (I) as an amorphous substance.

Additionally, it should be understood that solvates (eg hydrates) of the compounds of formula (I) are also within the scope of the present invention. The term solvate means a physical bonding of a compound of formula (I) with one or more solvent molecules, organic or inorganic. This physical bond includes a hydrogen bond. In some cases, the solvate can be isolated, for example, if one or more solvent molecules are included in the crystal lattice of the crystalline substance. The solvate encompasses both the dissolved phase and the recoverable solvates. Illustrative solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

Various forms of prodrugs are well known in the art and are described in

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic

Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and

H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); And

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim

M.Mayer, (Wiley-VCH, 2003).

In addition, the compounds of formula (I) after their preparation can be isolated and purified to obtain a composition containing, by weight, an amount equal to or greater than 99% of the compound of formula (I) (substantially pure), which is then used or formulated as described in this document. Such substantially pure compounds of formula (I) are also provided herein as part of the present invention.

The compounds of formula I and/or the examples provided herein may, in some cases, form salts, which are also within the scope of the present invention. Reference to a compound of Formula I and/or examples is herein understood to include reference to its salts, unless otherwise indicated. The term salt(s) as used herein means acidic and/or basic salts formed with inorganic and/or organic acids and bases. The term salt(s) as used herein includes zwitterions (internal salts) (and may be formed, for example, when R substituents contain an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkyl ammonium salts. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are suitable, for example, in isolation or purification steps that may be used during preparation. Salts of compounds of formula I can be obtained, for example, by reacting the compound I with some acid or base, such as an equivalent amount, in a medium, such as a salt-precipitating medium, or in an aqueous medium, followed by lyophilization. Used in the context of this document, the term pharmaceutically acceptable salts means derivatives of the disclosed compounds in which the parent compound is modified by obtaining its acidic or basic salts. Examples of pharmaceutically acceptable salts include, without limitation, mineral or organic acid salts with basic groups such as amino groups, and alkali or organic salts with acidic groups such as carboxyl groups. Pharmaceutically acceptable salts include conventional non-toxic or quaternary ammonium salts of the parent compound, formed from, for example, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids, as well as salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic , malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic and isetic, etc.

A base addition salt refers to those salts that retain the biological effectiveness and properties of free acids that are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In one aspect, the inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, without limitation, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. According to another aspect, the organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

The terms stable compound and stable structure are understood to mean a compound that is sufficiently stable to withstand isolation from a reaction mixture in a suitable degree of purity and formulation into an effective therapeutic agent. The present invention is intended to include stable compounds. Combinations of substituents and/or variables are allowed only if such combinations result in stable compounds.

A therapeutically effective amount is intended to include an amount of a compound of the present invention alone, or an amount of a combination of the claimed compounds, or an amount of a compound of the present invention in combination with other active ingredients that are effective as a ROMK inhibitory agent or are effective in treating or preventing the development of cardiovascular disease.

According to another aspect, disclosed herein is a method for treating or preventing one or more diseases or disorders that can be modulated by ROMK inhibition, comprising administering to a patient in need of such treatment or such prevention a therapeutically effective amount of at least one compound of formula (I) or compounds of formula (I) as described in any of the other embodiments or aspects, wherein such disease or disorder is treated by stimulation of diuresis or natriuresis.

According to another aspect, disclosed herein is a method of treating one or more diseases or disorders that can be treated by stimulating diuresis or natriuresis, wherein cardiovascular diseases include, without limitation, hypertension, coronary artery disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute decompensated heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, persistent heart muscle failure, nephrotic syndrome and acute renal failure.

As used herein, the term treatment or treatment encompasses the treatment of a disease state in a mammal, in particular a human, and includes:

(a) preventing the occurrence of a disease state in a mammal, in particular when such a mammal is predisposed to the disease state but has not yet been diagnosed as having it, (b) inhibiting the disease state, i.e. cessation of its development, and/or (c) relief of the disease state, i.e. the onset of regression of the disease state.

The compounds of the present invention are intended to include all isotopes of the atoms present in the present compounds, whether these isotopes occur in their natural environment or are concentrated to levels greater than those in their natural environment. Isotopes include those atoms that have the same atomic number but different mass numbers. As a general example, and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include ¹³ C and ¹⁴ C. For example, methyl (-CH ₃ ) also includes deuterated methyl groups such as -CD ₃ , -CHD2 or -CH2D.

Compounds of formula (I) may be administered by any route suitable for the condition being treated, which may depend on the need for site-specific treatment or the amount of compound of formula (I) to be delivered.

The present invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or excipients (collectively referred to herein as carriers) and, if necessary, , other active ingredients. Compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route and at a dose effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, transmucosally, or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intradermally, in unit dosage formulations containing conventional pharmaceutically acceptable carriers, excipients, and media. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional ingredients such as a lubricant such as magnesium stearate and a disintegrant such as crospovidone. The carrier mixture can be loaded into a gelatin capsule or compressed into a tablet. The pharmaceutical composition can be administered, for example, as an oral dosage form or as an infusion.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a liquid-containing capsule, a suspension, or a liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a certain amount of the active ingredient. For example, the pharmaceutical composition may be presented as a tablet or capsule containing an amount of the active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined using standard methods.

Any pharmaceutical composition discussed herein can be delivered, for example, orally through any acceptable and suitable oral preparations. Exemplary oral preparations include, but are not limited to, tablets, lozenges, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and tinctures. Pharmaceutical compositions intended for oral administration may be prepared according to any methods known in the art for the preparation of pharmaceutical compositions intended for oral administration. To obtain pharmaceutically acceptable preparations, the pharmaceutical composition of the present invention may contain at least one selected from sweeteners, flavors, colors, emollients, antioxidants and preservatives.

A tablet can be obtained, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the preparation of tablets. Examples of excipients include, without limitation, for example, inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate, granulating agents, and disintegrants, such as, for example, microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid. acid; binders such as, for example, starch, gelatin, polyvinylpyrrolidone and acacia; and lubricants, such as, for example, magnesium stearate, stearic acid and talc. In addition, the tablet may be uncoated, or it may be coated using known techniques, either to mask the off-taste of the off-tasting drug, or to delay disintegration of the tablet and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effects of the active.

- 27 043056 ingredient for a longer period of time. Illustrative water-soluble taste-masking materials include, without limitation, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Illustrative time delay materials include, without limitation, ethylcellulose and cellulose acetate butyrate.

Hard gelatin capsules can be obtained, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent such as, for example, calcium carbonate, calcium phosphate and kaolin.

Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier, such as, for example, polyethylene glycol, and at least one oily vehicle, such as, for example, peanut butter. oil, liquid paraffin and olive oil.

An aqueous suspension can be obtained, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for obtaining an aqueous suspension. Exemplary excipients suitable for preparing an aqueous suspension include, without limitation, for example, suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth and gum arabic, dispersing or wetting agents, such as, for example, naturally occurring phosphatide, such as lecithin, alkylene oxide condensates with fatty acids, such as, for example, polyoxyethylene stearate, ethylene oxide condensates with long-chain aliphatic alcohols, such as, for example, heptadecaethyleneoxyoxyethanol, ethylene oxide condensates with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitan monooleate, and condensates of ethylene oxide with partial esters derived from fatty acids and hexitan anhydrides, such as, for example, polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative, such as, for example, ethyl and n-propyl-p-hydroxybenzoate, at least one coloring agent, at least one flavor and/or at least one sweetener, including without limitation eg sucrose, saccharin and aspartame.

Oil suspensions can be prepared, for example, by suspending at least one compound of formula (I) in a vegetable oil, such as, for example, peanut oil, olive oil, sesame oil, and coconut oil, or in a mineral oil, such as, for example, liquid paraffin. The oil suspension may also contain at least one thickening agent such as, for example, beeswax, hard paraffin and cetyl alcohol. To obtain an acceptable oil suspension, at least one of the sweeteners described above and/or at least one flavoring agent can be added to the oil suspension. The oil suspension may further contain at least one preservative, including, without limitation, for example, an antioxidant such as, for example, butylated hydroxyanisole and alpha-tocopherol.

Dispersible powders and granules can be obtained, for example, by mixing at least one compound of formula (I) with at least one dispersing and/or wetting agent, at least one suspending agent and/or at least one preservative. Suitable dispersing agents, wetting agents and suspending agents have already been described above. Illustrative preservatives include, without limitation, for example, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including without limitation, for example, sweeteners, flavors and colors.

An emulsion of at least one compound of formula (I) can be obtained, for example, as an oil-in-water emulsion. The oil phase of emulsions containing compounds of formula (I) can be formulated from known ingredients in a known manner. The oil phase can be represented without limitation, for example, vegetable oil, such as, for example, olive oil and peanut oil, mineral oil, such as, for example, liquid paraffin, and mixtures thereof. Although this phase may contain only an emulsifier, it may contain a mixture of at least one emulsifier with fat or oil, or with both fat and oil. Suitable emulsifiers include, without limitation, for example, naturally occurring phosphatides, for example, soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate, and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier(s) with or without stabilizer(s) constitute the so-called emulsifying wax, and the wax, together with oil and fat, constitute the so-called emulsifying ointment base, which forms the oil-dispersed phase of cream formulations. The emulsion may also contain a sweetener, flavor, preservative and/or antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with wax, or other materials well known in the art.

Compounds of formula (I) can also be delivered, for example, intravenously, subcutaneously and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Illustrative injectable forms include, without limitation, for example, sterile aqueous solutions containing acceptable vehicles and solvents such as, for example, water, Ringer's solution, and isotonic sodium chloride solution, sterile oil-in-water microemulsions, and aqueous or oily suspensions.

Compositions for parenteral administration may be presented in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in oral formulations, or using other suitable dispersing or wetting agents and suspending agents. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and/or various buffers. Other excipients and routes of administration are well and widely known in the pharmaceutical field. The active ingredient may also be administered by injection as a composition with suitable carriers, including saline, dextrose or water, or with cyclodextrin (i.e. captisol), co-solvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).

The sterile injectable preparation may also be a sterile injectable solution or a sterile injectable suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Acceptable media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are usually used as the solvent or suspending medium. Any bland fixed oil can be used for this, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are also used in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can be obtained, for example, by:

1) dissolving at least one compound of formula (I) in an oil phase, such as, for example, a mixture of soybean oil and lecithin;

2) combining the oil phase containing the compound of formula (I) with a mixture of water and glycerol; And

3) processing this combination to obtain a microemulsion.

Sterile aqueous or oily suspension can be prepared in accordance with methods already known in the present field of technology. For example, a sterile aqueous solution or a sterile aqueous suspension may be prepared with a non-toxic, parenterally acceptable diluent or solvent such as, for example, 1,3-butanediol, and a sterile oily suspension may be prepared with a sterile, non-toxic, acceptable solvent or suspending medium, such as, for example, sterile fixed oils, for example synthetic mono- or diglycerides; and fatty acids such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants and media that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween varieties, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF) or other similar polymeric delivery matrices, blood serum proteins such as human serum albumin , buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glyceride and saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, zinc salts , colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, block polymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin. Cyclodextrins such as alpha, beta and gamma cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrins, or other solubilized derivatives, can also advantageously be used to improve delivery of the formulation compounds described herein.

Pharmaceutical compositions may be presented in a package or dispenser which may contain one or more unit dosage forms comprising a compound of formula (I). The package may, for example, include metal or plastic foil, such as a blister pack. The package or dispenser may be accompanied by instructions for use.

In order to provide medical agents for administration to patients, including humans and other mammals, the pharmaceutically active compounds of the present invention can be processed in accordance with conventional pharmaceutical methods. Pharmaceutical compositions may be subjected to conventional pharmaceutical manipulations such as sterilization and/or may contain conventional excipients such as preservatives, stabilizers, wetting agents, emulsifiers and buffers. Tablets and pills can additionally be provided with enteric coatings. Such compositions may also contain adjuvants such as wetting, sweetening, flavoring and flavoring agents.

The amounts of compounds administered and the dosage regimen for treating a disease state with the compounds and/or compositions of the present invention depend on a variety of factors, including age, weight, sex, health status of the subject, type of disease, severity of the disease, route and frequency of administration, and the particular compound used. Thus, the dosing regimen can vary widely, but can be easily determined using standard methods. A daily dose of from about 0.001 to 100 mg/kg of body weight, preferably from about 0.0025 to about 50 mg/kg of body weight, and most preferably from about 0.005 to 10 mg/kg of body weight, may be suitable. The daily dose can be administered in one to four doses per day. Other dosing regimens include one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of the present invention are usually combined with one or more excipients suitable for the indicated route of administration. When administered orally, compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic , sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for ease of administration. Such capsules or tablets may contain a controlled release formulation which may be present in a dispersion of the active compound in hydroxypropyl methylcellulose.

The pharmaceutical compositions of the present invention contain at least one compound of formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, excipient and medium. Alternative compositions of the present invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Pharmaceutical compositions may contain other therapeutic agents and may be formulated, for example, using traditional solid or liquid media or diluents, as well as pharmaceutical additives of a type suitable for the desired mode of administration (for example, excipients, binders, preservatives, stabilizers and flavors ), in accordance with techniques well known in the field of obtaining pharmaceutical formulations.

The present invention also covers an article. In the context of this document, the product is meant to include, without limitation, kits and packages. The product of the present invention contains:

(a) a first container;

(b) a pharmaceutical composition located in the first container, and the composition contains the first therapeutic agent containing the compound of the present invention or its pharmaceutically acceptable salt form; and (c) instructions for medical use of the drug, which indicates that the pharmaceutical composition can be used for the treatment of cardiovascular disorders, diuresis and/or natriuresis.

In accordance with another embodiment, the package leaflet states that the pharmaceutical composition may be used in combination (as previously defined) with a second therapeutic agent for the treatment of a cardiovascular disorder, diuresis and/or natriuresis. The product may further comprise (d) a second container, wherein components (a) and (b) are located in the second container, and component (c) is located inside or outside the second container. Located in the first and second containers means that the corresponding container holds the element within its boundaries.

The first container is a container used to store the pharmaceutical composition. This container may be for manufacturing, storage, shipping and/or retail/wholesale. The first container is meant to encompass a bottle, jar, vial, flask, syringe, tube (eg for a cream formulation) or any other container used to manufacture, contain, store or distribute a pharmaceutical product.

The second container is a container used to store the first container and, optionally, instructions for medical use of the drug. Examples of the second container include without

- 30 043056 restrictions boxes (eg cardboard or plastic), crates, cartons, packages (eg paper or plastic bags), bags and sacks. The package leaflet may be physically attached to the outside of the first container with tape, adhesive, staples, or other attachment method, or it may be inside the second container without any physical means of attachment to the first container. Alternatively, the instructions for medical use of the drug is located on the outside of the second container. If it is located on the outside of the second container, it is preferable that the instructions for medical use of the drug be physically attached using tape, glue, staples or other method of attachment. Alternatively, it may be attached to or in contact with the outside of the second container without being physically attached.

Instructions for medical use of the drug is a label, tag, marking or other written sheet that contains information related to the pharmaceutical composition in the first container. This information is usually determined by the regulatory authority that regulates the area in which the product will be sold (for example, the US Food and Drug Administration). Preferably, the instructions for medical use of the drug specifically indicate the indications for use for which the pharmaceutical composition has been approved. Instructions for medical use of the drug can be made from any material on which a person can read the information contained in it or on it. Preferably, the instruction for medical use of the drug is a printing material (eg, paper, plastic, cardboard, foil, paper or adhesive-based plastic) on which the necessary information has been formed (eg, printed or applied).

Utility.

The compounds of the present invention inhibit the activity of ROMK. Accordingly, the compounds of formula (I) are useful in the treatment of pathological conditions associated with ROMK inhibition.

The compounds described herein are intended for the treatment and/or prevention of any disorder that benefits from increased excretion of water and sodium from the body, or for any patient requiring diuresis or natriuresis. Specific disorders include any form of hypertension or heart failure (sharp decompensated and chronic, diastolic and systolic). In the treatment of heart failure, the compounds will be used to treat acute decompensated heart failure to reduce edema and other symptoms and/or to overcome resistance to other classes of diuretics or to shorten hospital stay. These compounds can also be used in heart failure after hospital discharge or during chronic therapy to treat symptoms and reduce the recurrence of acute decompensation and reduce the number of hospitalizations. Other disorders in which a diuretic or a natriuretic, or both the former and the latter, would provide a therapeutic or prophylactic effect include postoperative volume overload, any edematous condition, including idiopathic edema, pulmonary hypertension, including pulmonary arterial hypertension, cardiac muscle failure, nephrotic syndrome and acute renal failure.

The compounds of the present invention are useful in the treatment and/or prevention of various diseases in humans. The compounds of the present invention may be useful either as a standalone therapy or in combination with other therapies, which, from a therapeutic point of view, may provide a greater beneficial effect. Diseases for which the compounds of the present invention may be useful include cardiovascular disease and stimulation of diuresis or natriuresis.

One embodiment relates to a method for treating cardiovascular disease. In particular, cardiovascular diseases include, without limitation, hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute decompensated heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, insufficiency of the heart muscle, nephrotic syndrome and acute renal failure. For example, to treat a disorder according to the method of the present embodiment, a therapeutically effective amount may be administered.

One embodiment relates to a method for inducing diuresis or natriuresis.

In combination with the compounds described herein, one or more additional pharmacologically active agents can be administered, including any other diuretics from any other class of diuretics (thiazides, loop diuretics, potassium-sparing, osmotic agents, carbonic anhydrase inhibitors, mineralocorticoid receptor antagonists), acetylcholinesterase inhibitors , angiotensin receptor blockers, neutral endopeptidase inhibitors, dual angiotensin receptor antagonists and neutral endopeptidase inhibitors, aldosterone antagonists, natriuretic peptides, calcium channel blockers, relaxin or relaxin mimetics, inotropic agents, peripheral vasodilators or mineral antagonists corticoid receptors. One embodiment relates to compounds of formula (I) for use in therapy. According to the present embodiment, therapeutic use may include administering a therapeutically effective amount of a compound of formula (I).

The present invention also relates to the use of compounds of formula (I) for the preparation of a medicament for the treatment of cardiovascular disease. According to the present embodiment, a medicament use may include administering a therapeutically effective amount of a compound of formula (I) for the treatment of a cardiovascular disease.

The present invention also relates to the use of compounds of formula (I) for the preparation of a medicament for inducing diuresis or natriuresis.

According to one embodiment, the compounds of formula (I) inhibit ROMK activity with IC50 values less than 10 μM, eg, 0.001 to less than 10 μM, as measured by a thallium excretion assay. Preferably, compounds of formula (I) inhibit ROMK activity with IC ₅₀ values of less than 1 μM, eg 0.001 to less than 1 μM. Other compounds inhibit ROMK activity with IC ₅₀ values of 100 nM or less, eg 1 to 100 nM.

Examples of compounds of formula (I), which are given in the Examples section below, were tested in one or more of the assays described below.

Ways to get.

Below are the definitions of the symbols used.

Ag Aryl ACN Acetonitrile BF3.OEt2 Boron trifluoride etherate CH2CI2 dichloromethane CHCI3 Chloroform CDCh Deuterated chloroform CD3OD Deuterated methanol DCM dichloromethane DMAP 4-dimethylaminopyridine DMF Ν,Ν-dimethylformamide DMSO Dimethyl sulfoxide DMSO- _J6 Deuterated dimethyl sulfoxide Et Ethyl

- 32 043056

EtOAc ethyl acetate EtOH ethanol HATU (О-(7-azabenzotriazole-1 -πη)-Ν,Ν,Ν',Ν'- tetramethyluronium hexafluorophosphate) HCl Hydrochloric acid HCOOH Formic acid HCOONH ₄ ammonium formate KI Potassium iodide K ₂ COz Potassium carbonate KOAS potassium acetate K3PO4 potassium phosphate LiOH lithium hydroxide Me Methyl MeOH methanol NaH sodium hydride _NaHCO3 Bicarbonate of soda NaNO ₂ sodium nitrite _{Na2SO4 _} Sodium sulfate Na ₂ S ₂ O3 sodium thiosulfate _NH3 Ammonium _NH4OAc ammonium acetate Pd/C Palladium catalyst on a carbon carrier Pd ₂ (dba)3 Tris(dibenzylideneacetone)dipalladium (0) Pd(dppf) ₂ Cl ₂ :CH ₂ Cl ₂ [1,1 'Bis(diphenylphosphino)ferrocene]dichloropalladium(1 I), complex with dichloromethane POCI3 Phosphorus oxychloride THF Tetrahydrofuran TFA Trifluoroacetic acid XANTPHOS 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene IPA Isopropyl alcohol DEA diethylamine STAB Sodium triacetoxyborohydride

Synthesis.

A particularly useful compendium of synthetic methods that can be used to prepare the compounds of the present invention can be found in Larock R.C., Comprehensive Organic Transformations, VCH, New York (1989). Preferred methods include, without limitation, those described below. All sources of information mentioned in this document are hereby incorporated by reference in their entirety.

The novel compounds of the present invention can be prepared using the reactions and procedures described in this section. Also, in the description of the synthesis methods below, it should be understood that all proposed reaction conditions, including the choice of solvent, the atmosphere in which the reaction is carried out, the reaction temperature, the duration of the experiment, and the processing procedures, are chosen as standard conditions for such a reaction, which will be easily understood. a person skilled in the art. Those of skill in the art will readily appreciate the limitations on substituents that are compatible with such reaction conditions, and alternative methods must then be used.

It will also be understood that another important factor in planning any synthetic route in the art is the judicious choice of the protecting group used to protect the reactive functional groups present in the compounds described in the present invention. The authoritative source describing many alternatives for the practitioner in the art is Greene et al. (1991)).

Scheme 1 (Protective Groups in Organic Synthesis, Wiley and Sons

Amin or ΝΗί-PG

MeOH/EtOH S0-70 °C

NI and ^he in

PG

R

Vg'EU

Or R

Ar.

.PG N H

X * _Or NH

1. TFA, DCM or HCi in dioxane, rt

2. NaH or K ₂ COz, THF, k.t.

Ar.

Br E

hj, 56 pst

NH

KzROd, dioxane:H ₂ O100°C p ft

Pd(OAc) ₂₁ AcOH, rt

Intermediates with the general formula D can be synthesized according to Scheme 1.

Substituted epoxides (A) were converted to (B) by reaction with the appropriate amine. B was subjected to alkylation, acylation, or Mitsunobu inversion reactions with appropriately substituted alkylamines or alkyl/acyl halides to give (C). Compound C was deprotected using chloroethyl chloroformate, TFA, or Pd/C hydrogenation followed by cyclization to give intermediate (D). Intermediate D (X=N) was also synthesized alternatively using appropriately substituted aryl halides (E) where E was converted to (F) by a Suzuki coupling reaction of appropriately substituted halopyrazines followed by reduction of F under hydrogen pressure in the presence of palladium acetate( P) to obtain an intermediate product (D).

Scheme 2

. -9 ^R l _r PdCl ₂ (dtbpf), C$; CO3. toluene, 110*C

Ar.^ Br

E

1. NaBHi.

THFiMeOH, k.t.

or R2M0Br, THF. k.t.

or CAST, DCM. k.t.

Intermediates with general formula I can be synthesized according to Scheme 2.

Appropriately substituted aryl halides (E) were subjected to a C-H activation reaction in the presence of an N-protected and suitably substituted piperidinone/pyrrolidinone to give H. Compound H was subjected to reduction and/or fluorination followed by deprotection from N to give intermediates with a total formula (I).

Scheme 3 about Intermediate

And the product D OR ί.

t' NaBHjCN or J.

hr,, ^J W THF/MeOH. k.t.

v. fl

Intermediate D or ί

NaBH ₃ CN or STAB, THF/MeOH, rt

Y=N or CH etc.

Z=N, O, S, etc. d.

Compounds with the general formula K, L, N and O can be synthesized according to Scheme 3.

Aldehydes J and M were synthesized according to literature procedures and J and M were subjected to reductive amination with sodium triacetoxyborohydride-type borane reagents and appropriately substituted intermediates (D or I) to give compounds with the general formulas K, L, N and O .

- 34 043056

Scheme 4

Aldehyde J or M

T n ° x .L 1. TFA / DCM or HCI in dioxane, rt. ^x p ^C| 2. NaBH3CN or STAB, THF/MeOH, ^c.t.

X=OH, NH or O

Compounds with the general formula Q and R can be synthesized according to Scheme 4.

Intermediates P and C were synthesized according to literature procedures. Intermediates P and C were deprotected and reductively aminated an unprotected amine with appropriately substituted aldehydes (J or M) in the presence of sodium cyanoborohydride-type borane reagents, followed by cyclization to give compounds of the general formulas Q and R.

General methods.

In the demonstration examples, the following procedures were used, except where noted otherwise.

Analytical HPLC and HPLC/MS methods used in the characterization of the examples:

Reverse-phase analytical HPLC/MS was performed on Shimadzu LC 10AS systems connected to Waters ZMD mass spectrometers, or on a Waters Aquity system connected to a Waters Micromass ZQ mass spectrometer. Chiral analytical LC was performed on a Berger Analytical SFC instrument.

Method A: Ascentis Express C18 (2.1x50 mm), 2.7 microns; solvent A: 95% water, 5% acetonitrile, 0.1% TFA; solvent B: 95% acetonitrile, 5% water, 0.1% TFA; temperature: 50°C; gradient: 0-100% B for 3 minutes, then kept at 100% B for 1 minute; flow: 1.1 ml/min, UV 220 nm.

Method B: Ascentis Express C18 (2.1x50 mm), 2.7 microns; solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; solvent B: 95% acetonitrile, 5% water with 10 mM ammonium acetate; temperature: 50°C; gradient: 0-100% B for 3 minutes, then kept at 100% B for 1 minute; flow: 1.1 ml/min, UV 220 nm.

Method C: SunFire C18 (4.6x150 mm), 5.0 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 50-100% B for 15 minutes, then kept at 100% B for 5 minutes; flow: 1.1 ml/min, UV 220 nm.

Method D: Kinetex, XB C18 (2.6 µm x 75.3 mm); solvent A: 10 MMNH ₄ CO ₂ H in 98% water, 2% acetonitrile; solvent B: 10 mM NH4CO2H in 2% water, 98% acetonitrile; gradient: 20-100% B for 4 min, then kept at 100% B for 0.6 min; flow: 1.1 ml/min, UV 220 nm.

Method E: Sunfire C18 (4.6x150 mm), 3.5 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 10-100% B for 25 minutes, then kept at 100% B for 5 minutes; flow: 1.1 ml/min, UV 254 nm.

Method F: Sunfire C18 (4.6x150mm), 3.5 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 10-100% solvent B for 18 minutes, then kept at 100% B for 5 minutes; flow: 1.1 ml/min, UV 220 nm.

Method G: SXBridge Phenyl (4.6x150 mm), 3.5 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 10-100% solvent B for 18 minutes, then kept at 100% B for 5 minutes; flow: 1.1 ml/min, UV 220 nm.

Method H: ZORBAX SB C18 (4.6x50 mm), 5.0 microns; solvent A: 10 mM NH ₄ CO ₂ H in 98% water, 2% acetonitrile; solvent B: 10 mM NH4CO2H in 2% water, 98% acetonitrile; gradient: 30-100% B for 4 min, then held at 100% B for 0.6 min; flow: 1.0 ml/min, UV 220 nm.

Method I: Acquity VEN C8 (2.1x50 mm), 1.7 microns; solvent A: 10 mM ammonium acetate in 95% water, 5% acetonitrile; solvent B: 10 mM ammonium acetate in 5% water, 95% acetonitrile, gradient: 20-90% B over 1.1 min, then held at 90% B for 0.7 min; flow: 0.5 ml/min, UV 220 nm.

Method J: Kinetex XB-C18 (3x75 mm), 2.6 microns; solvent A: 0.1% HCOOH in water; solvent B: acetonitrile, gradient: 20-90% B over 1.1 min, then kept at 90% B for 0.7 min; flow: 0.5 ml/min, UV 220 nm.

Method K: Kinetex C18 (2.1x50 mm), 2.6 microns; solvent A: 5 mM ammonium acetate in 95%

- 35 043056 water, 5% acetonitrile; solvent B: 5 mM ammonium acetate in 5% water, 95% acetonitrile, gradient:

20-90% B for 1.1 min, then kept at 90% B for 0.6 min; flow: 0.7 ml/min, UV 220 nm.

Method L: Acquity VEN C18 (3x50 mm) 1.7 microns; Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in ACN, gradient: 20-90% B over 1.0 min, then held at 90% B for 0.6 min;

flow: 0.7 ml/min, UV 220 nm.

Method M: Xbridge Phenyl (21.2x250 ID), 5 microns; solvent A: 0.1% TFA in water, solvent B: acetonitrile, gradient: 5-25% B over 1.0 min, then held at 90% for 0.6 min. Flow: 0.7 ml/min, UV 220 nm.

Method N: ZORBAX SB C18 (4.6x50 mm), 5.0 micron; solvent A: 0.1% TFA in 95% water, 5% acetonitrile; solvent B: 0.1% TFA in 5% water, 95% acetonitrile, gradient: 0-100% B over 3 min; flow: 1.1 ml/min, UV 220 nm.

Method O: Acquity UPLC VEN C18 (3x50 mm), 1.7 microns; solvent A: 5 mM ammonium acetate in 95% water, 5% acetonitrile; solvent B: 5 mM ammonium acetate in 5% water, 95% acetonitrile, gradient: 20-90% B over 1.1 min, then held at 90% B for 0.6 min; flow: 0.7 ml/min, UV 220 nm.

Method P: Kinetex EVO C18 (4.6x100 mm), 2.6 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 20-100% B for 11 minutes, then kept at 100% B for 1.5 minutes; flow: 1.0 ml/min, UV 300 nm.

Method Q: Kinetex Biphenyl (4.6x11 mm), 2.6 microns; solvent A: 0.05% TFA in water; solvent B: acetonitrile, gradient: 20-100% B over 11 minutes, then kept at 100% B for 1.5 minutes; flow: 1.0 ml/min, UV 300 nm.

Method R: XBidge VEN XP C18 (2.1x50 mm), 2.5 microns; solvent A: 0.1% TFA in 95% water, 5% acetonitrile; solvent B: 0.1% TFA in 5% water, 95% acetonitrile, gradient: 0-100% B over 3 min; flow: 1.1 ml/min, UV 220 nm.

Method S: XBidge VEN XP C18 (2.1x50 mm), 2.5 microns; solvent A: 10 mM ammonium acetate in 95% water, 5% acetonitrile; solvent B: 10 mM ammonium acetate in 5% water, 95% acetonitrile, gradient: 0-100% B over 3 min; flow: 1.1 ml/min, UV 220 nm.

Method T: DAD-1 Kinetix biphenyl (4.6x100 mm), 2.6 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 0-100% B for 12.5 minutes, then held at 100% B for 1.5 minutes; flow: 1.0 ml/min, UV 300 nm.

Method U: DAD-1 Kinetex EVO C18 (4.6x100 mm), 2.6 microns; solvent A: 95% water, 5% acetonitrile, 0.05% TFA; solvent B: 5% water, 95% acetonitrile, 0.05% TFA; gradient: 0-100% B for 12.5 minutes, then held at 100% B for 1.5 minutes; flow: 1.0 ml/min, UV 300 nm.

SFC techniques and obtaining chiral purity.

Method I: Lux Amylose 2 (250x4.6 mm), 5 microns; 0.2% DEA in n-hexane:EtOH:5:95, flow: 2.0 ml/min, temperature: 25°C, UV: 270 nm.

Method II: Chiralpak AS-H (250x4.6 mm), 5 microns; 0.2% DEA in p-hexane: EtOH: 5:95, flow: 2.0 ml/min, temperature: 25° C., UV: 270 nm.

Method III: Chiralpak IE (250x4.6 mm), 5.0 microns; 0.2% DEA in EtOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method IV: Chiralcel IE (250x4.6 mm), 5 microns; 0.2% DEA in n-hexane: EtOH: 50:50, flow: 1.0 ml/min, temperature: 25° C., UV: 260 nm.

Method V: Chiralpak IB (250x4.6 mm), 5 microns; 0.1% DEA in EtOH, flow: 1.0 ml/min, temperature: 25°C, UV: 270 nm.

Method VI: Chiralpak ID (250x4.6 mm), 5 microns; 0.1% DEA in EtOH, flow: 1.0 ml/min; temperature: 25°C, UV: 254 nm.

Method VII: Chiralpak IF (250x4.6 mm), 5 microns; 0.2% DEA in EtOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method VIII: Chiralpak IA (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 4.0 ml/min, temperature: 25°C, UV: 280 nm.

Method IX: Chiralpak ID (250x4.6 mm), 5 microns; 0.2% TEA in n-hexane:EtOH (10:90) flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method X: Chiralcel OJ-H (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 4.0 ml/min, temperature: 30°C, UV: 296 nm.

Method XI: Chiralpak IC (250x4.6 mm), 5 microns; 0.1% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XII: Chiralpak ADH (250x4.6 mm), 5 microns; 0.2% DEA in MeOH+IPA (1:1), flow: 1.2 ml/min, temperature: 25°C, UV: 233 nm.

Method XIII: Chiralpak AS-H (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 1.2 ml/min, temperature: 23.3°C, UV: 271 nm.

- 36 043056

Method XIV: Chiralpak IB (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XV: Chiralpak ID (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XVI: Lux Amylose 2 (250x4.6 mm), 5 microns; 0.1% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XVII: Chiralpak IF (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XVIII: Chiralpak IE (250x4.6 mm), 5.0 microns; 0.2% DEA in MOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XIX: Lux Cellulose 4 (250x4.6 mm), 5.0 microns; 0.1% DEA in EtOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XX: Chiralcel OD-H (250x4.6 mm), 5 microns; 0.2% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XXI: Chiralcel OD-H (250x4.6 mm), 5 microns; 0.2% NH4OH in MeOH and ACN (1:1), flow: 4.0 ml/min, temperature: 30°C, UV: 290 nm.

Method XXII: Lux Cellulose C2 (250x4.6 mm), 5.0 microns; 0.2% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XXIII: Phenomenex IC (250x4.6 mm), 5 microns; 0.2% DEA in EtOH, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XXIV: Whelk-1(R,R) (250x4.6 mm), 5 microns; 0.1% DEA in MeOH, flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XXV: Cellulose-4 (250x4.6 mm), 5.0 microns; 0.1% DEA in ACN, flow: 1.0 ml/min, temperature: 25°C, UV: 254 nm.

Method XXVI: Chiralpak IC (250x4.6 mm), 5.0 micron; 0.2% ammonium in ACN:MeOH (1:1); flow: 1.0 ml/min, temperature: 25°C, UV: 220 nm.

Method XXVII: Chiralpak IC (250x4.6 mm), 5 microns; 0.2% NH4OH in MeOH+ACN (1:1), flow: 1.2 ml/min, temperature: 30°C, UV: 235 nm.

Method XXVIII: Lux cellulose-2 (250x4.6 mm), 5 microns; 0.2% NH4OH in MeOH, flow: 1.2 ml/min, temperature: 30°C, UV: 240 nm.

NMR used in the characterization of the examples.

NMR spectra were obtained using Bruker or JEOL Fourier transform spectrometers operating at the following frequencies: 1H NMR: 400 MHz or 300 MHz (Bruker). ¹³ C NMR: 100 MHz or 75 MHz (Bruker). Spectral data are presented in chemical shift format (multiplicity, binding constants, and number of hydrogen atoms). Chemical shifts are given in parts per million (ppm) from the internal standard tetramethylsilane (5 units, tetramethylsilane=0 ppm) and/or relative to solvent peaks that appear at 2.49 ppm in 1H NMR spectra. in the case of CD2HSOCD3, 3.30 ppm in the case of CD2HOD and 7.24 ppm. in the case of CHCl3, and which appear on the ¹³ C NMR spectra at 39.7 ppm. in the case of CD3SOCD ₃ , 49.0 ppm in the case of CD3OD and 77.0 ppm in the case of CDCl ₃ . All ¹³ C NMR spectra were separated by protons.

Intermediate 1-I: (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one.

Intermediate 1-II: (S)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one

Enantiomer-1 (1-1) Enantiomer-H (1-11)

Both enantiomers were synthesized according to literature procedures (WO 2010/129379).

Intermediate 2-I: (R)-4-methyl-5-(piperazin-2-yl)isobenzofuran-1(3H)-one.

Intermediate 2-II: (S)-4-methyl-5-(piperazin-2-yl)isobenzofuran-1(3H)-one

- 37 043056

Intermediate 2A: 5-bromo-4-methylisobenzofuran-1(3H)-one

Synthesized in accordance with the methods described in the literature (international PCT application, 2015095097).

Intermediate 2B: 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)isobenzofuran-1(3H)-one

A solution of intermediate 2A (12.50 g, 55.10 mmol), bispinacolatedibor (20.97 g, 83.00 mmol) and potassium acetate (16.21 g, 165.00 mmol) in dioxane (200 ml) was degassed with nitrogen within 20 min. PdCl ₂ (dppf) ₂ CH ₂ Cl ₂ (4.50 g, 5.51 mmol) was added and the resulting mixture, degassed again for 10 min, then heated at 100° C. for 12 h. The reaction mixture was cooled to ambient temperature media, filtered through Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was washed with n-hexane to give Intermediate 2B (8.55 g, 56.70%) as a black solid. The compound was carried directly to the next step without further purification. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.28 - 1.43 (m, 12 H), 2.46 (s, 3 H), 5.41 (s, 2 H), 7.65 (d, J=7.9 Hz, 1 H), 7, 72 - 7.87 (m, 1H). LCMS (Method-I): retention time 1.43 min, [M+H] 275.1.

Intermediate 2C: 4-methyl-5-(pyrazin-2-yl)isobenzofuran-1(3H)-one

A solution of 2-chloropyrazine (7.94 g, 69.30 mmol), intermediate 2B (19.00 g, 69.30 mmol) and tribasic potassium phosphate (36.80 g, 173.00 mmol) in a mixture of 1.4 -dioxane (100 ml) and H ₂ O (20 ml) were degassed with nitrogen for 10 min. PdCl ₂ (dppf) ₂ CH ₂ Cl ₂ (2.83 g, 3.47 mmol) was added and the resulting mixture re-degassed for 10 min, then heated at 100° C. for 12 h. The resulting mixture was cooled to ambient temperature media, filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-330 g, 40% EtOAc/n-hexane) to give Intermediate 2C (13.00 g, 83.00%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 3H), 5.50 (s, 2H), 7.72 (d, J=7.5 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.73 (d, J=2.5 Hz, 1H), 8.77-8.87 (m, 1H), 8.91 (d, J=2.0 Hz, 1H). LCMS (method-H): retention time 1.06 min, [M+H] 227.0.

Intermediate 2-I and 2-II.

To a stirred solution of intermediate 2C (13.00 g, 57.50 mmol) in acetic acid (150 mL) was added palladium(II) acetate (1.94 g, 8.62 mmol). The resulting mixture was stirred under H ₂ gas pressure (50 psi) at ambient temperature for 14 hours. The resulting mixture was filtered through Celite® and washed with MeOH. The filtrate was evaporated under reduced pressure and the racemate was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak ADH (250x4.6 mm) 5 microns; 0.2% DEA in MeOH+IPA (1:1), flow: 1.2 ml/min. Temperature: 23.8°C, UV: 235 nm]. The first eluted compound (retention time 2.98 min), designated Intermediate 2-I, was obtained (4.00 g, 30.00%) as a yellow semi-solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 3H), 2.37-2.39 (m, 1H), 2.57-2.68 (m, 2H), 2.71-2.85 (m, 4H), 2.91 (d, J=11.55 Hz, 1H), 3.94 (dd, J=9.79, 2.76 Hz, 1H), 5.38 (s, 2H), 7.64 (d, J= 8.03 Hz, 1H), 7.79 (d, J=8.03 Hz, 1H). LCMS (method-H) retention time 0.74 min, [M+H] 233.0. Chiral purity (XIT method): retention time 3.00 min, 99.0% e.i. SOR: [a] ²⁵ _D = -52.00 (c 0.05, MeOH). The second eluted compound (retention time 3.90 min), designated Intermediate 2-II, was obtained (4.00 g, 30.00%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 3H), 2.37-2.39 (m, 1H), 2.57-2.68 (m, 2H), 2.71-2.85 (m, 4H), 2. 91 (d, J=11.55 Hz, 1H), 3.94 (dd, J=9.79, 2.76 Hz, 1H), 5.38 (s, 2H), 7.64 (d, J = 8.03 Hz, 1H), 7.79 (d, J=8.03 Hz, 1H). LCMS (method-H) retention time 3.73 min, [M+H] 233.0. Chiral purity (method

- 38 043056

XIT): retention time 3.73 min, 100% e.i. SOR: [a] ²⁵ D=+ 62.00 (c 0.05, MeOH).

Intermediate 3-I: (R)-4-methyl-5-(morpholin-2-yl)isobenzofuran-1(3H)-one

Intermediate 3A-I:

(R)-5-(2-(benzyl(2-hydroxyethyl)amino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

To a stirred solution of intermediate 1-I (1.00 g, 5.26 mmol) in ethanol (5 mL) was added 2-(benzylamino)ethanol (0.75 mL, 5.26 mmol) and the resulting reaction mixture was stirred at 85 °C for 48 hours The resulting mixture was cooled to ambient temperature and concentrated under reduced pressure, diluted with water (30 ml) and was extracted with the addition of ethyl acetate (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was washed with n-hexane (50 ml) to give intermediate 3A-I (1.20 g, 66.90%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.11 (s, 3H), 2.56-2.72 (m, 4H), 3.40-3.53 (m, 3H), 3.72 (s, 2H), 4.45-4, 51 (m, 1H), 4.98 (dd, J=7.53, 4.52 Hz, 1H), 5.27-5.37 (m, 2H), 5.75 (s, 3H), 7 .18 - 7.34 (m, 3H), 7.62 (s, 1H). LCMS (method-H): retention time 1.48 min, [M+H] 342.2.

Intermediate 3B-I: (R)-5-(4-benzylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

To a solution of intermediate 3A-I (1.20 g, 3.51 mmol) in THF (25 mL) was added tri-N-butylphosphine (1.42 g, 7.03 mmol) followed by DIAD (0.82 mL, 4 .22 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with water (30 ml) and was extracted with the addition of ethyl acetate (2x40 ml). The combined organic layers were washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-40 g, 55% EtOAc/n-hexanes) to give Intermediate 3B-I (0.75 g, 66.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.18 - 2.22 (m, 3H), 2.23 - 2.28 (m, 1H), 2.51 - 2.56 (m, 1H), 2.75 (d, J=12.55 Hz, 1H), 2.85 (d, J=11.55 Hz, 1H), 3.55 (d, J=5.52 Hz, 2H), 3.73 - 3.80 (m, 1H), 3.99 (dd, J=11.55, 2.01 Hz, 1H), 4.82 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (d, J=2, 01 Hz, 2H), 7.24-7.29 (m, 1H), 7.34 (d, J=4.52 Hz, 4H), 7.58-7.70 (m, 2H). LCMS (Method-D): retention time 2.74 min, [M+H] 324.2.

Intermediate 3-I.

A solution of intermediate 3B-I (0.75 g, 2.32 mmol) in ethanol (50 mL) was purged with nitrogen for 2 min. 10% Pd/C (0.25 g, 2.32 mmol) was added and the resulting mixture was stirred at ambient temperature for 3 h under H2 atmosphere. The resulting reaction mixture was concentrated under reduced pressure, diluted with water, neutralized with water. NaHCO ₃ and extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (alumina-24 g, 5% MeOH/DCM) to give Intermediate 3-I (0.25 g, 46.20%). 1H NMR (400 MHz, DMSOd6) δ ppm 2.27 (s, 3H), 2.45 (d, J=2.51 Hz, 1H), 2.77-2.81 (m, 2H), 2.93 (dd, J=12.55, 2.51 Hz, 1H), 3.63 - 3.70 (m, 1H), 3.90 - 3.95 (m, 1H), 4.71 (dd, J=10.04, 2.51 Hz , 1H), 5.39 (d, J=3.01 Hz, 2H), 7.60 - 7.63 (m, 1H), 7.66 - 7.69 (m, 1H), (capable of exchange no protons were observed). LCMS (method-H): retention time 0.89 min, [M+H] 234.2.

- 39 043056

Intermediate 4: methylisobenzofuran-1(3H)-one

5-(1-((1H-pyrazol-4-yl)methyl)-4,4-difluoropiperidin-3-yl)-4-

Intermediate 4A: tert-Butyl 3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4oxo-piperidine-1-carboxylate

Solution of 5-bromo-4-methylisobenzofuran-1(3H)-one (1.70 g, 7.53 mmol), tert-butyl-4-oxopiperidine 1-carboxylate (2.50 g, 12.55 mmol) and Cs ₂ CO ₃ (4.91 g, 15.06 mmol) in toluene (50 ml) was degassed with nitrogen for 20 minutes. PdCl ₂ (dtbpf) (0.81 g, 1.25 mmol) was added and the resulting mixture was degassed again for 10 min and then heated at 110° C. for 12 h. The resulting mixture was cooled to ambient temperature, filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 60% EtOAc/n-hexanes) to give Intermediate 4A (0.90 g, 20.77%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.41 - 1.47 (m, 9H), 2.21 (s, 3H), 2.39 - 2.48 (m, 1H), 2.65 - 2.76 (m, 1H), 3, 47 (br. s., 2H), 4.04-4.21 (m, 3H), 5.41 (d, J=3.01 Hz, 2H), 7.39 (d, J=8.03 Hz, 1H), 7.65 (d, J=8.03 Hz, 1H). LCMS (method-H): retention time 1.92 min, [M+H ₂ O] 363.2.

intermediate

4V:

compound tert-butyl-4,4-difluoro-3-(4-methyl-1-oxo-1,3 dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of intermediate 4A (0.05 g, 0.14 mmol) in DCM (5 ml) at 0°C was added DAST (0.19 ml, 1.44 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours The resulting reaction mixture was concentrated under reduced pressure, diluted with water (10 ml), neutralized with water. NaHCO ₃ (10 ml) and extracted with DCM (3x20 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 35% EtOAc/n-hexanes) to give Intermediate 4B (0.02 g, 37.60%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.12 2.19 (m, 2H), 2.22 (s, 3H), 3.09 (br. s., 1H), 3.37 - 3.44 ( m, 1H), 3.60 (d, J=9.54 Hz, 1H), 3.98 (d, J=17.07 Hz, 1H), 4.13 (br. s., 1H), 5 .43 (d, J=5.52 Hz, 2H), 7.58 (d, J=7.03 Hz, 1H), 7.70 (d, J=8.03 Hz, 1H). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm - 93.57, - 111.02. LCMS (method-H): retention time 2.45 min, [M+H] 368.2.

Intermediate 4C: 5-(4,4-difluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

To a solution of intermediate 4B (0.24 g, 0.65 mmol) in DCM (25 ml) at 0°C was added 4N HCl in dioxane (5 ml, 1.14 mmol). The resulting mixture was stirred at ambient temperature for 2 hours. The resulting mixture was concentrated to dryness and diluted with water (10 ml). The aqueous layer was washed with ethyl acetate (2x20 ml), basified with 10% NaHCO ₃ solution and extracted with DCM (3x50 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 4C (0.12 g, 68.70%). 1HNMR (400 MHz, DMSO-d ₆ ) δ ppm 1.94 2.12 (m, 2H), 2.29 (s, 3H), 2.76 (td, J=12.93, 3.26 Hz, 1H), 2.96 - 3.06 (m , 2H), 3.14 (d, J=12.05 Hz, 1H), 3.51 3.63 (m, 1H), 5.38 - 5.43 (m, 2H), 7.52 - 7 .57 (m, 1H), 7.67 (d, J=8.03 Hz, 1H) (No exchangeable protons were observed). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm - 88.62, - 110.24. LCMS (method-H): time

- 40 043056 retention 1.34 min, [M+H] 268.0.

Intermediate 4.

To a solution of intermediate 4C (0.10 g, 0.37 mmol) in MeOH (2 mL) was added 1Hpyrazole-4-carbaldehyde (0.030 g, 0.37 mmol) and the resulting mixture was stirred at ambient temperature for 15 min. NaCNBH ₃ (0.071 g, 1.12 mmol) was added to this mixture and stirring was continued for 12 hours. The resulting mixture was diluted with water (15 ml) and extracted with DCM (3x20 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was washed with diethyl ether (20 ml) to give intermediate 4 (0.08 g, 61.60%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.08 - 2.18 (m, 2H) 2.23 (s, 3H) 2.76 (d, J=11.04Hz, 1H) 2.86 (d, J=11.55Hz, 1H) 3.45 (s, 2H) 3.65 - 3.80 (m, 2H) 4.78 (d, J=8.03 Hz, 1H) 5.33 - 5.43 (m, 2H) 7.41 (br. s., 1H) 7.52 - 7.71 (m, 3H) 12.64 (br. s., 1H). LCMS (method-H): retention time 1.121 min, [M+H] 348.2.

Intermediate 5-I: (R)-5-(4-((6-bromopyridin-3-yl)methyl)morpholin-2-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 5-I was prepared (0.25 g, 72.30%) using a synthetic procedure similar to that of intermediate 4 starting from 6 bromonicotinaldehyde (0.15 g, 0.85 mmol) and intermediate 3-I, LCMS (method-I): retention time 0.68 min, [M+H] 403.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 6: 6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile

K ₂ CO ₃ ( 4.31 g, 31.20 mmol). The resulting reaction mixture was degassed with nitrogen for 5 min, then copper(I) iodide (0.59 g, 3.12 mmol) was added, followed by trans-N,N'-dimethylcyclohexane-1,2-diamine (2.59 ml, 16.4 mmol). The resulting mixture was degassed again for 10 minutes and heated at 110° C. for 1 hour under microwave irradiation. The resulting mixture was cooled to ambient temperature, filtered through Celite® and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20-40% EtOAc/n-hexane) to give Intermediate 6 (1.15 g, 52.10%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.62 (s, 3H), 8.10 (s, 1H), 8.38 (s, 1H), 8.95 (s, 1H), 9.37 (s, 1H), 9.98 (s , 1H). LCMS (Method-D), retention time 1.68 min, [M+H] 213.2.

Intermediate 7: 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one

Synthesized in accordance with the methods described in the literature (international PCT application, 2010130773).

Intermediate 8:

yl)benzo[d]oxazol-2(3H)-one

3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

Intermediate 8 was obtained (1.30 g, 59.80%) as a yellow solid using intermediate 7 (1.50 g, 6.44 mmol) according to a procedure similar to described for intermediate 2A. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.31(s, 12

H), 3.37 (s, 3H), 7.34 (d, J=7.93 Hz, 1H), 7.41-7.54 (m, 2H). LCMS (Method-D): retention time 2.79 min, [M-H] 292.2 (water adduct).

Intermediate 9: 6-(4-formyl-5-methoxy-1H-pyrazol-1-yl)-4-methylnicotinonitrile O

^MeO ^ _N'N

Jy

CN

Intermediate 9A: dimethyl-2-((dimethylamino)methylene)malonate

Me oh oh

To a solution of dimethylmalonate (10.00 g, 76.00 mmol) in toluene (100 ml) was added DMF-DMA (20.27 ml, 151.00 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated at 100° C. for 5 hours. The resulting mixture was cooled to ambient temperature and concentrated under reduced pressure to give Intermediate 9A (13.00 g, 84.00%) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.92 - 3.07 (m, 6H), 3.66 - 3.72 (br.s., 3H), 3.74 - 3.79 (br.s., 3H), 7.53 (s , 1H). LCMS (Method-D): retention time 0.63 min, [M+H] 188.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 9B: methyl 5-methoxy-1H-pyrazole-4-carboxylate

Oh y—om

N.,/^OMe N H

To a solution of Intermediate 9A (13.00 g, 69.40 mmol) in EtOH (50 mL) was added NH2NH2-2HC! (7.29 g, 69.40 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated at 70° C. for 5 hours. The resulting mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in DCM (250 ml) and basified with saturated NaHCO ₃ solution (0.5 L). The organic layer was separated, washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-120 g, 45-50% EtOAc/n-hexanes) to give Intermediate 9B (2.50 g, 13.14%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 3.67 (s, 3H), 3.84 (s, 3H), 8.11 (d, J=2.27 Hz, 1H), 12.56 (br. s., 1H). LCMS (Method-D): retention time 0.48 min, [M+H] 157.0.

Intermediate 9C: methyl 1-(5-cyano-4-methylpyridin-2-yl)-5-methoxy-1H-pyrazole-4carboxylate

Intermediate 9C was obtained (0.80 g, 15.42%) as a beige solid using a synthetic procedure similar to that of intermediate 6 starting from intermediate 9B (2.50 g, 16 .01 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 2.64 (s, 3H), 3.87 (s, 3H), 4.11 (s, 3H), 7.81 (d, J=1.00 Hz, 1H), 8.57 (s, 1H ), 8.89 (s, 1H). LCMS (method-H): retention time 1.81 min, [M+H] 273.

- 42 043056

Intermediate 9D: 1-(5-cyano-4-methylpyridin-2-yl)-5-methoxy-1H-pyrazole-4carboxylic acid

To a solution of intermediate 9C (0.80 g, 2.94 mmol) in THF (25 ml) was added (CH ₃ ) ₃ SiOK (1.50 g, 11.75 mmol) and stirring was continued at ambient temperature for 16 hours The resulting mixture was diluted with water (80 ml), neutralized with solid citric acid and was extracted with the addition of ethyl acetate (2x80 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 9D (0.75 g, 61.30%) as a beige solid. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 2.59 (s, 3H), 4.00 (s, 3H), 7.86 (s, 1H), 8.78 (s, 1H), 8.85 (s, 1H), 12.37 - 12 .91 (br. s, 1H). LCMS (method-H): retention time 0.40 min, [M+H] 259.5.

Intermediate 9E: 6-(4-(hydroxymethyl)-5-methoxy-1H-pyrazol-1-yl)-4 methylnicotinonitrile

To a solution of Intermediate 9D (0.75 g, 2.90 mmol) in THF (15 mL) was added TEA (1.21 mL, 8.71 mmol) followed by isobutyl chloroformate (0.76 mL, 5.81 mmol) at 0°C in a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 16 hours. The resulting mixture was filtered through a Schott funnel and the filtrate was cooled to 0°C and treated with a solution of NaBH ₄ (0.22 g, 5.81 mmol) in water (2 ml) for 10 min. The resulting mixture was allowed to take ambient temperature and stirred for 16 h. The resulting mixture was diluted with saturated NH ₄ Cl solution (40 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with 10% NaHCO ₃ solution (30 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 9E (0.43 g, 53.30%) as a beige solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.54 (s, 3H), 3.96 (s, 3H), 4.30 (d, J=5.02 Hz, 2H), 4.97 (t, J=5.52 Hz, 1H), 7.72 (s, 1H), 8.37 (s, 1H), 8.75 (s, 1H). LCMS (Method-D): retention time 1.681 min, [M+H] 245.0.

Intermediate 9.

To a solution of Intermediate 9E (0.40 g, 1.64 mmol) in DCM (30 mL) was added Dess-Martin periodinan (1.39 g, 3.28 mmol) at ambient temperature under nitrogen and stirring was continued for 20 h. The resulting mixture was diluted with DCM (50 ml) and 10% NaHCO3 (50 ml) was added. The organic layer was separated and washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 9 (0.30 g, 68.10%) as a beige solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.61 (s, 3H), 4.05 (s, 3H), 7.91 (s, 1H), 8.90 (s, 1H), 9.18 (s, 1H), 9.85 (s , 1H). LCMS (method-H): retention time 2.13 min, [M+H] 243.0.

Intermediate 10: 6-bromo-4-cyclopropylnicotinonitrile

- 43 043056

Intermediate 10A: 6-bromo-4-iodonicotinonitrile

To a solution of diisopropylamine (7.79 ml, 54.60 mmol) in THF (100 ml) was added n-BuLi (21.86 ml, 54.60 mmol) at -78°C under nitrogen atmosphere. After 30 minutes, 6-bromonicotinonitrile (10.00 g, 54.6 mmol) in THF (20 ml) was added followed by iodine (15.26 g, 60.10 mmol) in THF (10 ml) and stirring was continued for 2 h. The resulting reaction mixture was diluted with saturated NH4Cl solution (40 ml) and extracted with ethyl acetate (2x200 ml). The combined organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep80 g, 10-15% EtOAc/n-hexanes) to give Intermediate 10A (6.50 g, 38.50%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.51 (s, 1H), 8.76 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 10.

To a solution of intermediate 10A (0.60 g, 1.94 mmol) in a mixture of toluene (10 ml) and water (2 ml) was added cyclopropylboronic acid (0.20 g, 2.33 mmol) followed by K ₃ PO ₄ (0.82 g, 3.88 mmol) and the resulting mixture was degassed for 15 minutes. Palladium(II) acetate (0.05 g, 0.19 mmol) and tricyclohexylphosphine (0.11 g, 0.39 mmol) were added. The resulting mixture was degassed again for 10 minutes and heated at 140° C. for 1 hour in a microwave reactor. The resulting mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 15-20% EtOAc/n-hexanes) to give Intermediate 10 (0.10 g, 23.08%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.93 - 1.02 (m, 1H), 1.04 - 1.13 (m, 1H), 1.19 - 1.35 (m, 2H), 2.05 - 2.21 (m, 1H ), 8.51 (s, 1H), 8.75 (s, 1H). LCMS (Method-D): retention time 2.25 min, [M+2H] 223.0.

Intermediate 11: 6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

To a solution of 1H-imidazole-4-carbaldehyde (0.50 g, 5.20 mmol) and 6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol) in DMF (10 ml) was added K ₂ CO ₃ (1.08 g, 7.81 mmol) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was heated at 90° C. for 1 hour. The resulting mixture was cooled to ambient temperature and diluted with ice water (30 ml). The resulting precipitate was filtered off and washed with ethanol (2 ml) to give intermediate 11 (0.30 g, 25.00%), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95 (d, J=1.19 Hz, 1H), 9.87 (s, 1H ). LCMS (method-L): retention time 0.75 min, [M+H] 229.1.

Intermediate 12-I:

(K)-6-(4-(((2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-1Hpyrazol-1-yl) -4-methylnicotinonitrile

Intermediate 12A-I: (K)-5-(2-Amino-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

- 44 043056

A solution of intermediate 1-I (1.00 g, 5.26 mmol) in MeOH (40 ml) at -10° C. was purged with excess ammonia gas and the resulting reaction mixture was stirred at 50° C. for 16 hours in a sealed tube. The resulting mixture was concentrated under reduced pressure and the residue washed with ether (30 ml) to give intermediate 12A-I (0.75 g, 68.80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.26 (s, 3H), 2.52-2.56 (m, 1H), 2.69 (dd, J=13.05, 4.02 Hz, 1H), 4.80 (dd, J= 8.03, 3.51 Hz, 1H), 5.38 (d, J=1.51 Hz, 3H), 7.65 (s, 2H), (2 exchangeable protons not observed). LCMS (method-H): retention time 0.54 min, [M+H] 208.2.

Intermediate 12-I.

To a solution of intermediate 6 (0.20 g, 0.94 mmol) in MeOH (5 ml) was added acetic acid (0.08 ml, 1.42 mmol) followed by intermediate 12A-I (0.23 g, 1.13 mmol) and the resulting mixture was stirred at ambient temperature for 10 minutes. NaCNBH ₃ (0.18 g, 2.83 mmol) was added to the reaction mixture and stirring was continued for 12 hours. The resulting mixture was diluted with water (20 ml), basified with 10% NaHCO ₃ solution and extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [Luna C18 (250x30ID) 5 microns; solvent A: 0.1% TFA in H2O, solvent B: acetonitrile, gradient: 20-100 over 14 min, flow: 25 ml/min, retention time 11.16 min, UV 220 nm] to give intermediate 12- I (0.09 g, 22.86%). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.28 (s, 3H), 2.63 (s, 3H), 2.77-2.67 (m, 1H), 3.03-2.93 (m, 1H), 3.62 (m, 2H), 3.86 (d, J=6.00 Hz, 2H), 5.10 - 5.03 (m, 1H), 5.25 (s, 2H), 7.80 - 7.74 (m , 3H), 7.95 (d, J=0.80 Hz, 1H), 8.49 (d, J=0.80 Hz, 1H), 8.59 (s, 1H). LCMS/HPLC (method-H): retention time 1.80 min, [M+H] 404.2, purity: 99.7%. (Method-C): retention time 10.54 min, purity: 99.70%. Chiral purity (method-VI): retention time 9.44 min, 100% e.i.

Intermediate 13-I: (R)-N-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4yl)methyl)-2-hydroxy-N-(2-hydroxy- 2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)acetamide o ^Meno A O

CN

To a stirred solution of intermediate 12-I (0.23 g, 0.57 mmol) and 2hydroxyacetic acid (0.05 g, 0.57 mmol) in DCM (10 ml) was added HATU (0.43 g, mmol) followed by the addition of DIPEA (0.29 ml, 1.71 mmol). The resulting mixture was stirred at ambient temperature overnight. Water (30 ml) was added to the resulting mixture, which was then extracted with DCM (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 10-12% MeOH in DCM) to give Intermediate 13-I (0.15 g, 57.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 - 2.35 (m, 3H), 2.58 (s, 3H), 3.14 - 3.29 (m, 1H), 3.37 - 3.68 (m, 1H), 4, 10 - 4.36 (m, 2H), 4.41 - 4.78 (m, 3H), 5.08 - 5.30 (m, 1H), 5.31 - 5.45 (m, 2H), 5.66 - 5.92 (m, 1H), 7.61 7.77 (m, 2H), 7.84 (s, 1H), 7.94 - 8.02 (m, 1H), 8.57 (s, 1H), 8.84 (s, 1H). LCMS/HPLC (Method-A): retention time 1.382 min, [M+H] 462.1, purity: 98.52%. (Method-B): retention time 1.372 min, [M+H] 462.1, purity: 99.62%.

Intermediate 14-I: (R)-5-(4-((1H-pyrazol-4-yl)methyl)morpholin-2-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 14-I was prepared (0.75 g, 27.90%) using a synthetic procedure similar to that of Intermediate 4 starting from Intermediate 3-I (2.00 g, 8.57 mmol ). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.87 (m, 1H), 2.11-2.20 (m, 1H), 2.23 (s, 3H), 2.76 (d, J=11.04 Hz, 1H) , 2.86 (d, J=11.55 Hz, 1H), 3.45 (s, 2H), 3.67-3.79 (m, 1H), 3.97 (d, J=9.54 Hz, 1H), 4.78 (d, J=8.03 Hz, 1H), 5.38 (d, J=2.01 Hz, 2H), 7.41 (br. s., 1H), 7 .57 - 7.62 (m, 2H), 7.64 - 7.69 (m, 1H), 12.64 (br. s., 1H). LCMS/HPLC (method-H): retention time 0.767 min, [M+H] 314.2.

- 45 043056

Intermediate 15: 4-methoxy-6-(4-(2-oxoethyl)-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 15A: 3-(diethoxymethyl)-2-ethoxytetrahydrofuran

Me ^ O V ⁰ T ^ Me

l/ ⁰

Oh \—Me

FeCl ₃ (0.02 g, 0.14 mmol) was added to a flask containing triethoxymethane (23.26 g, 157.00 mmol) and cooled to 10°C. The resulting reaction mixture was stirred at the same temperature for 30 minutes and 2,3-dihydrofuran (10.00 g, 143.00 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 10°C for 1 h, diluted with DCM (100 ml) and filtered through Celite®. The filtrate was concentrated under reduced pressure to give intermediate 15A (30.00 g, 96.00%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.09 - 1.29 (m, 9H), 1.76 (dd, J=12.55, 5.52 Hz, 1H), 1.84 - 2.13 (m, 1H), 2.29 - 2.57 (m, 1H), 3.38 - 3.81 (m, 6H), 3.82 - 4.14 (m, 2H), 4.33 (d, J=8.53 Hz, 1H) , 4.88 - 5.09 (m, 1H).

Intermediate 15B: 2-(1H-pyrazol-4-yl)ethanol

BUT

To a solution of NH ₂ NH ₂ -2HCl (18.75 g, 179.00 mmol) in a mixture of water (50 ml) and ethanol (25 ml) was added intermediate 15A (30.00 g, 137.00 mmol) at 0° WITH. The resulting mixture was stirred at 0° C. for 1 hour and at ambient temperature for 1 hour. Sodium carbonate (30.00 g) was added to the resulting mixture and evaporated to dryness under reduced pressure. The residue was washed with ethanol (100 ml) and evaporated to give intermediate 15B (15.00 g, 92.00%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.78 (t, J=6.38 Hz, 2H), 3.72 (d, J=7.25 Hz, 1H), 3.77 3.88 (m, 2H), 7.49 (s, 2H), 9.52 - 10.74 (m, 1H). LCMS (Method-I): retention time 0.40 min, [M+H] 113.0.

Intermediate 15C: 6-(4-(2-hydroxyethyl)-1H-pyrazol-1-yl)-4-methoxynicotinonitrile

K2CO3 (1.54 g, 11 .15 mmol) and XANTPHOS (0.52 g, 0.89 mmol) and the resulting reaction mixture was degassed with nitrogen for 5 min. Pd ₂ (dba) ₃ (0.41 g, 0.45 mmol) was added and the resulting mixture, degassed again for 5 min, then heated at 100°C for 16 h. The resulting mixture was cooled to ambient temperature, filtered through Celite® and the filtrate were concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 2-2.5% MeOH in DCM) to give Intermediate 15C (0.40 g, 36.70%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.65 (t, J=6.78 Hz, 2H), 3.61 (td, J=6.78, 5.02 Hz, 2H), 4.10 (s, 3H), 4.62 - 4 .76 (m, 1H), 7.58 (s, 1H), 7.81 (s, 1H), 8.47 (s, 1H), 8.73 (s, 1H). LCMS (Method-I): retention time 0.83 min, [M+H] 245.3.

Intermediate 15.

To a stirred solution of Intermediate 15C (0.20 g, 0.82 mmol) in DCM (10 mL) was added Dess-Martin periodinan (0.52 g, 1.23 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. The resulting mixture was diluted with 10% NaHCO ₃ (30 ml) and extracted with DCM (3x25 ml). The combined extracts were washed with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give intermediate 15 (0.20 g, 45.32%). LCMS (method-I): retention time

0.95 min, [M+H] 243.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 16: 6-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile

Intermediate 16A: methyl 5-cyanopicolinate

CN

To a stirred solution of 6-bromonicotinonitrile (3.00 g, 16.39 mmol) in MeOH (80 ml) and DMF (80 ml) was added PdCl ₂ (dppf)-CH ₂ Cl ₂ (2.68 g, 3.28 mmol ) and TEA (5.71 ml, 41.00 mmol). The resulting mixture was heated at 60°C in an atmosphere of CO (at a pressure of 50 pounds per square inch) for 14 hours the resulting mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (Redisep-40.00 g, 60% EtOAc/n-hexanes) to give Intermediate 16A (2.25 g, 85.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.93 (s, 3H), 8.20 (dd, J=8.03, 1.00Hz, 1H), 8.54 (dd, J=8.03, 2.01Hz, 1H), 9 .09 - 9.25 (m, 1H). LCMS (Method L): retention time 0.70 min, [M+H] 163.1.

Intermediate 16B: 5-cyanopicolinohydrazide nh ₂

To a stirred solution of intermediate 16A (2.25 g, 13.88 mmol) in EtOH (50 mL) was added hydrazine hydrate (3.39 mL, 69.40 mmol). The resulting mixture was stirred at 80°C for 14 h, then cooled to ambient temperature. The resulting precipitate was filtered off and washed with EtOH (30 mL) to give Intermediate 16B (1.90 g, 84.00%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.68 (d, J=4.02 Hz, 2H), 7.91-8.23 (m, 1H), 8.42-8.61 (m, 1H), 8.92-9.24 (m , 1H), 10.21 (br. s., 1H). LCMS (method-L): retention time 0.45 min, [M+H] 163.1.

Intermediate 16.

To a stirred solution of intermediate 16B (1.00 g, 6.17 mmol) in POCl ₃ (15 ml) was added 2-chloroacetic acid (0.58 g, 6.17 mmol). The resulting reaction mixture was heated under reflux at 100°C for 14 h, then cooled to ambient temperature. POCl ₃ was evaporated under reduced pressure and the mixture was diluted with ice water (100 ml). The acidic solution was made basic by slowly adding solid NaHCO ₃ and extracted with ethyl acetate (3x50 ml). The combined organic extracts were washed with brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 20% EtOAc/n-hexane) to give Intermediate 16 (0.25 g, 18.37%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 5.20 (s, 2H), 8.38 (dd, J=8.53, 1.00 Hz, 1H), 8.55-8.64 (m, 1H), 9.24 (dd, J= 2.01, 1.00 Hz, 1H). (method-I): retention time 0.84 min, [M+H] 221.4.

- 47 043056

Intermediate 17: 6-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-4-methylnicotinonitrile

Intermediate 17A: methyl 5-cyano-4-methylpicolinate

Intermediate 17A was obtained (1.05 g, 39.10%) as an off-white solid using a synthetic procedure similar to that of Intermediate 16A starting from 6-bromo-4-methylnicotinonitrile (3.00 g , 15.23 mmol). 1H MP (400 MHz, DMSO-d ₆ ) δ ppm 2.60 (s, 3H), 3.92 (s, 3H), 7.85-8.33 (m, 1H), 9.04 (s, 1H). (method-I): retention time 0.76 min, [M+H] 177.2.

Intermediate 17B: 5-cyano-4-methylpicolinohydrazide

Intermediate 17B was obtained (0.45 g, 82.00%) as a white solid using a synthetic procedure similar to that of Intermediate 16B starting from Intermediate 17A (0.55 g, 3.12 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H), 4.67 (br. s., 2H), 8.07 (s, 1H), 8.74-9.05 (m, 1H), 10.15 (br. s ., 1H). (method I): retention time 0.51 min, [M+H] 177.2.

Intermediate 17.

Intermediate 17 was obtained (0.20 g, 25.03%) as a yellow solid using a synthetic procedure similar to that of intermediate 16 starting from intermediate 17B (0.60 g, 3.41 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.64 (s, 3H), 5.20 (s, 2H), 8.36 (s, 1H), 9.13 (s, 1H). (method-I): retention time 0.93 min, [MH] 232.9.

Intermediate 18-I: tert-butyl-(R)-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

Intermediate 18A-P was obtained (40.00 g, 68.80%) as a brown solid using a synthetic procedure similar to that of Intermediate 12A-I starting from Intermediate 1-II (40, 00 g, 210.00 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.26 (s, 3H), 2.52-2.56 (m, 1H), 2.69 (dd, J=13.05, 4.02 Hz, 1H), 4.80 (dd, J= 8.03, 3.51 Hz, 1H), 5.38 (d, J=1.51 Hz, 3H), 7.65 (s, 2H). (No 2 exchangeable protons were observed). LCMS (method-H): retention time 0.54 min, [M+H] 208.2.

- 48 043056

Intermediate 18B-II: tert-Butyl-(S)-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

A stirred solution of intermediate 18A-II (40.00 g, 145.00 mmol) in DCM (400 ml) was cooled to 0°C. TEA (60.50 ml, 434.00 mmol) was added followed by BOC ₂ O (40.30 ml, 174.00 mmol). The resulting reaction mixture was stirred at ambient temperature overnight, diluted with water (200 ml) and extracted with DCM (3x200 ml). The combined organic layers were washed with brine (150 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-750 g, 2% MeOH in chloroform) to give intermediate 18V-P: (48.00 g, 80.00%) as a colorless oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.35 (s, 9H), 2.29 (s, 3H), 2.96 (ddd, J=13.70, 7.90, 6.00 Hz, 1H), 3.20 - 3.06 ( m, 1H), 4.89 - 5.02 (m, 1H), 5.38 (s, 2H), 5.54 (d, J=4.50 Hz, 1H), 6.89 (t, J = 5.80 Hz, 1H), 7.66 (s, 2H). LCMS (Method-I): retention time 0.93 min, [M+H] 308.4.

Intermediate 18C-I: tert-Butyl (R)-(2-(1,3-dioxoisoindolin-2-yl)-2-(4-methyl-1oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

To a stirred solution of Intermediate 18B-P (47.00 g, 113.00 mmol) in THF (800 mL) was added triphenylphosphine (65.30 g, 249.00 mmol) followed by DIAD (39.60 mL, 204. 00 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours, diluted with water (1.5 L) and extracted with ethyl acetate (3x500 ml). The combined organic layers were washed with brine (300 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep - 1.5 kg, 40% EtOAc/n-hexane) to give Intermediate 18C-I (50.00 g, 91.00%) as a colorless oil. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.191.33 (m, 9H), 2.28 (s, 3H), 3.63 (dt, J=13.79, 5.57 Hz, 1H), 3.94-4.15 (m, 1H) , 5.26-5.46 (m, 2H), 5.65 (dd, J=9.44, 4.15 Hz, 1H), 7.23 (s, 1H), 7.71 (d, J = 8.31 Hz, 1H), 7.78-7.94 (m, 5H). LCMS (Method-I): retention time 1.23 min, [M+H] 437.2.

Intermediate 18-I.

To a stirred solution of intermediate 18C-I (40.00 g, 92.00 mmol) in MeOH (500 ml) was added hydrazine hydrate (44.80 ml, 916.00 mmol). The resulting reaction mixture was heated at 60°C for 14 h, cooled to ambient temperature and diluted with ethyl acetate (200 ml). The resulting solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep - 330 g, 2% MeOH/chloroform) to give Intermediate 18-I (28.50 g, 91.00%) as a greenish oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.35 (s, 9H), 1.87-2.01 (m, 2H), 2.29 (s, 3H), 2.85-2.97 (m, 1H), 3.10 (dd, J=12.30, 6.27 Hz, 1H), 4.24-4.34 (m, 1H), 5.37 (s, 2H), 6.87-6.98 (m, 1H), 7 .64 (d, J=8.03 Hz, 1H), 7.75 (d, J=8.03 Hz, 1H). LCMS (Method-I): retention time 0.84 min, [M+H] 307.1.

Intermediate 19-I: (R)-N-(2-amino-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)ethyl)-2-chloroacetamide

- 49 043056

Intermediate 19A-I: tert-Butyl-(R)-(2-(2-chloroacetamido)-2-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)ethyl)carbamate

ABOUT

To a stirred solution of intermediate 18-I (0.50 g, 1.63 mmol) in DCM (20 mL) at 0°C was added TEA (0.68 mL, 4.90 mmol) followed by chloroacetyl chloride (0.13 ml, 1.63 mmol). The resulting reaction mixture was stirred at ambient temperature for 14 h, diluted with water (30 ml) and was extracted with the addition of DCM (3x30 ml). The combined organic extracts were washed with brine (30 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 2% MeOH in chloroform) to give Intermediate 19A-I (0.40 g, 64.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 9H), 2.34 (s, 3H), 3.15-3.26 (m, 2H), 4.08 (s, 2H), 5.25 (q, J=7, 36 Hz, 1H), 5.34 - 5.45 (m, 2H), 7.00 (t, J=5.77 Hz, 1H), 7.54 (d, J=8.03 Hz, 1H) , 7.68 (d, J=8.03 Hz, 1H), 8.76 (d, J=7.53 Hz, 1H). (method-H): retention time 1.53 min, [M+H)] 383.0.

Intermediate 19-I.

To a stirred solution of intermediate 19A-I (0.05 g, 0.13 mmol) in DCM (10 ml) was added TFA (1.00 ml, 12.98 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. . The resulting mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeCN (10 ml), water (0.3 ml) and Na ₂ CO ₃ (0.07 g, 0.65 mmol) was added and the resulting mixture was heated at 80°C for 1 h. The resulting mixture was cooled to ambient temperature and excess solid sodium carbonate was filtered off. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give intermediate 19-I (0.04 g, 95.00%) as a colorless oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.36 (s, 3H), 3.04-3.27 (m, 2H), 4.04-4.23 (m, 2H), 5.37-5.53 (m, 3H), 7, 61 (d, J=8.03 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H), 8.01 (br. s., 2H), 8.91 (d, J= 8.53 Hz, 1H). (method-I): retention time 0.53 min, [M-1] 281.3.

Intermediate 20: 6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde H

N^N^_ _Me

To a stirred solution of 6-bromonicotinaldehyde (1.25 g, 6.72 mmol) in DMF (10 ml) was added K ₂ CO ₃ (2.32 g, 16.80 mmol) and 4-methyl-1H-imidazole (0. 55 g, 6.72 mmol). The resulting mixture was heated at 100°C for 1 h, then cooled to ambient temperature. The reaction mixture was poured into ice water (30 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography (Redisep 40 g, 0-100% EtOAc/n-hexane)) to give Intermediate 20 (0.50 g, 39.70%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 7.76 (s, 1H), 7.95 (dd, J=6.00, 1.20 Hz, 1H), 8.39 (dd, J=6.60, 1.80 Hz, 1H), 8.55 (d, 1.20 Hz, 1H), 8.99 (s, 1H), 10.08 (s, 1H), LCMS: (method-H) retention time: 1.03 min, [M+1]: 188.0.

Intermediate 21: 1-(5-formylpyridin-2-yl)-1H-imidazole-4-carbonitrile

Intermediate 21 was obtained (0.40 g, 37.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 6-bromonicotinaldehyde (1.00 g, 5.38 mmol) and 1H-imidazole-4-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, J=8.53 Hz, 1H), 8.53 (dd, J=8.28, 2.26 Hz, 1H), 8.89 (d, J=1.51 Hz, 1H ), 9.03 (d, J=1.51 Hz, 1H), 9.05 - 9.10 (m, 1H), 10.14 (s, 1H). LCMS/HPLC: (method-H) retention time 0.85 min, [M+1]: 199.2.

- 50 043056

Intermediate 22: 6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinaldehyde

Intermediate 22 was obtained (0.30 g, 59.30%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and 3-methyl-1H-1,2,4-triazole (0.33 g, 4.03 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 7.99 (d, J=8.53 Hz, 1H), 8.47 (dd, J=8.53, 2.01 Hz, 1H), 9.02-9 .04 (m, 1H), 9.37 (s, 1H), 10.12 (s, 1H). LCMS/HPLC: (Method-H) retention time 0.88 min, [M+1]: 189.0.

Intermediate 23-I:

(R)-5'-(((2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-4methoxy-[2,2'- bipyridine]-5-carbonitrile

Intermediate 23A: 4-methoxy-6-(trimethylstannyl)nicotinonitrile

A solution of 6-chloro-4-methoxynicotinonitrile (2.00 g, 11.86 mmol) in dioxane (10 ml) was degassed with nitrogen for 20 minutes. Hexamethylditin (2.71 ml, 13.05 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium(II) chloride (0.77 g, 1.19 mmol) were added. The resulting reaction mixture was degassed again for 10 min, heated at 100°C for 12 h and cooled to ambient temperature. The resulting mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give Intermediate 23A: (5.00 g, 39.50%) as a dark oil. LCMS (Method-I): retention time 1.26 min, [M+H] 299.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 23B: 5'-formyl-4-methoxy-[2,2'-bipyridine]-5-carbonitrile

A solution of 6-bromonicotinaldehyde (1.10-6.51 mmol) in dioxane (20 ml) was degassed (g, 5.91 mmol with nitrogen) and intermediate compound 23A (4.83 g, over 20 min. Tetrakistriphenylphosphine palladium ( 0.68 g, 0.59 mmol) followed by the addition of copper (I) iodide (0.11 g, 0.59 mmol) and the resulting mixture was degassed again for 10 minutes The resulting reaction mixture was heated at 100°C for 16 h was then cooled to ambient temperature and filtered through Celite® The filtrate was concentrated under reduced pressure The residue was purified by column chromatography (Redisep-40 g, 0-40% EtOAc/n-hexane) to give intermediate 23B (1.60 g, 79.00%) as an off-white solid ¹ H NMR (300 MHz, DMSO-d6) δ ppm 4.16 (s, 3H), 8.22 (d, J=14.35 Hz , 1H), 8.46 (d, J=8.31 Hz, 1H), 8.55 - 8.72 (m, 1H), 8.99 (d, J=1.51 Hz, 1H), 9 .24 (s, 1H), 10.20 (s, 1H) LCMS/HPLC: (method H) retention time: 1.63 min, [M+1]: 240.0.

Intermediate 23-I.

To a solution of intermediate 23B (0.60 g, 1.75 mmol) in a mixture of DCM (20 ml) and MeOH (6 ml) was added 12A-I (0.36 g, 1.75 mmol) followed by AcOH (0 .40 ml, 7.02 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 h followed by the addition of NaBH(CH ₃ CO ₂ ) ₃ (0.37 g, 1.75 mmol). Stirring was continued for 12 hours.

- 51 043056

The reaction mixture was then diluted with water (15 ml) and extracted with DCM (2x100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by prep. HPLC [Symmetry C8 (300x19 ID) 9 microns; solvent A: 10 mM ammonium acetate, solvent B: acetonitrile, gradient: 0-100% B over 21 min, flow: 18 ml/min, retention time 12.50 min, UV 220 nm] to give intermediate 23-I (0.10 g, 13.76%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.22 (s, 3H), 2.58-2.71 (m, 2H), 3.89 (s, 2H), 4.12 (s, 3H), 5.04 (br. s., 1H ), 5.30-5.42 (m, 2H), 5.52 (br. s., 1H), 7.59-7.71 (m, 2H), 7.94 (dd, J=8, 19, 2.32 Hz, 1H), 8.15 (s, 1H), 8.38 (d, J=8.31 Hz, 1H), 8.67 (s, 1H), 8.91 (s, 1H), (no exchangeable protons were observed). LCMS/HPLC: (method-D) retention time: 1.70 min, [M+1]: 431.0.

Intermediate 24: 4-methyl-6-(4-(oxiran-2-yl)-1H-pyrazol-1-yl)nicotinonitrile)

Intermediate 24A: 4-methyl-6-(1H-pyrazol-1-yl)nicotinonitrile

Intermediate 24A was obtained (0.85 g, 60.60%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from 1H-pyrazole (0.52 g, 7.61 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.50 (s, 3H), 6.65 (s, 1H), 7.93 (s, 1H), 8.02 (s, 1H), 8.66(s, 1H), 8.85 (s , 1H). LCMS/HPLC: (method-H) retention time: 1.63 min, [M+1]: 185.0.

Intermediate 24B: 6-(4-bromo-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Bromine (0.59 ml, 11.54 mmol) in AcOH (3 ml) was added dropwise to a solution of intermediate 24A (0.85 g, 4.61 mmol) in AcOH (20 ml). The resulting mixture was stirred at ambient temperature for 16 hours. The resulting mixture was poured into ice water, followed by the addition of a saturated ammonium thiosulfate solution (10 ml). The resulting precipitate was filtered off and dried under reduced pressure to give Intermediate 24B (1.12 g, 92.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.60 (s, 3H), 8.02 (s, 1H), 8.08(s, 1H), 8.88 (s, 2H). LCMS/HPLC: (Method-D) retention time: 2.89 min, [M+2]: 265.0.

Intermediate 24C: 4-methyl-6-(4-vinyl-1H-pyrazol-1-yl)nicotinonitrile

To a stirred solution of intermediate 24B (1.12 g, 4.37 mmol) in THF (25 mL) was added tributylvinyltin (1.66 g, 5.25 mmol) and the resulting mixture was degassed with nitrogen for 15 min. Triphenylphosphine (0.34 g, 1.31 mmol) was added followed by palla acetate

- 52 043056 diy(P) (0.15 g, 0.66 mmol) and the mixture was degassed again for 10 minutes. The resulting reaction mixture was heated at 80°C for 48 h, then cooled to ambient temperature. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-10% EtOAc/n-hexane) to give Intermediate 24C (0.80 g, 87.00%) as an off-white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 5.76 (d, J=17.70 Hz, 1H), 5.23 (d, J=11.10 Hz, 1H), 6.61-6.71 (m , 1H), 8.02 (s, 1H), 8.17 (s, 1H), 8.73 (s, 1H), 8.85 (s, 1H). LCMS/HPLC: (method-H) retention time: 2.06 min, [M+1]: 211.2.

Intermediate 24.

To a stirred solution of intermediate 24C (0.40 g, 1.90 mmol) in tert-butanol (10 ml) and water (20 ml) was added NBS (0.40 g, 2.28 mmol) and the resulting mixture was heated at 40 °C for 1 h. The resulting mixture was cooled to 0°C and NaOH (0.23 g, 5.71 mmol) in water (5 ml) was added. The resulting mixture was stirred at ambient temperature for 2 hours, diluted with water (20 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and evaporated under reduced pressure to give intermediate 24 (0.30 g). LCMS: (Method-I) retention time: 1.06 min, [M+1]: 227.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 25-I: (R)-5-(4-((2-bromothiazol-5-yl)methyl)morpholin-2-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 25A: (2-bromothiazol-5-yl)methanol

To a stirred solution of methyl 2-bromothiazole-5-carboxylate (2.00 g, 9.01 mmol) in THF (40 mL) was added LiBH4 (1.96 g, 90 mmol) and stirring continued at ambient temperature for 48 h. The resulting mixture was evaporated under reduced pressure and the residue was diluted with water (50 ml) and was extracted with the addition of DCM (3x75 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep40 g, 0-35% EtOAc/n-hexane) to give Intermediate 25A (0.65 g, 37.20%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.63 (d, J=5.60 Hz, 2H), 5.67 (d, J=5.60 Hz, 1H), 7.53 (s, 1H). LCMS: (Method-D) retention time: 0.68 min, [M+2]: 196.0.

Intermediate 25B: 2-bromothiazole-5-carbaldehyde

Intermediate 25B was prepared (0.38 g, 64.00%) from Intermediate 25A (0.60 g, 3.09 mmol) as a white solid using a synthetic procedure similar to that of Intermediate 9 from 9E. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.55 (s, 1H), 10.00 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 25-I.

Intermediate 25-I was obtained (0.35 g, 45.60%) as an off-white solid using a synthetic procedure similar to that of Intermediate 23-I, starting from Intermediate 25B (0.18 g , 0.93 mmol) and Intermediate 3-I (0.22 g, 0.94 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.24 (s, 3H), 2.27-2.36 (m, 1H), 2.76-2.85 (m, 1H), 2.89-2.95 (m, 1H), 3, 68 - 3.77 (m, 1H), 3.78 (br. s., 2H), 3.95 - 4.05 (m, 1H), 4.64 (d, J=5.02 Hz, 1H ), 4.76 -4.85 (m, 1H), 5.39 (d, J=2.01 Hz, 2H), 7.56 (s, 1H) 7.59 - 7.63 (m, 1H ), 7.64 - 7.70 (m, 1H). LCMS: (Method-I) retention time: 1.23 min, [M+2]: 411.0.

- 53 043056

Intermediate 26-I: (R)-5-(4-(2-bromothiazole-5-carbonyl)morpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 26A: 2-bromothiazole-5-carboxylic acid

To a stirred solution of methyl 2-bromothiazole-5-carboxylate (1.50 g, 6.75 mmol) in THF (10 ml), MeOH (4 ml) and water (2 ml) was added LiOH (0.81 g, .80 mmol) and stirring was continued at ambient temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, diluted with water (10 ml) and acidified with 2N. HCl. The solid was filtered off and dried under reduced pressure to give Intermediate 26A (0.70 g, 49.80%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.21 (s, 1H), 13.83 (br.s., 1H). LCMS: (Method-D) retention time: 0.38 min, [M+2]: 208.0.

Intermediate 26-I.

To a stirred solution of intermediate 26A (0.40 g, 1.92 mmol) and intermediate 3-I (0.45 g, 1.92 mmol) in DCM (10 mL) was added TEA (0.80 mL, 5. 77 mmol) followed by the addition of propylphosphonic anhydride (1.22 g, 3.85 mmol) and stirring continued at ambient temperature for 3 hours. The resulting mixture was diluted with water (20 ml) and extracted with DCM (3x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with DCM/n-hexane to give Intermediate 26-I (0.80 g, 67.80%) as an off-white solid. LCMS: (Method-D) retention time: 2.06 min, [M+2]: 425.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 27: 1-(5-formylthiazol-2-yl)-1H-imidazole-4-carbonitrile

Intermediate 27 was obtained (0.12 g, 37.80%) as a light brown solid using a synthetic procedure similar to that of Intermediate 11 starting from Intermediate 25B (0.20 g, 1 .04 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.65 (s, 1H), 8.80 (s, 1H), 9.00 (s, 1H), 10.06 (s, 1H). LCMS: (Method-D) retention time: 0.96 min, [M+1]: 205.0.

Intermediate 28: 6-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 28A: (1H-1,2,3-triazol-4-yl)methanol

TMS-N ₃ (7.10 ml, 53.50 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) at ambient temperature. The resulting reaction mixture was heated at 95°C for 12 h, cooled to ambient temperature, diluted with DCM (100 ml) and filtered through Celite®. The filtrate was evaporated under reduced pressure to give intermediate 28A (3.30 g, 93.00%) as a brown liquid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.55 (d, J=3.51 Hz, 2H), 5.12 - 5.27 (m, 1H), 7.70 (br. s., 1H), 14.58 - 15.07 (br s., 1H). GCMS: retention time 9.36 min, [M] 99.0. The compound was carried directly to the next step without further purification.

Intermediate 28B: 6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

ΪΝΛ

CN

Intermediate 28B was obtained (0.50 g, 20.95%) as a light brown solid using a synthetic procedure similar to that of intermediate 6 starting from intermediate 28A (1.00 g, 10 .09 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H), 4.67 (d, J=5.52 Hz, 2H), 5.49-5.54 (m, 1H), 8.12 (d, J=1.00 Hz , 1H), 8.18 (s, 1H), 8.94 (s, 1H). LCMS (Method-D): retention time 0.951 min, [M+H] 216.2.

Intermediate 28.

Intermediate 28 was obtained (0.90 g, 64.20%) as a yellow solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 28B (1.40 g, 6.51 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.67 (s, 3H), 8.29 (s, 1H), 8.79 (s, 1H), 9.03 (s, 1H), 10.21 (s, 1H). LCMS (Method-D): retention time 1.32 min, [M+H] 214.2.

Intermediate 29: 2-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-2H-1,2,3triazole-4-carbaldehyde

ABOUT

ABOUT

Intermediate 29A: 5-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 29A was obtained (0.65 g, 13.78%) as a brown solid using a synthetic procedure similar to that of intermediate 6 starting from intermediate 28A (1.50 g, 15.14 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.42 (s, 3H), 4.65 (d, J=5.52 Hz, 2H), 5.43 (t, J=5.77 Hz, 1H), 7.49 (d, J=8 .53 Hz, 1H), 7.75 (dd, J=8.78, 2.26 Hz, 1H), 7.85 (d, J=2.26 Hz, 1H), 8.02 (s, 1H ). LCMS (Method-D): retention time 1.04 min, [M+H] 247.2.

Intermediate 29.

Intermediate 29 was obtained (0.12 g, 79.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 29A (0.15 g, 0.60 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.44 (s, 3H), 7.57 (d, J=8.78 Hz, 1H), 7.88 (dd, J=8.78, 2.26 Hz, 1H), 7.99 (d , J=2.26 Hz, 1H), 8.70 (s, 1H), 10.18 (s, 1H). LCMS (Method-D): retention time 1.687 min, [M+H] 245.2.

- 55 043056

Intermediate 30: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile.

Intermediate 30A: 6-azido-4-methylnicotinonitrile.

To a stirred solution of 6-bromo-4-methylnicotinonitrile (2.00 g, 10.15 mmol) in DMF (10 ml) was added sodium azide (1.32 g, 20.30 mmol) and stirring continued for 12 h at environment. The resulting mixture was diluted with water (300 ml) and extracted with ethyl acetate (3x200 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 20-35% EtOAc/n-hexane) to give Intermediate 30A (0.87 g, 54.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.62 (d, J=1.00 Hz, 3H), 8.28 (t, J=1.00 Hz, 1H), 10.21 (s, 1H). LCMS (Method-D): retention time 0.88 min, [M+H] 160.2.

Intermediate 30B: 6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 30B was prepared (0.21 g, 31.00%) using a synthetic procedure similar to that of Intermediate 28A, starting from Intermediate 30A (0.50 g, 3.14 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.65 (s, 3H), 4.63 (d, J=6.53 Hz, 2H), 5.33 - 5.39 (m, 1H), 8.30 (d, J=1.00 Hz , 1H), 8.71 (s, 1H), 9.00 (s, 1H). LCMS (Method-D): retention time 0.87 min, [M+H] 216.2.

Intermediate 30.

Intermediate 30 was prepared (0.13 g, 65.60%) from intermediate 30B using a synthetic procedure similar to that of intermediate 9 from intermediate 9E. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.64-2.70 (m, 3H), 8.39 (s, 1H), 9.06 (s, 1H), 9.58 (s, 1H), 10.13 (s, 1H). LCMS (Method-D): retention time 1.42 min, [M+H] 214.2.

Intermediate 31: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methoxynicotinonitrile

Intermediate 31A: 6-azido-4-methoxynicotinonitrile

Intermediate 31A was prepared (1.40 g, 67.00%) using a synthetic procedure similar to that of Intermediate 30A, starting from 6chloro-4-methoxynicotinonitrile (2.00 g, 11.86 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.10 (s, 3H), 7.81 (s, 1H), 7.89 (s, 1H). LCMS (Method-D): retention time 0.79 min, [M+H] 176.0.

Intermediate 31B: 6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-4-methoxynicotino-56 043056 nitrile

Intermediate 31B was prepared (0.23 g, 13.40%) using a synthetic procedure similar to that of intermediate 28A, starting from intermediate 31A (1.30 g, 7.42 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.15 - 4.19 (m, 3H), 4.64 (s, 2H), 7.89 (s, 1H), 8.71 (s, 1H), 8.89 (s, 1H), ( exchangeable protons were not observed). LCMS (Method-D): retention time 1.01 min, [M+H] 232.2.

Intermediate 31.

Intermediate 31 was prepared (0.12 g, 60.50%) from intermediate 31B (0.20 g, 0.86 mmol) using a synthetic procedure similar to that of intermediate 9 from intermediate 9E. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 4.19 (s, 3H), 7.99 (s, 1H), 8.96 (s, 1H), 9.59 (s, 1H), 10.14 (s, 1H). LCMS (Method-D): retention time 1.1.42 min, [M+H] 230.2.

Intermediate 32: 1-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1H-1,2,3triazole-4-carbaldehyde

Intermediate 32A: 5-nitrobenzo[d]oxazol-2(3H)-one no ₂

α)

ΗΝ λ-Q O

To a stirred solution of 2-amino-4-nitrophenol (5.00 g, 32.40 mmol) in THF (50 ml) was added CDI (6.84 g, 42.20 mmol) at 70° C. and stirring was continued at ambient temperature. environment for 3 hours the resulting mixture was concentrated under reduced pressure, diluted with water (200 ml) and was extracted with the addition of ethyl acetate (2x100 ml). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 32A (5.50 g, 94.00%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 7.49 (d, J=8.69 Hz, 1H), 7.82 (d, J=2.27 Hz, 1H), 8.02 (dd, J=8.69, 2.27 Hz, 1H ). (No exchangeable protons were observed). LCMS (method-H): retention time 0.69 min, [MH] 179.0.

Intermediate 32B: 3-methyl-5-nitrobenzo[d]oxazol-2(3H)-one

To a stirred solution of intermediate 32A (5.00 g, 27.80 mmol) in DMSO (55 mL) was added K2CO3 (4.22 g, 30.50 mmol), followed by methyl iodide (5.21 mL, 83.00 mmol) and stirring was continued at ambient temperature for 12 hours. The resulting mixture was cooled to 0°C and diluted with ice water (150 ml). The resulting suspension was stirred at ambient temperature for 1 hour. The resulting solid was filtered off, dried under reduced pressure to give Intermediate 32B (4.50 g, 83.00%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 7.57 (d, J=8.69 Hz, 1H), 8.09 (dd, J=8.69, 2.27 Hz, 1H), 8.21 (d, J=2.64 Hz, 1H ), 3.43 (s, 3H). LCMS (method-H): retention time 1.23 min, [M+H] 195.2.

- 57 043056

Intermediate 32C: 5-amino-3-methylbenzo[d]oxazol-2(3H)-one

NH ₂ ^Me 'N-^P o

To a solution of intermediate 32B (1.80 g, 9.27 mmol) in acetic acid (50 ml) was added 10% Pd/C (0.10 g, 0.93 mmol) and the resulting mixture was stirred at ambient temperature under atmospheric hydrogen for 14 hours. The resulting mixture was filtered through Celite®, then washed with 10% MeOH in DCM (20 ml). The filtrate was evaporated under reduced pressure to give intermediate 32C (1.20 g, 80.00%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.23 (s, 3H), 5.06 (br. s., 2H), 6.28 (dd, J=8.53, 2.51 Hz, 1H), 6.37 (d, J=2 .01 Hz, 1H), 6.95 (d, J=8.53 Hz, 1H). LCMS (Method-D): retention time 0.59 min, [M+H] 165.2.

Intermediate 32D: 5-azido-3-methylbenzo[d]oxazol-2(3H)-one

N ₃ ^Me 'N [

V-0

ABOUT

To a solution of intermediate 32C (1.50 g, 9.14 mmol) in ACN (20 mL) at 0°C was added tert-butyl nitrite (3.26 mL, 27.40 mmol) followed by azidotrimethylsilane (3.61 mL , 27.40 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours. It was diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give Intermediate 32D (1.00 g, 57.20%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.34 (s, 3H), 6.85 (dd, J=8.53, 2.01 Hz, 1H), 7.14 (d, J=2.51 Hz, 1H), 7.35 (d , J=8.53 Hz, 1H). LCMS (method-H): retention time 2.30 min, [M+H] 191.2.

Intermediate 32E: 5-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-3-methylbenzo[d]oxazol-2(3H)-one

To a stirred solution of intermediate 32D (1.30 g, 6.84 mmol) and prop-2-yn-1ol (0.83 g, 6.84 mmol) in tert-butanol (8 ml) and water (8 ml ) was added with freshly prepared 1 M sodium ascorbate solution (0.55 ml, 0.55 mmol), followed by the addition of copper (II) sulfate pentahydrate (0.014 g, 0.055 mmol). The resulting reaction mixture was stirred at ambient temperature for 8 h, diluted with DCM (200 ml) and washed with water (100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20-35% EtOAc/n-hexane) to give Intermediate 32E (1.40 g, 83.00%). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 3.32 (s, 3H), 4.62 (d, J=5.67 Hz, 2H), 5.35 (t, J=5.67 Hz, 1H), 7.52 (d, J=8 .69 Hz, 1H), 7.65 (dd, J=8.50, 2.08 Hz, 1H), 7.89 (d, J=2.27 Hz, 1H), 8.67 (s, 1H ). LCMS (method-H): retention time 0.62 min, [M+H] 247.0.

Intermediate 32.

Intermediate 32 was prepared (1.00 g, 78.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 32E (1.30 g, 5.28 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 3.41 (s, 3H), 7.58 (d, J=8.31 Hz, 1H), 7.69-7.80 (m, 1H), 7.98 (d, J=2.27 Hz , 1H), 9.55 (s, 1H), 10.13 (s, 1H). LCMS (Method-D): retention time 2.55 min, [M+H] 245.0.

- 58 043056

Intermediate 33: 1-(7-Fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1Hpyrazole-4-carbaldehyde

Intermediate 33A: 5-bromo-7-fluorobenzo[d]oxazol-2(3H)-one

A solution of 2-amino-4-bromo-6-fluorophenol (2.00 g, 9.71 mmol) and CDI (1.73 g, 10.68 mmol) in THF (20 ml) was heated at 70°C for 2 h. The resulting mixture was concentrated to dryness and diluted with water (30 ml). The precipitated solid was filtered off and dried under reduced pressure to give Intermediate 33A (2.00 g, 89.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.13 (d, J=1.50 Hz, 1H), 7.34 (dd, J=10.00, 2.0 Hz, 1H), 7.82 (br.s, 1H). LCMS: (Method-I) retention time: 1.17 min, [M+2]: 232.0.

Intermediate 33B: 5-bromo-7-fluoro-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 33B was obtained (1.90 g, 90.00%) as a black solid using a synthetic procedure similar to that of Intermediate 32B starting from Intermediate 33A (2.00 g, 8.62 mmol).

¹ H NMR (400 MHz, CDCl3) δ 3.40 (s, 3H), 6.94 (dd, J=1.60, 0.90 Hz, 1H), 7.10 (dd, J=9.3 , 1.8 Hz, 1H). LCMS: (Method-I) retention time: 1.17 min, [M+2]: 248.0.

Intermediate 33.

Intermediate 33 was obtained (0.06 g, 11.30%) as a brown solid using a synthetic procedure similar to that of Intermediate 6 starting from Intermediate 33B (0.50 g, 2.03 mmol) and pyrazole-4carbaldehyde (0.49 g, 5.08 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.41 (s, 3H), 7.73 (dd, J=11.55, 2.01 Hz, 1H), 7.79 (d, J=2.01 Hz, 1H), 8.32 (s , 1H) 9.26 (s, 1H), 9.93 (s, 1H). LCMS: (method-L) retention time: 0.95 min, [M+1]: 262.0.

Intermediate 34: 1-(3,7-dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1Hpyrazol-4-carbaldehyde

Intermediate 34A: 4-bromo-2-methyl-6-nitrophenol

To a suspension of 4-bromo-2-methylphenol (3.00 g, 16.04 mmol) in water (25 ml) was added AcOH (1.84 ml, 32.10 mmol) followed by the addition of nitric acid (3.58 ml, 80.00 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was diluted with water (50 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-15% EtOAc/n-hexane) to give intermediate 34A

- 59 043056 (1.20 g, 30.00%) as a yellow solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.34 (s, 3H), 8.38 (dd, J=3.02, 0.76 Hz, 1H), 8.59 (d, J=3.02 Hz, 1H), (capable of exchanging protons not observed). LCMS (Method-D) retention time: 2.93 min, [M+2]: 234.0.

Intermediate 34B: 2-amino-4-bromo-6-methylphenol

To a solution of tin(II) chloride (5.31 g, 28.00 mmol) and conc. HCl (6.00 ml, 197.00 mmol) in MeOH (25 ml) was added intermediate 34A (1.30 g, 5.60 mmol) at 0°C. The resulting mixture was stirred at ambient temperature for 14 h, concentrated under reduced pressure and diluted with water (100 ml). The mixture was podslushivaet using a saturated solution of NaHCO ₃ , filtered through Celite® and the filtrate was extracted with the addition of DCM (2x75 ml). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give Intermediate 34B (0.90 g, 80.00%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.15 (s, 3H), 4.83 (br. s., 2H), 6.44 (d, J=2.64 Hz, 1H), 6.61 (d, J=2.27 Hz, 1H), 8.06 (br. s., 1H). LCMS: (Method-D) retention time: 2.93 min, [M+2]: 204.0.

Intermediate 34C: 5-bromo-7-methylbenzo[d]oxazol-2(3H)-one

Intermediate 34C was obtained (0.85 g, 84.00%) as a light brown solid using a synthetic procedure similar to that of Intermediate 33A starting from Intermediate 34B (0.90 g, 4 .45 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H) 7.08 (d, J=1.51 Hz, 1H) 7.14 (s, 1H), 11.80 (br.s., 1H). LCMS: (Method-D) retention time: 2.93 min, [M+2]: 230.0.

Intermediate 34D: 5-bromo-3,7-dimethylbenzo[d]oxazol-2(3H)-one

Intermediate 34D was obtained (0.90 g, 89.00%) as a light brown solid using a synthetic procedure similar to that of Intermediate 32B starting from Intermediate 34C (0.95 g, 4 .17 mmol). ¹ H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3H), 3.37 (s, 3H), 6.94 (d, J=1.51 Hz, 1H), 7.08-7.10 (m, 1H). LCMS: (Method-H) retention time: 2.09 min, [M+H ₂ O]: 260.0.

Intermediate 34.

Intermediate 34 was obtained (0.08 g, 15.06%) as an off-white solid using a synthetic procedure similar to that of Intermediate 6 starting from Intermediate 34D (0.50 g, 2.07 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 3.38 (s, 3H), 7.58 (s, 1H), 7.70 (d, J=2.01 Hz, 1H), 8.28 (s, 1H ), 9.19 (s, 1H), 9.92 (s, 1H). LCMS: (method-L) retention time: 0.94 min, [M+1]: 258.4.

Intermediate 35: 1-(7-Methoxy-3-methyl-2-oxo-2,3-dihydrobeio[d]oxazol-5-yl)-1Hpyrazole-4-carbaldehyde

- 60 043056

Intermediate 35A: 4-bromo-2-methoxy-6-nitrophenol

Nitric acid (1.19 ml, 26.6 mmol) was added to a stirred solution of 4-bromo-2-methoxyphenol (4.50 g, 22.16 mmol) in diethyl ether (30 ml) and water (10 ml) within 5 min. The resulting reaction mixture was stirred at ambient temperature for 30 min, diluted with water (50 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-20% EtOAc/n-hexane) to give Intermediate 35A (2.50 g, 45.50%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.90 (s, 3H), 7.43 (d, J=2.51 Hz, 1H), 7.60-7.64 (m, 1H), 10.70 (br. s., 1H). LCMS: (Method-I) retention time: 0.94 min, [M+2]: 250.2.

Intermediate 35B: 2-amino-4-bromo-6-methoxyphenol

Intermediate 35B was obtained (1.50 g, 68.30%) as an off-white solid using a synthetic procedure similar to that of Intermediate 34B starting from Intermediate 35A (2.50 g, 10.08 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H), 4.79 (br. s., 2H), 6.36 (d, J=2.01 Hz, 1H), 6.43-6.47 (m, 1H), 8.34 (br. s., 1H). LCMS: (Method-D) retention time: 1.51 min, [M+2]: 220.0.

Intermediate 35C: 5-bromo-7-methoxybenzo[d]oxazol-2(3H)-one

Intermediate 35C was obtained (1.50 g, 82.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 33A starting from Intermediate 35B (1.63 g, 7.48 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.90 (s, 3H), 6.89 (d, J=1.13 Hz, 1H), 7.01 (d, J=1.51 Hz, 1H), 11.80 (br. s., 1H). LCMS: (Method-D) retention time: 1.79 min, [M+2]: 246.0.

Intermediate 35D: 5-bromo-7-methoxy-3-methylbenzo[d]oxazol-2(3H)-one

Intermediate 35D was obtained (1.40 g, 88.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 32B starting from Intermediate 35C (1.50 g, 6.15 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.31 (s, 3H), 3.91 (s, 3H), 7.06 (d, J=1.51 Hz, 1H), 7.19 (d, J=1.13 Hz, 1H). LCMS: (Method-H) retention time 1.84 min, [M+H2O]: 275.0.

Intermediate 35.

Intermediate 35 was obtained (0.24 g, 45.30%) as an off-white solid using a synthetic procedure similar to that of Intermediate 6 starting from Intermediate 35D (0.50 g, 1.94 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.34 (s, 3H), 4.00 (s, 3H), 7.42 (d, J=1.89 Hz, 1H), 7.51 (d, J=1.89 Hz, 1H), 8.30 (s, 1H), 9.28 (s, 1H), 9.93 (s, 1H). LCMS: (method-L) retention time: 0.90 min, [M+1]: 274.1.

- 61 043056

Intermediate 36: 6-(4-formyl-3-methyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 36 was obtained (0.21 g, 25.60%) as a beige solid using a synthetic procedure similar to that of intermediate 6 starting from 3-methyl-1H-pyrazole-4-carbaldehyde ( 0.40 g, 3.63 mmol) and 6-bromo-4-methylnicotinonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 2.6 (s, 3H), 8.01 (s, 1H), 8.90 (s, 1H), 9.28 (s, 1H), 10.00 (s , 1H). LCMS: (method-H) retention time 1.85 min, [M+H] 227.0.

Intermediate 37: 6-(3-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 37 was prepared (0.27 g, 30.50%) using a synthetic procedure similar to that of intermediate 6 starting from 1Hpyrazole-3-carbaldehyde (0.40 g, 4.16 mmol) and 6-bromo-4-methylnicotinonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.50 - 2.68 (s, 3H), 7.20 - 7.22 (s, 1H), 8.03 (s, 1H), 8.09 - 8.17 (s, 1H), 8, 95-8.99(s, 1H), 10.48(s, 1H). LCMS: (Method-I) retention time 1.00 min, [M+H] 213.0.

Intermediate 38-I: 5-((2R,6R)-6-(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 38A: methyl 6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrazine-2-carboxylate

Intermediate 38A was obtained (6.20 g, 75.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 2B (8.74 g, 31.90 mmol) and 6-chloropyrazine-2-carboxylate (5.00 g, 29.00 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.34 (s, 3H), 3.96 (s, 3H), 5.52 (s, 2H), 7.76 (d, J=8.03 Hz, 1H), 7.85 (d, J = 7.53 Hz, 1H), 9.16 (s, 1H), 9.26 (s, 1H). LCMS (Method-J): retention time 1.15 min, [M+H] 285.2.

Intermediate 38B: methyl 6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-2-carboxylate

- 62 043056

Intermediate 38B was prepared (4.00 g, 97.00%) using a synthetic procedure similar to that of Intermediate 2-I, starting from Intermediate 38A (4.00 g, 14.07 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.25 - 2.32 (m, 4H), 2.54 - 2.62 (m, 1H), 2.82 (d, J=12.55 Hz, 1H), 3.10 (d, J= 12.05 Hz, 1H), 3.54 - 3.60 (m, 1H), 3.70 (s, 3H), 4.06 (d, J=8.03 Hz, 1H), 5.32 - 5.43 (m, 2H), 7.62-7.71 (m, 1H), 7.76-7.83 (m, 1H), (2 exchangeable protons not observed). LCMS (Method-I): retention time 0.49 min, [M+H] 291.5.

Intermediate 38C: 1-(tert-butyl)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1,3-dicarboxylate

Intermediate 38C was prepared (4.50 g, 95.00%) using a synthetic procedure similar to that of Intermediate 18V-P, starting from Intermediate 38B (3.50 g, 12.06 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 - 1.51 (m, 9H), 2.26 - 2.39 (m, 3H), 2.74 - 2.95 (m, 1H), 3.06 (br. s., 1H) , 3.58 (d, J=8.03 Hz, 1H), 3.72 (s, 3H), 3.82-3.94 (m, 1H), 4.03 (d, J=8.53 Hz, 1H), 4.13 - 4.28 (m, 1H), 5.38 - 5.46 (m, 2H), 7.64 - 7.76 (m, 1H), 7.82 (d, J=7.53 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-I): retention time 1.17 min, [M+H] 391.6.

Intermediate 38D-I, II, III and IV: tert-Butyl-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a solution of intermediate 38C (6.20 g, 11.12 mmol) in a mixture of THF (50 ml) and EtOH (50 ml) was added LiCl (0.94 g, 22.23 mmol) and NaBH ₄ (0.84 g , 22.23 mmol) under nitrogen atmosphere and the resulting mixture was stirred at ambient temperature for 14 hours. The resulting mixture was quenched by adding 10% aqueous sodium bicarbonate solution (150 ml) and extracted by adding ethyl acetate (3x150 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC [Sunfire OBD (250x30 ID) 5 microns; solvent A: 10 mM ammonium acetate in water, solvent B: acetonitrile, gradient: 30-100% B over 16 min, flow: 25 ml/min] to give diastereomer I and II. Diastereomer I was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak ADH (250x4.6 mm) 5 microns; 0.2% NH4OH in MeOH, flow: 3.0 ml/min. Temperature: 30°C, UV: 210 nm]. The first eluted compound (retention time 2.67 min), designated Intermediate 38D-I, was obtained (1.10 g, 27.30%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.32 (s, 3H), 2.78 (dd, J=10.79, 3.26 Hz, 1H), 3.37 - 3.43 (m, 3H) , 3.79 - 4.11 (m, 4H), 4.73 (br. s., 1H), 5.41 (s, 2H), 7.69 (d, J=8.03 Hz, 1H) , 7.81 (d, J=8.03 Hz, 1H), (1 exchangeable proton not observed). LCMS (Method-I): retention time 0.97 min, [M+H] 363.2. Chiral purity (Method-XII): retention time 2.69 min, 100% e.i. SOR: [a] ²⁵ _D = -26.00 (c 0.1, MeOH).

The second eluted compound (retention time 3.72 min), designated Intermediate 38D-II, was obtained (1.10 g, 27.30%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.32 (s, 3H), 2.78 (dq, J=13.62, 2.99 Hz, 1H), 3.38 - 3.44 (m, 3H) , 3.82 - 4.12 (m, 4H), 4.74 (br. s., 1H), 5.41 (s, 2H), 7.69 (d, J=8.03 Hz, 1H) , 7.81 (d, J=8.03 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-I): retention time 0.97 min, [M+H] 363.2. Chiral purity (Method-XII): retention time 3.81 min, 100% e.i.

Diastereomer II was separated into two separate enantiomers by SFC [Luxcellulose-2 (250x21.5 mm) 5 microns; 0.2% NH4OH in MeOH+ACN (1:1) flow: 3.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 6.64 min), designated Intermediate 38D-III, was obtained (0.25 g, 6.21%) as an off-white solid. ¹ H NMR (400 MHz, DMSOd6) δ ppm 1.41 (s, 9H), 2.26-2.37 (m, 3H), 2.96 (br. s., 1H), 3.39 (br. s., 2H), 3.57 ( d, J=10.54 Hz, 2H), 3.70 3.92 (m, 3H), 4.67 (br. s., 1H), 5.40 (s, 2H), 7.68 (d , J=8.03 Hz, 1H), 7.84 (d, J=8.03 Hz, 1H), (no exchangeable proton observed). LCMS (Method-I): retention time 0.92 min, [M+H] 363.2. Chiral purity (method-XIX): retention time 6.69 min, 100% e.i. SOR: [a] ²⁵ D=+ 26.00 (c 0.1, MeOH). The second eluted compound (retention time 8.49 min), designated Intermediate 38D-IV, was obtained as a white solid (0.25 g, 6.21%). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.41 (s, 9H), 2.28-2.36 (m, 3H), 2.96 (br. s., 1H), 3.35-3.46 (m, 2H), 3.58 (br. s., 3H), 3.75 (d, J=14.05 Hz, 1H), 4.67 (t, J=5.27 Hz, 2H), 5.40 (s, 2H), 7.68 (d, J=8.03 Hz, 1H), 7.84 (d, J=8.03 Hz, 1H), (1 exchangeable proton not observed). LCMS (Method-I): retention time 0.92 min, [M+H] 363.2. Chiral purity (method-XIX): retention time 8.62 min, 100% e.i.

Intermediate 38-I.

To a solution of intermediate 38D-I (1.50 g, 4.14 mmol) in MeOH (50 ml) was added 4 N HCl in dioxane (20 ml, 80 mmol). The resulting mixture was stirred at ambient temperature for 1 hour and concentrated to dryness. The residue was diluted with MeOH (100 ml), cooled to 0° C. and purged with ammonia for 5 minutes. The resulting clear solution was concentrated under reduced pressure to give Intermediate 38-I (1.00 g, 92.00%). The compound was carried directly to the next step without further purification. ¹ H NMR (400 MHz, DMSOd ₆ ) δ ppm 2.31 (s, 3H), 2.59 - 2.77 (m, 2H), 2.82 - 2.95 (m, 2H), 3.38 - 3.44 (m, 2H), 3, 73 (br. s., 1H), 3.87 (d, J=11.04 Hz, 1H), 4.04-4.23 (m, 1H), 5.41 (s, 2H), 7, 70 (d, J=7.53 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-I): retention time 0.40 min, [M+H] 263.2. To determine the stereochemistry of intermediate 38-I, 5-((2R,6R)-4-(4-bromobenzoyl)-6(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)-one was prepared according to according to the method described in the literature (US2002/156081A1, 2002) and the absolute configuration was determined by single crystal X-ray diffractometry.

Intermediate 39-I: 5-(6-(hydroxymethyl-d2)piperazin-2-yl)-4-methylisobenzofuran1(3H)-one

D OH D

Intermediate 39A-I, II, III and IV: tert-Butyl 3-(hydroxymethyl-d2)-5-(4-methyl-1-oxo1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

ABOUT

Intermediate 39A-I, II, III and IV was prepared using a synthetic procedure similar to that of Intermediate 38A-I, II, III and IV, starting from Intermediate 38C (1.40 g, 2.51 mmol and NaBD ₄ (0.21 g, 5.02 mmol) The crude residue was purified by preparative HPLC [Sunfire OBD (250x30 ID) 5 µm, Solvent A: 10 mM ammonium acetate in water, Solvent B: acetonitrile, gradient: 30 -100% B over 16 min, flow: 25 ml/min] to give diastereomer I and II Diastereomer I was separated into two separate enantiomers by SFC [Chiralpak ADH (250 x 4.6 mm) 5 µm; 0.2% NH4OH in MeOH, flow: 3.0 g/min Temperature: 30°C, UV: 210 nm] The first eluted compound (retention time 2.67 min), designated as intermediate 39A-I, was obtained (0.20 g, 21.80%) as white solid Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (s, 9H), 2.33 (s, 3H), 2.39-2 .47 (m, 2H), 2.65 - 2.81 (m, 2H), 3.86 4.14 (m, 3H), 4.72 (s, 1H), 5.42 (s, 2H) , 7.70 (d, J=8.03 Hz, 1H), 7.82 (d, J=8.03 Hz, 1H). LCMS (Method-I):

- 64 043056 retention time 0.97 min, [M+H] 365.3. Chiral purity (Method-XII): retention time 2.27 min, 100% e.i. The second eluted compound (retention time 3.72 min), designated Intermediate 39A-P, was obtained (0.20 g, 21.80%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (s, 9H), 2.33 (s, 3H), 2.38-2.47 (m, 2H), 2.67-2.83 (m, 2H), 3.84-4, 08 (m, 3H), 4.69 - 4.75 (m, 1H), 5.42 (s, 2H), 7.70 (d, J=8.03 Hz, 1H), 7.82 (d , J=8.03 Hz, 1H). LCMS (Method-I): retention time 0.97 min, [M+H] 365.3. Chiral purity (Method-XII): retention time 2.97 min, 95.40% ee

Diastereomer II was separated into two separate enantiomers by SFC [Luxcellulose-2 (250x21.5 mm) 5 microns; 0.2% NH4OH in MeOH+ACN (1:1) flow: 70.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 6.59 min), designated Intermediate 39A-III, was obtained (0.05 g, 5.47%) as a white solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.28-2.36 (m, 3H), 2.64-2.74 (m, 2H), 2.87-3.02 (m, 1H), 3, 18 (s, 2H), 3.70-3.94 (m, 2H), 4.26 (d, J=9.54 Hz, 1H), 5.42 (s, 2H), 7.69 (d , J=8.03 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS (Method-I): retention time 0.93 min, [M+H] 365.3. Chiral purity (Method-XIX): retention time 6.56 min, 100% e.i. The second eluted compound (retention time 8.32 min), designated Intermediate 39A-IV, was obtained (0.05 g, 5.47%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.28 - 2.37 (m, 3H), 2.66 - 2.72 (m, 2H), 2.87 - 3.02 (m, 1H), 3, 18 (s, 2H), 3.70-3.94 (m, 2H), 4.26 (d, J=10.54 Hz, 1H), 5.42 (s, 2H), 7.69 (d , J=8.03 Hz, 1H), 7.85 (d, J=7.53 Hz, 1H). LCMS (Method-I): retention time 0.93 min, [M+H] 365.3. Chiral purity (method-XIX): retention time 8.32 min, 98% e.i.

Intermediate 39-1.

Intermediate 39-1 was obtained (0.13 g, 93.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 38-I starting from Intermediate 39A-I (0. 20 g, 0.55 mmol). ¹ NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3H), 2.57 - 2.69 (m, 2H), 3.17 (d, J=10.54 Hz, 1H), 3.21 - 3.31 (m, 2H) , 4.59 (d, J=9.54 Hz, 1H), 4.96 (br. s., 1H), 5.33-5.48 (m, 2H), 7.70 (d, J= 8.03 Hz, 1H), 7.80 (d, J=8.03 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-I): retention time 0.39 min, [M+H] 265.2.

Intermediate 40-I: 5-(6,6-dimethylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 40A: 5-(2-bromoacetyl)-4-methylisobenzofuran-1(3H)-one

Synthesized according to a similar procedure described in the literature (WO 2010/129379 A1,

2010).

Intermediate 40B: oxoacetaldehyde

2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-

To a solution of intermediate 40A (2.65 g, 7.88 mmol) in a mixture of DMSO (15 ml) and water (0.142 ml) was added 48% HBr in water (0.018 ml, 0.158 mmol) and the resulting mixture was heated at 80°C for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (50 ml), basified with 10% aqueous sodium bicarbonate solution (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 40B (1.00 g, 43.50%) as an off-white solid. The compound was carried directly to the next step without further purification. 1H NMR (400 MHz, DMSOd6) δ ppm 2.29 (s, 3H), 5.54 (br. s., 2H), 7.20 (dd, J=8.07, 0.98 Hz, 1H), 7.74-7.88 (m , 1H), 7.95 (d, J=8.31 Hz, 1H). LCMS (Method-I): retention time 0.82 min, [M-H] 203.0.

Intermediate 40C: tert-Butyl 3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzo- 65 043056 furan-5-yl)piperazine-1-carboxylate

To a solution of intermediate 40B (0.95 g, 3.72 mmol) in a mixture of THF (24 ml) and MeOH (6 ml) was added 2-methylpropane-1,2-diamine (0.33 g, 3.72 mmol) and the resulting mixture was stirred at ambient temperature for 1 hour. NaBH ₄ (0.28 g, 7.44 mmol) was added and the resulting mixture was stirred for 30 minutes. TEA (1.556 ml, 11.17 mmol) was added followed by BOC ₂ O (0.864 ml, 3.72 mmol) and the resulting mixture was stirred at ambient temperature for 14 h, diluted with water (100 ml) and extracted with DCM ( 3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 50% EtOAc/n-hexane) to give the racemate (1.10 g). The racemate was separated into two separate enantiomers by the SFC method [Chiralpak ADH (250x21.5 mm) 5 microns; 0.2% NH4OH in MeOH+ACN (1:1), flow; 3.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 3.02 min), designated Intermediate 40C-I, was obtained (0.40 g, 29.80%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.13 (d, J=16.56 Hz, 6H), 1.37 - 1.48 (m, 9H), 2.34 (s, 3H), 2.64 - 2.77 (m, 2H) , 3.71 (br. s., 1H), 3.97 (br. s., 1H), 4.26 (d, J=8.03 Hz, 1H), 5.33 - 5.48 (m , 2H), 7.70 (d, J=8.03 Hz, 1H), 7.83 (d, J=8.03 Hz, 1H), (no exchangeable proton observed). LCMS (Method-I): retention time 1.61 min, [M+H] 361.4. Chiral purity (Method XII): retention time 3.04 min, 100% e.i. The second eluted compound (retention time 4.42 min), designated Intermediate 40C-P, was obtained (0.40 g, 29.80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (d, J=16.56 Hz, 6H), 1.44 (s, 9H), 2.30 - 2.40 (m, 3H), 2.68 (d, J=2.01 Hz , 2H), 3.73 (br. s., 1H), 3.94 (s, 1H), 4.26 (d, J=9.54 Hz, 1H), 5.42 (s, 2H), 7.70 (d, J=8.03 Hz, 1H), 7.83 (d, J=8.03 Hz, 1H) (No 1 exchangeable proton observed). LCMS (Method-I): retention time 1.61 min, [M+H] 361.4. Chiral purity (Method-XII): retention time 4.44 min, 100% e.i.

Intermediate 40-I.

Intermediate 40-I was obtained (0.26 g, 90.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 38-I, starting from Intermediate 40C-I ( 0.40 g, 1.11 mmol). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.06 (s, 3H), 1.28 (s, 3H), 2.42 (s, 3H), 2.46 (dd, J=12.01, 10.51 Hz, 1H), 2.54 - 2.60 (m, 1H), 2.64 - 2.71 (m, 1H), 2.95 (dt, J=12.01, 1.50 Hz, 1H), 4.31 (dd, J =10.51, 2.75 Hz, 1H), 5.12 - 5.20 (m, 2H), 7.63 - 7.70 (m, 1H), 7.71 - 7.78 (m, 1H ), (2 exchangeable protons were not observed). LCMS (Method-I): retention time 0.47 min, [MH] 261.3.

Intermediate 41: 6-(4-formyl-1H-pyrazol-1-yl)-2-methoxynicotinonitrile

Intermediate 41A: 6-chloro-2-methoxynicotinonitrile and Intermediate 41B: 2-chloro-6-methoxynicotinonitrile

To a solution of 2,6-dichloronicotinonitrile (0.50 g, 2.89 mmol) in MeOH (10 ml) was added sodium methoxide (0.62 g, 2.89 mmol) at ambient temperature and the resulting mixture was stirred at 60°C within 12 hours the resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure. The residue was diluted with water (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine

- 66 043056 solution (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC [XBridge Phenyl (250x21.2 ID) 5 microns; solvent A: 0.1% TFA in water, solvent B: acetonitrile, gradient: 0-100% B over 20 min, flow: 20 ml/min, UV 220 nm]. The first eluted compound (retention time 15.34 min), designated as intermediate 41A, was obtained (0.10 g, 19.70%) as a white solid, 1H NMR (400 MHz, CDCl ₃ ) δ ppm. 4.08 (s, 3H), 7.02 (d, J=7.83 Hz, 1H), 7.82 (d, J=7.83 Hz, 1H). LCMS (Method-D): retention time 1.94 min, [M+1H] 169.2. The second eluted compound (retention time 16.74 min), designated Intermediate 41B, was obtained (0.04 g, 1.64%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H), 7.07 (s, 1H), 8.29 (d, J=8.53 Hz, 1H). LCMS (Method-D): retention time 1.89 min, [M+1H] 169.2. The structure of intermediate 41A and 41B was determined by single crystal X-ray diffractometry.

Intermediate 41.

Intermediate 41 was obtained (0.15 g, 62.20%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 11 starting from intermediate 41A (0.16 g, 0 .98 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.15 (s, 3H), 7.65-7.67 (d, J=6 Hz, 1H), 8.38 (s, 1H), 8.45-8.47 (d, J=6 Hz , 1H), 9.44 (s, 1H), 9.99 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 42: 2-(4-formyl-1H-imidazol-1-yl)-4,6-dimethylpyrimidine-5-carbonitrile

Intermediate 42A: 5-bromo-4,6-dimethylpyrimidin-2-amine

Synthesized in accordance with the methods described in the literature (WO 2011/103536 A1, 2011).

Intermediate 42B: 2-amino-4,6-dimethylpyrimidine-5-carbonitrile

To a solution of intermediate 42A (6.00 g, 29.70 mmol) in DMF (50 ml) was added copper (I) cyanide (3.99 g, 44.55 mmol) and the resulting mixture was heated at 180°C for 16 h. The resulting mixture was cooled to ambient temperature, diluted with water (50 ml) and ethyl acetate (100 ml). The resulting mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give Intermediate 42B (3.00 g, 54.00%). The compound was carried directly to the next step without further purification. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.322.41 (m, 6H), 7.533 (s, 2H). LCMS (Method-D): retention time 0.72 min, [M+H] 149.1.

Intermediate 42C: 2-bromo-4,6-dimethylpyrimidine-5-carbonitrile

Copper (II) bromide (8.14 g, 36.40 mmol) was added to a solution of isoamyl nitrite (4.91 ml, 36.4 mmol) in acetonitrile (50 ml) at 0°C. The resulting reaction mixture was stirred at ambient temperature for 10 min and intermediate 42B (2.70 g, 18.22 mmol) in acetonitrile (10 mL) was added and stirring was continued for 3 h. The resulting mixture was diluted with water (30 mL) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 10-20% EtOAc/n-hexane) to give Intermediate 42C (0.90 g, 23.90%). 1H NMR (400

- 67 043056

MHz, DMSO-d ₆ ) δ ppm 2.50-2.63 (m, 6H). LCMS (method-D): retention time 1.692 min, [M+H]

211.9.

Intermediate 42.

Triethylamine (2.18 ml, 15 .61 mmol). The resulting reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 40% EtOAc/n-hexane) to give Intermediate 42 (0.25 g, 21.14%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.89-2.73 (s, 6H), 8.80 (s, 2H), 9.88 (s, 1H). LCMS (Method-D): retention time 1.41 min, [M+H] 228.2.

Intermediate 43: 2-(4-formyl-1H-pyrazol-1-yl)-4-methylpyrimidine-5-carbonitrile

Intermediate 43A: (E)-2-((dimethylamino)methylene)-3-oxobutanenitrile

To a solution of 3-oxobutanenitrile (10.00 g, 120.00 mmol) in DMF (30 ml) was added DMF-DMA (19.34 ml, 144.00 mmol) and the resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with n-hexane (200 ml). The solid was filtered off and dried in vacuo to give Intermediate 43A (13.00 g, 78.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.17 (s, 3H), 3.25 (s, 3H), 3.29 (s, 3H), 7.83 (s, 1H). LCMS (method-L): retention time 0.54 min, [M+H] 139.2.

Intermediate 43B: 2-amino-4-methylpyrimidine-5-carbonitrile

To a stirred solution of intermediate 43A (12.00 g, 87.00 mmol) in EtOH (25 mL) was added guanidine carbonate (31.30 g, 174.00 mmol) and sodium acetate (21.37 g, 261.00 mmol) and the reaction mixture was stirred at 80° C. for 5 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness and diluted with n-hexane (200 ml). The solid was filtered off, washed with EtOH (30 ml) and dried in vacuo to give Intermediate 43B (9.50 g, 82.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.38 (s, 3H), 7.62 (s, 2H), 8.53 (s, 1H). LCMS (method-L): retention time 0.54 min, [M+H] 135.1.

Intermediate 43C: 2-bromo-4-methylpyrimidine-5-carbonitrile

To a solution of intermediate 43B (5.00 g, 37.30 mmol) in a mixture of THF (75 ml) and DMF (15 ml) was added copper (II) bromide (16.65 g, 74.50 mmol), isoamyl nitrite (7 .53 ml, 55.9 mmol) at ambient temperature and the resulting mixture was heated under reflux for 1 hour. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with DCM (200 ml), the solid precipitate was filtered off and washed with THF (200 ml). The combined organic filtrate was washed with 10% aqueous sodium bicarbonate (150 ml) and brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep 120 g, 0-15% EtOAc/n-hexane) to give Intermediate 43C (0.75 g, 10.00%). 1H NMR

- 68 043056 (400 MHz, DMSO-d ₆ ) δ ppm 2.65 (s, 3H), 9.08 (s, 1H). LCMS (method-L): retention time 0.92 min,

[M+2H] 199.1.

Intermediate 43.

Intermediate 43 was prepared (0.04 g, 14.00%) using a synthetic procedure similar to that of intermediate 15C, starting from intermediate 43C (0.30 g, 1.56 mmol) and 1H- pyrazole-4-carbaldehyde (0.18 g, 1.89 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.66 (s, 3H), 8.37 (s, 1H), 9.31 (s, 1H), 9.44 (s, 1H), 10.00 (s, 1H). LCMS (method-L): retention time 0.74 min, [M+H] 214.1.

Intermediate 44: 2-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methylpyrimidine-5carbonitrile

Intermediate 44A: 2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methylpyrimidine5-carbonitrile

To a solution of (2H-1,2,3-triazol-4-yl)methanol (0.75 g, 0.76 mmol) in DMF (10 mL) was added K2CO3 (1.08 g, 7.81 mmol), intermediate compound 43C (0.10 g, 0.50 mmol) and the resulting mixture was stirred at ambient temperature for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 44A (0.02 g, 18.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.75 (s, 3H), 4.68 (s, 2H), 8.22 (s, 1H), 9.37 (s, 1H), (1 exchangeable proton not observed). LCMS (Method-O): retention time 0.74 min, [MH] 215.1.

Intermediate 44.

Intermediate 44 was prepared (0.19 g, 77.00%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 44A (0.25 g, 1.16 mmol) and Dess periodinan -Martin (0.61 g, 1.44 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.80 (s, 3H), 8.80 (s, 1H), 9.42 (s, 1H), 10.23 (s, 1H). LCMS (Method-O): retention time 0.59 min, [M+H] 215.1.

Intermediate 45: 2-(4-formyl-1H-pyrazol-1-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 45A: 2-chloro-4-methoxypyrimidine-5-carbonitrile

Synthesized according to the procedures described in the literature (US2015/291629 A1, 2015).

Intermediate 45.

Intermediate 45 was obtained (0.15 g, 55.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 11, starting from intermediate 45A (0.20 g , 1.18 mmol) and 1H-pyrazole-4carbaldehyde (0.17 g, 1.77 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.20 (s, 3H), 8.38 (s, 1H), 9.18 (s,

1H), 9.48(s, 1H), 10.00(s, 1H). LCMS (Method-O): retention time 0.75 min, [M+H] 230.1.

Intermediate 46: 2-(4-formyl-1H-imidazol-1-yl)-4-methoxypyrimidine-5-carbonitrile

Intermediate 46 was obtained (0.75 g, 55.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 11 starting from intermediate 45A (1.00 g, 5.90 mmol)) and 1H-imidazole-4-carbaldehyde (1.13 g, 11.79 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.23 (s, 3H), 8.84 (s, 1H), 8.87 (s, 1H), 9.19 (s, 1H), 9.88 (s, 1H). LCMS (Method-I): retention time 0.80 min, [M+H] 230.2.

Intermediate 47: 6-(4-formyl-1H-imidazol-1-yl)-4-methylnicotinonitrile

Intermediate 47 was obtained (0.10 g, 9.28%) as an off-white solid using a synthetic procedure similar to that of Intermediate 15C starting from 6-bromo-4-methylnicotinonitrile (1.0 g , 5.08 mmol) and 1H-imidazole-4carbaldehyde (0.61 g, 6.34 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H), 8.17 (s, 1H), 8.79 (s, 1H), 8.84 (s, 1H), 8.95 (s, 1H), 9.86 (s , 1H). LCMS (method-L): retention time 0.73 min, [M+H] 213.1.

Intermediate 48: 4-(4-formyl-1H-imidazol-1-yl)-2-methoxybenzonitrile

To a stirred solution of 1H-imidazole-4-carbaldehyde (1.00 g, 10.41 mmol) in dioxane (5 mL) was added 4-bromo-2-methoxybenzonitrile (2.20 g, 10.41 mmol), N,N -dimethylglycine (1.073 g, 10.41 mmol) and Cs ₂ CO ₃ (3.39 g, 10.41 mmol) followed by the addition of copper (I) iodide (1.98 g, 10.41 mmol). The resulting reaction mixture was heated at 110°C for 16 h in a hermetically sealed tube. The resulting mixture was cooled to ambient temperature, concentrated to dryness in vacuo, diluted with water (40 ml) and extracted with DCM (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 48 (0.80 g, 33.80%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.04 (s, 3H), 7.56 (dd, J=8.35, 1.95 Hz, 1H), 7.66 (d, J=1.44 Hz, 1H), 7.97 (d , J=8.41 Hz, 1H), 8.67-8.72 (m, 1H), 8.85-8.89 (m, 1H), 9.84-9.87 (m, 1H). LCMS (Method-O): retention time 0.76 min, [M+H] 228.1.

- 70 043056

Intermediate 49: 1-(2-methylpyridin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 49 was obtained (0.50 g, 49.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 48 starting from 4-bromo-2-methylpyridine (1.00 g , 5.81 mmol) and 1H-pyrazole-4-carbaldehyde (0.84 g, 8.72 mmol). The compound was carried directly to the next step without further purification or characterization. LCMS (Method-O): retention time 0.69 min, [M+H] 188.2.

Intermediate 50: 2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

Intermediate 50A: 4,5-dimethyl-1H-imidazole

_me

Me

Synthesized according to literature procedures (Angewandte Chemie, 49, (2010), 5322 - 5326).

Intermediate 50.

K2CO3 (0.44 g, 3.21 mmol), 2-bromopyrimidine-5-carbaldehyde ( 0.20 g, 1.07 mmol) and the resulting mixture was stirred at ambient temperature for 1.5 hours. The resulting mixture was diluted with ethyl acetate (50 ml) and filtered through Celite®.

The filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 40% EtOAc/n-hexane) to give Intermediate 50 (0.18 g, 86.00%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.13 (d, J=0.49 Hz, 3H), 2.16 (s, 3H), 8.47 (s, 1H), 9.27 (s, 2H), 10.11 (s, 1H ). LCMS: Compound poorly ionized.

Intermediate 51-I: 4-methyl-5-((2R,6S)-6-methylpiperazin-2-yl)isobenzofuran-1(3H)one and Intermediate 51-II: 4-methyl-5-((2S ,6R)-6-methylpiperazin-2-yl)isobenzofuran-1(3Н)one

Intermediate 51A was obtained (14.00 g, 80.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 2B (20.00 g, 7.3 .00 mmol) and 2-chloro-6methylpyrazine (9.38 g, 73.0 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H), 2.59 (s, 3H) 5.50 (s, 2H), 7.69 (d, J=7.83 Hz, 1H), 7.81 (d, J= 7.83 Hz, 1H), 8.62(s, 1H), 8.69(s, 1H). LCMS (method-D): time

- 71 043056 retention 1.41 min, [M+H] 241.2.

Intermediate 51-I and 51-II.

Intermediate 51-I and 51-II was prepared using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from Intermediate 51A (10.00 g, 41.6 mmol). The racemate was separated into two separate enantiomers by SFC [Chiralpak IC (250x4.6 mm) 5 microns; 0.2% NH ₄ OH in MeOH+ACN (1:1), flow: 1.2 ml/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 4.83 min), designated Intermediate 51-I, was obtained (3.50 g, 41.00%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96 (d, J=6.02 Hz, 3H) 2.14 - 2.22 (m, 2H) 2.29 (s, 3H) 2.74 - 2.84 (m, 3H) 4.02 (dd, J=10.04, 2.51 Hz, 1H) 5.38 (s, 2H) 7.65 (d, J=8.03 Hz, 1H) 7.81 (d, J=8.03 Hz, 1H), (2 exchangeable protons were not observed). LCMS (Method-D): retention time 0.636 min, [M+H] 247.2. Chiral purity (Method-XXVII): retention time 4.86 min, 99.30% e.i. SOR: [a] ²⁵ D=-38.00 (c 0.10, MeOH). To determine the stereochemistry of intermediate 51-I, 5-((2R,6S)-4-(3,5dibromobenzoyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one was prepared as described in the literature by the method (WO2011/012896, 2011) and the absolute configuration was determined by single crystal X-ray diffractometry. The second eluted compound (retention time 6.12 min), designated Intermediate 51-II, was obtained (3.10 g, 36.00%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.97 (d, J=6.02 Hz, 3H), 2.12 2.26 (m, 2H), 2.29 (s, 3H), 2.74 - 2.84 (m, 3H), 4.02 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 (d , J=8.03 Hz, 1H), (2 exchangeable protons were not observed). LCMS (Method-D): retention time 0.548 min, [M+H] 247.2. Chiral purity (Method-XXVII): retention time 5.96 min, 96.00% e.i. SOR: [a] ²⁵ D=+32.00 (c 0.10, MeOH).

Intermediate 52-I: 5-((3R,4R)-4-hydroxypiperidin-3-yl)-4-methylisobenzofuran1(3H)-one hydrochloride

ABOUT

Me J. J

Intermediate 52A-I, II, III and IV: tert-Butyl-4-hydroxy-3-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

ABOUT

To a solution of intermediate 4A (4.00 g, 11.58 mmol) in MeOH (100 ml) was added NaBH ₄ (1.46 g, 23.16 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. the mixture was concentrated to dryness under reduced pressure and diluted with water (100 ml). The solid was filtered off and dried in vacuo to give diastereomer I (2.7 g). The filtrate was extracted by adding 10% MeOH in DCM (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give diastereomer II (0.8 g). Diastereomer I was separated into two separate enantiomers by SFC [Lux cellulose-2 (250x4.6 mm) 5 microns; 0.2% NH ₄ OH in MeOH, flow: 1.2 ml/min. Temperature: 30°C, UV: 240 nm]. The first eluted compound (retention time 3.98 min), designated Intermediate 52A-I, was obtained (1.20 g, 30.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.89-1.98 (m, 1H), 2.29 (s, 3H), 2.82 (d, J=9.54 Hz, 3H), 3.17 (d, J=4.02 Hz, 1H), 3.78 (br. s., 1H), 3.95 (br. s., 2H), 4.70 (br. s., 1H), 5 .40 (s, 2H), 7.55 (d, J=8.03 Hz, 1H), 7.66 (d, J=8.03 Hz, 1H). Chiral purity (Method XXVIII): retention time 3.98 min, 100% e.i. SOR: [a] ²⁵ D=-38.00 (c 0.1, MeOH). LCMS: Compound poorly ionized. The second eluted compound (retention time 5.85 min), designated Intermediate 52A-II, was obtained (1.30 g, 32.30%) as an off-white solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.89 - 1.98 (m, 1H), 2.29 (s, 3H), 2.82 (d, J=9.54 Hz, 3H), 3.17 (d, J=4.02 Hz, 1H), 3.78 (br. s., 1H), 3.95 (br. s., 2H), 4.70 (br. s., 1H), 5 .40 (s, 2H), 7.55 (d, J=8.03 Hz, 1H), 7.66 (d, J=8.03 Hz, 1H). Chiral purity (Method-XXVIII): retention time 5.85 min, 99.3% e.i. LCMS: Compound poorly ionized. Diastereomer II was separated into two separate enantiomers using a similar SFC procedure as for diastereomer I. The first eluted compound (8.61 min retention time), designated Intermediate 52A-III, was obtained (0.20 g, 5.00% ) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.40 (s, 9H), 1.64 1.82 (m, 2H), 2.26 (s, 3H), 3.06 (d, J=11.04 Hz, 1H), 3.17 ( d, J=5.52 Hz, 1H), 3.52 (br. s., 1H), 3.81 (br. s., 2H),

- 72 043056

3.97 (br. s., 1H), 4.82 (br. s., 1H), 5.39 (s, 2H), 7.56 (br. s., 1H), 7.59 - 7 .65 (m, 1H). Chiral purity (Method-XXVIII): retention time 8.61 min, 100% e.i. LCMS: Compound poorly ionized. The second eluted compound (retention time 9.82 min), designated Intermediate 52A-IV, was obtained (0.21 g, 5.20%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.40 (s, 9H), 1.64 - 1.82 (m, 2H), 2.26 (s, 3H), 3.06 (d, J=11.04 Hz, 1H), 3.17 (d, J=5.52 Hz, 1H), 3.52 (br. s., 1H), 3.81 (br. s., 2H), 3.97 (br. s., 1H), 4 .82 (br. s., 1H), 5.39 (s, 2H), 7.56 (br. s., 1H), 7.59 7.65 (m, 1H). Chiral purity (Method-XXVIII): retention time 9.82 min, 97.80% ee. LCMS: Compound poorly ionized.

Intermediate 52-I.

To a solution of intermediate 52A-I (1.20 g, 3.45 mmol) in DCM (50 ml) at 0°C was added 4N. HCl in dioxane (12.95 ml, 51.8 mmol). The resulting mixture was stirred at ambient temperature for 2 hours. The resulting mixture was concentrated to dryness, washed with diethyl ether (2x50 mL) and dried under reduced pressure to give Intermediate 52-I (0.90 g, 92.00%) as whitish solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.72 - 1.85 (m, 1H), 2.08 (d, J=13.05 Hz, 1H), 2.30 (s, 3H), 3.08 (d, J=9.04 Hz , 2H), 3.12-3.20 (m, 2H), 3.97 (br. s., 1H), 4.99 (br. s., 1H), 5.40 (d, J=5 .52 Hz, 2H), 7.61 (d, J=8.03 Hz, 1H), 7.70 (d, J=8.03 Hz, 1H), 8.96 (br. s., 1H) , 9.05 (br. s., 1H), (1 exchangeable proton not observed). LCMS (Method-D) retention time 0.395 min, [M+H] 248.0. To determine the stereochemistry of intermediate 52-I, 5-((3R,4R)-1(4-bromobenzoyl)-4-hydroxypiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one was prepared as described in literature method (WO2011/012896, 2011) and the absolute configuration was determined by single crystal X-ray diffractometry.

Example 1-I: (R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazole -1 -yl)nicotinonitrile

To a solution of intermediate 6 (0.05 g, 0.23 mmol) in MeOH (1 ml) was added intermediate 3-I (0.05 g, 0.23 mmol) and the resulting mixture was stirred at ambient temperature for 15 min. NaCNBH ₃ (0.04 g, 0.71 mmol) was added and stirring was continued for 12 h at ambient temperature. The resulting mixture was diluted with water (15 ml) and extracted with ethyl acetate (2x20 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [XBridge C18 (19x150 mm) 5 microns; solvent A: 0.1% TFA; solvent B: acetonitrile, gradient: 10-100% B over 25 min, flow: 15 ml/min, retention time 1.60 min, UV 220 nm] to give the compound according to example 1-I (0.02 g, 17 ,10%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.86 - 1.96 (m, 1H), 2.20 (s, 3H), 2.23 - 2.29 (m, 1H), 2.58 (s, 3H), 2.81 (d, J=11.74 Hz, 1H), 2.92 (d, J=11.49 Hz, 1H), 3.56 (s, 2H), 3.71-3.81 (m, 1H), 3, 99 (d, J=9.54 Hz, 1H), 4.81 (d, J=8.07 Hz, 1H), 5.38 (d, J=4.89 Hz, 2H), 7.57 - 7.63 (m, 1H), 7.64 -7.71 (m, 1H), 7.87 (s, 1H), 7.99 (s, 1H), 8.55 (s, 1H), 8 .83 (s, 1H). LCMS/HPLC (Method-A): retention time 1.25 min, [M+H] 430.0, purity: 100%. (method-B): retention time 1.90 min, [M+H] 430.0, purity: 98.3%. Chiral purity (Method-I): retention time 10.04 min, 100% e.i.

Example 2-I: (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1 H -pyrazol-1 -yl)nicotinonitrile

The compound of Example 2-I was obtained (0.11 g, 21.36%) as a white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 6 (0. 25 g, 1.17 mmol) and intermediate 2-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.79 (t, J=10.29 Hz, 1H), 2.03 - 2.18 (m, 1H), 2.25 (s, 3H), 2.66 - 2.67 (m, 4H) , 2.79 (t, J=9.04 Hz, 2H), 2.84 - 2.92 (m, 1H), 2.94 - 3.05 (m, 1H), 3.45 - 3.59 (m, 2H), 4.06

- 73 043056 (d, J=9.54 Hz, 1H), 5.36 (d, J=1.51 Hz, 2H), 7.63 (d, J=8.03 Hz, 1H), 7, 76 (d, J=8.03 Hz, 1H), 7.85 (s, 1H), 7.98 (s, 1H), 8.52 (s, 1H), 8.82 (s, 1H). HPLC (Method-F): retention time 5.62 min, purity: 98.55%. (Method-G): retention time 5.62 minutes, purity: 98.55%. LCMS (method-H): retention time 1.82 min, [M+H] 429.0. Chiral purity (Method-VII): retention time 4.29 min, 100% e.i.

Example 3-1: (R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl )benzo[d]oxazol-2(3H)-one

The compound of Example 3-I was obtained (0.006 g, 5.13%) as a white solid using a synthetic procedure similar to that of Intermediate 2B, starting from Intermediate 8 (0.06 g, 0. 24 mmol) and intermediate 5-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.99 (t, J=10.76 Hz, 1H), 2.23 (s, 3H), 2.26 - 2.35 (m, 1H), 2.79 (d, J=11.25 Hz , 1H), 2.90 (d, J=10.52 Hz, 1H), 3.42 (s, 3H), 3.64 (s, 2H), 3.74 - 3.83 (m, 1H) , 4.01 (d, J=11.49 Hz, 1H), 4.85 (d, J=8.80 Hz, 1H), 5.38 (d, J=3.67 Hz, 2H), 7 .43 (d, J=8.56 Hz, 1H), 7.60 - 7.66 (m, 1H), 7.66 7.71 (m, 1H), 7.83 - 7.92 (m, 2H), 7.96 (d, J=1.47 Hz, 1H), 8.01 (d, J=8.56 Hz, 1H), 8.61 (s, 1H). LCMS/HPLC (method-A): retention time 1.21 min, [M+H] 472.2, purity: 100%. (method-B): retention time 1.83 min, [M+H] 472.2, purity: 99.40%. Chiral purity (Method-XVIII): retention time 24.29 min, 100% e.i.

Example 4: 5-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1 yl)methyl)-1H-pyrazole-1 -yl)-3-methylbenzo[d]oxazol-2(3H)-one

The compound of Example 4 was prepared (0.01 g, 13.77%) using Intermediate 4 (0.05 g, 0.15 mmol) following a procedure similar to the synthetic protocol described for Intermediate 6. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.16 (br. s., 2H), 2.29 (s, 3H), 2.33 (s, 1H), 2.65-2.73 (m, 1H), 2.90 (br. s ., 1H), 3.01 (br. s., 1H), 3.39 (s, 3H), 3.63 (s, 2H), 3.68-3.80 (m, 1H), 5, 40 (q, J=15.41 Hz, 2H), 7.41 (d, J=8.56 Hz, 1H), 7.56 (dd, J=8.56, 2.20 Hz, 1H), 7.62 - 7.68 (m, 2H), 7.69 7.71 (m, 1H), 7.74 (d, J=2.20 Hz, 1H), 8.44 (s, 1H). LCMS/HPLC (Method-A): retention time 1.29 min, [M+H] 495.0, purity: 94.70%. (method-B): retention time 1.87 min, [M+H] 495.1, 95.90%.

Example 5: 6-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1 yl)methyl)-1H-pyrazol- 1 -yl)-4-methylnicotinonitrile

The compound according to Example 5 was prepared (0.01 g, 12.92%), compounds 6 (0.04 g, 0.19 mmol) and intermediate 4C using intermediate according to a procedure similar to the synthetic protocol described for compound according to example 1-I.

1H NMR (300 MHz, CDCl ₃ ) δ ppm 2.34 (s, 3H), 2.44 (br. s., 2H), 2.66 (s, 3H), 3.04 (d, J=10.58 Hz, 1H), 3.22 ( t, J=2.46 Hz, 1H), 3.64 (t, J=15.86 Hz, 2H), 4.09 - 4.18 (m, 1H), 4.20 - 4.40 (m , 2H), 5.26 - 5.33 (m, 2H), 7.48 (d, J=8.69 Hz, 1H), 7.80 (d, J=8.31 Hz, 1H), 7 .87 (s, 1H), 7.99 (s, 1H), 8.62 (s, 1H), 8.74 (s, 1H). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm - 96.34, - 110.26. LCMS/HPLC (Method-A): retention time 1.375 min, [M+H] 464.0, purity: 95.80%. (method-B): retention time 2.11 min, [M+H] 464.0, 95.20%.

Example 6-I: (R)-6-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 - 74 043056 yl)methyl )-1 H-pyrazol-1 -yl)-4-methylnicotinonitrile

The compound of Example 6-I was obtained (0.02 g, 22.08%) as an off-white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 9 (0 05 g, 0.20 mmol) and intermediate 2-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.87 (t, J=10.76 Hz, 1H), 2.14 (s, 1H), 2.26 (s, 3H), 2.55 (s, 3H), 2.80 (d, J =10.76 Hz, 2H), 2.85 - 2.93 (m, 1H), 2.99 (d, J=10.03 Hz, 1H), 3.40 (s, 2H), 3.95 (s, 3H), 4.09 (d, J=10.27 Hz, 1H), 5.37 (s, 2H), 7.64 (d, J=8.07 Hz, 1H), 7.73 - 7.78 (m, 2H), 8.38 (s, 1H), 8.74 (s, 1H), (no exchangeable protons were observed). LCMS/HPLC (Method-A): retention time 1.31 min, [M+H] 459, purity: 100%. (method-B): retention time 1.78 min, [M+H] 459, purity: 99.40%. Chiral purity (Method-XV): retention time 9.83 min, 82.80%e.

Example 7-I: (R)-4-methyl-5-(4-((1-(2-methylthiazol-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran- 1 (3Н)-one

The compound of Example 7-I was obtained (0.02 g, 17.25%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 6 starting from Intermediate 14-I (0 .10 g, 0.319 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.87 - 1.95 (m, 1H), 2.16 - 2.22 (m, 1H), 2.24 (s, 3H), 2.62 (s, 3H), 2.80 (d, J=11.00 Hz, 1H), 2.91 (d, J=11.74 Hz, 1H), 3.49 (s, 2H), 3.71-3.80 (m, 1H), 3, 99 (dd, J=11.49, 2.20 Hz, 1H), 4.81 (dd, J=10.03, 2.20 Hz, 1H), 5.33-5.44 (m, 2H) , 7.59 - 7.70 (m, 3H), 7.86 (s, 1H), 8.33 (s, 1H). LCMS/HPLC (Method-A): retention time 1.06 min, [M+H] 411.1, purity: 100%. (method-B): retention time 1.52 min, [M+H] 411.1, purity: 99.60%. Chiral purity (Method-XVI): retention time 11.36 min, 100% e.i.

Example 8-I: (R)-4-cyclopropyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazole -1 -yl)nicotinonitrile

The compound of Example 8-I was obtained (0.003 g, 4.27%) as an off-white solid using a synthetic procedure similar to that of Intermediate 6, starting from Intermediate 14-I (0.05 g, 0.16 mmol) and Intermediate 10 (0.05 g, 0.23 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02 - 1.11 (m, 2H), 1.26 - 1.40 (m, 2H), 2.19 - 2.30 (m, 4H), 3.61 (s, 2H), 3, 90 (d, J=11.49 Hz, 2H), 4.18 (d, J=11.25 Hz, 4H), 5.05 (br. s., 1H), 5.33-5.52 ( m, 2H), 7.45 (s, 1H), 7.63 (d, J=7.83 Hz, 1H), 7.74 (d, J=8.07 Hz, 1H), 7.98 ( s, 1H), 8.72 - 8.90 (m, 2H). LCMS/HPLC (method-A): retention time 1.40 min, [M+H] 456.1, purity: 100%. (Method-B): retention time 2.09 min, [M+H] 456.1, purity: 94.50%. Chiral purity (Method-V): retention time 10.54 min, 100% e.i.

- 75 043056

Example 9-I: (R)-4-methyl-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl) methyl)-1 H-pyrazol-1 -yl) nicotinonitrile

To a solution of intermediate 12-I (0.06 g, 0.149 mmol) in DCM (5 ml) was added dipyridyl-2-carbonate (0.03 mg, 0.15 mmol), TEA (0.04 ml, 0.29 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [XBridge C18 (19x150 mm) 5 µm; Solvent A: 10 mM ammonium acetate, Solvent B: methanol, gradient: 15-57% B over 20 minutes, then hold for 5 minutes at 100% B; flow: 15 ml/min, retention time 2.70 min, UV 220 nm] to give the compound of Example 9-I (0.13 g, 19.34%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.23 (s, 3H), 2.64 (s, 3H), 4.10 (t, J=9.04 Hz, 1H), 4.28-4.53 (m, 3H), 5.35 - 5.48 (m, 2H), 5.97 (dd, J=9.04, 7.03 Hz, 1H), 7.55 (d, J=8.03 Hz, 1H), 7.74 ( d, J=7.53 Hz, 1H), 7.89 (s, 1H), 8.00 (d, J=1.00 Hz, 1H), 8.64 (s, 1H), 8.85 ( s, 1H). LCMS/HPLC (Method-A): retention time 1.69 min, [M+H] 430.1, purity: 95.30%. (Method-B): retention time 1.70 min, [M+H] 430.1, purity: 94.30%. Chiral purity (Method-X): retention time 5.58 min, 100% e.i.

Example 10-I: (R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxomorpholino)methyl)-1 N-pyrazol-1 -yl) nicotinonitrile

To a stirred solution of intermediate 13-I (0.05 g, 0.11 mmol) in THF (10 mL) was added tri-n-butylphosphine (0.08 mL, 0.32 mmol) followed by diisopropyl azodicarboxylate (0.04 ml, 0.22 mmol). The resulting reaction mixture was stirred at ambient temperature for 1 h and diluted with water (30 ml). The resulting mixture was extracted with ethyl acetate (3x25 ml). The combined organic layers were washed with brine (25 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC [XBridge Phenyl (19x250 mm) 5 microns; solvent A: 10 mM CH ₃ COONH ₄ -PH-4.5, solvent B: acetonitrile; gradient: 40-65% over 24 min; flow: 17 ml/min, retention time 11.24 min, UV 254 nm] to give the compound according to example 10-I (0.001 g, 2.50%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.29 (s, 3H), 2.59 (s, 3H), 3.36-3.46 (m, 1H), 3.57 (dd, J=12.23, 3.18 Hz, 1H) , 4.28 - 4.51 (m, 3H), 4.60 (d, J=14.92 Hz, 1H), 5.29 (dd, J=10.52, 3.42 Hz, 1H), 5.34 - 5.50 (m, 2H), 7.58 - 7.66 (m, 1H), 7.67 - 7.76 (m, 1H), 7.91 (s, 1H), 8, 01 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H). LCMS/HPLC (method-A): retention time 1.67 min, [M+H] 444.1, purity: 100%. (method B): retention time 1.65 min, [M+H] 444.1, purity: 100%. Chiral purity (Method-I): retention time 22.89 min, 100% e.i.

Example 11-I: (R)-4-methoxy-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1 H -pyrazol-1 -yl)nicotinonitrile

The compound of Example 11-I was prepared (0.05 g, 32.65%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 15 (0.07 g, 0. 31 mmol) and intermediate 3-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.85 - 2.00 (m, 1H), 2.22 - 2.33 (m, 3H), 2.60 (br. s., 3H), 2.71 (d, J=5.87 Hz , 2H), 2.89 (d,

- 76 043056

J=11.98 Hz, 1H), 2.99 (d, J=11.49 Hz, 1H), 3.75 (t, J=11.13 Hz, 1H), 4.00 (d, J= 10.03 Hz, 1H), 4.10 (s, 3H), 4.80 (d, J=10.03 Hz, 1H), 5.30 - 5.51 (m, 2H), 7.58 ( s, 1H), 7.60 - 7.76 (m, 2H), 7.84 (s, 1H), 8.50 (s, 1H), 8.73 (s,

1H). LCMS/HPLC (Method-A): retention time 1.29 min, [M+H] 460.1, purity: 98.12%. (Method-B): retention time 1.95 min, [M+H] 460.1, purity: 97.20%. Chiral purity (Method-I): retention time 10.17 min, 100% e.i.

Example 12-I: (R)-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4oxadiazol-2- yl) nicotinonitrile

ABOUT

CN

To a stirred solution of intermediate 16 (0.04 g, 0.18 mmol) and intermediate 3-I (0.04 g, 0.18 mmol) in ACN (5 ml) was added K2CO3 (0.07 g, 0. 54 mmol) followed by the addition of KI (0.003 g, 0.02 mmol). The resulting mixture was stirred at ambient temperature for 14 h, diluted with water (25 ml) and was extracted with the addition of ethyl acetate (3x15 ml). The combined organic layer was washed with brine (15 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by HPLC [XBridge C18 (19x150 mm) 5 microns; solvent A: 0.1% trifluoroacetic acid; solvent B: acetonitrile; gradient: 5-32% over 20 min, flow: 15 ml/min, retention time 10.63 min, UV 220 nm] to give the compound of Example 12-I (0.058 g, 76.31%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.18 (t, J=10.64 Hz, 1H), 2.28 (s, 3H), 2.39 - 2.48 (m, 1H), 2.89 (d, J=11.00 Hz , 1H), 3.05 (d, J=11.49 Hz, 1H), 3.69 - 3.84 (m, 1H), 3.96 - 4.12 (m, 3H), 4.85 ( dd, J=9.90, 2.08 Hz, 1H), 5.31 - 5.47 (m, 2H), 7.57 - 7.63 (m, 1H), 7.65 - 7.73 ( m, 1H), 8.35 (dd, J=8.31, 0.98 Hz, 1H), 8.57 (dd, J=8.19, 2.08 Hz, 1H), 9.23 (dd , J=2.08, 0.86 Hz, 1H). LCMS/HPLC (Method-A): retention time 1.26 min, [M+H] 418.1, purity: 100%. (method-B): retention time 1.41 min, [M+H] 418.0, purity: 100%. Chiral purity (Method-VII): retention time 17.41 min, 100% e.i.

Example 13-I: (R)-4-methyl-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1 ,3,4-oxadiazol-2-yl)nicotinonitrile

ABOUT

CN

The compound of Example 13-I was prepared (0.02 g, 21.80%) using a synthetic procedure similar to that of the compound of Example 12-I, starting from Intermediate 17 (0.04 g, 0. 17 mmol) and intermediate 2-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.00 - 2.10 (m, 1H), 2.29 (s, 3H), 2.63 (s, 4H), 2.89 (t, J=10.76 Hz, 4H), 2.97 - 3.06 (m, 1H), 4.00 (s, 2H), 4.11 (d, J=8.56 Hz, 1H), 5.39 (s, 2H), 7.65 (d, J=8.07Hz, 1H), 7.77(d, J=7.83Hz, 1H), 8.32(s, 1H), 9.11(s, 1H). LCMS/HPLC (Method-A): retention time 1.12 min, [M+H] 431.1, purity: 100%. (method-B): retention time 1.66 min, [M+H] 431.1, purity: 99.56%. Chiral purity (method V): retention time 8.77 min, 100% ee

- 77 043056

Example 14-I: (R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1 H -imidazol-1 -yl)nicotinonitrile

The compound of Example 14-I was prepared (0.10 g, 20.13%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 11 (0.25 g, 1. 10 mmol) and intermediate 2-I.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (br. s., 1H), 2.19 (br. s., 1H), 2.27 (s, 3H), 2.81-3.05 (m, 5H), 3.50 ( s, 2H), 4.03 - 4.14 (m, 4H), 5.37 (s, 2H), 7.59 (s, 1H), 7.65 (d, J=8.07 Hz, 1H ), 7.78 (d, J=8.07 Hz, 1H), 7.95 (s, 1H), 8.58 (d, J=1.22 Hz, 1H), 8.74 (s, 1H ). LCMS/HPLC (method-A): retention time 0.99 min, [M+H] 445.1, purity: 100%. (Method-B): retention time 1.28 min, [M+H] 445.0, purity: 99.56%. Chiral purity (Method-V): retention time 7.10 min, 84.55%e.

Example 15-I: (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl) methyl)-1 H-pyrazol-1 -yl) nicotinonitrile

The compound of Example 15-I was obtained (0.008 g, 12.95%) as a white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 6 (0.03 g , 0.14 mmol) and intermediate 19-I. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.22 (s, 3H), 2.41 (dd, J=11.62, 6.24 Hz, 1H), 2.56 (s, 3H), 2.90 (dd, J=11.98, 4.16 Hz, 1H), 3.05 - 3.22 (m, 2H), 3.47 - 3.65 (m, 2H), 4.94 (br. s., 1H), 5.21 - 5.34 (m, 1H), 5.36 - 5.46 (m, 1H), 7.56 (d, J=8.07 Hz, 1H), 7.68 - 7.80 (m, 2H) , 7.96 (s, 1H), 8.18 (s, 1H), 8.28 (s, 1H), 8.76 (s, 1H). LCMS/HPLC (Method-A): retention time 1.23 min, [M+H] 443.1, purity: 96.48%. (method-B): retention time 1.51 min, [M+H] 443.1, purity: 100%. Chiral purity (method V): retention time 12.48 min, 92% e.i.

Example 16-I: (R)-4-methyl-5 -(4-((6-(4-methyl-1 H-imidazol-1 -yl)pyridin-3 -yl)methyl)morpholin-2yl)isobenzofuran- 1 (3Н)-one

Example 16-I was prepared (0.01 g, 9.26%) using a synthetic procedure similar to that of Intermediate 23-I, starting from Intermediate 20 (0.05 g, 0.26 mmol) and intermediate 3-I. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 3H), 2.22 (s, 3H), 2.23-2.36 (m, 2H), 2.77 (d, J=11.25 Hz, 1H), 2.87 (d, J=11.98 Hz, 1H), 3.61 (s, 2H), 3.69 - 3.85 (m, 1H), 3.99 (d, J=9.54 Hz, 1H) , 4.82 (d, J=7.58 Hz, 1H), 5.26-5.45 (m, 2H), 7.54-7.75 (m, 4H), 7.92 (dd, J = 8.31, 2.20 Hz, 1H), 8.39 (s, 2H). LCMS/HPLC (Method-A): retention time 0.83 min, [M+H] 405.1, purity: 99.20%. (Method-B): retention time 1.56 min, [M+H] 405.0, purity: 95.99%. Chiral purity (Method-X): retention time 12.55 min, 96.10% e.i.

Example 17-I: (R)-4-methoxy-5'-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl) -[2,2'-bipyridine]-5-carbonitrile

- 78 043056

A solution of intermediate 23-I (0.15 g, 0.35 mmol) in THF (20 mL) was added at 70°C with 1,1'-carbonyldiimidazole (0.06 g, 0.38 mmol) and the resulting reaction mixture was stirred for 1 hour. The resulting mixture was cooled to ambient temperature and evaporated under reduced pressure. The residue was diluted with water (15 ml) and extracted with DCM (3x15 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [Intertsil ODS (250x10 mm) 5 microns; solvent A: 10 mM NH ₄ OAc in H ₂ O, solvent B: acetonitrile, gradient: 20-65% over 14 min, flow: 17 ml/min retention time 15.06 min, UV 254 nm] to give compound according to example 17-I (0.02 g, 8.68%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.22 (s, 3H), 4.03 - 4.07 (m, 2H), 4.11 (s.3 H), 4.51 (d, J=16.00 Hz, 1H), 4, 62 (d, J=16.00 Hz, 1H), 5.22 - 5.48 (m, 2H), 6.02 (t, J=8.19 Hz, 1H), 7.59 (d, J = 8.56 Hz, 1H), 7.76 (d, J=8.07 Hz, 1H), 7.95 (d, J=8.07 Hz, 1H), 8.14 (s, 1H), 8.43 (d, J=8.07 Hz, 1H), 8.70 (s, 1H), 8.92 (s, 1H). LCMS/HPLC: (Method-A) retention time: 1.59 min, [M+1]: 457.1, purity: 100%. (Method-B) retention time: 1.65 min, [M+1]: 457.0, purity: 100%. Chiral purity (Method-XVII): retention time 6.39 min, 100% e.i.

Example 18-I: 6-(4-(1-hydroxy-2-((R)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile (Diastereomer-I & II)

To a solution of intermediate 24 (0.12 g, 0.53 mmol) in EtOH (10 mL) was added intermediate 3-I (0.12 g, 0.53 mmol) and the resulting reaction mixture was stirred at 85°C for 48 hours Ethanol was evaporated under reduced pressure and the residue was purified by HPLC [XBridge Phenyl (250x19 ID) 5 microns; solvent A: 10 mM NH ₄ HCO ₃ -PH-9.5, solvent B: acetonitrile; gradient: 0-62% over 15 min; flow: 16 ml/min, UV 254 nm]. The first eluted compound (retention time 15.33 min) designated as the compound according to Example 18-I Dia-I (Diastereomer-I) was obtained (0.009 g, 19.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.01 - 2.08 (m, 1H), 2.25 (s, 3H), 2.31 - 2.34 (m, 1H), 2.36 (d, J=3.01 Hz, 1H) , 2.58 (s, 3H), 2.65 - 2.68 (m, 1H) 2.85 (d, J=10.80 Hz, 1H), 3.07 (d, J=10.80 Hz , 1n), 3.72 - 3.80 (m, 1H), 3.95 - 4.03 (m, 1H), 4.79 (d, J=9.54 Hz, 1H), 4.85 ( d, J=6.53 Hz, 1H), 5.22 (d, J=5.02 Hz, 1H), 5.39 (d, J=4.52 Hz, 2H), 7.62 (d, J=8.00Hz, 1H), 7.67(d, J=8.00Hz, 1H), 7.90(s, 1H), 7.99(s, 1H), 8.54(s, 1H), 8.84 (s, 1H). LCMS (Method-H): retention time 1.93 min, [M+H] 460.1, purity: 98.60%. HPLC (Method-F): retention time 5.12 min, purity: 99.14%. (Method G): retention time 6.03 min, purity: 99.42%. Chiral purity (Method-X): retention time 10.19 min, 97.70%e.

The second eluted compound (retention time 17.02 min), designated as the compound according to Example 18-I Dia-II (Diastereomer-II), was obtained (0.008 g, 16.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.01 - 2.08 (m, 1H), 2.25 (s, 3H), 2.31 - 2.34 (m, 1H), 2.36 (d, J=3.01 Hz, 1H) , 2.58 (s, 3H), 2.65-2.68 (m, 1H) 2.96 (t, J=.11.80 Hz, 2H), 3.72-3.80 (m, 1H ), 3.95 - 4.03 (m, 1H), 4.79 (d, J=9.54 Hz, 1H), 4.85 (d, J=6.53 Hz, 1H), 5.22 (d, J=5.02 Hz, 1H), 5.39 (d, J=4.52 Hz, 2H), 7.62 (d, J=8.00 Hz, 1H), 7.67 (d , J=8.00 Hz, 1H), 7.90 (s, 1H), 7.99 (s, 1H), 8.54 (s, 1H), 8.84 (s, 1H). LCMS (Method-H): retention time 1.92 min, [M+H] 460.1, purity: 95.43%. HPLC (Method-F): retention time 5.11 min, purity: 90.01%. (method-G): retention time 6.00 min, purity: 88.76%. Chiral purity (Method-X): retention time 12.55 min, 96.10% e.i.

- 79 043056

Example 19-I: (R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2-yl )benzo[d]oxazol-2(3H)-one

The compound of Example 19-I was prepared (0.01 g, 16.97%) using a synthetic procedure similar to that of the compound of Example 3-I, starting from Intermediate 25-I (0.10 g, 0.12 mmol) and intermediate 8. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 1.94 - 2.07 (m, 1H), 2.24 (s, 3H), 2.28 - 2.37 (m, 1H), 2.83 - 2.91 (m, 1H), 2, 96 (d, J=11.74 Hz, 1H), 3.42 (s, 3H), 3.72 - 3.83 (m, 1H), 3.87 (s, 2H) 4.03 (d, J=9.29Hz, 1H), 4.83(s, 1H), 5.38(d, J=2.45Hz, 2H), 7.44(d, J=8.31Hz, 1H) , 7.67 (s, 1H) 7.69 (s, 1H) 7.70 (dd, J=8.00 Hz, 1.60 Hz, 1H), 7.75 (s, 1H) 7.79 ( d, J=1.71 Hz, 1H). LCMS/HPLC (Method-A): retention time 1.23 min, [M+H] 478.1, purity: 99.56%. (method-B): retention time 1.89 min, [M+H] 478.0, purity: 99.59%. Chiral purity (method X): retention time 9.67 min, 100% e.i.

Example 20-I: (R)-3-methyl-5-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholine-4carbonyl)thiazol-2-yl) benzo[d]oxazol-2(3H)-one

The compound of Example 20-I was prepared (0.01 g, 5.29%) using a synthetic procedure similar to that of the compound of Example 3-I, starting from Intermediate 26-I (0.15 g, 0.35 mmol) and intermediate 8.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.08 (s, 3H), 2.20 - 2.37 (m, 3H), 3.43 (s, 3H), 3.83 (dd, J=11.49, 8.80 Hz, 1H) , 4.12 (d, J=9.78 Hz, 1H), 4.15-4.31(br. s., 1H), 4.94 (d, J=10.03 Hz, 1H), 5 .42 (br. s., 2H), 7.49 (d, J=8.07 Hz, 1H), 7.66-7.83 (m, 3H), 7.87 (d, J=1, 71 Hz, 1H), 8.26 (s, 1H). LCMS/HPLC (Method-A): retention time 1.71 min, [M+H] 492.1, purity: 96.82%. (method-B): retention time 1.73 min, [M+H] 492.0, purity: 97.44%. Chiral purity (Method-XVI): retention time 3.40 min, 100% e.i.

Example 21-I: (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl )-1 H-imidazole-4-carbonitrile

The compound of Example 21-I was obtained (0.006 g, 9.11%) as a white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 27 (0.03 g , 0.17 mmol) and intermediate 2-I. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.84 - 2.00 (m, 1H), 2.26 (s, 3H), 2.78 - 2.94 (m, 4H), 3.02 (d, J=12.23 Hz, 1H) , 3.69 - 3.85 (m, 2H), 4.07 (d, J=8.56 Hz, 1H), 5.27 - 5.41 (m, 2H), 7.60 (s, 1H ), 7.66 (d, J=7.83 Hz, 1H), 7.77 (d, J=7.58 Hz, 1H), 8.64 (s, 1H), 8.85 (s, 1H ), (no exchangeable protons were observed). LCMS/HPLC (method-A): retention time 1.07 min, [M+H] 421.1, purity: 100%. (method-B): retention time 1.32 min, [M+H] 421.0, purity: 100%. Chiral purity (method-XVIII): retention time 11.69 min, 100% e.i.

Example 22-I: (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2H -1,2,3-triazol-2-yl)nicotinonitrile

- 80 043056

The compound of Example 22-I was prepared (0.01 g, 10.83%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 28 (0.04 g, 0. 19 mmol) and Intermediate 2-I (0.05 g, 0.206 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.87 - 1.95 (m, 1H), 2.17 - 2.23 (m, 1H), 2.26 (s, 3H), 2.61 (s, 3H), 2.80 3.03 (m, 4H), 3.77 (s, 2H), 4.10 (d, J=8.07 Hz, 1H), 5.37 (d, J=2.45 Hz, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.92 (s, 1H), (An exchangeable proton was observed). LCMS/HPLC (Method-A): retention time 1.15 min, [M+H] 430, purity: 96.70%. (method-B): retention time 1.36 min, [M+H] 430, purity: 100%. Chiral purity (method α-XVIII): retention time 26.46 min, 100% e.i.

Example 23-I: (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)- 1H -1,2,3-triazol-1 -yl)nicotinonitrile

The compound of Example 23-I was prepared (0.008 g, 8.83%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 30 (0.04 g, 0.19 mmol ) and intermediate 2-I. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.86 - 1.95 (m, 1H), 2.15 - 2.29 (m, 4H), 2.64 (s, 3H), 2.81 - 3.03 (m, 4H), 3, 75 (s, 2H), 4.09 (d, J=9.54 Hz, 1H), 5.32-5.43 (m, 2H), 7.64 (d, J=7.83 Hz, 1H ), 7.76 (d, J=7.83 Hz, 1H), 8.28 (s, 1H), 8.77 (s, 1H), 8.98 (s, 1H), (capable of exchanging protons not observed). LCMS/HPLC (method-A): retention time 1.43 min, [M+H] 430.0, purity: 98.88%, (method-B): retention time 1.23 min, [M+H] 430.1, purity: 98.70%. Chiral purity (method-IX): retention time 12.83 min. 98.50% e.i.

Example 24-I: Methyl-(R)-4-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-2-(4-methyl1-oxo -1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirred solution of the compound of Example 2-I (0.03 g, 0.06 mmol) in DCM (3.00 mL) at 0°C was added TEA (0.03 mL, 0.18 mmol) followed by methyl chloroformate ( 4.52 µl, 0.06 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, diluted with water (15 ml) and extracted with DCM (3x15 ml). The combined organic extracts were washed with brine (15 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [XBridge C18 (19x150 mm) 5 microns; solvent A: 10 mM ammonium acetate; solvent B: acetonitrile, gradient: 20-100% B over 15 min, flow: 15 ml/min, retention time 2.80 min, UV 220 nm] to give the compound of Example 24-I (0.003 g, 9.15 %). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.19 (br. s., 1H), 2.20-2.26 (m, 3H), 2.46 (d, J=4.89 Hz, 1H), 2.56 (s, 3H), 2.89 - 3.05 (m, 2H), 3.43 - 3.54 (m, 2H), 3.57 (s, 4H), 3.87 (d, J=11.98 Hz, 1H) , 5.25 - 5.33 (m, 1H), 5.34 - 5.43 (m, 2H), 7.69 (d, J=8.07 Hz, 1H), 7.76 (s, 1H ), 7.95 (s, 1H), 8.02 (d, J=8.07 Hz, 1H), 8.37 (s, 1H), 8.78 (s, 1H). LCMS/HPLC (method-A): retention time

- 81 043056

1.26 min, [M+H] 487.1, purity: 98.94%. (Method-B): retention time 2.02 min, [M+H] 487.1, purity: 100%. Chiral purity (Method-X): retention time 25.56 min, 86.55% e.i.

Compounds according to the examples listed in table. 1 was synthesized according to the procedures described in examples 1-24-I.

Example Structure Name LCMS (M+N) ⁺ wlc/lcm s Method: RT (min.), Purity NMR 1-P o Me + _N ' ^Ν 0^Mθ CN (5)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5- yl)morpholino)methyl)-1 H-pyrazol-1yl)nicotinonitrile 468.1 A: 1.27, 97.90% B: 1.89, 97.30% XVIII: 18.26, 100% e.i. Ή NMR (400 MHz, DMS(W ₆ ) δ ppm 1.86-1.96 (br, 1 H), 2.18-2.29 (m, 4 H), 2.58 (s, 3 H), 2.81 (d, J= 11.74 Hz, 1 H), 2.92 (d, J= 11.49 Hz, 1 H), 3.56 (s, 2 H), 3. 71 - 3.81 (t, 1 N), 3.99 (d, J= 9.54 Hz, 1 N), 4.81 (d, J= 8.07 Hz, 1 N), 5.38 ( d, J = 4.89 Hz, 2 N), 7.57 - 7.63 (t, 1 N), 7.64 - 7.71 (t, 1 N), 7.87 (s, 1 N) , 7.99 (s, 1 H), 8.55 (s, 1 H), 8.83 (s, 1 H). (R)-3 -methyl-5 -(4-((2- 400 MHz, DMSO-d6: δ 2.29 (s, 3 Η), (4-methyl-1-oxo-1,3- 3.03-3.41 (m, 3 Η), 3.39 (s, 3 Η), 3.96 (d, ABOUT dihydroisobenzofur A: 1.16, J = 12.40 Hz, 2 Η), 4.23-4.32 (t, 3 Η), 25-1 ^Me δ an-5- 96.80% 5.11 (d, J = 10.40 Hz, 1 Η), 5.43 (d, J = yl)morpholino)methyl 461.1 B: 1.66 4.00 Hz, 2 H), 7.47 (d, J = 8.80 Hz, 1 H), )-1 H-pyrazole-1- 98.20% 7.57 (dd, J= 2.40, 8.60 Hz, 1 H), 7.67 (d, yl)benzo[b]oxazole-2 XIV: 11.59, J= 8.00 Hz, 1 H), 7.73 (d, J= 2.00 Hz, 1 (ZN)-on 100% e.i. Η), 7.77 (d, J = 7.60 Hz, 1 Η), 7.89 (s, 1 Η), 8.62 (s, 1 Η). (7?)-6-(5-methoxy-4-(( Ή NMR (400 MHz, DMSO-Je) δ ppm 26-1 About th Me ^z CN 2-(4-m ethyl-1-oxo-1, 3-dihydroisobenzene uranium-5 - yl)morpholino)methyl)-1 H-pyrazol-1yl)-4-methylnicotinonitrile 460.1 A: 1.40, 100% B: 2.12, 100% XIV: 11.66, 100% e.i. 2.28 (s, 3 Η), 2.58 (s, 3 Η), 3.01 - 3.26 (m, 3 Η), 3.83 - 3.95 (m, 1 Η), 4, 01 (s, 3 Η), 4.10 - 4.31 (m, 3 Η), 4.99 - 5.12 (m, 1 Η), 5.42 (d, J = 3.51 Hz, 2 Η), 7.65 (s, 1 Η), 7.72 - 7.77 (m, 1 Η), 7.82 (s, 1 Η), 8.67 - 8.78 (m, 1 Η) , 8.81 (s, 1 Η), 10.15 - 10.34 (m, 1 Η). Ή NMR (400 MHz, DMSO-%) δ ppm (7?)-4-methoxy-6-(4-(( 1.98-2.0 (t.1 N), 2.25 (s, 3 N), 2.27 - 2-(4-m ethyl-1-oxo-1, A: 1.57 2.36 (t, 1 N), 2.79 - 2.90 (t, 1 N), 2.95 ABOUT 3-dihydroisobenzoate 100% - 3.02 (t, 1 H), 3.55 (br. s., 2 H), 3.71 - 27-1 °СХГ11 m ^Ν ^-ΟΜθ uranium-5 - yl)morpholino)methyl 446.1 B: 1.19, 99.86% 3.81 (t, 1 Η), 3.96 - 4.03 (t, 1 Η), 4.10 (s, 3 Η), 4.80 - 4.83 (m, 1 Η), 5, 39 (d, J )-1 H-imidazole-1 - V: 8.64 = 4.28 Hz, 2 Η), 7.58 - 7.64 (m, 2 Η), CN yl) nicotinonitrile 100% e.i. 7.65 - 7.69 (m, 1 Η), 7.99 (s, 1 Η), 8.61 (s, 1 Η), 8.75 (s, 1 Η).

- 82 043056

28-1 ABOUT (A)-6-(4-((2-(4-methyl -1-oxo-1,3-d ihydroisobenzofuran-5yl)morpholino)methyl)-1H-imidazol-1yl)nicotinonitrile 416.1 A: 1.43, 96.32% V: 8.62, 100% e.i. Ή NMR (400 MHz, DMSO-X) δ ppm 1.93 - 2.03 (m, 1 N), 2.25 (s, 3 N), 2.26 2.34 (t, 1 N), 2.82 - 2.88 (m, 1 N) , 2.93 - 3.01 (t, 1 N), 3.54 (s, 2 N), 3.71 - 3.80 (t, 1 N), 3.94 - 4.01 (t, 1 N), 4.79 - 4.84 (t, 1 N), 5.38 (d, J = 4.46 Hz, 2 N), 7.59 - 7.63 (t, 2 N), 7, 92 (s, 1 H), 8.02 (d, J = 8.68 Hz, 1 H), 8.50 (d, J = 2.26 Hz, 1 H), 8.59 (d, J= 1.10 Hz, 1 N), 8.96 (d, J = 2.08 Hz, 1 N). Me x? 4 CN Ή NMR (400 MHz, DMSO-X) δ ppm 29-1 0 °^Ol Me ts °A) (R)-3 -methyl-5-(4-((2(4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5- yl)morpholino)methyl)-1 H-imidazol-1 yl)benzo[(1]oxazol-2 (3H)-one 461.1 A: 1.43, 98.01% B: 1.08, 99.47% V: 10.25 99.38% e.i. 1.95 - 2.03 (t, 1 N), 2.25 (s, 3 N), 2.84 2.91 (t, 1 N), 2.97 - 3.03 (t, 1 N) , 3.38 (s, 3 N), 3.39-3.40 (t, 1 N), 3.50-3.53 (t, 2 N), 3.71-3.81 (t, 1 N), 3.96 - 4.03 (t, 1 N), 4.81 (dd, J = 10.12, 1.80 Hz, 1 N), 5.33 - 5.35 (t, 2 N ), 7.36 (d, J= 2.26 Hz, 1 N), 7.39 (d, J= 2.20 Hz, 1 N), 7.60 - 7.69 (t, 4 N), 8.17 (d, J = 1.22 Hz, 1 N). Ή NMR (400 MHz, DMSO-X) δ ppm 30-1 0 Xu, Me o^J V ^N > b ^{N N} VL \_% Me CN (7?)-4-methyl-6-(5-((2(4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5- yl)morpholino)methyl)-1,3,4-oxad iazol-2yl)nicotinonitrile 432.1 A: 1.39, 98.15% B: 1.54, 97.20% X: 6.62, 100% e.i. 2.22 - 2.33 (t, 4 H), 2.57 (br. s., 1 H), 2.63 (s, 3 H), 2.96 (d, J = 10.76 Hz, 1 Η), 3.11 (d, J= 11.74 Hz, 1 Η), 3.75 -3.86 (m, 1 Η), 4.04 (d, J= 8.80 Hz, 1 Η ), 4.13 (br. s., 2 H), 4.79 - 4.93 (m, 1 H), 5.40 (d, J = 2.93 Hz, 2 H), 7.58 - 7.66 (m, 1 H), 7.66-7.75 (m, 1 H), 8.32 (s, 1 H), 9.12 (s, 1 H). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 31-1 0 "bCu _N ^X"-<Xc" Me 0^ (7?)-4-methyl-6-(4-(2-(2-(4-methyl-1-oxo-1, 3-dihydroisobenzene uranium-5- yl)morpholino)ethyl)1 H-pyrazol-1yl)nicotinonitrile 444.1 A: 1.84, 99.37% B: 2.04, 99.95% XIX: 9.24, 100% e.i. 1.86 - 2.00 (m, 1 Η), 2.17 - 2.26 (m, 1 Η), 2.28 (s, 3 Η), 2.58 - 2.64 (m, 4 Η ), 2.68 - 2.77 (m, 2 Η), 2.83 - 2.92 (m, 2 Η), 2.99 (d, J= 11.25 Hz, 1 Η), 3.69 3.83 (m, 1 H), 4.00 (d, J= 11.00 Hz, 1 Η), 4.80 (d, J= 7.83 Hz, 1 Η), 5.29 5.46 (m, 2 Η), 7.66 (q, J= 8.07 Hz, 2 Η), 7.83 (s, 1 Η), 7.96 (s, 1 Η), 8.50 (s, 1 Η), 8.79 - 8.87 (m, 1 Η).

- 83 043056

Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 32-1 0 Me b^r ^NOM (7?)-4-methoxy-6-(5-((2-(4-methyl-1 -oxo-1, 3-dihydroisobenzophuranium-5 - yl)morpholino)methyl)thiazol-2- yl) nicotinonitrile 463.1 A: 1.31, 100% B: 1.98, 99.23% XV: 11.34, 100% e.i. 2.02 (t, J= 10.64 Hz, 1 Η), 2.22 (s, 3 Η), 2.28 - 2.37 (m, 1 Η), 2.82 - 3.00 (m , 2 Η), 3.68 - 3.88 (m, 1 Η), 3.90 (s, 2 Η), 4.02 (d, J= 13.21 Hz, 1 Η), 4.13 ( s, 3 Η), 4.84 (d, J = 7.83 Hz, 1 Η), 5.30 - 5.45 (m, 2 Η) 7.63 (s, 1 Η), 7.66 - 7.72 (m, 1 Η), 7.84 (s, 1 Η), 7.90-8.01 (m, 1 Η), 8.87 (s, 1 Η). 33-1 0 °*: Me O^P ΐΗΡ ^Ν Me (7?)-4-methyl-6-(5-(2-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5- yl)morpholine-4-carb onyl)thiazol-2yl)nicotinonitrile 461.2 A: 1.61, 99.48% A: 1.62, 100% V: 16.99 100% e.i. Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 2.20 (s, 3 H), 2.27 (br. s., 2 H), 2.32-2.36 (m, 1 H), 2.63 (s, 3 H), 2.66 - 2.70 (m, 1 H), 3.79 - 3.88 (m, 1 H), 4.11 (br. s., 1 H), 4.95 (d, J= 9.05 Hz , 1 H), 5.41 (br. s., 2 H), 7.68 - 7.76 (m, 2 H), 8.27 (s, 1 H), 8.40 (s, 1 H ), 9.03 (s, 1H). 34-1 0 Me O^P tHP OMe (7?)-4-methoxy-6-(5-(2 -(4-methyl-1 -oxo-1,3dihydroisobenzofur an-5- yl)morpholine-4-carb onyl)thiazol-2yl)nicotinonitrile 477.1 A: 1.82, 96.63% B: 1.81, 96.20% V: 17.05, 100% e.i. Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 2.20 (s, 3 Η), 2.27 (br. s., 2 Η), 2.31-2.35 (m, 1 Η), 2.67 (br. s., 1 H), 3.83 (t, J = 11.62 Hz, 1H), 4.04-4.11 (m, 1H), 4.14 (s, 3 H), 4.94 (d, J= 7.58 Hz, 1 H), 5.40 (br. s., 2 H), 7.65 - 7.78 (m, 2 H), 7.90 (s, 1 H), 8.39 (s, 1 H), 8.92(s, 1H). Ή NMR (400 MHz, DMSO-p) δ ppm 35-1 0 Me pl, T ome (7?)-4-methoxy-5'-((2-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5- yl)morpholino)methyl )-[2,2'-bipyridine]-5carbonitrile 457.1 A: 1.27, 94.23% B: 1.95, 95.37% X: 10.00, 100% e.i. 2.24 (s, 3 Η), 2.27-2.36 (m, 1 Η), 2.76 2.85 (m, 1 Η), 2.89 - 2.95 (m, 1 Η) , 3.68 - 3.77 (m, 1 Η), 3.78 (br. s., 2 Η), 3.95 4.05 (m, 1 Η), 4.64 (d, J= 5 .02 Hz, 1 H), 4.13 (s, 3 H), 4.98 (br. s., 1 H), 5.34 - 5.47 (m, 2 H), 7.64 (d , J= 8.07 Hz, 1 H), 7.72 (d, J = 7.34 Hz, 1 H), 8.06 (br. s., 1 H), 8.16 (s, 1 H ), 8.48 (d, J = 8.31 Hz, 1 H), 8.77 (br. s., 1 H), 8.94 (s, 1 H).

- 84 043056

36-1 0 M* (7? )-4-methy l-5 - (4- ((2 (4-methyl-1 H-imide az ol-1-yl) thiazol-5yl) methyl) morpholine- 2- yl)isobenzofuran-1(3N)-one 411.1 A: 0.88, 96.07% B: 1.59, 94.02% XIV: 6.91, 100% e.i. Ή NMR (400 MHz, DMSO+/6) δ ppm 2.16 (s, 3 H), 2.24 (s, 3 H), 2.22 - 2.43 (m, 2 H), 2.85 (d, J = 11.00 Hz, 1 H), 2.95 (d, J = 11.25 Hz, 1 H), 3.73 (d, J = 9.78 Hz, 1 H), 3.80 (s, 2 H), 4.02 (d, J= 9.78 Hz, 1 H), 4.80 (d, J= 7.83 Hz, 1 H) 5.33 - 5.47 (br, 2 H), 7.49 (s, 2 H) , 7.61 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 8.24 (s, 1 H). 37-1 0 (R)-1 -(5 -((2-(4-methyl -1-oxo-1,3-d ihydroisobenzofuran-5yl)morpholino)methyl)pyridine-2- yl)-1 H-imidazole-4-κ arbonitrile 390.0 A: 0.92, 95.02% B: 1.18, 95.73% X: 2.76, 100% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 2.23 (s, 3 N), 2.24 - 2.36 (t, 2 N), 2.77 (d, J= 11.49 Hz, 1 N), 2.89 (d, J= 11 .74 Hz, 1 N), 3.66 (s, 2 N), 3.72 - 3.86 (m, 1 N), 4.00 (d, J = 11.74 Hz, 1 N), 4 .75 4.93 (t, 1 N), 5.29 - 5.46 (t, 2 N), 7.52 - 7.73 (t, 2 N), 7.88 (d, J = 8, 31 Hz, 1 N), 8.05 (dd, 7= 8.31.2.20 Hz, 1 N), 8.50 (d, 7= 2.20 Hz, 1 N), 8.74 (d , 7= 1.22 Hz, 1 N), 8.91 (d, 7= 1.22 Hz, 1 N). 38-1 39-1 0 N n Me % _N ' b o °v^Ol Me % _N ' b (7?) -4-methy l-5 - (4- (( 1 (thiophene-3- yl)- 1 H-pyrazol-4yl)methyl)morpholine- 2- yl)isobenzofuran-1(3N)-one (7?)-4-methy l-5 -(4-(( 1 (pyrazine-2- yl)-1 H-pyrazol-4yl)methyl)morpholine- 2- yl)isobenzofuran-1(3N)-one 396.2.0 392.2 A: 0.96 96.60%, B: 1.50, 97.10% XVIII: 9.15, 100% e.i. A: 0.77, 95.20% B: 1.31, 95.20% XVIII: 21.35, 100% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.83 - 1.96 (t, 1 N), 2.18 - 2.21 (t, 1 N), 2.24 (s, ZN), 2.81 (d,7 \u003d 11.49 Hz, 1 H), 2.92 (d, 7= 11.49 Hz, 1 H), 3.50 (br. s., 2 H), 3.69 - 3.82 (t, 1 H), 3, 99 (d, 7= 11.74 Hz, 1 N), 4.81 (d, 7= 8.80 Hz, 1 N), 5.34 - 5.44 (t, 2 N), 7.50 - 7.56 (t, 1 N), 7.58-7.70 (t, 5 N), 8.29 (s, 1 N). Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.83 - 1.96 (t, 1 N), 2.18 - 2.21 (t, 1 N), 2.24 (s, ZN), 2.81 (d,7 \u003d 11.49 Hz, 1 H), 2.92 (d, 7= 11.49 Hz, 1 H), 3.50 (br. s., 2 H), 3.69 - 3.82 (t, 1 H), 3, 99 (d, 7 = 11.74 Hz, 1 N), 4.82 (dd, 7 = 10.03, 2.20 Hz, 1 N), 5.33 - 5.45 (t, 2 N), 7.57 - 7.69 (t, 2 N), 7.87 (s, 1 N), 8.49 - 8.56 (t, 2 N), 8.60 (d, 7 = 2.45 Hz , 1 H), 9.20 (d, 7 = 1.22 Hz, 1 H).

- 85 043056

40-1 0 ¢/ (7?)-4-(4-((2-(4-methyl -1-oxo-1,3-dihydro-isobenzofuran-5yl)morpholino)methyl)-1H-pyrazol-1yl)benzonitrile 415.2 A: 1.00, 96.90% B: 1.55, 96.50% XVIII: 11.29, 100% e.i. Ή NMR (400 MHz, DMSO-Te) δ ppm 1.92 (t, J= 10.76 Hz, 1 N), 2.18 - 2.21 (m, 1 N), 2.24 (s, 3 N), 2.82 (d, J= 11 .25 Hz, 1 N), 2.93 (d, J= 10.76 Hz, 1 N), 3.53 (s, 2 N), 3.71 - 3.81 (m, 1 N), 3 .99 (d, J = 9.29 Hz, 1 N), 4.81 (d, J = 7.83 Hz, 1 N), 5.32 - 5.43 (m, 2 N), 7.58 - 7.70 (w, 2 H), 7.79 (s, 1 H), 7.92 - 8.00 (m, 2 H), 8.00 - 8.06 (m, 2 H), 8 .60 (s, 1 H). Me O^J ΧΡ, ^Ν V ίΝ (7)-4-methy l-5-(4-(( 1 - Ή NMR (400 MHz, DMSO-Te) δ ppm (6-methylpyrazine-2- A: 0.87 1.84 - 1.97 (m, 1 N), 2.25 (s, 3 N), 2.45 0 yl)-1 H-pyrazole-4- 99.10% (s, 3 H), 2.76 - 2.85 (m, 2 H), 2.90 - 2.98 41-1 Ο(~ 1JL Me V- ^N N-jZ -Me yl)methyl)morpholine- 2- yl)isobenzofuran-1( 406.2 B: 1.44, 98.50% XVIII: 20.05, (m, 1 N), 3.58 (s, 2 N), 3.72 - 3.84 (m, 1 N), 3.96 - 4.03 (m, 1 N), 4.78 - 4 .87 (w, 1 H), 5.39 (d, J = 4.89 Hz, 2 H), 7.65 (d, ZN)-on 100% e.i. J = 14.92 Hz, 2 H), 7.85 (s, 1 H), 8.47 8.52 (br, 2 H), 8.99 (s, 1 H). Ή NMR (400 MHz, DMSO-Te) δ ppm 42-1 ο ο ^ζ A Me O^J Ρ,Ν ^Ν Ν=/ ~ΞΝ (7)-5 -(4-((2-(4-methyl -1-oxo-1,3-d ihydroisobenzofuran-5yl)morpholino)methyl)-1H-pyrazol-1yl)nicotinonitrile 416.2 A: 0.86, 93.10% B: 1.50, 97.10% 1.87 - 2.01 (m, 1 H), 2.22 - 2.29 (m, 4 H), 2.82 (br. s., 1 H), 2.94 (d, J = 11 .04 Hz, 1 N), 3.55 (s, 2 N), 3.77 (dd, J= 11.55, 9.04 Hz, 1 N), 4.01 (d, J= 9.54 Hz, 1 N), 4.82 (d, J= 8.03 Hz, 1 N), 5.34 - 5.42 (t, 2 N), 7.59 - 7.74 (t, 2 N) , 7.84 (s, 1 H), 8.62 (s, 1 H), 8.71 - 8.78 (t, 1 H), 8.93 (d, J= 1.51 Hz, 1 H ), 9.38 (d, J = 2.51 Hz, 1 H). Ή NMR (400 MHz, DMSO-Te) δ ppm 43-1 ο Γχ Me C ^N Lu_ Η (7)-3 -(4-((2-(4-methyl -1-oxo-1,3-d ihydroisobenzofuran-5yl)morpholino)methyl)-1H-pyrazol-1yl)benzonitrile 415.2 A: 1.02, 97.60%, B: 1.57, 96.70% XVIII: 11.61, 100% e.i. 1.88 (s, 1 H), 2.22 - 2.28 (t, 3 H), 2.83 (d, 7= 11.55 Hz, 1 H), 2.94 (d, 7= 10, 54 Hz, 1 H), 3.53 (s, 2 H) 3.77 (dd, J = 11.29, 9.29 Hz, 2 H), 4.01 (d, J = 9.54 Hz, 1 N), 4.82 (d, J= 8.03 Hz, 1 N), 5.39 (d, 7= 4.52 Hz, 2 N), 7.59 - 7.78 (t, 5 N ), 8.19 (dt, 7= 8.03, 1.76 Hz, 1 H), 8.31 (d, 7= 1.51 Hz, 1 H), 8.57 (s, 1 H).

- 86 043056

44-1 0 about ⁷ Me 0. XXI b (5)-4-methyl-5 -(4-(( 1 (pyridine-4- yl)-1 H-pyrazol-4yl)methyl)morpholine- 2- yl)isobenzofuran-1(3N)-one 391.2 A: 0.54, 99.20% B: 1.18, 98.9% Ή NMR (400 MHz, DMSO-Z) δ ppm 1.88 - 1.96 (m, 1 N), 2.24 (s, 4 N), 2.82 (d, J= 11.04 Hz, 1 N), 2.93 (d, J= 11 .55 Hz, 1 N), 3.53 (s, 2 N), 3.72 - 3.80 (m, 1 N), 4.00 (dd, J= 11.29, 1.76 Hz, 1 H), 4.82 (dd, J = 10.04, 2.51 Hz, 1 H), 5.38 (d, J = 4.52 Hz, 2 H), 7.65 - 7.69 (t , 2 H), 7.80 (s, 1 H), 7.85 (s, 2 H), 8.63 (s, 3 n). (5)-4-methy l-5 -(4-(( 1 - Ή NMR (400 MHz, DMSO-Z) δ ppm (4-(methylsulfonyl) 1.87 - 2.01 (t, 1 N), 2.22 - 2.29 (t, 3 N), 45-1 0 With/ or me 0'b phenyl)-1H-pyrazole-4 yl)methyl)morpholine- 2- yl)isobenzofuran-1( 468.2 A: 0.86, 99.30%, B: 1.32, 97.80% 2.34 (dt, J= 3.76, 1.63 Hz, 1 N), 2.82 (br. s., 1 N), 2.94 (d, J= 11.04 Hz, 1 N) , 3.21 (s, 3 H), 3.55 (s, 2 H), 3.77 (dd, J= 11.55, 9.04 Hz, 1 H), 4.01 (d, J= 9.54 Hz, 1 N), 4.82 (d, J= 8.03 Hz, 1 N), 5.34 - 5.42 (t, ZN)-on 2 H), 7.52 (s, 1 H), 7.54-7.67 (t, 6 H), 8.22 (s, 1 H). 46-1 0 CJ Me ^l i'Xb ^N '-N ^~Me Λ (5)-2-methyl-4-(4-((2(4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5- yl)morpholino)methyl)-1 H-pyrazol-1yl)benzonitrile 429.2 A: 1.09, 98.60% B: 1.68, 98.20% XVIII: 13.04, 100% e.i. Ή NMR (400 MHz, DMSO-Z) δ ppm 1.87 - 1.97 (t, 1 N), 2.24 (s, 4 N), 2.55 (s, 3 N), 2.82 (d, J= 11.55 Hz, 1 N) , 2.92 (d, J = 11.55 Hz, 1 H), 3.52 (br. s., 2 H), 3.76 (t, J = 11.04 Hz, 1 H), 4, 00 (d, J = 10.04 Hz, 1 Η), 4.81 (d, J = 9.04 Hz, 1 Η), 5.38 (d, J = 4.52 Hz, 2 Η), 7 .59 - 7.69 (m, 2 Η), 7.92 (s, 1 Η), 8.51 - 8.59 (m, 3 Η), 9.19 (s, 1 Η). Ή NMR (400 MHz, DMSO-Z) δ ppm 47-1 0 about ⁷ me oh _x Me^^ N (5)-3-methyl-4-(4-((2(4-methyl-1-oxo-1,3 dihydroisobenzofur an-5- yl)morpholino)methyl)-1 H-pyrazol-1yl)benzonitrile 429.2 A: 1.01, 97.80% B: 1.56, 99.10% 1.91 (t, J = 11.04 Hz, 1 Η), 2.24 (s, 4 Η), 2.33 (s, 3 Η), 2.83 (d, J = 11.04 Hz, 1 Η), 2.94 (d, J= 11.04 Hz, 1 Η), 3.53 (s, 2 Η), 3.76 (td, J = 11.29, 2.51 Hz, 1 Η ), 4.00 (dd, J= 11.04, 2.01 Hz, 1 Η), 4.81 (dd, J = 10.04, 2.01 Hz, 1 Η), 5.39 (d, J = 4.02 Hz, 2 Η), 7.56 - 7.64 (m, 2 Η), 7.65 - 7.70 (m, 1 Η), 7.73 (s, 1 Η), 7 .81 (dd, J= 8.03, 1.51 Hz, 1 Η), 7.92 (d, J= 1.51 Hz, 1 Η), 8.10 (s, 1 Η).

- 87 043056

48-1 o ιΑΑΑΛ Me 0% 4-. _N'7 (R)-5-(4-((2-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5yl)morpholino)methyl)-1H-pyrazol-1yl)picolinonitrile 416.2 A: 0.89, 94.50% B: 1.39, 94.60% Ή NMR (400 MHz, DMSO-Ts) δ ppm 1.85 - 1.99 (t, 1 H), 2.24 (s, 4 H), 2.83 (d, J= 11.55 Hz, 1 H), 2.94 (d, J= 11, 55 Hz, 1 N), 3.54 (s, 2 N), 3.70 - 3.83 (m, 1 N), 4.00 (d, J= 11.04 Hz, 1 N), 4, 82 (dd, ./ = 10.04, 2.01 Hz, 1 N), 5.38 (d, J= 5.52 Hz, 2 N), 7.57 - 7.71 (t, 2 N) , 7.87 (s, 1 H), 8.17 (d, J= 9.04 Hz, 1 H), 8.43 (dd, J= 8.53.2.51 Hz, 1 H), 8 .69 (s, 1 H), 9.28 (d, J = 2.01 Hz, 1 H). 49-1 O Me O^> O-OMe Λ (7?)-2-methoxy-4-(4-((2-(4-methyl-1-oxo-1, 3-dihydroisobenzophuranium-5 - yl)morpholino)methyl)-1 H-pyrazol-1yl)benzonitrile 445.1 A: 1.32, 97.40% B: 1.83, 97.60% Ή NMR (400 MHz, DMSO4/6) δ ppm 1.85 - 1.99 (t, 1 H), 2.24 (s, 4 H), 2.83 (d, J= 11.55 Hz, 1 H), 2.94 (d, J= 11, 55 Hz, 1 N), 3.54 (s, 2 N), 3.70 - 3.83 (t, 1 N), 4.00 - 4.05 (t, 4 N), 4.82 (br s., 1 N), 5.39 (d, J= 4.02 Hz, 2 N), 7.53 - 7.70 (t, 4 N), 7.78 - 7.84 (t, 2 H), 8.78 (s. 1 H). 50-1 O °0x ^Τ ^χ + ^'N' ^χχ γΝ _Ν Me % _Ν ' h?^ b (7?)-4-methy l-5 -(4-(( 1 (pyrazolo[1,5-a]pyri midin-5- yl)-1 H-pyrazol-4yl)methyl)morpholine2- yl)isobenzofuran-1(3N)-one 431.2 A: 0.08, 98.80% B: 1.41, 99.30% Ή NMR (400 MHz, DMSO4/6) δ ppm 1.87 - 1.98 (t, 1 H), 2.24 (s, 4 H), 2.82 (d, J= 11.04 Hz, 1 H), 2.94 (d, J= 11, 55 Hz, 1 N), 3.58 (s, 2 N), 3.77 (td, J = 11.42, 2.26 Hz, 1 N), 3.95 - 4.05 (t, 1 N ), 4.83 (dd, J= 9.79, 2.26 Hz, 1 N), 5.34 - 5.44 (t, 2 N), 6.56 - 6.64 (t, 1 N) , 7.50 - 7.73 (t, 3 N), 7.88 (s, 1 N), 8.22 (d, J = 2.51 Hz, 1 N), 8.60 (s, 1 N ), 9.19 (dd, 7=7.53, 1.00 Hz, 1 H). 51-1 o °0C1 ν ΆΓ^ ^ν Me ^N. ome q (7?)-3-methoxy-4-(4-((2-(4-methyl-1-oxo-1, 3-dihydroisobenzene uranium-5 - yl)morpholino)methyl)-1 H-pyrazol-1yl)benzonitrile 445.2 A: 1.03, 98.40% B: 1.59, 99.40% XVIII: 12.11, 100% e.i. Ή NMR (400 MHz, DMSO-g/b) δ ppm 1.86 - 1.94 (t, 1 N), 2.22 - 2.28 (t, 4 N), 2.81 (d, J = 12.05 Hz, 1 N), 2.92 (d , J = 11.55 Hz, 1 N), 3.53 (s, 2 N), 3.72 - 3.79 (t, 1 N), 3.98 (d, J = 2.01 Hz, 1 H), 4.00 (br. s., 3 H), 4.81 (dd, J= 10.04, 2.01 Hz, 1 H), 5.38 (d, J= 3.51 Hz, 2 N), 7.55 (dd, J= 8.28, 1.76 Hz, 1 N), 7.60 - 7.63 (t, 1 N), 7.65 - 7.69 (t, 1 H), 7.73 (s, 1 H), 7.76 (d, J = 1.51 Hz, 1 H), 7.90 (d, J = 8.53 Hz, 1 H), 8.28 (s, 1 H).

- 88 043056

52-1 th ^Me V Ν (A)-4-methyl-6-(3-methyl-4-((2-(4-methyl-1-o xo-1,3-dihydroisobenzofuran-5yl)morpholino)methyl)-1H-pyrazole -1yl)nicotinonitrile 444.1 A: 1.26, 100% B: 2.13, 98.47% XIV: 10.49, 99.69% Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.94 (s, 2 N) 2.23 (s, 3 N) 2.32 (s, 3 N) 2.56 (s, 3 N) 2.77 - 2.84 (t, 1 N) 2 .89 (s, 1 N) 3.49 (s, 2 N) 3.75 (d, J= 1.71 Hz, 1 N) 3.96 - 4.03 (t, 1 N) 4.80 ( d, J= 8.31 Hz, 1 N) 5.38 (d, J = 3.91 Hz, 2 N) 7.60 - 7.64 (m, 1 N) 7.66 - 7.70 (t , 1 H) 7.91 (s, 1 H) 8.45 (s, 1 H) 8.79 (s, 1 H). 'H NMR (400 MHz, DMSO-i/b) δ ppm 53-1 0 Me N~ _n b Me ⁷ ^ N (/?)-4-methy l-6-(3 -((2(4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5- yl)morpholino)methyl)-1 H-pyrazol-1yl)nicotinonitrile 430.2. A: 1.17, 100% B: 2.04, 95.89% XVIII: 11.72, 100% 1.98 - 2.08 (t, 1 N) 2.23 (s, 3 N) 2.28 2.36 (t, 1 N) 2.59 (s, 3 N) 2.75 - 2.82 (t, 1 N) 2.88 - 2.94 (t, 1 N) 3.56 - 3.68 (t, 1 N) 3.90 - 3.97 (t, 1 N) 4.00 - 4 .19 (t, 2 N) 4.64 - 4.73 (t, 1 N) 5.39 (d, J = 6.11 Hz, 2 N) 6.60 (s, 1 N) 7.61 ( s, 1 N) 7.65 - 7.71 (t, 1 N) 7.81 (d, J= 1.71 Hz, 1 N) 7.99 (s, 1 N) 8.87 (s, 1 N). Ή NMR (400 MHz, DMSO-t/b) δ ppm 2-Π 0 %e CN (5)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1H-pyrazo l-1yl)nicotinonitrile 429.2 E: 10.23, 99.23% G: 11.07, 99.52% II: 3.56 100% e.i. 1.79 (t, J= 10.29 Hz, 1 N), 2.03 - 2.18 (t, 1 N), 2.25 (s, 3 N), 2.66 - 2.67 (t , 4 N), 2.79 (t, J= 9.04 Hz, 2 N), 2.84 - 2.92 (t, 1 N), 2.94 - 3.05 (t, 1 N), 3.45 - 3.59 (t, 2 N), 4.06 (d, J = 9.54 Hz, 1 N), 5.36 (d, J = 1.51 Hz, 2 N), 7, 63 (d, J = 8.03 Hz, 1 H), 7.76 (d, J = 8.03 Hz, 1 H), 7.85 (s, 1 H), 7.98 (s, 1 H ), 8.52 (s, 1 H), 8.82 (s, 1 H). (7?)-5-(5-methox and-4-(( Ή NMR (400 MHz, CDCh) δ ppm 2.37 3 - (4-methyl-1 -oxo-1, (s, 3 Η), 2.72 - 2.79 (t, 1 Η), 2.95 - 3.04 0 3-dihydroisobenzoate A: 1.19, (t, 2 Η), 3.33 - 3.39 (t, 1 Η), 3.46 (s, 3 54-1 °vXl/x ^ΜΘΗΝ 4θο ^Λ ν uranium-5 yl)piperazine-1 - 490.1 98.00% B: 1.55 Η), 3.47 - 3.50 (m, 1 Η), 3.51 - 3.60 (m, 2 Η), 3.89 - 3.96 (m, 1 Η), 4.03 (s , 3 H), ό yl)methyl)-1 H-pyrazo 98.47% 4.19 - 4.25 (m, 1 Η), 4.72 - 4.77 (m, 1 Η), /a Μβ-Νχ/Ο l-1- XVIII: 14.42, 5.27 (s, 2h), 7.22 - 7.25 (m, 2h), 7.32 - If 0 yl)-3-methylbenzo[(1] o 100% e.i. 7.36 (m, 1 H), 7.81 (d, J= 6.50 Hz, 2 H), xazol-2(3N)-one 8.05 (s, 1h).

- 89 043056

55-1 0 χχ_. N Me X ^N Κ.Μθ F ϊΑθ (7/)-7-fluoro-3-methyl-5-(4-((3-(4-methyl-1-ox-co-1,3-dihydroisobe nosofuran-5yl)piperazin-1yl)methyl)-1 H -pyrazo 478.0 A: 1.18, 98.05% B: 1.52, 98.34% XI: 13.14, Ή NMR (400 MHz, DMSO-k,) δ ppm 1.75 - 1.85 (m, 1 H), 2.05 - 2.15 (m, 1 H), 2.26 (s, 3 H), 2.75 - 3.01 (w, 4 H ), 3.39 (s, 3 H), 3.49 (s, 2 H), 4.10 (d, J = 9.54 Hz, 1 H), 5.37 (s, 2 H), 7 .57 - 7.70 (w, 4 H), 7.78 (d, J = 7.83 Hz, 1 H), 8.46 (s, 1 yl)benzo[b]oxazol-2 (3N)-one 100% e.i. H), (no exchangeable protons were observed). 56-1 0 ABOUT at N Me χ> V to ,Me /=< ^N MeO οΑθ (//)-7-metho xi-3 -methy l-5 - (4- ((3 - (4-methyl-1 -oxo-1,3 - dihydroisobenzofuran-5 yl) piperazin-1 yl) methyl) - 1 H-pyrazo l-1- yl)benzo[<1]oxazol-2 (3N)-one 490.2 A: 0.90, 92.18% B: 1.20, 95.48% XX: 10.23, 100% e.i. Ή NMR (400 MHz, DMSO-k,) δ ppm 1.79-1.91 (m, 1 N), 2.12-2.20 (t, 1 N), 2.27 (s, 3 N), 2.86-3.04 (t, 4 N ), 3.35 (s, 3 H), 3.51 (br. s., 2 H), 3.96 (s, 3 H), 4.16 (br. s., 1 H), 5, 38 (d, J= 2.20 Hz, 2 H), 7.31 (d, J= 1.96 Hz, 1 H), 7.39 (d, J= 1.96 Hz, 1 H), 7 .64 - 7.70 (t, 2 H), 7.78 (d, J = 8.07 Hz, 1 H), 8.47 (s, 1 H), (no exchangeable protons were observed). (7/)-3,7-d imethyl-5 -(4- Ή NMR (400 MHz, CD ₃ OD) δ ppm 2.42 57-1 0 o ⁷ ^ X^V^X ^Μ θ χ> tk ΛΑ _Ο ((3-(4-methyl-1-oxo-1,3-dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1 H-pyrazo l-1- yl)benzo[<1]oxazole-2 474.1 A: 1.61, 97.04% B: 1.49, 98.74% XIV: 9.11, 100% e.i. (s, 3 N), 2.44 (s, 3 N), 2.65 - 2.78 (t, 2 N), 3.45 (s, 3 N), 3.45 - 3.58 (t , 4 H), 3.89 (s, 2 H), 4.77 (d, J = 2.51 Hz, 1 H), 5.42 (s, 2 H), 7.38 (d, 1, 51 Hz, 1 N), 7.41 (d, J = 2.01 Hz, 1 H), 7.72 (d, J = 8.03 Hz, 1 H), 7.76 (s, 1 H), 7.85 (d, J= 8.03 Hz, 1 N), 8.28 (s, 1 N), (capable (ZN)-on proton exchange was not observed). Ή NMR (400 MHz, DMSO-k,) δ ppm 58-1 0 about ⁷ XX η ^χ Α ^/ν 'Ν' Me NY.___) χ> t^N* °Α> (7/)-3 -methyl-5 -(4-((3 (4-methyl-1-oxo-1,3 dihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)-1 H-pyrazo l- 1- yl)benzo[<1]oxazole-2 460.0 A: 1.08, 95.95% B: 1.38, 95.74% V: 9.53, 92.68% e.i. 1.91 (s, 1 Η), 2.17 (s, 1 Η), 2.27 (s, 3 Η), 2.87 (br. s., 2 H), 2.98 (br. s ., 1 H), 3.06 (br. s., 1 H), 3.38 (s, 3 H), 3.52 (br. s., 2 H), 4.19 (br. s. , 1 H), 5.38 (d, J= 2.45 Hz, 2 H), 7.41 (d, J= 8.56 Hz, 1 H), 7.57 (dd, J = 8.68 , 2.32 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 7.72 - 7.80 (m, 2 H), 8.42 (s, 1 (ZN)-on H), (no exchangeable protons were observed).

- 90 043056

59-1 o Me HN^> _N ' ^N ^^~OMe CN (A) -4-methoxy-6- (4- (( 3 - (4-methyl-1 -oxo-1, 3-dihydroisobenzoph uran-5 yl) piperazin-1 yl) methyl) -1 H-pyrazo l- 1yl) nicotinonitrile 445.1 A: 1.15, 98.35% B: 1.51, 98.43% V: 8.30, 98.31% e.i. Ή NMR (400 MHz, DMSO-Te) δ ppm 1.93 (br. s., 1 H), 2.20 (br. s., 1 H), 2.27 (s, 3 H), 2.85 (br. s., 2 H), 2 .95 - 3.12 (m, 2 H), 3.56 (br. s., 2 H), 4.10 (s, 3 H), 4.20 (br. s., 1 H), 5 .30 - 5.47 (m, 3 H), 7.60 (s, 1 H), 7.65 - 7.72 (m, 1 H), 7.73 - 7.81 (m, 1 H) , 7.87(s, 1H), 8.54(s, 1H), 8.73(s, 1H). 61-1 0 ΛΤΠΐ T £ 1 II N Me HN^JV _N ' (R) -3 -methyl-5 - (4- ((3 (4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5 -yl) piperazin-1 yl) methyl) -1 Η-1,2, 3-t riazol-1yl)benzo[c!]oxazol-2 (3N)-one 461.0 A: 1.07, 96.74% B: 1.24, 98.65% V: 8.68, 100% e.i. Ή NMR (400 MHz, DMSO-Te) δ ppm 2.02 (br. s., 1 H), 2.28 (s, 3 H), 2.33 (s, 1 H), 2.67 (s, 1 H), 2.90 (d, J = 11.74 Hz, 2 H), 2.98 (br. s., 1 H), 3.08 (d, J = 11.00 Hz, 1 H), 3.40 (s, 3 H), 3.74 (s, 2 H), 4.19 (br. s., 1 H), 5.33 - 5.44 (m, 2 H), 7.52 (d, J = 8.56 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 7.78 (d, J = 7.83 Hz, 1 H), 7.88 (d, J = 1.96 Hz, 1 H ), (no exchangeable protons were observed). 62-1 o G -'N'' ^N ^Me ™ VV 4 CN (2?)-6-(5-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran-5yl)piperazin-1 yl)methyl)-1,3,4-oxadiazol- 2yl) nicotinonitrile 417.0 A: 0.99, 100% B: 1.14, 98.88% XX: 8.88, 100% e.i. Ή NMR (400 MHz, DMSO-Te) δ ppm 2.04 (t, J= 10.27 Hz, 1 N), 2.29 (s, 3 N), 2.33 (d, J= 1.96 Hz, 1 N), 2.80 - 2, 94 (br, 3 H), 3.00 (d, J= 11.74 Hz, 1 H), 4.00 (s, 2 H), 4.09 (d, J= 10.03 Hz, 1 H ), 5.38 (s, 2 H), 7.65 (d, J= 7.83 Hz, 1 H), 7.76 (d, 7=7.83 Hz, 1 H), 8.35 ( d, 7= 8.31 Hz, 1 N), 8.57 (dd, 7= 8.19, 2.08 Hz, 1 N), 9.22 (d, 7= 2.20 Hz, 1 N) , (no exchangeable protons were observed). 63-1 0 °bCX Me HN^ L. ome (7?)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-[2,2' -bipi ridin]-5-carbonitry l 456.1 A: 1.23, 100% B: 1.63, 100% VIII: 13.51, 100% e.i. Ή NMR (400 MHz, DMSCM,) δ ppm 1.91 (br. s., 1 H), 2.16 - 2.20 (br. s, 1 H), 2.20 (s, 3 H), 2.80 (t, 7= 11.13 Hz, 2 Η), 2.87 - 3.10 (m, 2 Η), 3.53 - 3.76 (m, 2 Η), 4.12 (s, 3 Η), 4.12-4, 19 (br.s, 1 Η), 5.26 - 5.43 (m, 2 Η), 7.66 (d, 7= 7.58 Hz, 1 Η), 7.78 (d, 7= 7 .83 Hz, 1 H), 7.96 (dd, 7=8.31.1.96 Hz, 1 H), 8.15 (s, 1 H), 8.41 (d, 7= 8.07 Hz, 1 Η), 8.68 (s, 1 Η), 8.91 (s, 1 Η), (no exchangeable protons were observed).

- 91 043056

64-1 o ΝΝ V_ _C NN==/ (R)-1-(5-((3-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5yl)piperazin-1yl)methyl)pyridin-2yl)-1H-pyrazol-4- carbonitrile 415.1 A: 1.19, 100% B:1.54 100% IV: 14.93, 99.42% e.i. Ή NMR (400 MHz, DMSO-Je) δ ppm 1.85 (t, J = 10.39 Hz, 1 Η), 2.15 (d, J = 10.76 Hz, 1 Η), 2.22 (s, 3 Η), 2.64 - 2, 84 (m, 2 Η), 2.86 - 3.04 (m, 2 Η), 3.54 - 3.68 (m, 2 Η), 4.08 (d, J = 10.76 Hz, 1 Η), 5.36 (d, J = 2.20 Hz, 2 Η), 7.64 (d, J = 8.07 Hz, 1 Η), 7.77 (d, J = 8.07 Hz, 1 Η), 7.90 - 7.97 (m, 1 Η), 7.99 - 8.07 (m, 1 Η), 8.37 - 8.48 (m, 2 Η), 9.39 ( s, 1 H), (no exchangeable protons were observed). 65-1 0 (R)-1-(5-((3-(4-methyl-1-oxo-1,3-d-hydroisobenzofuran-5yl)piperazin-1yl)methyl)pyridin-2yl)-1 H-imide azol-4 -κ arbonitrile 415.2 A: 0.84, 98.26% B: 1.08, 98.91% IV: 15.06, 98.12% e.i. Ή NMR (400 MHz, DMSO-Je) δ ppm 1.86 (t, J = 9.90 Hz, 1 Η), 2.14 (d, J = 10.76 Hz, 1 Η), 2.23 (s, 3 Η), 2.76 (t, J = 8.07 Hz, 2 H), 2.90 (d, J= 10.52 Hz, 1 H), 2.99 (d, J= 11.00 Hz, 1 H), 3.55 3, 69 (m, 2 Η), 4.08 (d, J = 7.83 Hz, 1 Η), 5.36 (d, J = 3.42 Hz, 2 Η), 7.65 (d, J = 8.07 Hz, 1 H), 7.77 (d, J= 8.07 Hz, 1 H), 7.87 (d, J = 8.31 Hz, 1 H), 8.02 (dd, J = 8.56, 1.96 Hz, 1 Η), 8.47 (d, J = 1.96 Hz, 1 Η), 8.74 (d, J = 1.22 Hz, 1 Η), 8, 91 (d, 7=1.22 Hz, 1 H), (no exchangeable protons were observed). 66-1 0 m.nyuh1 (/?)-4-methy l-5 - (4- ((6 (4-methyl-1 H-imide az ol-1 -yl) pyridin-3 yl) methyl) piperazin- 2- yl)isobenzofuran-1(3N)-one 404.2 F: 6.15, 97.63% G: 6.93, 98.08% V: 6.36, 100% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.84 (t, J = 9.90 Hz, 1 N), 2.17 (s, 4 N), 2.33 (d, J = 1.71 Hz, 3 N), 2.71-2, 81 (br, 2H), 2.86 - 2.93 (br, 1H), 2.99 (d, J = 11.25 Hz, 1H), 3.51 -3.62 (br, 2H) , 4.07 (d, J = 9.54 Hz, 1 H), 5.36 (s, 2 H), 7.62 - 7.66 (br, 2 H), 7.70 (d, J = 8.31 Hz, 1 N), 7.77 (d, J= 8.07 Hz, 1 N), 7.90 (dd, J= 8.19, 2.08 Hz, 1 N), 8.33 - 8.50 (w, 2 H), (no exchangeable protons were observed). 67-1 About • ^ny S% Xu. (/?)-4-methy l-5 -(4-((6(3-methyl-1Н-1,2,4-tr iazol-1- yl) pyridin-3 yl) methyl) piperazine- 2- yl)isobenzofuran-1(3N)-one 405.1 A: 1.01, 100% B: 1.25, 99.51% V: 6.16, 96.66% e.i. Ή NMR (400 MHz, DMSO-d ₆ ) δ 1.75-1.92 (m, 1 Η), 2.08-2.18 (m, 1 Η), 2.22 (s, 3 Η), 2.38 (s, 3 Η), 2.64-2.82 (m, 2 Η), 2.91 (d, J = 11.74 Hz, 1 Η), 2.96-3.05 (m , 1 Η), 3.48-3.71 (m, 2 Η), 4.08 (d, J = 7.83 Hz, 1 Η), 5.36 (s, 2 Η), 7.64 ( d, J = 8.07 Hz, 1 H), 7.78 (dd, J = 8.19, 3.30 Hz, 2 H), 7.99 (dd, J = 8.31, 1.96 Hz , 1 Η), 8.41 (d, J = 2.20 Hz, 1 Η), 9.19 (s, 1 Η), (no exchangeable protons were observed).

- 92 043056

68-1 0 s/ (7/)-6-(4-((4-acetyl-3-(4-methyl-1-oxo-1,3dihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)-1 H-pyrazo l- 1- yl)-4-methylnicotino nitrile 471.1 A: 1.16, 100% B: 1.77, 100% X: 9.45, 100% e.i. Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 2.05 (d, J= 13.69 Hz, 3 Η), 2.13 - 2.31 (m, 4 Η), 2.40 (br. s., 1 H), 2.57 (s, 3 H), 2.91 - 3.15 (m, 2 H), 3.46 - 3.66 (m, 3 H), 3.72 (br. s., 1 H), 5.15 - 5 .42 (m, 2 H), 5.72 (br. s., 1 H), 7.68 (d, J= 8.07 Hz, 1 H), 7.81 (br. s., 1 H ), 7.96(s, 1H), 8.06-8.51(m, 2H), 8.78(s, 1H). ΝχΡ ^Me A Y>'Ν ρΧ ^Μ θ CN 69-1 O (/ XI ϊΝ Ό P (7/)-4-methyl-6-(4-((3 (4-methyl-1-oxo-1,3 dihydroisobenzofur an-5- yl) -4- (methyl su l f he yl) piperazin-1yl) methyl) -1 H-pyrazo L-1 - 507.0 A: 1.27, 100% B: 1.85, 100% XIX: 11.31, 87.54% e.i. Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 2.07 (s, 1 H), 2.28 (s, 3 H), 2.45 (dd, J= 11.37, 5.75 Hz, 1 H), 2.55 - 2.69 (m , 3 H), 2.73-2.84 (m, 4 H), 2.90 (d, J = 10.76 Hz, 1H), 3.44-3.51 (m, 1H), 3, 53 - 3.65 (m, 3 H), 5.15 (t, J= 3.67 Hz, 1 H), 5.25 - 5.34 (m, 1 H), 5.37 - 5.47 (m, 1 H), 7.71 (d, J = 8.07 Hz, 1 H), 7.76 (s, 1 H), yl) nicotinonitrile 7.95 (s, 1 H), 8.15 (d, J = 8.07 Hz, 1 H), 8.40 (s, 1 H), 8.79 (s, 1 H). (7/)-4-methyl-6-(4-((4- Ή NMR (400 MHz, DMSOP ₆ ) δ ppm 70-1 ABOUT Q XI me-M Χ^ ^ν X- methyl-3-(4-methyl-1-o xo-1,3-dihydroisobenzofuran-5yl)piperazin-1yl)methyl)-1H-pyrazol-1yl)nicotinonitrile 443.0 F: 5.36, 95.73% XX: 6.21, 95.67% X: 4.82, 91.28% e.i. 1.88 (br. s., 1 H), 1.94 (s, 3 H), 2.26 (br. s., 4 H), 2.30 - 2.35 (m, 1 H), 2.57 (s, 3 H), 2.71 (d, J= 10.54 Hz, 1 H), 2.81 2.97 (m, 2 H), 3.41 - 3.47 (m, 1 H), 3.50 (s, 2 H), 5.30 - 5.43 (m, 2 H), 7.65 (s, 2 H), 7.84 (s, 1 H), 7, 98 (s, 1 H), 8.52 (s, 1 H), 8.83 (s, 1 H). (7/)-3 -methyl-5 -(4-((3 - Ή NMR (400 MHz, DMSO-d ₆ ) δ 2.22 (s, O (4-methyl-1-oxo-1,3- 3 H), 2.33-2.44 (m, 1 H), 2.94 (dd, J= 71-1 XX Me 0 ο Χρ* ο-^ο dihydroisobenzofur an-5- yl)-5-oxopiperazine -1- yl)methyl)-1 H-pyrazo l-1- yl)benzo[(1]oxazol-2 (3N)-one 474.0 A: 1.09, 97.66% B: 1.32, 94.12% IV: 6.81, 100% ee 11.98, 4.40Hz, 1H), 3.14(s, 2H), 3.39(s, 3H), 3.47-3.63(m, 2H), 4.95 (br. s., 1 H), 5.29 (s, 1 H), 5.36-5.45 (m, 1 H), 7.39 (d, J= 8.80 Hz, 1 H) , 7.44-7.52(m, 1H), 7.54-7.63(m, 2H), 7.67-7.77(m, 2H), 8.16(s, 1 H), 8.21(s, 1H).

- 93 043056

72-1 0 ΜθQ %' (R)-3 -methyl-5 -(4-((3 (4-methyl-1 -oxo-1,3 dihydroisobenzofur an-5- yl)-5-oxopiperazine -1- yl)methyl)-1 Η-1,2,3 -t riazole-1- yl)benzo[d]ocazol-2 (ZN)-one 475.0 A: 1.21, 97.22% B: 1.12, 100% V: 13.58, 88% e.i. Ή NMR (400 MHz, DMSO-d ₆ ) δ 2.25 (s, 3N), 2.43 (dd, J= 11.74, 6.60 Hz, 1 Η), 3.04 (dd, J= 12.10, 4.77 Hz, 1 Η), 3.21 (s, 2 Η), 3.40 (s, 3 Η), 3.78 (s, 2 Η), 4.96 (br. s ., 1 Η), 5.23-5.42 (m, 2 Η), 7.46-7.59 (m, 3 Η), 7.72 (d, J= 8.07 Hz, 1H), 7.82 (d, J= 1.96 Hz, 1H), 8.17 (s, 1H), 8.45 (s, 1H). 73-1 0 ^MeH V ^N'N 0 A (R)-1-(5-((3 -(4-methyl -1 -oxo-1,3 -d ihydroisobenzofuran-5yl) -5-oxopiperazine -1- yl)methyl)pyridin-2yl)-1H-1,2,4-triazole -3-carbonitrile 430.1 A: 1.35, 100% B: 1.43, 100% XIV: 8.05 91.59% e.i. Ή NMR (400 MHz, DMSO-L) δ ppm 2.22 (s, 3 Η), 3.01 (d, J = 9.78 Hz, 1 Η), 3.11 - 3.25 (m, 3 Η), 3.76 (br. s., 2 H), 4.98 (br. s., 1 H), 5.38 (q, J = 15.65 Hz, 2 H), 7.58 (d, J = 7.83 Hz, 1 H) , 7.74 (d, J = 8.07 Hz, 1 H), 7.83 - 7.90 (m, 1 H), 7.91 - 7.97 (m, 1 H), 8.25 ( s, 1 H), 8.42 (s, 1 H), 9.69 (s, 1 H). 74-1 O Me NY^ °L> (7?)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofur n-5- yl)-5-oxopiperazine -1- yl)methyl)-[2,2'-bipyridine]-5-carbonitr l 470.1 A: 1.32, 94.19% B: 1.51, 94.93% XVIII: 14.74, 95.27% e.i. Ή NMR (400 MHz, DMSOA) δ ppm 2.17 (s, 3 Η), 2.41 - 2.45 (m, 1 Η), 2.91 2.94 (m, 1 Η), 3.16 (q, J = 16.30 Hz, 2 Η), 3.57 - 3.76 (m, 2 Η), 4.13 (s, 3 Η), 4.96 (br. s., 1 H), 5.20 - 5.31 (m , 1 H), 5.33 - 5.43 (m, 1 H), 7.58 (d, J= 8.07 Hz, 1 H), 7.70 - 7.80 (m, 2 H), 8.11 (s, 1 H), 8.22 (s, 1 H), 8.31 (d, J = 8.07 Hz, 1 H), 8.46 (s, 1 H), 8.91 (s, 1H). 75-1 o Me HN A LA N G ^N V" (//)-6-(4-methy l-1 -oke o-1,3 -dihydroisobenzofuran-5- yl)-4-((6-(3-methyl-1 H-1,2,4-triazol-1yl)pyridin-3 yl)methyl)piperazin2-one 419.1 A: 1.06, 100% B: 1.18, 100% XIV: 7.21, 94.14% e.i. Ή NMR (400 MHz, DMSOA) δ ppm 2.20 (s, 3 H), 2.38 (s, 3 H), 2.41-2.44 (m, 1H), 2.93-2.96 (m, 1 H), 3.05 - 3.19 (m, 2 H), 3.65 (s, 2 H), 4.96 (br. s., 1 H), 5.29 - 5.46 (m, 2 H), 7, 58 (d, J= 8.07 Hz, 1 H), 7.72 (dd, J= 15.77, 8.19 Hz, 2 H), 7.82 (dd, J= 8.44, 2, 08 Hz, 1 H), 8.21 (s, 1 H), 8.30 (d, J = 1.96 Hz, 1 H), 9.17 (s, 1 H).

- 94 043056

76-1 O 0W (/?)-6-(4-methy l-1-oke 0-1,3-dihydroisobenzofuran-5yl)-4-((6-(4-methyl-1 H-imidazol-1 yl)pyridine- 3 yl)methyl)piperazin2-one 418.0 A: 0.90, 100% B: 1.21, 100% IV: 13.83, 94.47% e.i. Ή NMR (400 MHz, DMSO-Z) δ ppm 2.16 (s, 3 Η), 2.20 (s, 3 Η), 2.44 (dd, J = 11.86, 6.48 Hz, 1 Η), 2.93 (dd, J= 11 .74, 4.40 Hz, 1 Η), 3.03 - 3.19 (m, 2 Η), 3.62 (s, 2 Η) 4.95 (br. s., 1 H), 5, 37 (q, J = 15.65 Hz, 2 H), 7.57 (d, J = 8.07 Hz, 1 H), 7.60 - 7.66 (m, 2 H), 7.67 - 7.76(m, 2H), 8.20(s, 1H), 8.25(s, 1H), 8.37(s, 1H). 77-1 0 ⁰ -b- CN (7?)-4-methyl-6-(4-((4methyl-3 -(4-methyl-1-o xo-1,3-dihydroisobenzofuran-5yl)-5-oxopiperazine -1- yl)methyl)-1 H-pyrazo l-1- yl) nicotinonitrile 457.2 A: 1.15, 97.87% B: 1.39, 99.90% XI: 9.28, 100% e.i. Ή NMR (400 MHz, DMSO-r/b) δ ppm 2.23 (s, 3 Η), 2.56 (s, 3 Η), 2.65 (s, 4 Η), 2.67 - 2.69 (m, 1 Η), 2.86 - 2, 90 (m, 1 Η), 3.07 - 3.12 (m, 1 Η), 3.31 - 3.57 (m, 2 Η), 4.97 (t, J= 4.0 Hz, 1 Η), 5.25 - 5.29 (m, 1 Η), 5.39 - 5.43 (m, 1 Η), 7.35 (d, J = 8.0 Hz, 1 Η), 7, 60 (s, 1 Η), 7.76 (d, J = 8.0 Hz, 1 Η), 7.93 (s, 1 Η), 8.09 (s, 1 Η), 8.72 (s , 1 H). 78-1 0 Me % _N 0 b\ ^N ^b° ^Me CN (7?)-4-methoxy-6-(4-((5 -(4-methyl-1 -oxo-1, 3-dihydroisobenzene uranium-5 - yl)-2-oxooxazol id in-3- yl)methyl)-1 H-imide a zol-1- yl) nicotinonitrile 446.0 A: 1.45, 95.92% B: 1.31, 95.39% III: 18.26, 91.42% e.i. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.24 (s, 3 Η), 3.33 - 3.38 (m, 1 Η), 4.11 (s, 3 Η), 4.10 - 4.14 (m, 2 Η), 4, 31 - 4.35 (m, 1 Η), 5.41 (d, J = 7.03 Hz, 2 Η), 5.94 - 6.01 (m, 1 Η), 7.57 (d, J = 8.01 Hz, 1 Η), 7.60 (s, 1 Η), 7.75 (d, J= 7.95 Hz, 1 Η), 8.04 (s, 1 Η), 8.64 (s, 1 Η), 8.75 (s, 1 Η). 79-1 80-1 0 °Cy.^, ^w b Μθ CN 0 °bCL /x ^'^tbhhhk ¹ " Μ y ⁰ b* οΑθ (7?) -6- (5-methoxy-4- (( 5 - (4-methyl-1 -oxo-1, 3-dihydroisobenzene uranium-5 - yl)-2-oxooxazol id in-3- yl)methyl)-1 H-pyrazo l-1- yl)-4-methylnicotino nitrile (7?)-3-methyl-5-(4-((5(4-methyl-1-oxo-1,3 dihydroisobenzofur an-5- yl)-2-oxooxazol id in-3- yl)methyl)-1 H-pyrazo l-1- yl)benzo[c1]oxazol-2 (3N)-one 460.1 461.1 A: 2.19, 100% B: 2.19, 100% XVIII: 9.18, 100% e.i. A: 1.50, 98.39% B: 1.48 98.56% V: 13.40, 97.89% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 2.22 (s, 3 Η), 2.55 (s, 3 Η), 3.23-3.28 (m, 1 Η), 3.95 (s, 3 Η), 4.04-4, 08 (m, 1 Η), 4.28 (d, J= 6.85 Hz, 2 Η), 5.40 (d, J = 7.58 Hz, 2 Η), 5.92 - 5.98 ( m, 1 Η), 7.55 (d, J = 8.0 Hz, 1 Η), 7.73 - 7.78 (m, 2 Η), 8.50 (s, 1 Η), 8.76 (s, 1 H). Ή NMR (400 MHz, DMSO-Z) δ ppm 2.23, (s, 3 N), 3.39 (s, 3 N), 4.05 - 4.12 (m, 2 N), 4.38 (d, J = 19.56 Hz, 2 N ), 5.40 (d, J = 7.58 Hz, 2 H), 5.92 - 6.01 (m, 1 H), 7.43 (s, 1 H), 7.51 - 7.59 (m, 2 H), 7.69-7.79 (t, 3 H), 8.48 (s, 1 H).

- 95 043056

Example 81-I: 6-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl)methyl )-1 H-pyrazol-1 -yl)-4-methylnicotinonitrile

The compound of Example 81-I was obtained (0.130 g, 30.10%) as an off-white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 38-I (0. 35 g, 1.32 mmol) and intermediate 6 (0.20 g, 0.94 mmol). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.73 (dt, J=15.90, 10.15 Hz, 2H), 2.26 (s, 3H), 2.57 (s, 3H), 2.82 (d, J=10.03 Hz , 1H), 2.88 - 3.02 (m, 2H), 3.37 - 3.43 (m, 2H), 3.53 (s, 2H), 4.17 (d, J=8.07 Hz, 1H), 4.61 (br. s., 1H), 5.37 (s, 2H), 7.64 (d, J=8.07 Hz, 1H), 7.78 (d, J= 8.07 Hz, 1H), 7.84 (s, 1H), 7.98 (s, 1H), 8.51 (s, 1H), 8.82 (s, 1H), (not observed 1 capable of proton exchange). HPLC (Method U): retention time 4.78 min, purity: 99.33%, (Method-T): retention time 4.90 min, purity: 98.18%, LCMS (Method-D): retention time 1, 66 min, [M+H] 459.2. Chiral purity (method XIX): retention time 11.50 min, 100% e.i.

Example 82-I: 6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-2H-1, 2,3-triazol-2-yl)-4-methylnicotinonitrile

The compound of Example 82-I was obtained (0.25 g, 46.60%) as an off-white solid using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 40-I ( 0.30 g, 0.117 mmol) and Intermediate 28 (0.25 g, 0.117 mmol).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 1.07 (s, 3H), 1.32 (s, 3H), 1.83 (t, J=10.1 Hz, 1H), 1.92 ( d, J=10.3 Hz, 1H), 2.06 (br. s., 1H), 2.29 (s, 3H), 2.57 (d, J=10.0 Hz, 1H), 2 .62 (s, 3H), 2.88 (d, J=8.6 Hz, 1H), 3.79 - 3.70 (m, 2H), 4.41 (d, J=8.8 Hz, 1H), 5.39 (s, 2H), 7.66 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 8.21(s, 1H), 8.94(s, 1H). HPLC (Method-U): retention time 4.84 min, purity: 96.03%, (Method-T): retention time 6.27 min, purity: 97.15%, LCMS (Method-D): retention time 2.15 min, [M+H] 458.4. Chiral purity (Method-XV): retention time 4.60 min, 100% e.i. SOR: [a] ²⁵ D=-30.00(c 0.l, DMSO).

Example 83-I: 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazine-1- yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

The compound of Example 83-I was prepared (0.045 g, 20.41%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 51-I (0.12 g, 0. 49 mmol) and Intermediate 28 (0.102 g, 0.49 mmol). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02 (d, J=5.9 Hz, 3H), 1.80 (br. s., 2H), 2.27 (s, 3H), 2.64 (s, 3H), 2.84 ( br. s., 2H), 2.96 (br. s., 1H), 3.75 (s, 2H), 4.15 (br. s., 1H), 5.45 - 5.30 (m , 2H), 7.64 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.20 (s , 1H), 8.92 (s, 1H), (1 exchangeable proton was not observed). HPLC (Method-U): retention time 6.50 min, purity: 97.70%. (method-T): retention time

- 96 043056

7.53 min, purity: 98.10%. LCMS (Method-J): retention time 1.86 min, [M+H] 444.2, purity:

99.60%. Chiral purity (Method-XIV): retention time 7.27 min, 100% e.i.

Example 84-I: 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl )-1 H-1,2,3-triazol-1 -yl)-4-methylnicotinonitrile

The compound of Example 84-I was prepared (0.02 g, 20.68%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 52-I (0.05 g, 0.49 mmol) and Intermediate 30 (0.04 g, 0.49 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.62 (d, J=6.8 Hz, 1H), 1.92 (d, J=10.5 Hz, 1H), 2.18-2.06 (m, 1H), 2.25 (s , 4H), 2.67 - 2.60 (m, 3H), 2.80 (d, J=10.0 Hz, 1H), 2.94 (br. s., 1H), 3.07(br s., 1H), 3.75 (br. s., 3H), 4.56 (d, J=5.1 Hz, 1H), 5.46-5.26 (m, 2H), 7, 53 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1 H), 8.28 (s, 1H), 8.77 (s, 1H), 8 .98 (s, 1H). LCMS/HPLC (Method-R): retention time 0.89 min, [M+H] 445.2, purity: 95.00%, (Method-S): retention time 1.20 min, [M+H] 445.2, purity: 100%. Chiral purity (Method XVIII): retention time 14.30 min, 98.40% e.i.

Compounds according to the examples listed in table. 2 were synthesized according to the procedures described in examples 1-I - 24-I and 81-I - 84-I

Example Structure Name LCMS (M+N) ⁺ hhm/lhm With Method: RT (min.), Purity NMR 85-1 86-1 o .......Cn^Vn Me HN^ Nn nH _Me Μθ~0Ν O °e Μθ κτΛ H>-OMe Μθ^CN 2,4-dimethyl-6-(4(((35,5R)-3 -methyl5 -(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-2H1,2,3-triazole -2yl)nicotinonitrile l 4-Methoxy-2methyl-6-(4(((35,5R)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1H1,2,3-triazole -1yl)nicotinonitrile l 458.3 474.3 S: 1.50, 96.42% R: 1.15, 96.95% V: 7.33, 98.50% e.i. S: 1.50, 94.55% R: 1.49, 99.47% XVIII: 13.27, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 5.9 Hz, 3 Η), 1.84 (br. s., 2 Η), 2.24 - 2.31 (m, 3 Η), 2.60 (s, 3 Η), 2.69 - 2.74 (m, 3 Η), 2.77 - 2.88 (m, 2 Η), 3.00 (br. s. , 1 H), 3.77 (s, 2 H), 4.20 (br. s., 1 H), 5.31-5.46 (m, 2 H), 7.67 (d, J= 7.6 Hz, 1 H), 7.80 (d, J= 8.1 Hz, 1 H), 7.94 (s, 1 H), 8.19 (s, 1 H), (not observed 1 capable of proton exchange). Ή NMR (400 MHz, DMSO-d6) δ 1.20 1.34 (m, 3 Η), 2.37 (s, 4 Η), 2.68 (s, 3 Η), 3.18 (s, 2 Η), 3.94 - 3.99 (m, 2 Η), 4.15 (s, 3 Η), 4.78 (br. s., 1 Η), 5.37 - 5.56 (m, 2 H), 7.75 (s, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.88 (d, J= 7.8 Hz, 1 H), 8, 50 (s, 1 Η), 8.86 (s, 1 Η), 9.44 (s, 1 H), (1 exchangeable proton was not observed).

- 97 043056

87-ΠΙ 88-ΠΙ 0 _{ν χ} ^Μ θ ΗΝ^^ζ| ^Ν ™ C>Me CN Ο Λη ΤΎ^Ν-^% ^Me HN_J V ™ ^N ^Me 6-(4-((3(hydroxymethyl)5 -(4-methyl-1-oxo- 1,zdihydroisobenzoph uran-5yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)-4- methylnicotinoni tril, (Enantiomer-III) 6-(4-((3(hydroxymethyl)5 -(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1H1,2,3-triazol- 1- silt) -4- methylnicotinoni tril, (Enantiomer-III) 459.3 460.2 S: 1.39, 100% R: 1.15, 100% XXIV: 5.80, 100% e.i. S: 1.28, 100% R: 1.09, 97.86% XIX: 7.63, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.98 2.14 (m, 1 Η), 2.27 (s, 3 Η), 2.41 (d, J= 10.3 Hz, 1 Η), 2.58 (s, 3 H), 2.65 (d, J= 9.3 Hz, 1 H), 2.73 (d, J= 7.1 Hz, 1 H), 2.92 (d, J = 15.7 Hz, 1 Η), 3.46 - 3.58 (m, 3 Η), 3.76 (br. s., 1 Η), 4.40 (d, J= 5.6 Hz , 1 H), 4.58 (br. s., 1 H), 5.29 - 5.45 (m, 2 H), 7.65 (d, J = 8.1 Hz, 1 H), 7 .87 (s, 1 H), 7.93 - 8.05 (m, 2 H), 8.53 (s, 1 H), 8.84 (s, 1 H), (1 exchangeable proton). Ή NMR (400 MHz, DMSO-d6) δ 2.02 2.17 (m, 1 Η), 2.27 (s, 3 Η), 2.45 (br. s., 1 Η), 2.63 - 2.69 (m, 4 H), 2.79 (d, J= 9.8 Hz, 1 H), 2.91 (d, J= 12.5 Hz, 1 H), 3.53 (br. s., 1 H), 3.74 (s, 3 H), 4.40 (br. s., 1 H), 4.59 (br. s., 1 H), 5.38 (d, J = 2.4 Hz, 2 H), 7.64 (d, J= 8.3 Hz, 1 H), 7.96 (d, J= 7.8 Hz, 1 H), 8.30 (s, 1 H), 8.79 (s, 1 H), 9.01 (s, 1 H), (1 exchangeable proton was not observed). 89-ΙΠ 0 Υ Me HNy) C _N ° ^HN ^~0Me 6-(4-((3(hydroxymethyl)5 -(4-methyl-1-oxo- 1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1Hpyrazol-1-yl)-4methoxynicotino nitrile, (Enantiomer-III) 475.3 S: 1.34, 96.27% R: 1.11, 97.98% VI: 17.65, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.99 2.11 (m, 2 Η), 2.21 - 2.31 (m, 3 Η), 2.40 (dd, J= 11.1, 3 .8 Hz, 1H), 2.64 (d, 7= 8.1 Hz, 1 Η), 2.73 (d, J= 7.6 Hz, 1 Η), 2.90 - 2.96 (m , 1 Η), 3.51 (s, 3 Η), 3.75 (d, J= 8.3 Hz, 1 Η), 4.11 (s, 3 Η), 4.36 - 4.43 ( m, 1 H), 4.57 (br. s., 1 H), 5.32-5.42 (m, 2 H), 7.61 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.88 (s, 1 H), 7.97 (d, J= 8.1 Hz, 1 H), 8.53 (s, 1 H), 8.74 (s, 1H). 90-1 ABOUT bOL Y°H b~Me CN 6-(4-((3(hydroxymethyld2)-5 -(4-methyl-1 oxo-1,3dihydroisobenzene uran-5yl)piperazin-1yl)methyl)-111pyrazol-1-yl)-4- methylnicotinoni tril, (Enantiomer-1) 461.3 S: 1.33, 100% R: 1.05, 99.36% XVIII: 14.17, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.73 (br. s., 2 H), 1.92 (s, 1 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 2.83 (d, J= 10.3 Hz, 1 H), 2.88 - 3.03 (m, 2 H), 3.54 (br. s., 2H), 4.18 ( d,J = 10.0 Hz, 1 H), 4.60 (br. s., 1 H), 5.30 - 5.49 (m, 2 H), 7.66 (d, J= 8, 1 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.53 (s, 1 H), 8.84 (s, 1 H).

- 98 043056

91-1 ooo-. T r^N^rf^ Me we J UD ^ΗΝ γ ^k N ^X N^_ _CN ⁴ OH Me l-(5-(((3A,5A)-3(hydroxymethyl)5 -(4-methyl-1-oxo1,zdihydroisobenzoph uran-5yl)piperazin-1yl)methyl)pyridin-2-yl)-3-methyl1Н- pyrazole-4carbonitrile 460.3 S: 1.13, 100% R: 0.96, 100% XV: 5.55, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.80 (d, J = 10.3 Hz, 2 Η), 2.26 (s, 3 Η), 2.42 (s, 3 Η), 2.81 (d, J = 9.0 Hz, 1 Η), 2.92 (d, J= 11.5 Hz, 2 Η), 3.37 (br. s„ 2 Η), 3.65 (s, 2 Η), 4.21 (br. s., 1 H), 4.65 (br. s., 1 H), 5.30 5.47 (m, 2 H), 7.67 (d, J= 7.8 Hz, 1 H), 7.80 (d, J= 8.3 Hz, 1 H), 8.84 (s, 2 H), 9.36 (s, 1 H), (not observed 2 capable of exchanging protons). 92-1 0 Me Μθ(ΐΝ 6-(4-(((37?,47?)-4hydroxy-3-(4methyl-1-oxo-1,3dihydroisobenzoph uran-5yl)piperidin-1 yl)methyl)-1Hpyrazol-1-yl)-2, 4dimethylnicotino nitrile 458.2 S: 1.47, 99.34% R:l,06, 100% XXI: 3.85, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.54 - 1.70 (w, 1 H), 1.93 (d, J = 9.78 Hz, 1 H), 1.98 - 2.10 (w, 1 H), 2.18 (t , J = 10.76 Hz, 1 H), 2.24 (s, 3 H), 2.54 (s, 3 H), 2.66 (s, 3 H), 2.73 (d, J= 10.03 Hz, 1 N), 2.92 (d, J= 12.23 Hz, 1 N), 3.01 - 3.12 (br, 1 N), 3.43 3.57 (br, 2 H), 3.72 (br. s., 1 H), 4.56 (br. s., 1 H), 5.26-5.44 (m, 2 H), 7.52 (d, J = 8.07 Hz, 1 H), 7.59 - 7.67 (m, 1 H), 7.82 (s, 2 H), 8.49 (s, 1 H). 93-1 94-1 O zM z ΧΎ ίΤ Λ 0 ^Z Y Φ \ Q..... ^E O ⁴ $ 2-methoxy-6-(4(((35,5R)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1Hpyrazol-1yl)nicotinonitri l 5-((25.65)-4-((2(4,5-dimethyl-1nimidazol-1yl)pyrimidin-5 yl)methyl)-6methylpiperazin2-yl)-4methylisobenzofur an-1(3H)-one 459.2 433.3 S: 1.60, 95.30% R: 1.12, 95.10% S: 1.44, 100% R: 0.77, 98.00% XXI: 6.06 96.51% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.05 (d, J= 5.1 Hz, 3 Η), 1.76 (br. s., 2 Η), 2.31 - 2.19 (m, 3 Η), 2.83 (d, J= 9.5 Hz, 2 H), 3.00 (br. s., 1 H), 3.52 (s, 2 H), 4.13 - 3.99 (m, 4 H), 4, 17 (d, J= 9.3 Hz, 1 H), 5.49 5.26 (m, 2 H), 7.56 (d, J= 8.3 Hz, 1 H), 7.64 - 7 .66 (d, J= 8 Hz, 1H), 7.80 (d, J= 7.8 Hz, 1H), 7.86 (s, 1H), 8.35 (d, J= 8.3 Hz, 1H), 8.59(s, 1H). Ή NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 6.1 Hz, 3 Η), 1.81 (d, J = 10.3 Hz, 2 Η), 2.11 (s , 3 Η), 2.31 - 2.20 (m, 3 Η), 2.46 (s, 3 Η), 2.80 (br. s., 3 H), 3.61 (s, 2 H ), 4.20 (d, J = 5.1 Hz, 1 H), 5.52 - 5.30 (m, 2 H), 7.67 (d, Y=7.8 Hz, 1H), 7, 81 (d, J = 8.l Hz, 1 H), 8.31 (s, 1 H), 8.77 (s, 2 H), (1 exchangeable proton was not observed).

- 99 043056

95-1 φ \—/ Q 4,6-dimethyl-2-(4(((35,5R)-3 -methyl5 -(4-methyl-1-oxo1,zdihydroisobenzoph uran-5yl)piperazin-1 yl)methyl)-1nimidazol-1yl)pyrimidin- 5 carbonitrile 458.2 S: 1.36, 100% R: 0.96, 100% XIX: 9.54 92.65% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.23 (d, J = 10.8 Hz, 3 Η), 2.34 (s, 3 Η), 2.70 (s, 6 Η), 3, 09 (br. s., 2 H), 3.69 (br. s., 4 H), 4.63 (br. s., 1 H), 5.55 - 5.33 (m, 2 H) , 7.15 (br.s., 1H), 7.80 (br.s., 2H), 7.89 (br.s., 1H), 8.60 (br.s., 1H ), (1 exchangeable proton was not observed). 96-1 0 °tQ. - hC V ^Me ύ. CN 4-methyl-2-(4(((35.55)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-111pyrazol-1yl)pyrimidine-5carbonitrile 444.3 S: 1.21, 100% B: 0.86, 100% XVIII: 14.76, 97.78% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 4.6 Hz, 3 Η), 1.76 (br. s., 2 Η), 2.26 (s, 3 Η) , 2.69 (s, 3 H), 2.82 (br. s., 2 H), 3.01 (br. s., 1 H), 3.17 (d, J = 4.9 Hz, 1 H), 3.54 (br. s., 2 H), 4.20 (br. s., 1 H), 5.45-5.30 (m, 2 H), 7.66 (d, J= 7.8 Hz, 1 H), 7.78 (d, J= 8.1 Hz, 1 H), 7.88 (s, 1 H), 8.56 (s, 1 H), 9, 18(s, 1H). 97-1 0 ^t'YnV) ^Me hnJ V νΗ_ _0Mθ v? UIVIG CN L 459.3 S: 1.25, 99.45% R: 8.78, 100% Ή NMR (400 MHz, DMSO-d6) δ 1.28 (d, J = 6.4 Hz, 3 Η), 2.36 (s, 3 Η), 2.63 - 2.55 (m, 1 Η ), 2.81 - 2.70 (m, 1 H), 3.30 (d, J= 11.0 Hz, 2 H), 3.66 (br. s., 1 H), 3.92 ( br. s., 3 H), 4.13 (s, 3 H), 4.79 (d, J= 12.2 Hz, 1 H), 5.57 - 5.35 (m, 2 H), 7.66 (s, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 8.14 (s, 1 H), 8.88 - 8.75 (m, 2 H). 98-1 About °cO 4-methyl-6-(4(((35.55)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1nimidazol-1yl)nicotinonitrile 443.3 R: 0.85, 97.18% S: 1.25 98.65% XVIII: 13.30, 95.52% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.04 (d, J = 6.1 Hz, 3 Η), 1.84 (br. s., 2 H), 2.32 - 2.23 (m , 3 H), 2.56 (s, 3 H), 2.90 - 2.78 (m, 2 H), 3.00 (br. s., 1 H), 3.52 (s, 2 H ), 4.18 (br. s., 1 H), 5.50 - 5.26 (m, 2 H), 7.66 (d, J= 8.1 Hz, 1 H), 7.80 ( d, J= 7.8 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.63 - 8.45 (m, 1 H), 8.86 (s, 1 H), (1 exchangeable proton was not observed).

- 100 043056

99-1 x „. - f” ^β Suome CN 4-methoxy-2-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,zdihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1 FIpyrazol-1yl)pyrimidin-5 carbonitrile 460.3 R: 0.92, 96.64% S: 1.27, 98.14% XVIII: 14.63, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.1 Hz, 3 Η), 1.73 (td, J = 10.5, 3.8 Hz, 2 Η), 1, 88 (s, 1 Η), 2.27 (s, 3 Η), 2.80 (d, J = 10.5 Hz, 2 Η), 2.97 (br. s., 1 Η), 3, 52 (s, 2 Η), 4.26 - 4.08 (m, 4 Η), 5.48 - 5.28 (m, 2 Η), 7.65 (d, J = 8.3 Hz, 1 Η), 7.80 (d, J= 8.1 Hz, 1 Η), 7.89 (s, 1 Η), 8.59 (s, 1 Η), 9.07 (s, 1 Η). 100-1 O X -r^Y^N ^Me HN^ N- _N Me nA ^N _v )kMe CN 4-methyl-2-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-2H1,2,3-triazol- 2yl)pyrimidine-5 carbonitrile 445.2 S: 1.14, 94.5% R: 8.87, 97.32% XI: 16.27, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.4 Hz, 3 Η), 1.87 - 1.69 (m, 2 Η), 2.30 2.21 (m , 3 Η), 2.78 - 2.70 (m, 3 Η), 2.82 (d, J= 11.0 Hz, 2 Η), 2.98 (br. s., 1 Η), 3 .78 (s, 2 Η), 4.18 (d, J = 8.1 Hz, 1 Η), 5.45 - 5.27 (m, 2 Η), 7.66 (d, J = 8, 1 Hz, 1 Η), 7.80 (d, J = 8.1 Hz, 1 Η), 8.26 (s, 1 Η), 9.31 (s, 1 Η), (not observed 1 capable of proton exchange). 101-1 ABOUT Me Al \_J+OMe CN 2-methoxy-4-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1nimidazol-1yl)benzonitrile 458.2 S: 1.28, 95.64% R: 0.88, 100% XI: 5.88, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.10 0.93 (m, 4 Η), 1.83 - 1.68 (m, 2 Η), 2.26 (s, 3 Η), 2, 84 (t, J= 8.1 Hz, 2 Η), 3.00 - 2.91 (m, 1 Η), 3.46 (s, 2 Η), 4.08 - 3.95 (m, 3 Η), 4.15 (d, J= 8.6 Hz, 1 Η), 5.37 (s, 2 Η), 7.41 (dd, J= 8.4, 1.8 Hz, 1 Η) , 7.48 (s, 1 Η), 7.65 (d, J = 8.1 Hz, 1 Η), 7.92 - 7.75 (m, 3 Η), 8.40 (s, 1 Η ). 102-1 O °uOi — ¹ HN^ %n Me E L V|/ Me 4-methyl-5(((27/,65)-6-methyl4-((1-(2methylpyridin-4yl)-1 H-pyrazol-4yl)methyl)piperazin-2yl)isobenzofuran -1(ZN)-on 418.2 S: 1.21, 100%. R: 0.63, 100%. XI: 4.31, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ 1.34 1.23 (m, 3 Η), 2.44 - 2.34 (m, 3 Η), 2.59 (br. s., 1 H) , 2.69 - 2.63 (m, 3 H), 3.17 (d, J = 8.1 Hz, 2 H), 3.67 (br. s., 1 H), 3.80 (br s., 2 H), 4.77 (d, J= 10.8 Hz, 2 H), 5.46 (q, J= 15.5 Hz, 2 H), 7.90 - 7.76 ( m, 2 H), 8.05 7.9 l(m, 2 H), 8.09 (s, 1 H), 8.73 (d, J = 6.1 Hz, 1 H), 8.81 (s, 1 H), (1 exchangeable proton was not observed).

- 101 043056

103-1 O Me ιΛΛ bpjPoMe CN 4-Methoxy-2-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,zdihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1nimidazol-1yl)pyrimidin-5 carbonitrile 460.2 S: 1.28, 97.98%. R: 0.90, 97.82%. XVIII: 18.68, 100% e.i. L NMR (400 MHz, DMSO-d6) δ 1.03 (d, J = 6.1 Hz, 3 Η), 1.88 - 1.74 (m, 2 Η), 1.92 (s, 1 Η) , 2.31 - 2.24 (m, 3 Η), 2.85 (t, J = 8.2 Hz, 2 Η), 2.97 (br. s., 1 Η), 3.56 - 3 .48 (m, 2 Η), 4.24 - 4.07 (m, 4 Η), 5.47 - 5.30 (m, 2 Η), 7.66 (d, J = 7.8 Hz, 1 Η), 7.87 - 7.74 (m, 2 Η), 8.62 (d, J= 1.2 Hz, 1 Η), 9.09 (s, 1 Η). 104-1 0 C %N ^{0Н N} ^Me CN 2-(4-(((37/,57/)-3(hydroxymethyl)5 -(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-2H1,2,3-triazol- 2yl)-4methylpyrimidine5-carbonitrile 461.2 S: 0.95, 96.95%. R: 0.82, 100%. DNMR (400 MHz, DMSO-d6) 1.94 - 1.72 (m, 2 Η), 2.28 (s, 3 Η), 2.79 - 2.70 (m, 4 Η), 3.05 - 2.80 (m, 4 Η), 3.45 - 3.35 (m, 1 Η), 3.80 (s, 2 Η), 4.20 (d, J= 7.8 Hz, 1 Η) , 4.64 (t, J = 5.3 Hz, 1 Η), 5.48 - 5.32 (m, 2 Η), 7.66 (d, J = 8.1 Hz, 1 Η), 7 .80 (d, J= 8.1 Hz, 1 Η), 8.26 (s, 1 Η), 9.30 (s, 1 Η). 105-1 0 °bO ₄ ^Me nO%> ^ώβ Pp CN 4-methyl-6-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-111- pyrazol-1yl)nicotinonitrile l 443.3 R: 1.01, 100% S: 1.48, 100% XXV: 6.28, 97.70% e.i. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J= 6.1 Hz, 3 Η), 1.72 (br. s., 2 Η), 2.25 (s, 3 Η), 2.58 (s, 3 Η), 2.79 (d, J= 11.2 Hz, 2 H), 2.96 (br. sn 1 H), 3.52 (s, 2 H), 4.16 (br. s., 1 H ), 5.44 - 5.27 (m, 2 H), 7.64 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.84 (s, 1 H), 7.98 (s, 1 H), 8.51 (s, 1 H), 8.82 (s, 1 H), (1 exchangeable proton not observed). 106-1 O Me ^Me HN^J ^ν ν4 _Μθ CN 4-methyl-6-(4(((35.57/)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-1H1,2,3-triazol- 1yl) nicotinonitrile l 444.3 R: 0.99, 100% S: 1.29, 98.10% XII: 19.17, 98.2% e.i. L NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J= 5.9 Hz, 3 H), 1.80 (br. s., 2 H), 2.27 (s, 3 H), 2.64 (s, 3 H), 2.84 (br. s., 2 H), 2.96 (br. s. 1 H), 3.75 (s. 2 H), 4.15 (br. s. 1 H), 5.45 - 5.30 (m, 2 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 8.28 (s , 1 H), 8.77 (s, 1 H), 8.98 (s, 1 H), (1 exchangeable proton was not observed).

- 102 043056

107-1 108-1 0 to -hQTQ Me 'X-to-ome CN 0 Me N^( Me 4-methoxy-6-(4(((35.55)-3 -methyl5 -(4-methyl-1 -oxo- 1,zdihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-2H1,2,3-triazol-2yl)nicotinonitri l 3-methyl-1-(5(((35.55)-3-methyl5-(4-methyl-1-oxo1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)pyrimide in-2-yl)-1Hpyrazole -4carbonitrile 460.3 444.1 R: 1.02, 95.00% S: 1.30, 94.00% XVIII: 16.50, 100% e.i. R: 1.01, 99.20% S: 1.33, 99.00% XII: 8.83, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J = 4.6 Hz, 3 H), 1.83 (br. s., 2 H), 2.26 (s, 3 H), 2.81 (d, J = 6, 6 Hz, 2 H), 2.97 (br. s „ 1 H), 3.77 (br. s „ 2 H), 4.23 - 4.07 (m, 4 H), 5.50 - 5 .28 (m, 2 H), 7.72 - 7.49 (m, 2 H), 7.79 (d, J = 7.6 Hz, 1 H), 8.22 (s, 1 H), 8.82 (s, 1 H), (1 exchangeable proton not observed). Ή NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J = 6.1 Hz, 3 Η), 1.91 - 1.67 (m, 2 Η), 2.25 (s, 3 Η), 2.42 (s, 3 Η) , 2.79 (t, J = 9.3 Hz, 2 Η), 2.99 (br. s., 1 H), 3.63 (s, 2 H), 4.17 (d, J = 8 .8 Hz, 1 H), 5.50 - 5.24 (m, 2 H), 7.66 (d, 7= 8.1 Hz, 1H), 7.81 (d, 7=7.8 Hz , 1 H), 8.83 (s, 2 H), 9.35 (s, 1 H), (1 exchangeable proton was not observed). 109-1 0 Nh <% _n ™' 5-(4-(((35.55)-3(hydroxymethyl)5 -(4-methyl-1-oxo- 1,3dihydroisobenzoph uran-5yl)piperazin-1yl)methyl)-2H1,2,3-triazol-2yl)-3methylbenzo[c1]oxazol-2(3H)-one 491.2 R: 1.26, 100% S: 1.05, 95.00% XXVI: 3.72, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.93 - 1.74 (m, 2 Η), 2.28 (s, 3 Η), 2.74 (s, 2 Η), 3.03 - 2.80 (m, 2 Η), 3, 37 (br.s., 2 Η), 3.42 (s, 2 Η), 3.80 - 3.68 (m, 2 Η), 4.20 (d, 7 = 8.1 Hz, 1 Η ), 4.65 (t, 7= 5.5 Hz, 1 Η), 5.46 - 5.33 (m, 2 Η), 7.49 (d, 7= 8.8 Hz, 1 Η), 7.67 (d, 7= 7.8 Hz, 1 Η), 7.75 (dd, 7= 8.9, 2.1 Hz, 1 Η), 7.81 (d, 7= 8.1 Hz , 1 Η), 7.84 (d, 7 = 2.4 Hz, 1 Η), 8.05 (s, 1 Η), (1 exchangeable proton was not observed). 110-1 O 6-(4-(((35.45)-4hydroxy-3-(4methyl-1-oxo-1,3dihydroisobenzoph uran-5yl)piperidin-1yl)methyl)-1Hpyrazol-1-yl)-4- methylnicotinoni tril 444.2 C: 6.01, 99.30% G: 6.78, 99.30% X: 6.97 99% ee Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.62 (d, 7= 12.47 Hz, 1 N), 1.93 (d, 7= 10.76 Hz, 1 N), 2.04 (t, 7= 11.25 Hz, 1 N) , 2.14 - 2.20 (m, 1 N), 2.25 (s, 3 N), 2.58 (s, 3 N), 2.74 (d, 7= 11.74 Hz, 1 N ), 2.93 (d, 7= 10.03 Hz, 1 H), 3.01 - 3.12 (m, 1 H), 3.49 - 3.56 (br, 2 H), 3.71 (br. s., 1 H), 4.59 (br. s., 1 H), 5.37 (d, 7= 7.34 Hz, 2 H), 7.53 (d, 7= 7, 83 Hz, 1 Η), 7.59 - 7.65 (m, 1 Η), 7.85 (d, J=l.71 Hz, 1 Η), 7.98 (d, 7= 0.73 Hz , 1 Η), 8.52 (s, 1 Η), 8.83 (d,7= 1.96 Hz, 1 Η).

- 103 043056

111-1 ^N O>~OMe CN 6-(4-(((37.47)-4- hydroxy-3-(4methyl-1-oxo-1,3dihydroisobenzoph uran-5yl)piperidin-1 yl)methyl)-2H1,2,3-triazol-2yl)-4- methoxynicotino nitrile 461.1 R: 0.90, 95.30% S: 1.20, 94.00% XVIII: 16.31, 100% e.i. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.70 - 1.54 (m, 1 Η), 1.93 (d, J = 10.3 Hz, 1 Η), 2.16 (t, J = 11.2 Hz, 1 Η), 2, 35 - 2.21(m, 4 Η), 2.75 (d, J = 11.0 Hz, 1 Η), 2.93 (d, J = 11.7 Hz, 1 Η), 3.16 - 3.03 (m, 1 Η), 3.88 3.59 (m, 3 Η), 4.12 (s, 3 Η), 4.61 (d, J= 5.6 Hz, 1 Η), 5.50 - 5.22 (m, 2 Η), 7.54 (d, J = 8.1 Hz, 1 Η), 7.63 (d, 7= 8.1 Hz, 1 Η), 7, 68 (s, 1 Η), 8.22 (s, 1 Η), 8.82 (s, 1 Η). 112-1 ABOUT OME CN 6-(4-(((37.47)-4hydroxy-3-(4methyl-1-oxo-1,3dihydroisobenzoph uran-5yl)piperidin-1yl)methyl)-1Hpyrazol-1-yl)-4- methoxynicotino nitrile 460.2 R: 0.94, 100% S: 1.30, 100% XVIII: 12.2, 99.1% e.i. Ή NMR (400 MHz, DMSO-d6) δ ppm 1.63 (br. s., 1 H), 1.91 (s, 1 H), 2.05 (br. s., 1 H), 2.25 (s, 4 H), 2.75 ( br. s., 1 H), 2.92 (br. s., 1 H), 3.07 (br. s., 1 H), 3.53 (br. s., 2 H), 3, 72 (br. s., 1 H), 4.10 (s, 3 H), 4.57 (br. s., 1 H), 5.45-5.26 (m, 2 H), 7, 54 (br. s., 1 H), 7.72-7.57 (m, 2 H), 7.87 (br. s., 1 H), 8.52 (br. s., 1 H) , 8.74 (s, 1H).

Intermediate 53: 4-methyl-6-(trimethylstannyl)nicotinonitrile

Me

Me

Intermediate 53 was prepared (1.80 g, crude) as a black syrup using a synthetic procedure similar to that of Intermediate 23A starting from 6-bromo-4-methylnicotinonitrile (1.00 g, 5.5 08 mmol). LCMS (method I): retention time 1.40 min, [M+H] 283.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 54-I: 5-((3R,4R)-1-((2-bromothiazol-5-yl)methyl)-4-hydroxypiperidin-3yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 54-I was obtained (0.30 g, 21.77%) as an off-white solid using a synthetic procedure similar to that of Intermediate 23-I, starting from Intermediate 52-I (0. 36 g, 1.30 mmol) and Intermediate 25B (0.25 g, 1.30 mmol). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.56 - 1.58 (m, 1H), 1.89 - 1.90 (m, 1H), 2.10 (br. S., 1H), 2.20 - 2.22 (m, 4H) , 2.80 (br. S., 1H), 2.90 (br. S., 1H), 3.10 (br. S., 1H), 3.80-3.85 (m, 3H), 4.62 (br. S., 1H), 5.25-5.27 (m, 2H), 7.50-7.52 (m, 2H), 7.70 (d, J=8.00 Hz , 1H). LCMS (method I): retention time 1.01 min, [M+H] 423.2.

Intermediate 55-I: 5-((2R,6S)-4-((2-bromothiazol-5-yl)methyl)-6-methylpiperazin-2-yl)4-methylisobenzofuran-1(3H)-one

- 104 043056

Intermediate 55-I was obtained (0.40 g, 60.60%) as an off-white solid using a synthetic procedure similar to that of Intermediate 23-I, starting from Intermediate 51-I (0.38 g, 1.56 mmol) and Intermediate 25B (0.30 g, 1.56 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (s, 3H), 1.80 (br. s, 2H), 2.30 (s, 3H), 2.80 (br. s, 2H), 2.84 (br. s., 1H ), 3.85 (s, 2H), 4.16 (br. s., 1H), 5.37 (br. s., 2H), 7.79 (d, J=8.00 Hz, 1H) , 7.91 - 7.92 (m, 2H), (1 exchangeable proton was not observed). LCMS (Method-I): retention time 1.10 min, [M+H] 422.2.

Intermediate 56: 1-(2-methoxypyridin-4-yl)-1H-imidazole-4-carbaldehyde

Intermediate 56 was obtained (0.20 g, 19.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 11 starting from 1H-imidazole-4-carbaldehyde (0.51 g , 5.32 mmol) and 4-bromo-2-methoxypyridine (1.00 g, 5.32 mmol). ¹ H NMR (400 MHz, DMSO-d ₈ ) δ ppm 3.92 (s, 3H), 7.36 (d, J=1.60 Hz, 1H), 7.48-7.50 (m, 1H), 8.31 (d, J=6.00 Hz , 1H), 8.32 (d, J=1.20 Hz, 1H), 8.71 (d, J=6.00 Hz, 1H), 9.82 (s, 1H). LCMS (Method-D): retention time 1.08 min, [M+H] 204.2.

Intermediate 57: 1-(2-(difluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 57 was obtained (0.12 g, 55.90%) as an off-white solid using a synthetic procedure similar to that of intermediate 11 starting from 1H-pyrazole-4-carbaldehyde (0.11 g , 1.15 mmol) and (4-bromo-2-(difluoromethyl)pyridine (0.20 g, 0.96 mmol). LCMS (method-S): retention time 0.49 min, [M+H] 224 3. The compound was taken directly to the next step without further purification or characterization.

Intermediate 58: 1-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazole4-carbaldehyde

Intermediate 58A: 4-bromo-1-(difluoromethyl)pyridin-2(1H)-one

To a solution of 4-bromo-2-chloropyridine (1.25 g, 6.72 mmol) in ACN (100 ml) was added NaHCO ₃ (8.73 g, 10 mmol) and the resulting reaction mixture was heated at 80°C for 30 min. A solution of 2,2-difluoro2-(fluorosulfonyl)acetic acid (5.38 ml, 52.00 mmol) in MeCN (15 ml) was added over 10 min and the resulting mixture was heated at 80°C for 2 h. The resulting mixture was cooled to ambient temperature, diluted with water (50 ml), alkalized with 10% aq. NaHCO ₃ and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 58A (3.00 g, 25.80%) as a pale yellow liquid. 1H NMR (400 MHz DMSO-d ₆ ) δ ppm 6.6 (dd, J=1.20, 3.20 Hz, 1H), 7.56 (d, J=3.20 Hz, 1H), 7.75 (t, J=5.60 Hz, 1H ), 7.8 (d, J=3.20 Hz, 1H). LCMS (Method-D): retention time 1.64 min [M+H] 224.2.

- 105 043056

Intermediate 58.

Intermediate 58 was obtained (0.10 g, 50.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from 1H-pyrazole-4-carbaldehyde (0.09 g , 0.89 mmol) and Intermediate 58A (0.20 g, 0.90 mmol). LCMS (Method-D): retention time 0.73 min. [M+H] 240.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 59: (2-(5-cyano-4-methylpyridin-2-yl)oxazol-4-yl)methylmethanesulfonate

Intermediate 59A: ethyl 2-(5-cyano-4-methylpyridin-2-yl)oxazole-4-carboxylate

Ethyloxazole-4-carboxylate (1.00 g, 7.09 mmol), Cs ₂ CO ₃ (4 .62 g, 14.17 mmol) and tri-o-tolylphosphine (0.21 g, 0.80 mmol). The resulting reaction mixture was degassed with nitrogen for 20 min. Pd(OAc) ₂ (0.16 g, 0.80 mmol) was added and the resulting mixture was degassed again for 10 min and then heated at 110° C. for 12 h. The resulting mixture was cooled to ambient temperature, filtered through Celite® and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 30% EtOAc/n-hexane) to give Intermediate 59A (0.25 g, 13.71%) as a white solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (t, J=7.0 Hz, 3H), 2.60 (s, 3H), 4.34 (q, J=7.00 Hz, 2H), 8.31 (s, 1H), 9.07(s, 1H), 9.10(s, 1H). LCMS (Method-D): retention time 1.99 min, [M+H] 258.2.

Intermediate 59B: 6-(4-(hydroxymethyl)oxazol-2-yl)-4-methylnicotinonitrile

To a solution of Intermediate 59A (0.13 g, 0.51 mmol) in THF (10 ml) was added DIBAL-H (2.10 ml, 2.53 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h The resulting mixture was diluted with saturated NH ₄ Cl solution (2 ml), water (10 ml) and extracted with 10% MeOH in DCM (2x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 59B (0.06 g, 55.20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65 (s, 3H), 4.49 (br. s., 2H), 5.32 (br. s., 1H), 8.20 (s, 1H), 8.21 (s, 1H) , 9.03 (s, 1H). LCMS (Method D): retention time 0.93 min [M+H] 216.2.

Intermediate 59.

To a solution of Intermediate 59B (0.04 g, 0.19 mmol) in DCM (10 mL) was added TEA (0.08 mL, 0.56 mmol) and mesyl chloride (0.02 mL, 0.24 mmol) at 0 °C and the resulting reaction mixture was stirred at ambient temperature for 30 min. The resulting mixture was diluted with water (5 ml) and extracted with DCM (2x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 60-70% EtOAc/n-hexane) to give Intermediate 59 (0.04 g, 73.40%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.60 (s, 3H), 3.23 (s, 3H), 5.75 (s, 2H), 8.25 (s, 1H), 8.56 (s, 1H), 9.06 (s , 1H). LCMS (Method-D): retention time 1.65 min, [M+H] 294.0.

- 106 043056

Intermediate 60: 6-(5-formyloxazol-2-yl)-4-methylnicotinonitrile O

CN

Intermediate 60A: ethyl 2-(5-cyano-4-methylpyridin-2-yl)oxazole-5-carboxylate O

CN

Intermediate 60A was obtained (0.50 g, 34.30%) as an off-white solid using a synthetic procedure similar to that of intermediate 59A, starting from ethyloxazole-5-carboxylate (0.80 g, 5 .67 mmol) and 6-bromo-4-methylnicotinonitrile (1.11 g, 5.67 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34 (t, J=7.00 Hz, 3H), 2.60 (s, 3H), 4.34 (q, J=7.00 Hz, 2H), 8.26 (s, 1H), 8.30 (s, 1H), 9.10 (s, 1H). LCMS (Method-D): retention time 2.26 min, [M+H] 258.2.

Intermediate 60B: 6-(5-(hydroxymethyl)oxazol-2-yl)-4-methylnicotinonitrile.

To a solution of intermediate 60A (0.10 g, 0.34 mmol) in a mixture of THF (10 ml) and MeOH (2 ml) was added NaBH ₄ (0.05 g, 1.17 mmol) at 0°C and the resulting reaction the mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was diluted with water (20 ml) and extracted with 10% MeOH in DCM (2x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-4 g, 60-70% EtOAc/n-hexane) to give Intermediate 60B (0.04 g, 47.80%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.60 (s, 3H), 5.65 (t, J=5.60 Hz, 1H), 5.85-5.99 (m, 1H), 7.36 (s, 1H), 8.18 (s, 1H), 9.03 (s, 1H), (1 exchangeable proton not observed). LCMS (Method-I): retention time 0.70 min, [M+H] 216.2.

Intermediate 60.

Intermediate 60 was obtained (0.06 g, 87.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 60B (0.07 g, 0.32 mmol) and periodinan DessMartin (0.18 g, 0.43 mmol). LCMS (Method-I): retention time 0.60 min, [M+H] 214.2. The compound was taken directly to the next step without further purification or characterization.

Intermediate 61: 1-(6-(difluoromethyl)pyridin-3-yl)-1H-imidazole-4-carbaldehyde:

Intermediate 61 was obtained (0.03 g, 13.98%) as an off-white solid using a synthetic procedure similar to that of intermediate 6, starting from 4-bromo-2-(difluoromethyl )pyridine (0.20 g, 0.96 mmol) and 1H-imidazole-4carbaldehyde (0.09 g, 0.96 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.00 (t, J=7.20 Hz, 1H), 7.94 - 7.91 (m, 1H), 8.44 - 8.41 (m, 1H), 8.64 (s, 1H) , 9.85 (s, 1H)), 8.80 (d, J=1.60 Hz, 1H), 9.16 (d, J=3.20 Hz, 1H).

LCMS (Method-I): retention time 0.66 min [M+H] 224.0.

Intermediate 62: 4-methyl-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 62 was prepared (0.21 g, 54.10%) using a synthetic procedure similar to that of intermediate 15C, starting from 4methyl-1H-imidazole (0.24 g, 2.89 mmol) and 6-chloro-4-methylnicotinaldehyde (0.30 g, 1.93 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (d, J=0.98 Hz, 3H), 2.69 (s, 3H), 7.75 (d, J=1.22 Hz, 1H), 7.80 (s, 1H), 8.53 (d, J=1.22 Hz, 1H), 8.85 (s, 1H), 10.21 (s, 1H). LCMS (Method-D): retention time 1.20 min, [M+H] 202.2.

Intermediate 63: 2-methyl-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 63 was prepared (0.25 g, 64.40%) using a synthetic procedure similar to that of intermediate 15C, starting from 4methyl-1H-imidazole (0.24 g, 2.89 mmol) and 6-chloro-2-methylnicotinaldehyde (0.30 g, 1.93 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.19 (d, J=0.98 Hz, 3H), 2.69 (s, 3H), 7.75 (d, J=1.22 Hz, 1H), 7.80 (s, 1H), 8.53 (d, J=1.22 Hz, 1H), 8.85 (s, 1H), 10.21 (s, 1H). LCMS (Method-D): retention time 1.20 min, [M+H] 202.2.

Intermediate 64: 5'-formyl-4,6'-dimethoxy-[2,2'-bipyridine]-5-carbonitrile

Intermediate 64A: 6-chloro-2-methoxynicotinaldehyde

Synthesized in accordance with the methods described in the literature (EP 1405859 A1, 2004).

Intermediate 64.

Intermediate 64 was obtained (0.15 g, 39.10%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 23B, starting from intermediate 23A (0.62 g, 2 .09 mmol) and Intermediate 64A (0.30 g, 1.75 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.14 - 4.24 (m, 6H), 8.15 - 8.22 (m, 2H), 8.28 - 8.36 (m, 1H), 8.95 - 9.01 (m, 1H ), 10.27 - 10.35 (m, 1H). LCMS (Method-D): retention time 2.603 min, [M+H] 270.1.

Intermediate 65: 5-fluoro-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 65 was obtained (0.18 g, 59.70%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 11 starting from 4-methyl-1H-imidazole (0. 18 g, 2.20 mmol) and 6-bromo-5-fluoronicotinaldehyde (0.30 g, 1.47 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.18 - 2.24 (m, 3H), 7.63 - 7.72 (m, 1H),

- 108 043056

8.31 - 8.44 (m, 2H), 8.87 - 8.92 (m, 1H), 10.04 - 10.13 (m, 1H). LCMS (method-D): retention time

1.16 min, [M+H] 206.0.

Intermediate 66: 6-(4-formyl-5-methyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 66 was obtained (0.09 g, 14.60%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from 3-methyl-1H-pyrazole-4-carbaldehyde ( 0.40 g, 3.63 mmol) and 6-bromo-4-methylnicotinonitrile (0.54 g, 2.72 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.15 (s, 3H), 2.32 (s, 3H), 7.89-7.94 (m, 1H), 7.97-8.07 (m, 1H), 8.38-8, 46 (m, 1H), 8.75-8.83 (m, 1H). LCMS (Method-O): retention time 1.14 min, [M+H] 227.0.

Intermediate 67: 6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)nicotinaldehyde

Intermediate 67A: (6-chloro-4-(trifluoromethyl)pyridin-3-yl)methanol

To a stirred solution of 6-chloro-4-(trifluoromethyl)nicotinate (2.00 g, 8.35 mmol) in toluene (25 ml) at -78°C was added 1M DIBAL-H in toluene (12.52 ml, 12. 52 mmol) and the resulting mixture was stirred at -78°C for 2 hours, the resulting reaction mixture was diluted with a saturated solution of NH ₄ Cl (40 ml) and was extracted with the addition of ethyl acetate (2x75 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 67A (2.20 g, 87.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.70 (s, 2H), 5.65-5.77 (m, 1H), 7.88 (s, 1H), 8.76 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 67B: 6-chloro-4-(trifluoromethyl)nicotinaldehyde

Intermediate 67B was prepared (0.97 g, 75.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 67A (1.30 g, 6.14 mmol) and Dess periodinan -Martin (2.61 g, 6.14 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 9.11 (s, 1H), 10.24 (q, J=1.71 Hz, 1H). LCMS: Compound poorly ionized.

Intermediate 67.

Intermediate 67 was prepared (0.23 g, 47.20%) using a synthetic procedure similar to that of intermediate 15C, starting from intermediate 67B (0.30 g, 1.43 mmol) and 4- methyl-1H-imidazole (0.17 g, 2.15 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.72 - 3.76 (m, 3H), 6.88 - 6.95 (m, 2H), 7.10 - 7.17 (m, 2H), 7.77 - 7.81 (m, 1H ). LCMS (method-O): retention time 1.05 min, [M+H] 256.4.

Intermediate 68: 2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

- 109 043056

Intermediate 68A: 4,5-dimethyl-1H-imidazole ^H ^ _N

Me

Me

Synthesized according to the procedures described in the literature (Angewandte Chemie, 5322 5326, 49, 2010).

Intermediate 68.

To a solution of 2-bromopyrimidine-5-carbaldehyde (0.20 g, 1.07 mmol) in ACN (20 ml) was added K ₂ CO ₃ (443 mg, 3.21 mmol) followed by the addition of intermediate 68A (0.16 g, 1.60 mmol) and the resulting reaction mixture was stirred at 50°C for 1.5 h. The resulting mixture was cooled to ambient temperature, diluted with ethyl acetate (30 ml) and filtered through Celite®. The filtrate was evaporated under reduced pressure to give intermediate 68 (0.19 g, 86.00%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.13 (d, J=0.49 Hz, 3H), 2.16 (s, 3H), 8.47 (s, 1H), 9.27 (s, 2H), 10.11 (s, 1H ). LCMS: Compound poorly ionized.

Intermediate 69: 4-methoxy-6-(4-methyl-1H-imidazol-1-yl)nicotinaldehyde

Intermediate 69A: methyl 6-chloro-4-methoxynicotinate

Synthesized according to the methods described in the literature (US 2015/166505 A1, 2015).

Intermediate 69B: (6-chloro-4-methoxypyridin-3-yl)methanol

To a stirred solution of intermediate 69A (2.20 g, 10.91 mmol) in DCM (30 mL) was added 1M DIBAL-H in heptane (16.37 mL, 16.37 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 1 h. The resulting reaction mixture was diluted with a saturated solution of NH ₄ Cl (40 ml) and was extracted by adding DCM (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20% EtOAc/n-hexane) to give Intermediate 69B (1.20 g, 63.30%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.88 (s, 3H) 4.46 (dd, J=5.52, 1.00 Hz, 2H), 5.19 (t, J=5.77 Hz, 1H), 7.11 (s, 1H), 8.16(s, 1H). LCMS (Method-I): retention time 0.69 min, [M+H] 174.4.

Intermediate 69C: 6-chloro-4-methoxynicotinaldehyde

Intermediate 69C was prepared (0.75 g, 63.20%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 69B (1.20 g, 6.91 mmol) and Dess periodinan -Martin (2.93 g, 6.91 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.02 (s, 3H), 7.45 (s, 1H), 8.55 (s, 1H), 10.24 (s, 1H). LCMS (Method-D): retention time 1.06 min, [M+H] 172.2.

Intermediate 69.

Intermediate 69 was prepared (0.12 g, 37.80%) using a synthetic procedure similar to that of intermediate 68 starting from intermediate 69C (0.25 g, 1.46 mmol) and 4- methyl-1H-imidazole (0.24 g, 2.91 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 4.09 (s, 3H), 7.49 (s, 1H), 7.81 (s, 1H), 8.56 (d, J=1.00 Hz, 1H ), 8.63 (s, 1H), 10.23 (s, 1H). LCMS (Method-I): retention time 0.89 min, [M+H] 218.3.

- 110 043056

Intermediate 70: 2-(5-(difluoromethyl)-4-methyl-1H-imidazol-1-yl)pyrimidine-5carbaldehyde

Intermediate 70A: tert-Butyl-5-formyl-4-methyl-1H-imidazole-1-carboxylate

About me

N γ N

NO^/ \ Me θΑ'Μβ Me

Intermediate 70A was obtained (2.80 g, 73.30%) as a white solid using a synthetic procedure similar to that of intermediate 18B-P, starting from 4-methyl-1H-imidazole-5- carbaldehyde (2.00 g, 18.16 mmol) and BOC20 (5.06 ml, 21.80 mmol). LCMS (Method-I): retention time 1.07 min, [M-56] 155.9. The compound was carried directly to the next step without further purification or characterization.

Intermediate 70B: tert-butyl-5-(difluoromethyl)-4-methyl-1H-imidazole-1-carboxylate

Intermediate 70B was prepared (0.85 g, 51.30%) using a synthetic procedure similar to that of Intermediate 4B starting from Intermediate 70A (1.50 g, 7.14 mmol) and DAST ( 1.89 ml, 14.27 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.58 (s, 9H), 2.44 (t, J=2.26 Hz, 3H), 6.82-7.18 (m, 1H), 8.19 (s, 1H). The compound is poorly ionized.

Intermediate 70C: 5-(difluoromethyl)-4-methyl-1H-imidazole

Intermediate 70C was prepared (0.48 g, 99.00%) using a synthetic procedure similar to that of Intermediate 4C, starting from Intermediate 70B (0.85 g, 3.66 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.38 (t, J=2.08 Hz, 3H), 7.06 - 7.52 (m, 1H), 9.02 (s, 1H), (1 exchangeable proton not observed). LCMS (method I): retention time 0.58 min, [M+H] 133.4.

Intermediate 70.

Intermediate 70 was prepared (0.10 g, 20.90%) using a synthetic procedure similar to that of intermediate 68 starting from intermediate 70C (0.28 g, 1.68 mmol) and 2- chloropyrimidine-5-carbaldehyde (0.20 g, 1.40 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.69 (t, J=2.32 Hz, 3H), 6.92 - 7.26 (m, 1H), 8.62 (s, 1H), 9.34 (s, 2H), 10.15 (s, 1H). LCMS (Method-D): retention time 1.50 min, [M+H] 239.0.

Intermediate 71-I and 71-II: 4-methyl-5-(3-methylpiperazin-2-yl)isobenzofuran-1(3H)one

- 111 043056

Intermediate 71A: 4-methyl-5-(3-methylpyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 71A was obtained (3.00 g, 65.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 2C, starting from intermediate 2B (5.00 g, 18.24 mmol) and 2-chloro-3methylpyrazine (2.81 g, 21.89 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.03 (s, 3H), 2.32 (s, 3H), 5.49 (s, 2H), 7.51 (d, J=8.03 Hz, 1H), 7.79 (d, J = 7.53 Hz, 1H), 8.56 - 8.64 (m, 2H). LCMS (Method-O): retention time 0.77 min, [M+H] 241.4.

Intermediate 71-I and 71-II.

Intermediate 71-I and 71-II was prepared using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from Intermediate 71A (10.00 g, 41.6 mmol). The racemate was separated into two separate enantiomers by SFC [Chiralpak AD-H (250x4.6 mm), 5 microns; 0.2% NH4OH in MeOH+ACN (1:1), flow: 1.2 ml/min. Temperature: 27°C, UV: 235 nm]. The first eluted compound (retention time 3.37 min), designated Intermediate 71-I, was obtained (0.65 g, 21.13%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.7 (d, J=6.02 Hz, 3H), 2.14-2.22 (m, 2H), 2.29 (s, 3H), 2.74-2.84 (m, 3H), 4.02 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 (d , J=8.03 Hz, 1H), (2 exchangeable protons were not observed). LCMS (Method-O): retention time 0.77 min, [M+H] 241.4. The second eluted compound (retention time 4.79 min), designated Intermediate 71-II, was obtained (1.20 g, 39.00%) as a brown solid. LCMS (Method-O): retention time 0.77 min, [M+H] 241.4. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.70 (d, J=6.02 Hz, 3H), 2.14 - 2.22 (m, 2H), 2.29 (s, 3H), 2.74 - 2.84 (m, 3H) , 4.02 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.81 ( d, J=8.03 Hz, 1H), (2 exchangeable protons were not observed).

intermediate

1(3Н)-one compound 72:

5-(4-Hydroxy-4-methylpiperidin-3-yl)-4-methylisobenzofuran Intermediate

72A:

dihydroisobenzofuran-5-yl)piperidine-1-carboxylate tert-butyl-4-hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-

To a stirred solution of intermediate 4A (1.80 g, 5.21 mmol) in THF (20 ml) was added a 3M solution of methylmagnesium chloride in THF (5.21 ml, 15.63 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with saturated NH4C1 solution (40 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 20-40% EtOAc/n-hexane) to give Intermediate 72A (1.00 g, 53.10%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.94 (s, 3H), 1.39 (s, 9H), 1.59 (br. s., 2H), 1.89 (s, 1H), 2.27 (s, 3H), 2, 88 - 2.96 (m, 1H), 3.52 - 3.65 (m, 1H), 3.79 - 3.94 (m, 1H), 4.61 - 4.72 (m, 1H), 5.40 (s, 2H), 7.61 (d, J=8.03 Hz, 1H), 7.82-7.93 (m, 1H), (1 exchangeable proton not observed). LCMS (Method-D): retention time 2.22 min, [M+H] 362.2.

Intermediate 72.

Intermediate 72 was obtained (0.90 g, 87.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 19-I, starting from Intermediate 72A (1.00 g, 2 .77 mmol) and TFA (4 ml, 51.9 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (s, 3H), 1.71 - 1.84 (m, 1H), 1.87 - 1.96 (m, 1H), 2.28 (s, 3H), 2.96 - 3, 02 (m, 1H), 3.26 (br. s., 2H), 3.37 (br. s., 2H), 5.41 (d, J=5.02 Hz, 2H), 7.66 (d, J=8.03 Hz, 1H),

- 112 043056

7.76 (d, J=8.53 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-O) retention time 0.52 min, [M+H] 262.2.

Intermediate 73-I: 5-(4-hydroxy-5,5-dimethylpiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one hydrochloride (Diastereomer I: Enantiomer-I)

Intermediate 73A: tert-Butyl 3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxo-piperidine-1-carboxylate

Intermediate 73A was obtained (2.30 g, 28.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 4A, starting from intermediate 2A (5.00 g, 22.02 mmol) and tert-butyl 3,3dimethyl-4-oxopiperidine-1-carboxylate (10.01 g, 44.0 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01 1.07 (m, 3H), 1.21 - 1.26 (m, 3H), 1.46 (s, 9H), 2.28 (s, 3H), 2.11 - 2.18 (m, 4H), 4.34-4.44 (m, 1H), 5.35-5.44 (m, 2H), 7.35-7.42 (m, 1H), 7.60-7 .70 (m, 1H). LCMS (Method-O): retention time 1.29 min, [M+H] 374.6.

Intermediate 73B-I and 73B-P: tert-butyl-4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of intermediate 73A (3.50 g, 9.37 mmol) in MeOH (20 ml) was added 2M LiBH ₄ in THF (4.69 ml, 9.37 mmol) and the resulting reaction mixture was stirred at ambient temperature for over 2 hours. The resulting mixture was concentrated to dryness under reduced pressure, diluted with water (50 ml) and extracted with 10% MeOH in DCM (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative HPLC [Sunfire C18 (250x4.6 mm) 5 microns; 10 mM ammonium acetate in water, solvent B: acetonitrile, gradient: 30-100% B over 16 min, flow: 25 ml/min UV: 250 nm] to give diastereomer I and II. Diastereomer I was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak AD-H (250x4.6 mm), 5 microns; 0.2% NH ₄ OH in MeOH, flow: 1.2 ml/min. Temperature: 30°C, UV: 240 nm]. The first eluted compound (retention time 4.17 min), designated as intermediate 73B-I, was obtained (0.75 g, 21.31%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82 - 0.98 (m, 6H), 1.41 (s, 9H), 2.28 (s, 3H), 2.61 - 2.85 (m, 2H), 3.01 - 3, 14 (m, 1H), 3.54 - 3.69 (m, 1H), 3.79 - 3.99 (m, 1H), 4.53 - 4.67 (m, 1H), 5.40 ( s, 2H), 7.59 (s, 1H), 7.66 (s, 1H), (1 exchangeable proton not observed). LCMS (Method-D): retention time 2.69 min, [M-55] 320.2. Chiral purity (Method-XXXII: 4.3 min retention time, 100% ee). %) as an off-white solid ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.82-0.98 (m, 6H), 1.41 (s, 9H), 2.28 (s, 3H), 2.61 - 2.85 (m, 2H), 3.01 - 3.14 (m, 1H), 3.54 - 3.69 (m, 1H), 3.79 - 3 .99 (m, 1H), 4.53 - 4.67 (m, 1H), 5.40 (s, 2H), 7.59 (s, 1H), 7.66 (s, 1H), (not 1 exchangeable proton was observed) LCMS (Method-D): retention time 2.47 min, [M-55] 320.2 Chiral purity (Method-XXXII: retention time 8.43 min, 99.50% e .And.

Intermediate 73-I.

Intermediate 73-I was obtained (0.60 g, 96.00%) as an off-white solid with

- 113 043056 using a synthetic procedure similar to that of intermediate 52-I and starting from intermediate 73B-I (0.75 g, 1.20 mmol) and 4N HCl in dioxane (6 ml, 24.00 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00 (s, 3H), 1.12 (s, 3H), 2.31 (s, 4H), 2.92 3.02 (m, 1H), 3.07 - 3.17 (m, 3H ), 3.42 - 3.49 (m, 1H), 3.70 - 3.80 (m, 1H), 4.81 - 4.91 (m, 1H), 5.36 - 5.45 (m , 2H), 7.61-7.67 (m, 1H), 7.72-7.77 (m, 1H). LCMS (Method-D): retention time 0.53 min, [M+H] 276.2.

Intermediate 74: 2-(4-formyl-2H-1,2,3-triazol-2-yl)-4,6-dimethylpyrimidine-5carbonitrile

Intermediate 74A: 2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4,6-dimethylpyrimidine-5-carbonitrile

Intermediate 74A was prepared (0.80 g, 9.84%) using a synthetic procedure similar to that of intermediate 42 starting from intermediate 28A (3.50 g, 35.30 mmol) and intermediate 42C (7.49 g, 35.30 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.68 - 2.76 (m, 6H), 4.69 (s, 2H), 8.21 (s, 1H), (1 exchangeable proton not observed).

Intermediate 74.

Intermediate 74 was prepared (0.81 g, 86.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 74A (0.95 g, 4.13 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.79 (s, 6H), 8.79 (s, 1H), 10.24 (s, 1H). LCMS (Method-D): retention time 0.706 min, [M+H] 229.0.

Intermediate 75: 5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran5-yl)piperazin-1-yl)methyl)oxazol-2(3H )-He

Intermediate 75A: ethyl 2-oxo-3-trityl-2,3-dihydrooxazole-5-carboxylate

To a stirred solution of ethyl 2-oxo-2,3-dihydrooxazole-5-carboxylate (1.50 g, 9.55 mmol, commercial) in DCM (20 mL) was added TEA (3.99 mL, 28.6 mmol) followed by the addition of trityl chloride (2.66 g, 9.55 mmol) and the resulting mixture was stirred at ambient temperature for 14 h. The resulting mixture was diluted with water (30 ml) and extracted with DCM (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 10-20% EtOAc/n-hexane) to give Intermediate 75A (3.20 g, 84.00%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.22 (t, J=7.10 Hz, 3H), 4.22 (q, J=7.10 Hz, 2H), 7.22-7.42 (m, 15H), 7.50 (s , 1H). LCMS: Compound poorly ionized.

- 114 043056

Intermediate 75B: 5-(hydroxymethyl)-3-trityloxazol-2(3H)-one

Intermediate 75B was obtained (1.70 g, 59.40%) as a white solid using a synthetic procedure similar to that of Intermediate 60B starting from Intermediate 75A (3.20 g, 8.01 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 4.15 (d, J=4.79 Hz, 2H), 5.24 (t, J=5.04 Hz, 1H), 6.63 (s, 1H), 7.18 - 7.44 (m , 15 N). LCMS: Compound poorly ionized.

Intermediate 75C: 2-oxo-3-trityl-2,3-dihydrooxazole-5-carbaldehyde

Intermediate 75C was prepared (1.00 g, 59.20%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 75B (1.7 g, 4.76 mmol). ¹ H NMR (300 MHz, DMSO-d6) δ ppm 7.18 - 7.44 (m, 15 H), 8.167 (s, 1H), 9.25 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 75D: 5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-3- trityloxazole-2(3Н)-one

Intermediate 75D was prepared (0.52 g, 63.10%) using a synthetic procedure similar to that of intermediate 4 starting from intermediate 75C (0.50 g, 1.41 mmol) and intermediate 51-I (0.45 g, 1.83 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.95 - 1.04 (m, 3H), 1.64 - 1.79 (m, 2H), 2.24 (s, 4H), 2.61 - 2.74 (m, 3H), 2, 83-2.95(m, 2H), 5.41(s, 2H), 6.63-6.71(m, 1H), 7.13-7.38(m, 15H), 7.64 - 7.71 (m, 1H), 7.74 - 7.82 (m, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 3.12, [M+H] 586.6.

Intermediate 75.

To a solution of intermediate 75D (0.52 g, 0.89 mmol) in DCM (10 ml) was added TFA (3 ml, 38.9 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 2 h The resulting mixture was concentrated to dryness, diluted with diethyl ether (100 ml), the solid was filtered off and dried in vacuo to give (0.32 g, 64.25%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (d, J=6.53 Hz, 3H), 2.37 (s, 5H), 3.02 - 3.14 (m, 2H), 3.53 (d, J=4.52 Hz , 2H), 3.61 - 3.74 (m, 1H), 4.74 - 4.83 (m, 1H), 5.47 (d, J=10.54 Hz, 2H), 6.88 ( d, J=2.01 Hz, 1H), 7.82 (s, 1H), 7.87 (s, 1H), 10.49 - 10.56 (m, 1H), (no exchangeable proton). LCMS (Method-O): retention time 0.57 min, [M+H] 344.4.

Intermediate 76: 1-(3-methyl-5-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrazole-4carbaldehyde

Intermediate 76A: 2-chloroethyl (3-bromo-5-methylphenyl)carbamate

- 115 043056

To a stirred solution of 3-bromo-5-methylaniline (5.00 g, 26.9 mmol) in THF (100 mL) was added K2CO3 (11.14 g, 81 mmol) followed by 2-chloroethyl chloroformate (4.16 mL, 40.3 mmol) and the resulting reaction mixture was heated under reflux for 4 hours. The resulting mixture was cooled to ambient temperature, diluted with 5% NaHCO ₃ solution (100 ml) and extracted with the addition of ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 76A (7.00 g, 89.00%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.25 (s, 3H), 3.81-3.95 (m, 2H), 4.32-4.42 (m, 2H), 7.04 (s, 1H), 7.26 (s, 1H), 7.55 (s, 1H), 9.96 (s, 1H). LCMS (Method-D): retention time 2.99 min, [M+H] 291.0.

Intermediate 76B: 3-(3-bromo-5-methylphenyl)oxazolidin-2-one

To a solution of intermediate 76A (7.00 g, 23.93 mmol) in THF (80 ml) was added NaH (2.39 g, 59.80 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. the mixture was diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 50% EtOAc/n-hexane) to give Intermediate 76B (4.20 g, 68.50%) as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 2.32 (s, 3H), 3.98 - 4.08 (m, 2H), 4.41 - 4.49 (m, 2H), 7.16 (s, 1H), 7.29 - 7, 36 (m, 1H), 7.69 (t, J=1.76 Hz, 1H). LCMS (Method-D): retention time 2.37 min, [M+H] 257.4.

Intermediate 76.

Intermediate 76 was prepared (0.06 g, 7.00%) using a synthetic procedure similar to that of intermediate 6 starting from intermediate 76B (0.96 g, 3.75 mmol) and 1H- pyrazole-4-carbaldehyde (0.30 g, 3.12 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.25 - 2.43 (m, 3H), 3.99 - 4.19 (m, 2H), 4.31 - 4.53 (m, 2H), 6.47 - 6.62 (m, 1H ), 7.06 7.14 (m, 1H), 7.19 - 7.24 (m, 1H), 7.41 - 7.58 (m, 1H), 8.28 (s, 1H), 9 .24 (s, 1H). LCMS (Method-O): retention time 1.05 min, [M+H] 272.3.

Intermediate 77: 6-(1H-1,2,4-triazol-1-yl)nicotinaldehyde

Intermediate 77 was prepared (0.3 g, 49.30%) using a synthetic procedure similar to that of intermediate 20, starting from 6 bromonicotinaldehyde (0.50 g, 2.69 mmol) and 4H-1, 2,4-triazole (0.204 g, 2.96 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=8.31 Hz, 1H), 8.41 (br. s., 1H), 8.51 (d, J=7.83 Hz, 1H), 9.07 (br. s., 1H), 9.52 (br. s., 1H), 10.15 (br. s., 1H). LCMS (Method-O): retention time 0.62 min, [M+H] 175.2.

Intermediate 78: 6-(4-formyl-1H-pyrazol-1-yl)-4-isopropoxynicotinonitrile

Intermediate 78 was obtained (0.45 g, 54.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 20 starting from 6-chloro-4-isopropoxynicotinonitrile (0. 61 g, 3.12 mmol) and N-pyrazole-116 043056

4-carbaldehyde (0.30 g, 3.12 mmol). Ή NMR (400 MHz, DMSO4) δ ppm 1.36 (d, J=6.05 Hz, 6H), 5.09 5.16 (m, 1H), 7.69 (s, 1H), 8.39 (s, 1H), 8.84 ( s, 1H), 9.37 (d, J=0.55 Hz, 1H), 9.99 (s, 1H). LCMS (Method J): retention time 2.36 min, [M+H] 257.2.

Intermediate 79: 1-(5-formylpyridin-2-yl)-1H-pyrazole-4-carboxamide

Intermediate 79A: 2-chloro-5-(1,3-dioxolan-2-yl)pyridine (Intermediate-I)

Ethane-1,2-diol (2.63 g, 42.4 mmol), p-TsOH (0.67 g, 3.53 mmol) and the resulting mixture was heated under reflux using a Dean-Stark apparatus for 6 hours. The resulting mixture was cooled to ambient temperature and washed with saturated NaHCO ₃ solution (50 ml) and brine (50 ml) . The separated organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 79A (5.50 g, 77.00%) as a yellow liquid. ¹ H NMR (400 MHz, DMSO4) δ ppm 3.95 - 4.00 (m, 4H), 5.85(s, 1H), 7.56 (m, J=8.25, 0.43 Hz, 1H), 7.91 (dd, J= 8.25, 2.45 Hz, 1H), 8.48 (dd, J=1.83, 0.49 Hz, 1H). LCMS (Method-O): retention time 0.85 min, [M+H] 188.3.

Intermediate 79B: ethyl 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-4carboxylate

Me

Intermediate 79B was obtained (0.80 g, 27.40%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from intermediate 79A (1.50 g, 8.08 mmol) and 1H-pyrazole-4-carboxylate (1.25 g, 8.89 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.09 Hz, 3H), 3.98 - 4.02 (m, 2H), 4.08 - 4.13 (m, 2H), 4.28 (q, J= 7.09 Hz, 2H), 5.90 (s, 1H), 8.01 (dd, J=8.44, 0.60 Hz, 1H), 8.08 - 8.11 (m, 1H), 8.23 (d, J=0.69 Hz, 1H), 8.58 (d, J=2.13 Hz, 1H), 9.00 (d, J=0.69 Hz, 1H). LCMS (Method-J): retention time 2.39 min, [M+H] 290.1.

Intermediate 79C: 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide

To a stirred solution of intermediate 79B (0.35 g, 1.21 mmol) in EtOH (10 ml) was added ammonium hydroxide (10 ml, 257 mmol) and the resulting mixture was heated at 60° C. for 40 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness, diluted with water (20 ml) and extracted with 10% MeOH in DCM (3x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 79C (0.20 g, 55.30%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.98 - 4.03 (m, 2H), 4.09 - 4.13 (m, 2H), 5.90 (s, 1H), 7.24 (br. s, 1H), 7.84 ( br. s, 1H), 7.98 -8.01 (m, 1H), 8.09 (d, J=2.14 Hz, 1H), 8.15 (d, J=0.55 Hz, 1H ), 8.57 (d, J=2.02 Hz, 1H), 9.15 (d, J=0.61 Hz, 1H). LCMS (Method-J): retention time 0.60 min, [M+H] 261.1.

Intermediate 79.

To a stirred solution of intermediate 79C (0.20 g, 0.77 mmol) in toluene (3 ml) and water (0.5 ml) was added p-TsOH (0.22 g, 1.15 mmol). ) and the resulting mixture was heated at 70°C for 1 h. The resulting mixture was concentrated to dryness, diluted with water (30 ml) and the resulting solid precipitate was separated by vacuum filtration and dried in vacuum to obtain intermediate compound 79 (0.120 g, 62.80% ) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (br. s., 1H), 7.88 (br. s., 1H), 8.13 (d, J=8.53 Hz, 1H), 8.22 (d, J=0, 69 Hz, 1H), 8.46 (dd, J=8.53, 2.20 Hz, 1H), 9.05 (dd, J=2.13, 0.69 Hz, 1H), 9.24 ( d, J=0.69 Hz, 1H), 10.12 (s, 1H). LCMS (Method-J): retention time 0.60 min, [M+H] 216.1.

Intermediate 80: 1-(5-formylpyridin-2-yl)-1H-pyrazole-3-carbonitrile

Intermediate 80 was obtained (0.45 g, 84.00%) as a yellow solid using a synthetic procedure similar to that of intermediate 20 starting from 1H-pyrazole-3-carbonitrile (0.02 g , 2.96 mmol) and 6-bromonicotinaldehyde (0.05 g, 2.69 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.53 (d, J=2.40 Hz, 1H), 8.19 (d, J=8.00 Hz, 1H), 8.49-8.52 (M, 1H), 8.99 (d , J=2.40 Hz, 1H), 9.07 (d, J=1.20 Hz, 1H), 10.15 (s, 1H). LCMS (method-D): retention time 1.95 min, [M+H] 199.0.

Intermediate 81: 4-ethoxy-6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile

Intermediate 81A: 6-chloro-4-ethoxynicotinonitrile

Synthesized according to the methods described in the literature (PCT 2016091042, 2016).

Intermediate 81.

Intermediate 81 was prepared (0.30 g, 41.70%) using a synthetic procedure similar to that of intermediate 20 starting from intermediate 81A (0.30 g, 1.66 mmol) and 1H- pyrazole-4-carboxylate (0.20 g, 1.66 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (d, J=7.20 Hz, 3H), 4.40 (q, J=7.20 Hz, 2H), 8.38 (s, 1H), 8.69 (s, 1H), 8.84 (s, 1H), 9.36 (s, 1H), 9.98 (s, 1H). LCMS (Method-D): retention time 2.12 min, [M+H] 243.2.

Intermediate 82: 1-(3,4-dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-1Hpyrazole-4-carbaldehyde

Intermediate 82A: 5-bromo-3,4-dimethylbenzo[d]oxazol-2(3H)-one

Synthesized according to the procedures described in the literature (PCT2017/001991, 2017).

- 118 043056

Intermediate 82.

K ₂ CO ₃ (0, 90 g, 6.50 mmol) and degassed with nitrogen for 5 min. Copper (I) iodide (0.25 g, 1.30 mmol) was added to the resulting reaction mixture, followed by N,N-dimethylglycine (0.13 g, 1.30 mmol) and heated at 110°C for 16 h The resulting mixture was cooled to ambient temperature, diluted with water (40 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 20-40% EtOAc/n-hexane) to give (0.35 g, 40.80%) as a brown solid, 1 H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.39 (s, 3H), 3.34 (s, 3H), 7.42 (d, J=1.89 Hz, 1H), 7.51 (d, J=1.89 Hz, 1H), 8.30 (s, 1H), 9.28 (s, 1H), 9.93 (s, 1H). LCMS: (Method-I) retention time: 0.84 min, [M+1]: 258.4.

Intermediate 83: 6-(4-methyl-1H-imidazol-1-yl)pyridazine-3-carbaldehyde

Oh nl.

Q Me

Intermediate 83A: ethyl 6-(4-methyl-1H-imidazol-1-yl)pyridazine-3-carboxylate

Intermediate 83A was prepared (0.18 g, 72.00%) using a synthetic procedure similar to that of intermediate 20 starting from 4methyl-1H-imidazole (0.11 g, 1.34 mmol) and ethyl 6-chloropyridazine-3-carboxylate (0.20 g, 1.07 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.12 Hz, 3H), 2.22 (d, J=0.94 Hz, 3H), 4.41-4.47 (m, 2H), 7.86 (t , J=1.19 Hz, 1H), 8.28 (d, J=9.20 Hz, 1H), 8.30 (d, J=8.80 Hz, 1H), 8.64 (d, J \u003d 1.32 Hz, 1H). LCMS: Compound poorly ionized.

Intermediate 83B: (6-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)methanol

To a solution of intermediate 83A (0.10 g, 0.43 mmol) in THF (5 ml) was added sodium borohydride (0.17 g, 0.43 mmol) at ambient temperature. MeOH (0.2 ml) was added dropwise and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride solution, concentrated to dryness, diluted with water (10 ml) and extracted with DCM (2x25 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 83B (0.05 g, 61.00%). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.20 (s, 3H), 4.77 (d, J=5.52 Hz, 2H), 5.69 (t, J=5.95 Hz, 1H), 7.76 (s, 1H), 7.89 (d, J=9.07 Hz, 1H), 8.13 (d, J=9.11 Hz, 1H), 8.51 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 83.

Intermediate 83 was prepared (0.04 g, 85.00%) using a synthetic procedure similar to that of intermediate 9 starting from Intermediate 83B (0.04 g, 0.21 mmol). LCMS: Compound poorly ionized. The compound was carried directly to the next step without further purification or characterization.

- 119 043056

Intermediate 84: 6-(3-formylpyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 84A: 6-(3-(hydroxymethyl)pyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 84A was prepared (0.30 g, 68.00%) using a synthetic procedure similar to that of intermediate 20 starting from 6-bromo4-methoxynicotinonitrile (0.40 g, 1.88 mmol) and pyrrolidin-3-ylmethanol (0.19 g, 1.88 mmol). LCMS (method-L): retention time 1.26 min, [M+H] 234.2. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.90-1.92(m, 1H), 2.01-2.10(m, 1H), 2.32-2.35(m, 1H), 2.39-2.47(m, 2H ), 2.52 - 2.54 (m, 3H), 3.37 - 3.49 (m, 1H), 3.92 (s, 3H) 4.73 - 4.78 (m, 1H), 6 .00 (s, 1H), 8.26 (s, 1H).

Intermediate 84.

Intermediate 84 was prepared (0.05 g, crude) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 84A (0.05 g, 0.214 mmol) and Dess-Martin periodinan (0 .09 g, 0.214 mmol). LCMS (method-L): retention time 0.47 min, [M+H] 232.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 85: 6-(3-formylpyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 85A: 6-(3-(hydroxymethyl)pyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 85A was prepared (0.30 g, 25.00%) using a synthetic procedure similar to that of intermediate 20 starting from 6-bromo4-methylnicotinonitrile (0.40 g, 2.03 mmol) and pyrrolidin-3-ylmethanol (0.20 g, 2.03 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.70 - 1.80 (m, 1H), 1.97 - 2.07 (m, 1H), 2.37 - 2.45 (m, 1H), 2.55 - 2.58 (m, 1H ), 2.66 - 2.69 (m, 1H), 2.90 (m, 1H), 3.17 - 3.26 (m, 2H), 3.38 (s, 1H), 3.50 - 3.60 (m, 2H), 4.74 (t, J=4.98 Hz, 1H), 6.46 (s, 1H), 7.95-7.97 (m, 1H), 8.37 (s, 1H). LCMS (Method-L): retention time 1.30 min, [M+H] 218.2.

Intermediate 85.

Intermediate 85 was prepared (0.50 g, 68.10%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 85A (0.05 g, 0.230 mmol) and Dess-Martin periodinan (0.10 g, 0.230 mmol). LCMS: Compound poorly ionized. The compound was carried directly to the next step without further purification or characterization.

Intermediate 86: 6-(4-formyl-2-oxopyrrolidin-1-yl)-4-methylnicotinonitrile

- 120 043056

Intermediate 86A: methyl 1-(5-cyano-4-methylpyridin-2-yl)-5-oxopyrrolidine-3-carboxylate

Intermediate 86A was obtained (0.50 g, 76.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 15C, starting from 6-bromo-4-methylnicotinonitrile (0. 50 g, 2.54 mmol) and methyl 5oxopyrrolidine-3-carboxylate (0.36 g, 2.54 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.45-2.55 (m, 4H), 2.82-3.00 (m, 2H), 3.43-3.52 (m, 1H), 3.65-3.72 (m, 2H ), 4.22 (m, 2H), 8.34 (s, 1H), 8.78 (s, 1H). LCMS (method-L): retention time 1.03 min, [M+1] 260.1.

Intermediate 86B: 6-(4-(hydroxymethyl)-2-oxopyrrolidin-1-yl)-4-methylnicotinonitrile

Intermediate 86B was prepared (0.10 g, 22.00%) using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 86A (0.50 g, 1.93 mmol) and NaBH ₄ (0.18 g, 4.82 mmol). ¹ H NMR (400 MHz, DMSOd6) δ ppm 2.30 - 2.35 (m, 3H), 2.70 - 2.80 (m, 2H), 3.37 - 3.45 (m, 3H), 3.75 - 3.85 (m, 1H ), 4.00-4.10(m, 1H), 4.80-4.90(m, 1H), 8.37(s, 1H), 8.76(s, 1H). LCMS (Method-O): retention time 0.75 min, [M+H] 232.1.

Intermediate 86.

Intermediate 86 was prepared (0.08 g, 68.10%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 86B (0.08 g, 0.346 mmol) and Dess-Martin periodinan (0.15 g, 0.346 mmol). LCMS (method-L): retention time 0.72 min, [M+H] 230.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 87: 6-(4-formyl-2-oxopyrrolidin-1-yl)-4-methoxynicotinonitrile

- 121 043056

Intermediate 87A: methyl 1-(5-cyano-4-methoxypyridin-2-yl)-5-oxopyrrolidine-3-carboxylate

Intermediate 87A was obtained (0.50 g, 59.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 15C, starting from 6-bromo-4-methoxynicotinonitrile (0. 50 g, 2.35 mmol) and methyl 5oxopyrrolidine-3-carboxylate (0.34 g, 2.35 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.82 - 3.00 (m, 2H), 3.43 - 3.52 (m, 1H), 3.70 (m, 2H), 3.90 (s,l H), 4.00 (s , 3H), 4.22-4.35 (m, 2H), 8.12 (s, 1H), 8.65 (s, 1H). LCMS (method-L): retention time 1.01 min, [M+H] 276.9.

Intermediate 87B: 6-(4-(hydroxymethyl)-2-oxopyrrolidin-1-yl)-4-methoxynicotinonitrile

Intermediate 87B was prepared (0.20 g, 44.50%) using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 87A (0.50 g, 1.82 mmol) and NaBH4 ( 0.17 g, 4.54 mmol). LCMS (method-L): retention time 0.73 min, [M+H] 248.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 87.

Intermediate 87 was prepared (0.15 g, 68.10%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 87B (0.18 g, 0.73 mmol) and Dess periodinan -Martin (0.31 g, 0.73 mmol). LCMS (method-L): retention time 0.71 min, [M+H] 246.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 88: 6-(5-formyl-2-oxooxazolidin-3-yl)-4-methylnicotinonitrile

Intermediate 88A: 5-(hydroxymethyl)oxazolidin-2-one

Synthesized in accordance with the methods described in the literature (US 2014/206677 A1, 2014).

Intermediate 88B: 6-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)-4-methylnicotinonitrile

Intermediate 88B was obtained (0.35 g, 35.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 15C, starting from Intermediate 88A (0.50 g, 4 .27 mmol) and 6-bromo-4-methylnicotinonitrile (0.72 g, 4.27 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.45 (s, 3H), 3.53 - 3.61

- 122 043056 (m, 1H), 3.66 - 3.73 (m, 1H), 3.99 (dd, J=10.38, 5.93 Hz, 1H), 4.15 - 4.23 ( m, 1H), 4.72 - 4.79 (m, 1H), 5.22 (t,

J=5.21 Hz, 1H), 8.15(s, 1H), 8.75(s, 1H). LCMS (method-L): retention time 0.82 min, [M+1] 234.2.

Intermediate 88.

Intermediate 88 was prepared (0.16 g, 64.00%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 88B (0.25 g, 1.07 mmol) and Dess periodinan -Martin (0.57 g, 1.34 mmol). LCMS: Compound poorly ionized. The compound was carried directly to the next step without further purification or characterization.

Intermediate 89: 1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 89 was prepared (0.40 g, 75.00%) using a synthetic procedure similar to that of intermediate 20 starting from 2-bromo5-(methylsulfonyl)pyridine (0.50 g, 2.12 mmol) and 1H-pyrazole-4-carbaldehyde (0.20 g, 2.12 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.43 - 3.90 (s, 3H), 8.20 - 8.22 (m, 2H), 8.40 (s, 1H), 8.54 - 8.57 (m, 1H), 9, 00 - 9.04 (m, 1H), 10.00 (s, 1H). LCMS (method-L): retention time 0.76 min, [M+H] 252.1.

Intermediate 90: 2-(4-formyl-1H-imidazol-1-yl)-4-methylpyrimidine-5-carbonitrile

Intermediate 90 was obtained (0.05 g, 9.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 15C, starting from intermediate 43C (0.62 g, 3 .12 mmol) and 1H-imidazole-4carbaldehyde (0.25 g, 2.60 mmol). 1H NMR (300 MHz, DMSO-de) δ ppm 2.70 (s, 3H), 8.80 (s, 2H), 9.30 (s, 1H), 9.80 (s, 1H). LCMS (method-O): retention time 0.76 min, [M+H] 214.4.

Intermediate 91: 6'-(methylsulfonyl)-[2,3'-bipyridine]-5-carbaldehyde

Intermediate 91A: 2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridine

Intermediate 91A was prepared (0.05 g, crude) using a synthetic procedure similar to that of intermediate 2B, starting from 5-bromo-2-(methylsulfonyl)pyridine (0.05 g, 0.21 mmol) and bis(pinacolato)diboron (0.07 g, 0.26). LCMS (Method-O): retention time 0.94 min, [M+H] 284.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 91.

Intermediate 91 was obtained (0.30 g, 64%) as an off-white solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 91A (0.50 g, 1.77 mmol) and 6-123 043056 bromonicotinaldehyde (0.33 g, 1.77 mmol). LCMS (method-O): retention time 0.94 min, [M+H]

263.2. The compound was carried directly to the next step without further purification or characterization.

intermediate carbonitrile compound

92: 2-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methoxypyrimidine-5 Intermediate midin-5-carbonitrile

compound

92A: 2-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methoxypyri-

Intermediate 92A was obtained (0.90 g, 65.70%) as an off-white solid using a synthetic procedure similar to that of intermediate 42 starting from intermediate 45A (1.00 g, 5.90 mmol) and Intermediate 28A (0.88 g, 8.85 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.18 (s, 3H), 4.69 (d, J=5.84 Hz, 2H), 5.59 (t, J=5.87 Hz, 1H), 8.25 (s, 1H), 9.18(s, 1H). LCMS (Method-O): retention time 0.60 min, [M+H] 233.2.

Intermediate 92.

Intermediate 92 was prepared (0.02 g, crude) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 92A (0.03 g, 5.90 mmol) and Dess-Martin periodinan (0.06 g, 0.129 mmol). LCMS: Compound poorly ionized. The compound was carried directly to the next step without further purification or characterization.

Intermediate 93: 6-(4-formyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4methoxynicotinonitrile

Intermediate 93A: 1H-imidazole-4-carboxylate methyl-1-(5-cyano-4-methoxypyridin-2-yl)-2-oxo-2,3-dihydro-

Intermediate 93A was obtained (4.20 g, 70.70%) as a brown solid using a synthetic procedure similar to that of Intermediate 15C starting from 6-chloro-4-methoxynicotinonitrile (4.27 g , 25.3 mmol) and methyl 2-oxo2,3-dihydro-1H-imidazole-4-carboxylate (3.00 g, 21.11 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.79 (s, 3H), 4.03 (s, 3H), 7.9 (s, 1H), 8.32 (s, 1H), 8.71 (s, 1H), (not observed 1 capable to proton exchange). LCMS (method-D): retention time 1.81 min, [M+1] 275.

- 124 043056

Intermediate 93B: methyl-1-(5-cyano-4-methoxypyridin-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate

To a stirred solution of intermediate 93A (2.00 g, 7.29 mmol) in DMF (5 ml) was added Cs ₂ CO ₃ (4.75 g, 14.59 mmol) followed by the addition of iodomethane (0.91 ml, 14 .6 mmol) and the resulting mixture was stirred at ambient temperature for 12 hours DMF was evaporated under reduced pressure and the mixture was diluted with water (50 ml). The solid was filtered off and washed with water (50 ml), diethyl ether (50 ml) and dried in vacuo to give Intermediate 93B (1.70 g, 81.00%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.44 (s, 3H), 3.82 (s, 3H), 4.04 (s, 3H), 8.02 (s, 1H), 8.24 (s, 1H), 8.76 (s , 1H). LCMS (Method-D): retention time 2.34 min, [M+1] 289.2.

Intermediate 93C: 6-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1yl)-4-methoxynicotinonitrile

Intermediate 93C was obtained (0.85 g, 92.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 93B (1.00 g, 3 .47 mmol) and NaBH ₄ (0.26 g, 6.94 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.24 (s, 3H), 4.01 (s, 3H), 4.36 (br.s, 2H), 5.25 (br.s, 1H), 7.29 (s, 1H), 8 .28 (s, 1H), 8.69 (s, 1H). LCMS (method-D): retention time 1.24 min, [M+1] 261.

Intermediate 93.

Intermediate 93 was prepared (0.100 g, 50.00%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 93C (0.20 g, 0.76 mmol) and periodinan.

Dess-Martin (0.39 g, 0.92 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.46 (s, 3H), 4.01 (s, 3H), 8.25 (s, 1H), 8.54 (s, 1H), 8.81 (s, 1H), 9.52 (s , 1H). LCMS (method-D): retention time 1.91 min, [M+1] 259.

Intermediate 94: 6-(4-formyl-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4methoxynicotinonitrile

Intermediate 94A: methyl 1-(5-cyano-4-methoxypyridin-2-yl)-3-isopropyl-2-oxo2,3-dihydro-1H-imidazole-4-carboxylate

Intermediate 94A was obtained (0.48 g, 41.00%) as a yellow solid using a synthetic procedure similar to that of Intermediate 93B, starting from Intermediate 93A (1.00 g, 3.65 mmol) and 2-iodopropane (1.24 g,

- 125 043056

7.29 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.45 (d, J=8.00 Hz, 6H), 3.8 (s, 3H), 4.04 (s, 3H), 5.0 (t,

J=8.00 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 8.76 (s, 1H). LCMS (method-D): retention time 2.70 min,

[M+1] 317.2.

Intermediate 94B: 6-(4-(hydroxymethyl)-3-isopropyl-2-oxo-2,3-dihydro-1nimidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 94B was obtained (0.35 g, 96.00%) as a yellow solid using a synthetic procedure similar to that of Intermediate 60B starting from Intermediate 94A (0.40 g, 1.26 mmol) and NaBH ₄ (0.10 g, 2.53 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.45 (d, J=8.00 Hz, 6H), 4.01 (s, 3H), 4.26-4.35 (m, 3H), 5.25 (br.s, 1H), 7 .28 (s, 1H), 8.28 (s, 1H), 8.68 (s, 1H), LCMS (method-O): retention time 0.9 min, [M+1] 289.2.

Intermediate 94.

Intermediate 94 was prepared (0.25 g, 49.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 94B (0.38 g, 1.32 mmol) and Dess periodinan -Martin (0.67 g, 1.58 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (d, J=8.00 Hz, 6H), 4.01 (s, 3H), 5.0 (t, J=8.00 Hz, 1H), 8.25 (s, 1H), 8.61 (s, 1H), 8.87 (s, 1H), 9.45 (s, 1H). LCMS (method-D): retention time 2.3 min, [M+1] 287.2.

Intermediate 95: 3-methyl-1-(2-methylpyrimidin-4-yl)-2-oxo-2,3-dihydro-1nimidazole-4-carbaldehyde

Intermediate 95A: methyl 1-(5-cyano-4-methoxypyridin-2-yl)-2-oxo-2,3-dihydro1 H-imidazole-4-carboxylate

4-Chloro-2-methylpyrimidine (1.63 g, 12.67 mmol) followed by the addition of Cs ₂ CO ₃ (6.88 g, 21.11 mmol) and the resulting reaction mixture was heated at 100°C for 4 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness in under reduced pressure and diluted with water (50 mL), the resulting solid was filtered off and dried in vacuo to give Intermediate 95A (1.20 g, 36.40%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.67 (s, 3H), 3.82 (s, 3H), 7.85 (s, 1H), 8.3 (d, 6.0 Hz, 1H), 8.6 (d, 6.0 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 1.06 min, [M+1] 235.2.

Intermediate 95B: methyl 3-methyl-1-(2-methylpyrimidin-4-yl)-2-oxo-2,3-dihydro1 H-imidazole-4-carboxylate

Intermediate 95B was prepared (0.50 g, 47.00%) using a synthetic procedure similar to that of intermediate 93B, starting from pro-126 043056 Intermediate 95A (1.00 g, 4.27 mmol ) and 2-iodomethane (0.5 ml, 8.54 mmol). 1H NMR (400 MHz,

DMSO-d ₆ ) δ ppm 2.63 (s, 3H), 3.42 (s, 3H), 3.82 (s, 3H), 8.04 (s, 1H), 8.15 (d, J=6.00 Hz, 1H ), 8.75 (d, J=6.00

Hz, 1H). LCMS (Method-D): retention time 1.54 min, [M+1] 249.2.

Intermediate 95C: 4-(hydroxymethyl)-3-methyl-1-(2-methylpyrimidin-4-yl)-1,3dihydro-2H-imidazol-2-one

Intermediate 95C was obtained (0.20 g, 45.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 95B (0.50 g, 2.014 mmol) and NaBH ₄ (0.15 g, 4.03 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 3.22 (s, 3H), 4.36 (d, 5.2 Hz, 2H), 5.24 (s, 1H), 7.3 (s, 1H), 8.15 (d, J=6.00 Hz, 1H), 8.65 (d, J=6.00 Hz, 1H). LCMS (Method-D): retention time 0.55 min, [M+1] 221.5.

Intermediate 95.

Intermediate 95 was prepared (0.13 g, 64.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 95C (0.20 g, 0.91 mmol) and Dess periodinan -Martin (0.46 g, 1.09 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.66 (s, 3H), 3.45 (s, 3H), 8.2 (d, 6.0 Hz, 1H), 8.54 (s, 1H), 8.81 (d, 6.0 Hz, 1H), 9.54 (s, 1H). LCMS (Method-D): retention time 1.08 min, [M+1] 219.2.

Intermediate 96-I: 5-((2R,6S)-4-((6-bromopyridin-3-yl)methyl)-6-methylpiperazin-2yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 51-I (0.44 g, 1.77 mmol) was added to a stirred solution of 6-bromonicotinaldehyde (0.300 g, 1.61 mmol) in THF (20 mL) and the resulting mixture was stirred at ambient temperature for 10 min. Sodium triacetoxyborohydride (0.68 g, 3.23 mmol) was added and stirring was continued for 48 h. The resulting mixture was diluted with aq. NaHCO ₃ solution (30 ml) and extracted with ethyl acetate (2x40 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 65-70% EtOAc/n-hexane) to give Intermediate 96-I (0.32 g, 47.00%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01 (d, J=6.02 Hz, 3H), 1.70 - 1.79 (m, 2H), 2.24 (s, 3H), 2.72 (t, J=8.78 Hz , 2H), 2.96 (td, J=6.53, 3.01 Hz, 1H), 3.52 (s, 2H), 4.15 (dd, J=10.04, 2.51 Hz, 1H), 5.38 (s, 2H), 7.59 - 7.67 (m, 2H), 7.68 - 7.72 (m, 1H), 7.80 (d, J = 8.03 Hz , 1H), 8.31 (d, J=2.01 Hz, 1H), (1 exchangeable proton was not observed). LCMS (method-D): retention time 1.95 min, [M+H] 417.

Intermediate 97: yl)-4-methylisobenzofuran-1 (3H)-one

5-((2R,6S)-4-((1H-1,2,4-triazol-3-yl)methyl)-6-methylpiperazin-2-

Intermediate 97A:

methyl-1-trityl-1Н-1,2,4-triazole-3-carboxylate O

Meo

^N'N Ph

Ph

Intermediate 97A was prepared (8.00 g, 45.10%) using a synthetic procedure similar to that of Intermediate 75A, starting from 1H-127 043056

1,2,4-triazole-3-carboxylate (5.00 g, 39.30 mmol) and trityl chloride (13.16 g, 47.20 mmol). 1H NMR (400

MHz, DMSO-d6) δ ppm 3.83 (s, 3H), 7.05-7.09 (m, 5H), 7.40-7.42 (m, 10 H), 8.38 (s, 1H), LCMS: compound poorly ionized .

Intermediate 97B: (1-trityl-1H-1,2,4-triazol-3-yl)methanol | ^H0 ^%G% ⁿ 'n' Ph Y-Ph

Ph

Intermediate 97B was obtained (1.00 g, 50.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 97A (2.00 g, 5.41 mmol) and NaBH ₄ (0.60 g, 16.24 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.45 (d, J=6.02 Hz, 2H), 5.30 (t, J=6.02 Hz, 1H), 7.05-7.09 (m, 5H), 7.37-7, 42 (m, 10 H), 8.04 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 97C: 1-trityl-1H-1,2,4-triazole-3-carbaldehyde

Intermediate 97C was prepared (0.75 g, 90.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 97B (0.80 g, 2.34 mmol) and Dess periodinan - Martina (2.00 g, 4.70 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.05-7.09(m, 5H), 7.40-7.42(m, 10H), 8.38(s, 1H), 9.45(s, 1H). LCMS: compound poorly ionized.

Intermediate 97D: 4-methyl-5-((2R,6S)-6-methyl-4-((1-trityl-1H-1,2,4-triazol-3yl)methyl)piperazin-2-yl)isobenzofuran -1(3Н)-one

Intermediate 97D was obtained (0.90 g, 71.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 96-I, starting from Intermediate 97C (0.75 g , 2.21 mmol) and Intermediate 51-I (0.60 g, 2.43 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.28 Hz, 3H), 1.69 1.86 (m, 2H), 2.23 (s, 3H), 2.68 - 2.78 (m, 2H), 2.90 (br. s., 1H), 3.60 (s, 2H), 4.10 (d, J=7.10 Hz, 1H), 5.39 (s, 2H), 7.01 - 7.07 (m, 6H), 7.31-7.38 (m, 9H), 7.64-7.69 (m, 1H), 7.75-7.79 (m, 1H), 8, 04 (s, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 4.045 min, [M+H] 570.4.

Intermediate 97.

Intermediate 97 was prepared (0.18 g, 28.20%) using a synthetic procedure similar to that of Intermediate 4C starting from Intermediate 97D (1.00 g, 1.75 mmol) and 4M HCl in dioxane (0.88 ml, 3.51 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (d, J=6.28 Hz, 3H), 1.72 - 1.85 (m, 2H), 2.25 (s, 3H), 2.76 (d, J=10.24 Hz , 2H), 2.94 (br. s., 1H), 3.62 (s, 2H), 4.14 (d, J=9.25 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.09 Hz, 1H), 7.78 (d, J=8.26 Hz, 1H), 8.12 (br. s., 1H), 13.9 (br. s., 1H). (No 1 exchangeable proton was observed). LCMS (Method-D): retention time 0.63 min, [M+H] 328.2.

Intermediate 98: 6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 98 was prepared (0.30 g, 25.00%) using a synthetic procedure similar to that of intermediate 20, starting from 1H-128 043056 imidazole-4-carbaldehyde (0.50 g, 5. 20 mmol) and 6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol). 1H

NMR (400 MHz, DMSO-d6) δ ppm 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95 (d, J=1.19 Hz, 1H), 9.87 (s, 1H ).

LCMS (method-L): retention time 0.75 min, [M+H] 229.1.

Intermediate 99: 6-(4-formyl-5-methyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 99A: ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate

Intermediate 99A was obtained (5.20 g, 35.70%) as a brown solid using a synthetic procedure similar to that of Intermediate 28A starting from ethyl but-2-inoate (10.00 g, 89 .00 mmol) and azidotrimethylsilane (17.76 ml, 134.00 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, J=7.09 Hz, 3H), 2.51 (br. s., 3H), 4.30 (q, J=6.93 Hz, 2H), 15.36 (br. s., 1H). LCMS (Method-D): retention time 0.68 min, [M+H] 156.2.

Intermediate 99B: ethyl 1-(5-cyano-4-methylpyridin-2-yl)-5-methyl-1H-1,2,3-triazole4-carboxylate and intermediate 99C: ethyl 2-(5-cyano -4-methylpyridin-2-yl)-5-methyl-2H1,2,3-triazole-4-carboxylate

Intermediate 99B and 99C were prepared using a synthetic procedure similar to that of Intermediate 20 starting from Intermediate 99A (5.00 g, 32.20 mmol) and 6-bromo-4-methylnicotinonitrile (7.62 g, 38.70 mmol). Regioisomers were separated into individual isomers by HPLC [YMC trait (250x20 mm) 5 microns; solvent A: 10 mM NaHCO ₃ ; solvent B: acetonitrile:MeOH (1:1), gradient: 50-100% B over 15 min, flow: 20 ml/min, UV: 254]. The first eluted compound (retention time 10.42 min), designated Intermediate 99B, was obtained (0.50 g, 5.50%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 - 1.38 (m, 3H), 2.67 (s, 3H), 2.83 (s, 3H), 4.39 (q, J=7.03 Hz, 2H), 8.20 (s, 1H), 9.07 (s, 1H). LCMS (Method-D): retention time 2.37 min, [M+H] 272.0. The second eluted compound (retention time 11.65 min), designated as intermediate 99C, was obtained (3.10 g, 28.40%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.33 - 1.38 (m, 3H), 2.56 (s, 3H), 2.64 (s, 3H), 4.39 (q, J=7.03 Hz, 2H), 8.18 (s, 1H), 8.97 (s, 1H). LCMS (method-D): retention time 2.45 min, [M+H] 272.0.

Intermediate 99D: 6-(4-(hydroxymethyl)-5-methyl-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 99D was obtained (0.25 g, 48.80%) as a brown solid using a synthetic procedure similar to that of Intermediate 60B and using

- 129 043056 Intermediate 99C (0.60 g, 2.21 mmol) and NaBH ₄ (0.17 g, 4.43 mmol) as starting compounds. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.39 (s, 3H), 2.60 (s, 3H), 4.62 (d, J=5.52 Hz, 2H), 5.39 (t,

J=5.77 Hz, 1H), 8.04 (s, 1H), 8.89 (s, 1H). LCMS (Method-D): retention time 1.16 min, [M+H] 230.0.

Intermediate 99.

Intermediate 99 was prepared (0.25 g, 48.80%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 99D (0.20 g, 0.87 mmol) and Dess periodinan -Martin (0.74 g, 1.75 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 2.66 (s, 3H), 8.24 (s, 1H), 9.01 (s, 1H), 10.23 (s, 1H). LCMS (Method-D): retention time 1.95 min, [MH] 226.1.

Intermediate 100: 6-(4-formyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 100A: 6-(4-(hydroxymethyl)-5-methyl-1H-1,2,3-triazol-1-yl)-4-methylnicotinonitrile

Intermediate 100A was obtained (0.28 g, 71.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 99B (0.40 g, 1.47 mmol) and NaBH4 (0.11 g, 2.95 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H), 2.64 (s, 3H), 4.55 (d, J=5.52 Hz, 2H), 5.19 (t, J=5.77 Hz, 1H), 8.16 (s, 1H), 9.0 (s, 1H). LCMS (Method-D): retention time 1.22 min, [M+H] 230.2.

Intermediate 100.

Intermediate 100 was prepared (0.20 g, 56.00%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 100A (0.25 g, 1.09 mmol) and Dess perioddinan -Martin (0.70 g, 1.64 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.66 (s, 3H), 2.72 (s, 3H), 8.24 (s, 1H), 9.01 (s, 1H), 10.28 (s, 1H). LCMS (Method-D): retention time 1.97 min, [M+H] 228.2.

Intermediate 101: 1-(2-(5-cyano-4-methylpyridin-2-yl)-2H-1,2,3-triazol-4-yl)ethylmethanesulfonate

Intermediate 101A: 6-(4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)-4-methylnicotinonitrile

Intermediate 101A was obtained (0.74 g, 80.00%) as a yellow solid using a synthetic procedure similar to that of Intermediate 72A starting from Intermediate 28 (0.80 g, 3.75 mmol). 1H NMR (400 MHz,

- 130 043056

DMSO-d ₆ ) δ ppm 1.48 (d, J=6.53 Hz, 3H), 2.62 (s, 3H), 4.93 - 5.00 (m, 1H), 5.58 (d, J=5.02 Hz , 1H), 8.10 - 8.11 (m, 1H), 8.17 (s, 1H), 8.93 (s, 1H). LCMS (Method-D): retention time 1.05 min, [M+H] 230.0.

Intermediate 101.

Intermediate 101A was obtained (0.20 g, 56.70%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 59 starting from intermediate 101A (0.25 g, 1 .09 mmol) and mesyl chloride (0.102 ml, 1.31 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (d, J=6.80 Hz, 3H), 2.64 (s, 3H), 3.28 (s, 3H), 6.03 (q, J=6.80 Hz, 1H), 8.16 (s, 1H), 8.40 (s, 1H), 8.97 (s, 1H). LCMS (Method-D): retention time 1.56 min, [M+H] 308.2.

Intermediate 102: 2-methyl-6-(trimethylstannyl)pyridazin-3(2H)-one

me me. I.Me Sn C ² O

Intermediate 102A: 6-chloro-2-methylpyridazin-3(2H)-one

Cl

ABOUT

To a stirred solution of 6-chloropyridazin-3(2H)-one (0.35 g, 2.68 mmol) in DMF (10 mL) was added K ₂ CO ₃ (0.93 g, 6.70 mmol) followed by methyl iodide (0.20 ml, 3.22 mmol) and stirred at ambient temperature for 1 hour. The resulting reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 102A (0.25 g, 56.10%) as an off-white solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.75 (s, 3H), 6.92 (d, J=9.76 Hz, 1H), 7.19 (d, J=9.76 Hz, 1H). LCMS (Method-D): retention time 0.66 min, [M+1] 145.2.

Intermediate 102.

Intermediate 102 was prepared (0.15 g, crude) using a synthetic procedure similar to that of intermediate 23A, starting from intermediate 102A (0.10 g, 0.69 mmol) and 1.1. 1,2,2,2-hexamethyldistannan (0.16 ml, 0.76 mmol). LCMS (Method-O): retention time 1.30 min, [M+1] 275.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 103: 5-(5-(hydroxymethyl)piperazin-2-yl)-4-methylisobenzofuran1(3H)-one (Diastereomer I)

Intermediate 103A: 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloropyrazine

Sk ^N Me II _L X ^Me

Si Me Me' Me

To a stirred solution of (5-chloropyrazin-2-yl)methanol (0.50 g, 3.46 mmol) in DCM (10 mL) was added imidazole (0.94 g, 13.84 mmol) followed by TBDMS-Cl ( 1.04 g, 6.92 mmol) and stirring was continued at ambient temperature for 12 hours. The resulting reaction mixture was diluted with water (40 ml) and extracted with DCM (2x40 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 5-10% EtOAc/n-hexane) to give Intermediate 103A (0.85 g, 89.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.11 (s, 6H), 0.91 (s, 9H), 4.84 (s, 2H), 8.50 (s, 1H), 8.75 (d, J=1.00 Hz, 1H ). LCMS (method-D): retention time 3.69 min, [M+H] 259.

Intermediate 103B: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyrazin-2-yl)-4- 131 043056 methylisobenzofuran-1(3H)-one

Me

Intermediate 103B (1.80 g, 44.0%) was obtained as a brown solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 103A (2.83 g, 10.94 mmol) and Intermediate 2B (3.00 g, 10.94 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.15 (s, 6H), 0.94 (s, 9H), 2.33 (s, 3H), 4.93 (s, 2H), 5.50 (s, 2H), 7.71 (d , J=8.00 Hz, 1H), 7.8 (d, J=8.00 Hz, 1H), 8.81 (s, 1H), 8.84 (d, J=1.51 Hz, 1H ). LCMS (Method-D): retention time 3.78 min, [M+H] 371.2.

Intermediate 103C and 103D: 5-(5-(((tert-butyldimethylsilyl)oxy)methyl)piperazin2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 103C and 103D were prepared using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from intermediate 103B (2.30 g, 6.21 mmol). The two diastereomers were separated by column chromatography (Redisep-40 g, 5-10% EtOAc/n-hexane). The first eluted compound, designated Intermediate 103C, was obtained (0.35 g, 30.40%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.06 (s, 6H), 0.89 (s, 9H), 2.29 (s, 3H), 2.43 (br. s., 2H), 2.73-2.75 (m, 1H ), 2.90 2.92 (m, 1H), 3.02 - 3.07 (m, 1H), 3.43 - 3.54 (m, 2H), 3.88 - 3.93 (m, 1H), 5.38 (s, 2H), 7.65 (d, J=8.03 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H), (no 2 capable of proton exchange). LCMS (method-D) retention time 2.34 min, [M+H] 377.3. The second eluted compound, designated Intermediate 103D, was obtained (0.08 g, 7.00%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.08 (s, 6H), 0.89 (s, 9H), 2.26 (s, 1H), 2.29 (s, 3H), 2.55-2.68 (m, 1H), 2 .85 - 2.98 (m, 2H), 3.78 (dd, J=9.54, 7.03 Hz, 1H), 3.90 - 3.99 (m, 3H), 5.37 (s , 2H), 7.65 (d, J=8.03 Hz, 1H), 7.84 (d, J=8.03 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-D) retention time 2.61 min, [M+H] 377.3.

Intermediate 103.

To a stirred solution of intermediate 103C (0.15 g, 0.40 mmol) in DCM (5 ml) was added 1.4 M HCl in dioxane (0.011 ml, 0.362 mmol) and the resulting mixture was stirred at ambient temperature for 16 h. The resulting mixture was concentrated to dryness under reduced pressure and the residue was washed with diethyl ether (2x10 ml). The resulting solid was redissolved in ACN (3 ml) and K2CO3 (0.30 g) was added and the resulting mixture was stirred at ambient temperature for 3 h. The solid was filtered off and dried in vacuo to give intermediate 103 (0.08 g , 79.00%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 - 2.23 (m, 2H), 2.30 (s, 3H), 2.86 - 2.92 (m, 1H), 2.99 - 3.04 (m, 1H), 3, 27 3.31 (m, 3H), 3.89-3.93 (m, 1H), 4.55 (s, 1H), 5.39 (s, 2H), 7.65 (d, J=8 .07 Hz, 1H), 7.79 (d, J=8.56 Hz, 1H). (No 2 exchangeable protons were observed). LCMS (Method-D): retention time 0.55 min, [M+H] 263.2.

Intermediate 104: 6-(4-(chloromethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

- 132 043056

Intermediate 104A: 6-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 104A was obtained (0.30 g, 41%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 60B starting from Intermediate 6 (0.50 g, 2.36 mmol) and NaBH ₄ (0.09 g, 2.36 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.6 (s, 3H), 4.45 (d, J=5.6 Hz, 2H), 5.1 (t, J=5.60 Hz, 1H), 7.86 (s, 1H), 7.99 (s, 1H), 8.5 (s, 1H), 8.85 (s, 1H). LCMS (Method-D): retention time 1.33 min, [M+H] 215.2.

Intermediate 104.

Intermediate 104 was prepared (0.02 g, 69.00%) using a synthetic procedure similar to that of intermediate 59 starting from intermediate 104A (0.20 g, 0.93 mmol) and mesyl chloride ( 0.087 ml, 1.120 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.6 (s, 3H), 4.8 (s, 2H), 7.86 (s, 1H), 7.99 (s, 1H), 8.5 (s, 1H), 8.85 (s , 1H). LCMS (method-L): retention time 1.24 min, [M+2] 234.9.

Intermediate 105-I and 105-II: 5-(6-(2-hydroxypropan-2-yl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one

Enantiomer-1:(105-1) Enantiomer-ll :(105-11)

Intermediate 105A: 2-(6-chloropyrazin-2-yl)propan-2-ol

To a stirred solution of methyl 6-chloropyrazine-2-carboxylate (2.50 g, 14.49 mmol) in THF (50 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (12.07 mL, 36.2 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was diluted with saturated NH ₄ Cl solution (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 0.40% EtOAc/n-hexane) to give Intermediate 105A (0.70 g, 28.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.44 (s, 6H), 5.58 (br,s 1H), 8.66 (s, 1H), 8.86 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 105B: 5-(6-(2-hydroxypropan-2-yl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 105B was obtained (0.65 g, 78.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 105A (0.50 g, 2.92 mmol) and Intermediate 2B (0.80 g, 2.92 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51 (s, 6H), 2.27 - 2.37 (m, 3H), 5.50 (s, 2H), 5.54 (s, 1H), 7.71 - 7.77 (m, 1H), 7.79 - 7.85 (m, 1H), 8.77 (s, 1H), 8.95 (s, 1H). LCMS (Method-I): retention time 0.82 min, [M+H] 285.1.

Intermediate 105-I and 105-II.

Intermediate 105-I and 105-II were prepared using a synthetic procedure similar to

- 133 043056 that of intermediate 2-I and 2-II, and starting from intermediate 105B (0.65 g, 2.28 mmol). The crude residue was purified by preparative HPLC [Lux-cellulose C5 (250x30 mm) 5 microns; Solvent: 0.1% DEA+ACN : IPA(90:10), gradient: 100% over 17 min, flow: 30 ml/min, UV: 254] to give pure racemates. The racemic mixture was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak ADH (250x21 mm) 5 microns; 0.2% NH ₄ OH in MeOH, flow: 60.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 5.16 min), designated Intermediate 105-I, was obtained (0.04 g, 5.27%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.13 (d, J=3.01 Hz, 6H), 2.23 - 2.34 (m, 6H), 2.55 - 2.72 (m, 2H), 2.84 (t, J= 9.79 Hz, 2H), 4.03 (d, J=9.54 Hz, 1H), 4.34 (s, 1H), 5.39 (s, 2H), 7.68 (d, J= 8.03 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.62 min, [M+H] 291.2. Chiral purity (Method-XII): retention time 3.89 min, 100% e.i. The second eluted compound (retention time 6.50 min), designated Intermediate 105-II, was obtained (0.04 g, 5.27%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.13 (d, J=3.01 Hz, 6H), 2.20 - 2.36 (m, 6H), 2.57 - 2.70 (m, 2H), 2.84 (t, J= 8.53 Hz, 2H), 4.03 (d, J=7.03 Hz, 1H), 4.34 (s, 1H), 5.39 (s, 2H), 7.68 (d, J= 7.53 Hz, 1H), 7.85 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.613 min, [M+H] 291.2. Chiral purity (XIT method): retention time 4.94 min, 100% e.i.

Intermediate 106: 5-(4-Hydroxypyrrolidin-3-yl)-4-methylisobenzofuran-1(3H)onehydrochloride (Diastereomer I)

ABOUT

I T NH.HCI Me )--/

BUT

Intermediate 106A: tert-Butyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)4-oxopyrrolidine-1-carboxylate

Intermediate 106A was obtained (0.80 g, 10.96%) as an off-white solid using a synthetic procedure similar to that of intermediate 4A, starting from intermediate 2A (5.00 g, 22.02 mmol) and tert-butyl-3oxopyrrolidine-1-carboxylate (6.93 g, 37.4 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.27 - 1.59 (m, 9H), 2.15 - 2.30 (m, 3H), 3.62 (dd, J=10.79, 8.78 Hz, 1H), 3.80 - 3.91 (m, 1H), 3.94 - 4.09 (m, 1H), 4.22 - 4.33 (m, 1H), 4.37 - 4.48 (m, 1H), 5, 32 - 5.41 (m, 2H), 7.38 (d, J=8.03 Hz, 1H), 7.58 (d, J=8.03 Hz, 1H). LCMS (Method-I): retention time 1.11 min, [MH] 330.3.

Intermediate 106B and 106C: tert-Butyl-3-hydroxy-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate

Intermediate 106B and 106C were prepared using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 106A (0.80 g, 2.41 mmol) and NaBH ₄ (0.18 g, 4.83 mmol). The two diastereomers were separated by supercritical fluid chromatography (SFC) [Chiralpak AD-H (250x21 mm) 5 microns; 0.2% NH ₄ OH in MeOH, flow: 70.0 g/min. Temperature: 30°C, UV: 240 nm]. The first eluted compound (retention time 4.08 min), designated Intermediate 106B, was obtained (0.29 g, 36.00%) as an off-white solid. 1H NMR: Showed a mixture of diastereomers. LCMS (Method-D): retention time 1.96 min and 2.02 min, [(M-100)+H] 334.1. Chiral purity (Method-XII): retention time 2.44 min, 100% e.i.

The second eluted compound (retention time 7.31 min), designated as intermediate 106C, was obtained (0.30 g, 37.30%) as an off-white solid. 1H NMR: Showed

- 134 043056 mixture of diastereomers. LCMS (Method-D): retention time 1.95 min and 2.02 min, [(M-100)+H] 334.1.

Chiral purity (Method-XII): retention time 4.55 min, 100% e.i.

Intermediate 106.

Intermediate 106 was obtained (0.20 g, 99.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 52-I, starting from intermediate 106B (0.25 g, 0 .75 mmol). LCMS (method I): retention time 0.46 min, [M+H] 234.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 107: 5-(4-Fluoropyrrolidin-3-yl)-4-methylisobenzofuran-1(3H)one hydrochloride

ABOUT

F

Intermediate 107A: tert-Butyl 3-fluoro-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidine-1-carboxylate

ABOUT

Intermediate 107 was prepared (0.22 g, crude) using a synthetic procedure similar to that of Intermediate 4B, starting from Intermediate 106A (0.35 g, 1.05 mmol) and DAST (0.05 mmol). 69 ml, 5.25 mmol). LCMS: Compound poorly ionized. The compound was carried directly to the next step without further purification or characterization.

Intermediate 107.

Intermediate 107 was obtained (0.18 g, 99.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 52-I, starting from intermediate 108A (0.25 g, 0 .75 mmol).

LCMS (Method-I): retention time 0.47 min and 0.57 min, [M+H] 216.5. The compound was carried directly to the next step without further purification or characterization.

Intermediate 108: 6-(4-formyl-1H-pyrazol-1-yl)-4-(trifluoromethyl)nicotinonitrile

ABOUT

CN

Intermediate 108A: 6-chloro-4-(trifluoromethyl)nicotinonitrile

Synthesized in accordance with the methods described in the literature (WO 2006/68618 A1, 2006).

Intermediate 108.

Intermediate 108 was obtained (0.40 g, 48.10%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from intermediate 107A (0.77 g, 3.75 mmol) and 1H-pyrazole-4carbaldehyde (0.30 g, 3.12 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.35(s, 1H), 8.47(s, 1H), 9.37(s, 1H), 9.49(s, 1H), 10.02(s, 1H). LCMS: Compound poorly ionized.

Intermediate 109-I: (5R,8aR)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one

- 135 043056

Intermediate 109A-I: tert-butyl (5R,8aR)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3-oxotetrahydro-3H-oxazolo[3,4-a ]pyrazine-7(1H)-carboxylate

To a stirred solution of intermediate 38D-I (0.75 g, 2.07 mmol) in THF (20 mL) was added K ₂ CO ₃ (0.86 g, 6.21 mmol) followed by triphosgene (0.61 g , 2.07 mmol) and the resulting reaction mixture was heated at 70°C for 16 h. The resulting mixture was cooled to ambient temperature, diluted with water (30 ml) and was extracted with the addition of ethyl acetate (3x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 50% EtOAc/n-hexane) to give Intermediate 109A-I (0.700 g, 87.00%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 - 1.23 (m, 9H), 2.32 (s, 3H), 2.96 (br. s., 1H), 3.49 (dd, J=12.00, 4.00 Hz , 1H), 4.01 - 4.11 (m, 3H), 4.44 - 4.50 (m, 1H), 4.78 - 4.80 (m, 1H), 5.15 (d, J =5.00 Hz, 1H), 5.35 - 5.41 (m, 2H), 7.58 (d, J=6.50 Hz, 1H), 7.68 (d, J=6.50 Hz , 1H). LCMS (Method-I): retention time 1.34 min, [M+H] 389.2.

Intermediate 109-I.

Intermediate 109-I was obtained (0.40 g, 77.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 4C starting from Intermediate 109A-I (0.70 g , 1.80 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.29 - 2.38 (m, 3H), 3.00 - 3.23 (m, 2H), 3.34 - 3.44 (m, 1H), 3.60 (br. s., 2H) , 3.90 4.07 (m, 1H), 4.25-4.37 (m, 1H), 4.43-4.54 (m, 1H), 5.10 (dd, J=11.55 , 3.51 Hz, 1H), 5.35 - 5.52 (m, 2H), 7.61 - 7.67 (m, 1H), 7.67 - 7.76 (m, 1H). LCMS (Method-I): retention time 0.5 min, [M+H] 289.2.

Intermediate 110: 6-(5-formylisoxazol-3-yl)-4-methylnicotinonitrile

Intermediate 110A: 6-formyl-4-methylnicotinonitrile

To a stirred solution of 6-bromo-4-methylnicotinonitrile (2.00 g, 10.15 mmol) in DMF (15 ml) was added solid Na ₂ CO ₃ (1.08 g, 10.15 mmol) at ambient temperature, in nitrogen atmosphere. The resulting reaction mixture was degassed with nitrogen gas for 10 min and tert-butyl isocyanide (1.01 g, 12.18 mmol), 1,4-bis(diphenylphosphino)butane (0.13 g, 0.30 mmol), palladium(P ) (0.07 g, 0.30 mmol) and triethylsilane (1.18 g, 10.15 mmol). The resulting mixture was heated to 65°C for 5 h and cooled to ambient temperature. The resulting mixture was filtered through Celite® and the filtrate was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 110A (0.30 g, 20.00%). ¹ NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.61 (s, 3H), 8.01 (s, 1H), 9.15 (s, 1H), 10.01 (s, 1H). LCMS (Method-D): retention time 2.45 min, [M+H] 147.0. The compound was carried directly to the next step without further purification or characterization.

- 136 043056

Intermediate 110B: (E)-6-((hydroxyimino)methyl)-4-methylnicotinonitrile

To a stirred solution of intermediate 110A (0.50 g, 3.00 mmol) in EtOH (10 mL) were added hydroxylamine hydrochloride (0.26 g, 3.70 mmol) and sodium acetate (0.30 g, 3.70 mmol) at ambient temperature, under nitrogen atmosphere. The resulting suspension was heated to 75°C for 25 minutes. The resulting mixture was cooled to ambient temperature, diluted with water (60 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was suspended in DCM (5 ml) and the solid was collected by vacuum filtration and dried in vacuo to give Intermediate 110B (0.30 g, 60.00%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.52 (s, 3H), 7.86 (s, 1H), 8.12 (s, 1H), 8.92 (s, 1H), 12.13 (s, 1H). LCMS (Method-H): retention time 0.77 min, [M+H] 162.2.

Intermediate 110C: 6-(5-(hydroxymethyl)isoxazol-3-yl)-4-methylnicotinonitrile

To a solution of intermediate 110B (0.20 g, 1.24 mmol) in DMF (10 ml) was added N-chlorosuccinimide (0.17 mg, 1.24 mmol) and the resulting reaction mixture was heated at 50° C. for 1 h. the mixture was cooled to ambient temperature and prop-2-yn-1-ol (0.07 g, 1.24 mmol) was added followed by TEA (0.17 ml, 1.24 mmol) and stirred for 3 hours. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 30% EtOAc/n-hexane) to give Intermediate 110C (0.08 g, 30.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.55 2.63 (m, 3H), 4.67 (dd, J=6.02, 1.00 Hz, 2H), 5.76 (t, J=6.02 Hz, 1H), 6, 95 (s, 1H), 8.16 (s, 1H), 9.06 (s, 1H). LCMS (Method-I): retention time 0.9 min, [M+H] 216.0.

Intermediate 110.

Intermediate 110 was obtained (0.75 g, 95.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 110C (0.08 g, 0.37 mmol) and DessaMartin periodinan (0.24 g, 0.56 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.50-2.51 (m, 3H), 7.92 (s, 1H), 8.27 (s, 1H), 9.12 (s, 1H), 9.99 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 111: 6-(4-formyl-1H-imidazol-1-yl)-2,4-dimethylnicotinonitrile

Intermediate 111 was obtained (0.08 g, 29.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 6-chloro-2,4-dimethylnicotinonitrile (0. 20 g, 1.18 mmol) and 1H-imidazole-4carbaldehyde (0.12 g, 1.12 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.55 - 2.61 (m, 3H), 2.73 (s, 3H), 7.98 (s, 1H), 8.76 (d, J=0.98 Hz, 1H), 8.81 (d, J=1.22 Hz, 1H), 9.88 (s, 1H). LCMS (Method-I): retention time 0.92 min, [M+1] 227.5.

- 137 043056

Intermediate 112: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-2,4-dimethylnicotinonitrile

Intermediate 112A: 6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-2,4-dimethylnicotinonitrile and Intermediate 112B: 6-(4-(hydroxymethyl)-2H-1 ,2,3-triazol-2-yl)-2,4dimethylnicotinonitrile

Intermediate 112A and Intermediate 112B were prepared using a synthetic procedure similar to that of Intermediate 20 starting from Intermediate 28A (1.00 g, 10.09 mmol) and 6-chloro-2,4-dimethylnicotinonitrile (1.85 g, 11.10 mmol). The first eluted compound, designated Intermediate 112A, was obtained (0.30 g, 12.97%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.63 (s, 3H), 2.74 (s, 3H), 4.64 (d, J=6.00 Hz, 2H), 5.37 (t, J=6.00 Hz, 1H), 8.12 (s, 1H), 8.69 (s, 1H). LCMS (Method-I): retention time 0.77 min, [M+1] 230.4. The second eluted compound, designated Intermediate 112B, was obtained (0.32 g, 13.83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H), 2.71 (s, 3H), 4.67 (d, J=6.00 Hz, 2H), 5.53 (t, J=6.00 Hz, 1H), 7.95 (s, 1H), 8.16 (s, 1H). LCMS (Method-I): retention time 0.74 min, [M+1] 230.4.

Intermediate 112.

Intermediate 112 was obtained (0.30 g, 66.20%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 112A (0.32 g, 1.40 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.65 (s, 3H), 2.76 (s, 3H), 8.21 (s, 1H), 9.56 (s, 1H), 10.13 (s, 1H). LCMS (Method-I): retention time 0.98 min, [M-1] 228.4.

Intermediate 113: 6-(4-formyl-2H-1,2,3-triazol-2-yl)-2,4-dimethylnicotinonitrile

Intermediate 113 was obtained (0.40 g, 86.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 112B (0.32 g, 1.40 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.64 (s, 3H), 2.76 (s, 3H), 8.11 (s, 1H), 8.77 (s, 1H), 10.21 (s, 1H). LCMS (Method-I): retention time 0.93 min, [M+H] 228.4.

- 138 043056

Intermediate 114: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-2-methoxy-4-methylnicotinonitrile

Intermediate 114A: 6-chloro-2-methoxy-4-methylnicotinonitrile and Intermediate 114B: 2-chloro-6-methoxy-4-methylnicotinonitrile

Cl

MeO

Me

ome

Cl

Me

CN

Intermediate 114A

CN

Intermediate connection 114V

To a stirred solution of 2,6-dichloro-4-methylnicotinonitrile (15.00 g, 80.00 mmol) in MeOH (100 ml) was added sodium methoxide (14.89 ml, 80.00 mmol) and the resulting mixture was stirred at ambient temperature. media for 16 hours the resulting mixture was diluted with water (300 ml) and was extracted with the addition of DCM (3x250 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The residue was purified by SFC [Column: Lux cellulose-2 (50x250 mm) 5 microns; 10% 0.2% DEA in IPA; total flow: 150 g/min; UV: 220 nm] to give Intermediate 114A (5.50 g, 32.30%) as an off-white solid (retention time: 6.3 min). 1H NMR (400 MHz, DMSOd ₆ ) δ ppm 2.46 (s, 3H), 3.99 (s, 3H), 7.27 (s, 1H). LCMS: (Method-I) retention time: 1.22 min, [M+1] 183.3. Intermediate 114B (6.50 g, 40.40%) as an off-white solid (retention time: 5.8 minutes). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.43 (s, 3H), 3.91 (s, 3H), 6.94 (s, 1H). LCMS (Method-I): retention time 1.29 min, [M+1] 183.4.

Intermediate 114C: 6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-2-methoxy-4methylnicotinonitrile and Intermediate 114D: 6-(4-(hydroxymethyl)-1H-1 ,2,3-triazol-1-yl)2-methoxy-4-methylnicotinonitrile

Intermediate 114C and Intermediate 114D were prepared using a synthetic procedure similar to that of Intermediate 20, starting from Intermediate 114A (2.21 g, 12.11 mmol) and Intermediate 28A (1.00 g, 10.09 mmol). The first eluted compound, designated Intermediate 114C, was obtained (0.15 g, 5.45%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 4.07 (s, 3H), 4.67 (d, J=5.52 Hz, 2H), 5.51 (t, J=5.77 Hz, 1H), 7.68(s, 1H), 8.16(s, 1H). LCMS (Method-I): retention time 0.82 min, [M+1] 246.4. The second eluted compound, designated Intermediate 114D, was obtained (0.25 g, 9.60%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.55 - 2.62 (m, 3H), 4.05 - 4.15 (m, 3H), 4.61 - 4.72 (m, 2H), 5.38 (t, J=5.77 Hz, 1H), 7.83 (s, 1H), 8.76 (s, 1H). LCMS (Method-I): retention time 0.81 min, [M+1] 246.4.

Intermediate 114.

Intermediate 114 was obtained (0.08 g, 36.90%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 114D (0.23 g, 0.89 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.67 (s, 3H), 4.18 (s, 3H), 7.86 (s, 1H), 8.79 (s, 1H), 10.21 (s, 1H). LCMS (Method-I): retention time 1.03 min, [M+1] 244.4.

- 139 043056

Intermediate 115: 6-(4-formyl-2H-1,2,3-triazol-2-yl)-2-methoxy-4-methylnicotinonitrile

Intermediate 115 was obtained (0.38 g, 82.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 114C (0.40 g, 1.63 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.62 (s, 3H), 4.11 (s, 3H), 7.85 (s, 1H), 8.78 (s, 1H), 10.21 (s, 1H). LCMS (Method-I): retention time 1.06 min, [M+H] 244.0.

Intermediate 116-I and 116-II: 4-methyl-5-(piperidin-3-yl)isobenzofuran-1(3H)-one O

Me

Intermediate 116A: 4-methyl-5-(pyridin-3-yl)isobenzofuran-1(3H)-one

Intermediate 116A was prepared (0.42 g, 85.00%) using a synthetic procedure similar to that of intermediate 2C, starting from intermediate 2A (0.50 g, 2.20 mmol) and pyridine- 3-ylboronic acid (0.27 g, 2.20 mmol). ¹ H NMR (400 MHz, CD3OD) δ ppm 2.29 (s, 3H), 5.45 (s, 2H), 7.52 (d, J=7.53 Hz, 1H), 7.56-7.70 (m, 1H), 7.83 (d, J=7.53 Hz, 1H), 7.93 (dt, J=7.91, 1.82 Hz, 1H), 8.46-8.76 (m, 2H). LCMS (Method-D): retention time 1.71 min, [M+H] 226.2.

Intermediate 116-I and 116-II.

To a solution of intermediate 116A (0.42 g, 1.87 mmol) in EtOH (50 mL) was added HCl (0.57 mL, 18.65 mmol) and degassed with nitrogen for 5 min. Platinum (IV) oxide (0.09 g, 0.37 mmol) was added and the reaction mixture was stirred under H ₂ gas at ambient temperature for 12 hours. The resulting mixture was filtered through Celite® and washed with EtOH (40 ml). The filtrate was evaporated under reduced pressure and the racemate was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak IC (250x4.6 mm) 5.0 microns; 0.2% DEA in MeOH, flow: 1.6 ml/min, temperature: 25° C., UV: 220 nm]. The first eluted compound (retention time 8.18 min), designated as intermediate 116-I, was obtained (0.12 g, 27.80%) as a brown solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.61 - 2.02 (m, 4H), 2.26 - 2.47 (m, 3H), 2.69 - 2.85 (m, 2H), 3.02 - 3.26 (m, 3H ), 5.37 (s, 2H), 7.29-7.60 (m, 1H), 7.70 (d, J=8.03 Hz, 1H), (1 exchangeable proton not observed). LCMS (Method-D): retention time 0.47 min, [M+H] 232.2. The second eluted compound (retention time 10.32 min), designated as intermediate 116-II, was obtained (0.08 g, 18.55%) as a brown solid. ¹ H NMR (400 MHz, CD3OD) δ ppm 1.62 - 1.79 (m, 2H), 1.81 - 2.01 (m, 2H), 2.23 - 2.43 (m, 3H), 2.59 - 2.84 (m, 2H ), 2.95 - 3.24 (m, 3H), 5.36 (s, 2H), 7.49 (d, J=8.03 Hz, 1H), 7.68 (d, J=8, 53 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 0.52 min, [M+H] 232.2.

Intermediate 117: 2-(4-formyl-1H-pyrazol-1-yl)isonicotinonitrile

- 140 043056

Intermediate 117 was prepared (0.03 g, 22.99%) using a synthetic procedure similar to that of intermediate 20, starting from 1Hpyrazole-4-carbaldehyde (0.05 g, 0.55 mmol) and 2-Bromisonicotinonitrile (0.10 g, 0.55 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (dd, J=4.88, 1.38 Hz, 1H), 8.09 - 8.38 (m, 2H), 8.64 (dd, J=5.00, 0.75 Hz, 1H),

9.08 (d, J=0.75 Hz, 1H), 10.02 (s, 1H). LCMS (Method-D): retention time 1.42 min, [M+H] 199.0.

Intermediate 118A and 118B: 5-(5-hydroxypiperidin-3-yl)-4-methylisobenzofuran1(3H)-one

Intermediate 118C was obtained (1.30 g, 24.15%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 2A (3.12 g, 13.73 mmol) and (5methoxypyridin-3-yl)boronic acid (3.00 g, 19.62 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H), 3.89 (s, 3H), 5.47 (s, 2H), 7.38-7.47 (m, 1H), 7.53 (d, J=7, 53 Hz, 1H), 7.77 (d, J=8.03 Hz, 1H), 8.20 (d, J=1.51 Hz, 1H), 8.37 (d, J=3.01 Hz , 1H). LCMS (Method-D): retention time 1.58 min, [M+H] 256.2.

Intermediate 118D: 5-(5-hydroxypyridin-3-yl)-4-methylisobenzofuran-1(3H)-one

ABOUT

HE

A solution of intermediate 118C (1.70 g, 6.66 mmol) in 33% HBr in AcOH (28.2 ml, 166 mmol) was heated at 120°C for 20 h. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure to give Intermediate 118D (1.20 g, 31.40%) as a brown solid. LCMS (Method-I): retention time 0.71 min, [M+H] 242.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate connection 118A and 118B.

A solution of intermediate 118A (1.20 g, 4.97 mmol) in AcOH (100 ml) was degassed with nitrogen for 5 minutes. Platinum (IV) oxide (0.01 ml, 0.50 mmol) was added and the resulting mixture was stirred under H ₂ gas pressure (50 psi) at ambient temperature for 28 hours. The resulting mixture was filtered through Celite® and washed MeOH (40 ml). The filtrate was evaporated under reduced pressure. The two diastereomers were separated by HPLC [Xterra RP 18 (250x4.6 mm) 5 microns; solvent A: 10 mM ammonium bicarbonate, solvent B: ACN+MeOH (1:1), gradient: 0-100% B over 18 min, flow: 1 ml/min, UV: 254 nm]. The first eluted compound (retention time 10.33 min), designated Intermediate 118A: Dia-I, was obtained (0.20 g, 16.26%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.87 - 2.02 (m, 2H), 2.18 - 2.36 (m, 3H), 2.81 (d, J=12.05 Hz, 1H), 2.94 - 3.08 ( m, 2H), 3.17 (s, 2H), 3.45-3.58 (m, 1H), 4.69 (br. s., 1H), 5.37 (s, 2H), 6, 66 (br. s., 1H), 7.45 (d, J=8.03 Hz, 1H), 7.63 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.49 min, [M+H] 248.1. The second eluted compound (retention time 12.13 min), designated Intermediate 118B:Dia-II, was obtained (0.07 g, 5.69%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75 (s, 2H), 1.92 (s, 2H), 2.28 - 2.38 (m., 4H), 2.81 (d, J=12.05 Hz, 1H), 3, 17 (s, 1H), 3.61-4.21 (m, 2H), 5.37 (br. s., 2H), 6.65 (br. s., 1H), 7.06-7, 32 (m, 1H), 7.38-7.95 (m, 1H). LCMS (Method-D): retention time 0.50 min, [M+H] 248.2.

Intermediate 119A and 119B: 5-(5-methoxypiperidin-3-yl)-4-methylisobenzofuran- 141 043056

1(3Н)-one

Intermediate 119A and 119B was prepared using a synthetic procedure similar to that of intermediate 118A and 118B, starting from intermediate 118C (1.27 g, 4.97 mmol). The two diastereomers were separated by HPLC [Xterra RP 18 (250x4.6 mm) 5 microns; solvent A: 10 mM ammonium bicarbonate, solvent B: ACN+MeOH (1:1), gradient: 0-100% B over 18 min, flow: 1 ml/min, UV: 254 nm]. The first eluted compound (retention time 14.48 min), designated Intermediate 119A: Dia-I, was obtained (0.20 g, 15.39%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.35 - 1.85 (m, 5H), 2.16 - 2.38 (m, 4H), 3.17 (s, 3H), 4.09 (d, J=9.54 Hz, 2H) , 4.46 (br. s., 1H), 5.39 (d, J=2.93 Hz, 2H), 7.49 (d, J=7.83 Hz, 1H), 7.65 (d , J=8.31 Hz, 1H). LCMS (Method-D): retention time 0.78 min, [M+H] 262.2. The second eluted compound (retention time 17.38 min), designated Intermediate 119B: Dia-II, was obtained (0.20 g, 15.39%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.35 - 1.85 (m, 5H), 2.16 - 2.38 (m, 4H), 3.17 (s, 3H), 4.09 (d, J=9.54 Hz, 2H) , 4.46 (br. s., 1H), 5.39 (d, J=2.93 Hz, 2H), 7.49 (d, J=7.83 Hz, 1H), 7.65 (d , J=8.31 Hz, 1H). LCMS (Method-D): retention time 0.77 min, [M+H] 262.2.

Intermediate 120: 2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyrimidine-5-carbaldehyde

Intermediate 120 was prepared (0.10 g crude) using a synthetic procedure similar to that of intermediate 20 starting from 2-bromopyrimidine-5-carbaldehyde (0.10 g, 0.54 mmol) and 3 ,5-dimethyl-4H-1,2,4-triazole (0.05 g, 0.54 mmol). LCMS (Method-I): retention time 0.49 min, [M+H] 204.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 121: 2-(4-formyl-1H-pyrazol-1-yl)-3-methylisonicotinonitrile O ⁿ EgH t N Hme fl

Intermediate 121A: 4-cyano-3-methylpyridine 1-oxide

CN /G N I

ABOUT

To a solution of 3-methylisonicotinonitrile (5.00 g, 42.30 mmol) in DCM (100 mL) was added 3-chloroperoxybenzoic acid (14.61 g, 85.00 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for for 16 hours the resulting mixture was diluted with water (50 ml), podslushivaet 10% NaHCO ₃ solution and was extracted with the addition of ethyl acetate (2x75 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 121A (3.50 g, 61.30%) as a pale yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 2.38 (s, 3H), 7.84 - 7.85 (d, J=6.80 Hz, 1H), 8.21 - 8.23 (dd, J=1.20 Hz, 6.80 Hz , 1H), 8.41 (s, 1H). LCMS (Method-D): retention time 0.44 min, [M+H] 135.2.

- 142 043056

Intermediate 121B: 2-(4-formyl-1H-pyrazol-1-yl)-3-methylisonicotinonitrile

CN

A stirred solution of intermediate 121A (3.5 g, 26.1 mmol) in POCl ₃ (48.6 ml, 52 mmol) was heated at 100°C for 3 hours. The resulting mixture was cooled to ambient temperature and poured into cold water (50 ml), basified with 10% NaHCO ₃ solution and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-80 g, 0-20% EtOAc/n-hexane) to give Intermediate 121B (0.62 g, 15.57%) as a pale yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.41-2.83 (m, 3H), 7.44 (d, J=5.00 Hz, 1H), 8.39 (dd, J=5.00, 0.75 Hz, 1H). LCMS (Method-D): retention time 1.66 min, [M+H] 153.2.

Intermediate 121.

Intermediate 121 was prepared (0.03 g, 30.25%) using a synthetic procedure similar to that of intermediate 20, starting from 1Hpyrazole-4-carbaldehyde (0.03 g, 0.33 mmol) and intermediate 121B (0.05 g, 0.33 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.56 - 2.69 (m, 3H), 7.82 - 8.07 (m, 1H), 8.12 - 8.40 (m, 1H), 8.48 - 8.82 (m, 1H ), 8.90-9.29 (m, 1H), 9.99 (s, 1H). LCMS (Method-D): retention time 1.43 min, [M+H] 213.2.

Intermediate 122-I: 5-(5-fluoropiperidin-3-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 122A: ethyl-(4-methoxybenzyl)glycinate

To a stirred solution of (4-methoxyphenyl)methanamine (19.05 mL, 146 mmol) in DCM (250 mL) was added TEA (20.32 mL, 146 mmol) followed by ethyl bromoacetate (16.13 mL, 146 mmol) at 0 °C and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water (250 ml) and extracted with DCM (3x250 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-220 g, 35-40% EtOAc/n-hexane)) to give Intermediate 122A (21.00 g, 63.90%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.22 - 1.30 (m, 3H), 3.39 (s, 2H), 3.74 (s, 2H), 3.80 (s, 3H), 4.19 (q, J=7, 03 Hz, 2H), 6.68-6.96 (m, 2H), 7.13-7.30 (m, 3H). LCMS (Method-D): retention time 1.80 min, [M+H] 224.0.

Intermediate 122B: ethyl N-(4-methoxybenzyl)-N-(2-oxopropyl)glycinate

To a stirred solution of intermediate 122A (21.00 g, 71.90 mmol) in EtOH (250 ml) was added NaHCO ₃ (11.29 g, 134 mmol) followed by 1-chloropropan-2-one (11.04 ml , 134 mmol) at 0°C and the resulting mixture was stirred at ambient temperature for 16 hours. The resulting mixture was filtered through Celite® and washed with EtOH (50 ml) and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-220 g, 20% EtOAc/n-hexane) to give Intermediate 122B (21.00 g, 80.00%) as a pale yellow liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.26 (t, J=7.25 Hz, 3H), 2.12 (s, 3H), 3.44 (s, 2H), 3.49

- 143 043056 (s, 2H), 3.77 (s, 2H), 3.80 (s, 3H), 4.16 (q, J=7.09 Hz, 2H), 6.70 - 6.98 (m, 2H), 7.26 (s, 2H). LCMS (Method-D): retention time 2.19 min, [M+H] 280.2.

Intermediate 122C: 1-(4-methoxybenzyl)-5-oxo-1,2,5,6-tetrahydropyridin-3yltrifluoromethanesulfonate

To a stirred solution of intermediate 122B (16.30 g, 58.40 mmol) in THF (50 mL) was added 1M potassium tert-butoxide in THF (58.4 mL, 58.4 mmol) followed by 2-[N, Nbis(trifluoromethanesulfonyl)amino]-5-chloropyridine (22.91 g, 58.4 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with a solution of NH ₄ Cl (50 ml) and was extracted by adding diethyl ether (2x75 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-80 g, 12-15% EtOAc/n-hexane) to give Intermediate 122C (4.40 g, 20.64%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.25 (s, 2H), 3.47 (s, 2H), 3.67 (s, 2H), 3.71-4.02 (m, 3H), 6.15 (t, J=1, 25 Hz, 1H), 6.74 - 6.96 (m, 2H), 7.12 - 7.24 (m, 2H). LCMS (Method-D): retention time 2.81 min, [M+H] 366.2.

Intermediate 122D: 1-(4-methoxybenzyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,6-dihydropyridin-3(2H)-one

To a solution of intermediate 122C (4.20 g, 11.50 mmol) in dioxane (100 mL) was added intermediate 2B (3.15 g, 11.50 mmol) followed by tribasic potassium phosphate (4.88 g, 22 .99 mmol) and the resulting mixture was degassed with argon for 15 min. PdCh(dppf) ₂ CH ₂ Cl ₂ (0.47 g, 0.58 mmol) was added and the resulting reaction mixture was stirred at 40° C. for 12 h. The resulting mixture was cooled to ambient temperature, filtered through Celite® and washed with ethyl acetate (50 ml). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (Redisep-40 g, 70% EtOAc/n-hexane) to give Intermediate 122D (3.20 g, 72.80%). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.22 (s, 3H), 3.31 (s, 2H), 3.37 (s, 2H), 3.68 (s, 2H), 3.78-3.83 (m, 3H), 5 .08 - 5.34 (m, 2H), 6.07 (t, J=1.76 Hz, 1H), 6.84 - 6.89 (m, 2H), 7.22 - 7.24 (m , 1H), 7.25-7.29 (m, 2H), 7.76 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 2.39 min, [M+H] 364.2.

Intermediate methylisobenzofuran-1(3H)-one

122E and 122F: 5-(5-hydroxy-1-(4-methoxybenzyl)piperidin-3-yl)-4-

To a solution of intermediate 122D (2.00 g, 5.50 mmol) in MeOH (50 ml) was added nickel(II) chloride hexahydrate (2.62 g, 11.01 mmol) followed by NaBH4 (0.416 g, 11. 01 mmol) and the resulting reaction mixture was stirred at 50°C for 2 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with 10% NH4Cl solution (50 ml) and extracted by adding 10% MeOH in CHCl ₃ (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. A mixture of diastereomers was separated by column chromatography (Redisep - 40 g, 10% MeOH/CHCl ₃ ). The first eluted compound, designated Intermediate 122E: Dia-I, was obtained (0.70 g, 34.60%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59 - 1.80 (m, 4H), 2.06 - 2.27 (m, 4H), 3.39 - 3.60 (m, 4H), 3.63 - 3.78 (s, 3H ), 3.82 (br. s., 1H), 4.60 (d, J=5.02 Hz, 1H), 5.13-5.43 (m, 2H), 6.88 (d, J = 9.04 Hz, 2H), 7.13 - 7.36 (m, 2H), 7.62 (s, 2H). LCMS (method-J): retention time 1.14 min,

- 144 043056

[M+H] 368.1. The second eluted compound, designated Intermediate 122F: DiaII, was obtained (0.90 g, 44.50%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.39 (q, J=12.05 Hz, 1H), 1.70 - 1.97 (m, 3H), 2.21 (s, 3H), 2.63 - 2.82 (m, 1H) , 2.98 (d, J=5.52 Hz, 1H), 3.04 3.21 (m, 1H), 3.38 - 3.56 (m, 3H), 3.60 - 3.81 ( m, 3H), 4.82 (d, J=5.02 Hz, 1H), 5.36 (s, 2H), 6.73-6.95 (m, 2H), 7.21 (d, J =9.04 Hz, 2H), 7.45 (d, J=8.03 Hz, 1H), 7.63 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.93 min, [M+H] 368.1.

Intermediate 122G-I and 122G-II: 5-(5-fluoro-1-(4-methoxybenzyl)piperidin-3-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 122G-I and 122G-II were prepared using a synthetic procedure similar to that of Intermediate 4B, starting from Intermediate 122E (0.03 g, 0.33 mmol) and DAST (0.43 mL, 3.27 mmol). The racemate was separated into two separate enantiomers by the SFC method [Chiralpak AD-H (250x4.6 mm) 5.0 microns; 0.2% NH4OH in ACN+NaOH (1:1), flow: 70.0 g/min, temperature: 30°C, UV 230 nm]. The first eluted compound (retention time 5.0 min), designated Intermediate 122G-I, was obtained (0.120 g, 20.00%) as a pale yellow solid. Ή NMR (300 MHz, CDCl ₃ ) δ ppm 1.57 (s, 1H), 1.72 (t, J=12.22 Hz, 1H), 2.00 (t, J=11.06 Hz, 1H), 2.12 (td, J=9 .91, 5.28 Hz, 1H), 2.24 (s, 2H), 2.26 - 2.32 (m, 1H), 2.36 (s, 1H), 2.82 (d, J= 11.23 Hz, 1H), 3.12 - 3.36 (m, 1H), 3.50 - 3.63 (m, 2H), 3.80 (s, 3H), 4.65 - 4.89 (m, 1H), 5.23 (s, 2H), 6.81-6.89 (m, 2H), 7.15-7.24 (m, 2H), 7.41 (d, J=7 .93 Hz, 1H), 7.73 (d, J=7.93 Hz, 1H). ¹⁹ F NMR (300 MHz, CDCl ₃ ) δ ppm -180.45. LCMS (Method-D): retention time 3.09 min, [M+H] 370.2. The second eluted compound (7.0 min retention time), designated Intermediate 122G-II, was obtained (0.110 g, 18.23%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.55 (br. s., 1H), 1.61-1.81 (m, 1H), 2.00 (t, J=11.29 Hz, 1H), 2.06-2.17 (m , 1H), 2.24 (s, 2H), 2.27 (br. s., 1H), 2.35 (s, 1H), 2.82 (d, J=11.04 Hz, 1H), 3.18 (br. s., 1H), 3.32 (br. s., 1 h, 3.46 - 3.65 (m, 2H), 3.80 (s, 2H), 4.58 - 4.92 (m, 1H), 5.15 - 5.28 (m, 2H), 6.73 - 6.94 (m, 2H), 7.11 - 7.24 (m, 2H), 7, 41 (d, J=8.03 Hz, 1H), 7.73 (d, J=8.03 Hz, 1H) LCMS (method-D): retention time 2.91 min, [M+H] 370 .5 ¹⁹ F NMR (400 MHz, CDCl3) δ ppm -180.46.

Intermediate 122-I.

A solution of intermediate 122G-I (0.12 g, 0.33 mmol) in AcOH (10 ml) was purged with nitrogen for 5 minutes. To the resulting reaction mixture was added 20% Pd(OH) ₂ /C (0.01 g, 0.06 mmol) and stirred at ambient temperature for 12 h under H ₂ atmosphere. The resulting mixture was filtered through Celite®, washed with EtOH (10 ml) and the filtrate was concentrated under reduced pressure, diluted with water. NaHCO ₃ solution (20 ml) and extracted with ethyl acetate (2x30 ml).

The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 122-I (0.08 g, 95.00%) as a brown solid. 1H NMR (400 MHz, DMSOd ₆ ) δ ppm 2.22 (br. s., 1H), 2.29 (s, 3H), 2.31 (s, 1H), 2.34 (br. s., 1H), 2.37 (s, 1H) , 2.43 (s, 1H), 2.82 (d, J=12.55 Hz, 1H), 3.10 (t, J=10.79 Hz, 1H), 3.24 (d, J= 12.55 Hz, 2H), 4.48 - 4.77 (m, 1H), 5.39 (s, 2H), 7.54 (d, J=8.53 Hz, 1H), 7.66 ( d, J=8.03 Hz, 1H). ¹⁹ F NMR (300 MHz, DMSO-d ₆ ) δ ppm -175.06. LCMS (Method-D): retention time 1.32 min, [M+H] 250.2.

Intermediate 123-I, II, III and IV: 5-(6-(1-hydroxyethyl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one

- 145 043056

Intermediate 123A: 5-(6-(hydroxymethyl)pyrazin-2-yl)-4-methylisobenzofuran1(3H)-one

Intermediate 123A was prepared (6.00 g, 87.00%) using a synthetic procedure similar to that of intermediate 2C, starting from intermediate 2B (7.02 g, 25.60 mmol) and (6 -chloropyrazin-2-yl)methanol (3.70 g, 25.60 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.98 - 1.23 (m, 2H), 2.24 - 2.36 (m, 3H), 5.49 (s, 2H), 7.42 - 7.60 (m, 1H), 7, 70 (d, J=7.53 Hz, 1H), 7.81 (d, J=8.03 Hz, 1H), 8.77 (d, J=6.53 Hz, 2H). LCMS (Method-D): retention time 0.92 min, [M+H] 257.0.

Intermediate 123B: 6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrazine-2carbaldehyde

About □SP

Me

H

Intermediate 123B was prepared (4.40 g, 55.40%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 123A (8.00 g, 31.20 mmol) and Dess periodinan - Martina (26.50 g, 62.40 mmol). 1H (400 MHz, CDCl ₃ ) δ ppm 2.42 (s, 3H), 5.37 (s, 2H), 7.69 (d, J=7.75 Hz, 1H), 7.94 (d, J=7.75 Hz, 1H), 8.99 (s, 1H), 9.21 (s, 1H), 10.12-10.29 (m, 1H). LCMS (Method-D): retention time 1.18 min, [M+H] 255.0.

Intermediate 123C: 5-(6-(1-hydroxyethyl)pyrazin-2-yl)-4-methylisobenzofuran1(3H)-one

ABOUT

Me

Me^OH

Intermediate 123C was obtained (0.95 g, 89.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 72A, starting from Intermediate 123 B (1.00 g, 3.93 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.47 (d, J=6.53 Hz, 3H), 2.22 - 2.39 (m, 3H), 4.90 (dd, J=6.53, 4.52 Hz, 1H), 5 .51 (s, 2H), 5.69 (d, J=4.80 Hz, 1H), 7.73 (d, J=8.03 Hz, 1H), 7.83 (d, J=8, 03 Hz, 1H), 8.82 (s, 2H). LCMS (method I): retention time 0.78 min, [M+H] 271.2.

Intermediate 123-I, II, III and IV.

Intermediate 123-I was prepared using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from intermediate 123C (0.90 g, 3.33 mmol). The racemate was separated into four individual enantiomers by SFC [Chiralpak IC (250x4.6 mm) 5.0 microns; 0.2% NH ₄ OH in ACN+MeOH (1:1), flow: 4.0 ml/min, temperature: 30° C., UV: 235 nm]. The first eluted compound (retention time 12.40 min), designated as intermediate 123-I, was obtained (0.08 g, 8.69%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.01 - 1.11 (m, 3H), 1.56 - 1.76 (m, 2H), 2.15 - 2.27 (m, 3H), 2.29 - 2.36 (m, 3H ), 2.82 (d, J=11.74 Hz, 2H), 3.17 (s, 1H), 4.00 (dd, J=9.78, 2.45 Hz, 1H), 4.66 (br. s., 1H), 5.28 - 5.44 (m, 2H), 7.67 (d, J=8.07 Hz, 1H), 7.75 - 7.89 (m, 1H) . LCMS (Method-D): retention time 0.51 min, [M+H] 277.2. The second eluted compound (retention time 12.80 min), designated as intermediate 123-II, was obtained (0.03 g, 3.26%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 0.98 - 1.17 (m, 3H), 1.33 (dt, J=13.76, 7.18 Hz, 1H), 2.05 (s , 1H), 2.12 - 2.25 (m, 2H), 2.25 - 2.37 (m, 4H), 2.75 - 2.92 (m, 2H), 3.82 - 4.13 (m, 2H), 4.51-4.72 (m, 1H), 5.39 (s, 2H), 7.56-7.72 (m, 1H), 7.82 (dd, J=7 .95, 4.03 Hz, 1H). LCMS (Method-D): retention time 0.51 min, [M+H] 277.2. The third eluted compound (retention time 15.0 min), designated as intermediate 123-III, was obtained (0.18 g, 19.56%) as a pale yellow solid. 1H NMR (400 MHz,

- 146 043056

DMSO-d ₆ ) δ ppm 0.96 - 1.15 (m, 3H), 2.10 - 2.37 (m, 4H), 2.59 - 2.72 (m, 1H), 2.84 (d, J=13.05 Hz, 1H), 2.96 (d, J=11.04 Hz, 1H), 3.18 (s, 3H), 3.45 - 3.61 (m, 1H), 4.04 (dd, J=9 .79, 2.76 Hz, 1H), 4.46 (br. s., 1H), 5.19 5.49 (m, 2H), 7.67 (d, J=8.03 Hz, 1H) , 7.74 - 7.89 (m, 1H). LCMS (Method-D): retention time 0.59 min, [M+H] 277.2. The fourth eluted compound (retention time 17.47 min), designated as intermediate 123-IV, was obtained (0.15 g, 16.30%) as a pale yellow solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.09 (d, J=6.02 Hz, 3H), 2.21 (d, J=11.55 Hz, 1H), 2.26-2.34 (m, 3H), 2.57-2 .70 (m, 1H), 2.83 (d, J=12.05 Hz, 1H), 2.95 (d, J=10.04 Hz, 1H), 3.17 (s, 3H), 3 .51 (d, J=4.52 Hz, 1H), 3.91 - 4.18 (m, 1H), 4.46 (d, J=4.02 Hz, 1H), 5.27 - 5.48 ( m, 2H), 7.66 (d, J=8.03 Hz, 1H), 7.81 (d, J=8.03 Hz, 1H). LCMS (Method-D): retention time 0.59 min, [M+H] 277.2.

Intermediate 124: 5-(6-(difluoromethyl)piperazin-2-yl)-4-methylisobenzofuran-1(3H)one

Intermediate 124A: 5-(6-(difluoromethyl)pyrazin-2-yl)-4-methylisobenzofuran-1(3H)one

stva

Intermediate 124A was obtained (0.07 g, 64.40%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 4B, starting from intermediate 123B (0.10 g, 0 .39 mmol) and DAST (0.10 ml, 0.78 mmol). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.39 (s, 3H), 5.35 (s, 2H), 6.46-6.98 (m, 1H), 7.65 (d, J=7.53 Hz, 1H), 7.91 (d, J=8.03 Hz, 1H), 8.79 - 9.07 (m, 2H). LCMS (Method-D): retention time 2.16 min, [M+H] 277.2.

Intermediate 124.

Intermediate 124 was obtained (0.30 g, crude) as a pale yellow solid using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from intermediate 124A (0. 28 g, 1.01 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.94 - 1.05 (m, 1H), 1.84 - 1.95 (m, 3H), 2.15 - 2.40 (m, 2H), 2.74 - 3.00 (m, 2H ), 3.06 - 3.22 (m, 2H), 4.00 - 4.22 (m, 1H), 5.27 - 5.43 (m, 2H), 5.67 - 6.02 (m , 1H), 7.57 7.73 (m, 1H), 7.80 (dd, J=8.03, 4.02 Hz, 1H). LCMS (Method-I): retention time 0.87 min, [M+H] 283.2.

Intermediate 125: 1-(5-methylpyrazin-2-yl)-1H-pyrazole-4-carbaldehyde

To a solution of 2-chloro-5-methylpyrazine (2.00 g, 15.56 mmol) in DMF (50 ml) was added 1H-pyrazole-4-carbaldehyde (2.24 g, 23.34 mmol) followed by Cs ₂ CO ₃ (10.14 g, 31.10 mmol) and the resulting reaction mixture was heated at 100°C for 6 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep - 80 g, 0-100% EtOAc/n-hexane) to give Intermediate 125 (1.10 g, 37.10%) as a pale yellow solid. Ή NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 8.36 (s, 1H), 8.54 (s, 1H), 9.14 (s, 1H), 9.31 (s, 1H), 9.98 (s , 1H). LCMS (method-D): retention time 1.25 min, [M+H]

- 147 043056

189.2.

Intermediate 126: 1-(6-methoxypyrimidin-4-yl)-1H-pyrazole-4-carbaldehyde

O ^N

N \~~U~OMe

Intermediate 126 was obtained (1.50 g, 53.10%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 4-chloro-6-methoxypyrimidine (2.00 g , 13.84 mmol) and 1H-pyrazole-4carbaldehyde (1.99 g, 20.75 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.03 (s, 3H), 7.30 (d, J=1.00 Hz, 1H), 8.38 (s, 1H), 8.84 (s, 1H), 9.37 (s, 1H ), 9.99 (s, 1H). LCMS (Method-D): retention time 1.60 min, [M+H] 205.2.

Intermediate 127: 1-(2-methoxypyrimidin-5-yl)-1H-pyrazole-4-carbaldehyde

ABOUT

OME

Intermediate 127 was obtained (0.20 g, 18.51%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from 1H-pyrazole-4-carbaldehyde (0.76 g , 7.94 mmol) and 5-bromo-2-methoxypyrimidine (1.00 g, 5.29 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 3.99 (s, 3H), 8.36 (s, 1H), 9.14 (s, 2H), 9.22 (s, 1H), 9.94 (s, 1H). LCMS (Method-D): retention time 1.0 min, [M+H] 205.2.

Intermediate 128: 1-(2-methylpyrimidin-5-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 128 was obtained (0.02 g, 18.39%) as an off-white solid using a synthetic procedure similar to that of intermediate 6 starting from 1H-pyrazole-4-carbaldehyde (0.08 g , 0.87 mmol) and 5-bromo-2-methylpyrimidine (0.10 g, 0.58 mmol). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.62-2.89 (m, 3H), 8.39 (s, 1H), 9.25 (s, 2H), 9.34 (s, 1H), 9.95 (s, 1H). LCMS (Method-D): retention time 0.71 min, [M+H] 189.2.

Intermediate 129: 6-(3-formylisoxazol-5-yl)-4-methylnicotinonitrile O

1^0

Me

CN

Intermediate 129A: ethyl 5-(tributylstannyl)isoxazole-3-carboxylate

ABOUT

Λ/N

ECG to 'o

Sn(n-Bu) ₃

To a solution of ethyl 2-chloro-2-(hydroxyimino)acetate (0.72 g, 4.76 mmol) in diethyl ether (15 mL) was added tributylstannylacetylene (0.92 mL, 3.17 mmol) followed by TEA ( 0.88 ml, 6.35 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was filtered through Celite® and washed with diethyl ether (50 ml).

- 148 043056

The filtrate was evaporated under reduced pressure to give intermediate 129A (0.60 g, 43.90%) as a pale yellow liquid. 1H NMR (300 MHz, CDCl ₃ ) δ ppm 0.76 - 0.95 (m, 12 N),

1.02 - 1.11 (m, 2H), 1.13 - 1.24 (m, 3H), 1.24 - 1.35 (m, 5H), 1.37 - 1.47 (m, 4H ), 1.48-1.72 (m, 4H), 4.27-4.58 (m, 2H), 6.80 (s, 1H). LCMS (Method-D): retention time 2.76 min, [M+H] 432.2.

Intermediate 129B: ethyl 5-(5-cyano-4-methylpyridin-2-yl)isoxazole-3-carboxylate

ABOUT

A/N

EtCT γ '□ LU~ ^Me

CN

A stirred solution of intermediate 129A (0.06 g, 1.27 mmol) and 6-bromo-4-methylnicotinonitrile (0.25 g, 1.27 mmol) in dioxane (10 ml) was degassed with nitrogen for 20 minutes. Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (0.09 g, 0.13 mmol) was added to the stirred solution and degassed again for 10 minutes. The resulting reaction mixture was heated at 110°C for 16 h then cooled to ambient temperature and filtered through Celite®. The filtrate was obtained, concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 12-14% EtOAc/n-hexane) to give Intermediate 129B (0.07 g, 21.45%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.39 - 1.52 (m, 3H), 2.55 - 2.81 (m, 3H), 4.35 - 4.67 (m, 2H), 7.42 (s, 1H), 7, 95 (s, 1H), 8.72-8.96 (m, 1H). LCMS (method-H): retention time 2.71 min, [M+1] 258.2.

Intermediate 129C: 6-(3-(hydroxymethyl)isoxazol-5-yl)-4-methylnicotinonitrile no^o

CN

Intermediate 129C was prepared (0.01 g, 71.70%) using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 129B (0.02 g, 0.58 mmol) and NaBH ₄ (0.09 mg, 2.33 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 - 2.64 (m, 3H), 4.60 (br. s., 2H), 5.61 (d, J=4.02 Hz, 1H), 7.40 - 7.66 (m , 1H), 8.14 (s, 1H), 8.96-9.10 (m, 1H). LCMS (Method-D): retention time 2.79 min, [M+H] 216.2.

Intermediate 129.

Intermediate 129 was prepared (0.08 g, 55.00%) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 129C (0.01 g, 0.46 mmol) and Dess periodinan - Martina (26.5 g, 62.40 mmol). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.01 - 2.20 (m, 3H), 7.39 (s, 1H), 7.96 (s, 1H), 8.89 (s, 1H), 10.25 (s, 1H). LCMS (Method-D): retention time 0.75 min, [M+H] 214.0.

Intermediate 130-I: 5-((2R,6S)-4-((1H-imidazol-4-yl)methyl)-6-methylpiperazin-2yl)-4-methylisobenzo-furan-1(3H)-one

ABOUT

Me

Intermediate 130A: tert-butyl-4-formyl-1H-imidazole-1-carboxylate

HE IS WITH. Nv>

Vos

To a stirred solution of 1H-imidazole-4-carbaldehyde (2.00 g, 20.81 mmol) in THF (20 ml) was added DMAP (0.64 g, 5.20 mmol) and TEA (5.80 ml, 41. 60 mmol) followed by the addition of Vossanhydride (5.80 ml, 24.98 mmol) and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The resulting mixture was concentrated to dryness under reduced pressure and diluted with water (50 ml). The solid was filtered off and dried in vacuo to give Intermediate 130A (2.50 g, 49.00%) as a pale yellow solid. 1H NMR

- 149 043056 (400 MHz, DMSO-d6) δ ppm 1.59 (s, 9H), 8.37-8.39 (d, J=5.40 Hz, 2H), 9.80 (s., 1H). LCMS (method-O):

retention time 1.00 min, [M-56] 141.2.

Intermediate 130B-I: tert-Butyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl )methyl)-1 H-imidazole-1-carboxylate

Intermediate 130B-I was prepared (0.8 g, 22.39%) using a synthetic procedure similar to that of intermediate 4 starting from intermediate 51-I (1.30 g, 5.28 mmol ) and Intermediate 130A (1.24 g, 6.33 mmol). ¹ H NMR (400 MHz, CD3OD) δ ppm 0.60 - 0.62 (d, J=6.00 Hz, 3H), 1.59 (s, 9H), 1.37-1.43 (m, 2H), 2.29-2.31 ( m, 2H), 2.66 (s, 3H), 2.94 (s, 2H), 3.69-3.71 (m, 1H), 4.71 (s, 2H), 6.8 (s , 1H), 7.05-7.07 (m, 1H), 7.12-7.14 (m, 1H), 7.25 (s, 1H), 7.51 (s, 1H), (not 1 exchangeable proton was observed). LCMS (Method-O): retention time 1.17 min, [M+1] 427.3.

Intermediate 130-I.

Intermediate 130-I was prepared (0.65 g, 99.90%) using a synthetic procedure similar to that of intermediate 38-I, starting from intermediate 130B-I (0.70 g, 1. 64 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.40 (d, J=6.60 Hz, 3H), 2.39 (s, 3H), 2.82 (m, 2H), 2.98 (m, 1H), 3.48 (s, 2H ), 3.97 (s, 2H), 4.9 (br. s., 1H), 5.40-5.53 (m, 2H), 7.75 (s, 1H), 7.81 (d , J=7.80 Hz, 1H), 8.23 (d, J=8.10 Hz, 1H), 9.1 (s, 1H), 10.20 (bs, 2H). LCMS (method O): retention time 0.51 min, [M+H] 327.4.

Intermediate 131-I: (R)-6-(4-(((2-amino-2-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)ethyl)amino)methyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 131A-I: (R)-2-(2-amino-1-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)ethyl)isoindoline-1,3-dione

Intermediate 131A-I was prepared (0.15 g, 97.00%) using a synthetic procedure similar to that of intermediate 19-I, starting from intermediate 18C-I (0.20 g, 0.458 mmol ) and TFA (2 ml, 26.0 mmol). 1H NMR (400 MHz, DMSOd6) δ ppm 2.33 - 2.37 (m, 3H), 3.16 (dd, J=13.05, 5.02 Hz, 1H), 3.66 (dd, J=13.05, 9.54 Hz, 1H), 5.35 - 5.41 (m, 2H), 5.50 (dd, J=9.79, 5.27 Hz, 1H), 7.70 (s, 1H), 7.76 - 7 .81 (m, 1H), 7.82-7.89 (m, 4H). (No 2 exchangeable protons were observed). LCMS (Method-I): retention time 0.81 min, [M+H] 337.3.

- 150 043056

Intermediate 131B-I: (R)-6-(4-(((2-(1,3-dioxouzoindolin-2-yl)-2-(4-methyl-1-oxo1,3-dihydroisobenzofuran-5-yl )ethyl)amino)methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile

ABOUT

Intermediate 131B-I was obtained (1.1 g, 45.60%) as an off-white solid using a synthetic procedure similar to that of Intermediate 4 starting from Intermediate 131A-I (1.7 g , 3.03 mmol) and 6-(4-formyl-Spyrazol-1-yl)-4-methylnicotinonitrile (0.98 g, 3.03 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.27 2.36 (m, 3H), 2.57 (s, 3H), 3.13 (dd, J=12.30, 5.27 Hz, 1H), 3.63 - 3.75 (m , 3H), 5.37 (d, J=3.01 Hz, 2H), 5.67 (dd, J=10.04, 5.02 Hz, 1H), 7.68 (d, J=8, 03 Hz, 1H), 7.75 (s, 1H), 7.81 (d, J=8.03 Hz, 1H), 7.84 (s, 4H), 7.94 (s, 1H), 8 .43 (s, 1H), 8.80 (s, 1H). (No 1 exchangeable proton was observed). LCMS (Method-I): retention time 1.46 min, [M+H] 533.5.

Intermediate 131-I.

Intermediate 131-I was prepared (0.03 g, 51.00%) using a synthetic procedure similar to that of intermediate 18-I, starting from intermediate 131B-I (0.13 g, 0. 12 mmol) and hydrazine hydrate (0.06 ml, 1.22 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.15-2.29 (m, 5H), 2.32 - 2.38 (m, 1H), 2.57 (s, 3H), 2.60 - 2.70 (m, 1H), 3.17 (s, 1H), 3.59 3.76 (m, 2H), 4.31 (dd, J=8.56, 4.16 Hz, 1H), 5.35 (s, 2H), 7.63 (d, J=8.07 Hz, 1H), 7.76 (d, J=8.07 Hz, 1H), 7.84 (s, 1H), 7.97 (s, 1H), 8.50 (s, 1H), 8.83 (s, 1H). LCMS/HPLC (Method-R): retention time 0.98 min, [M+H] 403.1, purity: 98.53%. (Method-S): retention time 1.28 min, [M+H] 403.1, purity: 98.81%. Chiral purity (Method-XVIII): retention time 5.86 min, 100% e.i.

Intermediate 132-I: (R)-5-(4-((5-bromopyrimidin-2-yl)methyl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 132A: 5-bromo-2-(bromomethyl)pyrimidine

AIBN (0.48 g, 2.89 mmol) and N _- bromosuccinimide (5.14 g , 28.9 mmol) and the resulting mixture was heated at 80° C. for 48 hours. The resulting mixture was cooled to ambient temperature. The solid precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-80 g, 0-15% EtOAc/n-hexane) to give Intermediate 132A (1.05 g, 12.98%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.68 (s, 2H), 9.03 (s, 2H). LCMS (Method-I): retention time 1.03 min, [M+1] 252.9.

Intermediate 132-I.

To a stirred solution of Intermediate 123A (0.38 g, 1.63 mmol) and Intermediate 2-I (0.41 g, 1.63 mmol) in THF (20 ml) was added DIPEA (0.69 ml, 3. 97 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (40 ml) and was extracted with the addition of ethyl acetate (3x40 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 2-4% MeOH/CHCl ₃ ) to give Intermediate 132-I (0.32 g, 28.40%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.89 - 2.06 (m, 1H), 2.20 - 2.36 (m, 4H), 2.74 - 3.01 (m, 4H), 3.74 (s, 2H), 4, 01 - 4.13 (m, 1H), 5.38 (s, 2H), 7.64 (d, J=8.07 Hz, 1H), 7.78 (d, J=8.07 Hz, 1H ), 8.96 (s, 2H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 1.17 min, [M+H] 405.0.

Intermediate 133: 6-(4-formyl-2H-1,2,3-triazol-2-yl)-4-methoxy-2-methylnico- 151 043056 tinonitrile

Intermediate 133A: bis(2,4,6-trichlorophenyl)malonate

A mixture of malonic acid (20.00 g, 192.00 mmol), 2,4,6-trichlorophenol (76.00 g, 384.00 mmol) and POCl ₃ (50 ml) was heated at reflux for 12 hours. the mixture was cooled to 70°C and poured into ice water. The solid was collected by filtration, washed with water and dried in vacuo to give Intermediate 133A (70.30 g, 67.20%) as a pale yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 3.91-4.17(m, 2H), 7.33-7.59(m, 4H). LCMS: Compound poorly ionized.

Intermediate 133B: 4-hydroxy-2-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile

A mixture of 3-aminoacrylonitrile (10.25 g, 151.00 mmol) and intermediate 133A (70.30 g, 152.00 mmol) in diglyme (75 mL) was heated at 120°C for 2.5 h. The mixture was cooled to ambient temperature and poured into Et ₂ O (40 ml) and filtered. The precipitate was washed with Et ₂ O (15 ml) to give intermediate 133B (13.50 g, 59.70%) as a dark brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.25-2.41 (m, 3H), 5.49 (s, 1H), 11.85 (br. s., 2H). LCMS (Method-I): retention time 0.32 min, [M+1] 151.3.

Intermediate 133C: 4,6-dichloro-2-methylnicotinonitrile

A stirred solution of intermediate 133B (10.70 g, 71.30 mmol) in POCl ₃ (6.64 ml, 71.3 mmol) was heated at 100° C. for 16 h. The resulting mixture was concentrated under reduced pressure, diluted with water (200 ml), podslushivaet solid Na ₂ CO ₃ and was extracted with the addition of ethyl acetate (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-120 g, 0-5% EtOAc/n-hexane) to give Intermediate 133C (8.50 g, 57.40%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.69 (s, 3H), 8.02 (s, 1H). LCMS: (Method-I): retention time 1.16 min, [M+1] 188.3.

Intermediate 133D: 6-chloro-4-methoxy-2-methylnicotinonitrile and Intermediate 133E: 4-chloro-6-methoxy-2-methylnicotinonitrile

Intermediate 133D and Intermediate 133E were prepared using a synthetic procedure similar to that of Intermediate 114A, starting from Intermediate 133C (8.50 g, 45.40 mmol). The first eluted compound, designated Intermediate 133D, was obtained (5.50 g, 66.30%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.57 (s, 3H), 4.02 (s, 3H), 7.35 (s, 1H). LCMS (Method-I): retention time 0.99 min, [M+1] 183.3. The second eluted compound, designated Intermediate 133E, was obtained (1.50 g, 18.07%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.62 (s, 3H) 3.94 (s, 3H) 7.17 (s, 1H). LCMS (method-I): retention time 1.24 min, [M+1] 183.3.

Intermediate 133F: 6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-methoxy-2methylnicotinonitrile and intermediate and 133G: 6-(4-(hydroxymethyl)-1H- 1,2,3-triazol-1yl)-4-methoxy-2-methylnicotinonitrile

133F 133G

Intermediate 133F and Intermediate 133G were prepared using a synthetic procedure similar to that of Intermediate 20, starting from Intermediate 133D (1.84 g, 10.09 mmol) and Intermediate 28A (1.00 g, 10.09 mmol). The first eluted compound, designated Intermediate 133F, was obtained (0.37 g, 10.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.65 (s, 3H), 4.11 (s, 3H), 4.68 (d, J=5.02Hz, 2H), 5.55 (t, J=5.77Hz, 1H) , 7.56 (s, 1H), 8.17 (s, 1H). LCMS (Method-I): retention time 0.75 min, [M+1] 246.1. The second eluted compound, designated Intermediate 133-I, was obtained (0.27 g, 9.33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.67 (s, 3H), 4.14 (s, 3H), 4.64 (d, J=4.02 Hz, 2H), 5.27-5.42 (m, 1H), 7.74 (s, 1H), 8.68 (s, 1H). LCMS (Method-I): retention time 0.80 min, [M+1] 246.1.

Intermediate 133.

Intermediate 133 was obtained (0.35 g, 94.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 133F (0.38 g, 1.53 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.70 (s, 3H), 4.15 (s, 3H), 7.73 (s, 1H), 8.79 (s, 1H), 10.22 (s, 1H). LCMS (Method-I): retention time 0.92 min, [M+H] 244.1.

Intermediate 134: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-methoxy-2-methylnicotinonitrile

Intermediate 134 was obtained (0.26 g, 95.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 133G (0.28 g, 1.12 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.70 (s, 3H), 4.17 (s, 3H), 7.84 (s, 1H), 9.56 (s, 1H), 10.14 (s, 1H). LCMS (Method-I): retention time 1.00 min, [M-H] 242.1.

Intermediate 135: 1-(4-Methoxy-1,3,5-triazin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 135 was obtained (0.70 g, 32.80%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 1H-pyrazole-4-carbaldehyde (1.00 g , 10.41 mmol) and 2-chloro-4-methoxy-1,3,5-triazine (1.52 g, 10.41 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.11 (s, 3H), 8.39 (s, 1H), 8.60 (s, 1H), 9.47 (s, 1H), 10.01 (s, 1H). LCMS (Method-I): retention time 0.62 min, [M+H] 206.2.

- 153 043056

Intermediate methylisobenzofuran-1(3H)-one

136-I: 5-((2R,6R)-6-(hydroxymethyl)-1-methylpiperazin-2-yl)-4-

Intermediate 136A-I: tert-Butyl (3R,5R)-3-(hydroxymethyl)-4-methyl-5-(4-methyl-1oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

Sodium cyanoborohydride (0.51 g, 8.16 mmol) and the resulting mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water (30 ml) and extracted with DCM (3x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 0-2% MeOH/CHCl ₃ ) to give Intermediate 136A-I (0.15 g, 96.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (d, J=2.20 Hz, 9H), 1.98 (d, J=2.20 Hz, 3H), 2.20 (br. s., 1H), 2.33 (br. s., 3H), 2.61 - 2.80 (m, 3H), 3.17 (dd, J=5.26, 3.06 Hz, 1H), 3.46 (d, J=10.52 Hz, 2H), 3.73 (br. s., 2H), 4.11 (d, J=5.38 Hz, 1H), 4.71 (br. s., 1H), 5.43 (br s., 1H), 7.72 (br. s., 1H). LCMS (Method-I): retention time 1.06 min, [M+H] 377.3.

Intermediate 136-I.

Intermediate 136-I was obtained (0.10 g, 91.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 38-I, starting from Intermediate 136A-I (1, 00 g, 10.41 mmol) and 4M HCl in dioxane (5 ml, 20.00 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.98 (s, 3H), 2.33 (s, 3H), 2.55 (br. s., 1H), 2.77 (t, J=11.86 Hz, 1H), 2.90 ( t, J=11.98 Hz, 1H), 3.07 - 3.21 (m, 2H), 3.36 - 3.53 (m, 2H), 3.63 - 3.75 (m, 1H) , 3.91 (d, J=10.27 Hz, 1H), 4.85 (t, J=5.14 Hz, 1H), 5.31-5.48 (m, 2H), 7.73 ( s, 2H). LCMS (Method-I): retention time 0.46 min, [M+H] 277.2.

Intermediate 137: 1-(5-formylpyrimidin-2-yl)-1H-imidazole-4-carbonitrile O

Intermediate 137 was obtained (0.40 g, 37.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 2-chloropyrimidine-5-carbaldehyde (1.00 g , 5.38 mmol) and 1H-imidazole-4carbonitrile. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm, 8.90 (s, 2H), 9.26 (s, 1H), 10.11 (s, 1H), 10.14 (s, 1H). LCMS (Method-H): retention time 0.91 min, [M+1] 200.05.

Intermediate 138: 2-(4-methyl-1H-imidazol-1-yl)pyrimidine-5-carbaldehyde

To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (3.00 g, 21.05 mmol) in DMSO (20 mL) was added K ₂ CO ₃ (7.27 g, 52.60 mmol) followed by 4-methyl- 1H-imidazole (2.59 g, 31.6 mmol) and the resulting mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was poured into ice water (50 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with brine (50 ml), dried over

- 154 043056 anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 80% EtOAc/n-hexane) to give Intermediate 138 (1.40 g, 34.30%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm

2.20 (s, 3H), 7.72 (t, J=1.2 Hz 1H), 8.56 (d, J=1.2 Hz, 1H), 9.26 (s, 2H) 10, 09 (s, 1H). LCMS (Method-D):

retention time 1.07 min, [M+H] 189.1.

Intermediate 139: 1-(5-formylpyrimidin-2-yl)-3-methyl-1H-pyrazole-4-carbonitrile

Intermediate 139 was prepared (0.30 g, 40.10%) using a synthetic procedure similar to that of intermediate 20 starting from 2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and 4-methyl-1H-pyrazole-3-carbonitrile (0.41 g, 3.86 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.30 (d, J=1.00 Hz, 3H), 8.65 (s, 1H), 8.90 (s, 1H), 9.36 (s, 1H), 10.15 (s, 1H ). LCMS (Method-D), retention time 1.54 min, [M+H] 214.0.

Intermediate 140: 6-(4-methyl-1H-1,2,3-triazol-1-yl)nicotinaldehyde

ABOUT

Intermediate 140 was prepared (0.25 g, 46.70%) using a synthetic procedure similar to that of intermediate 20, starting from 6-bromonicotinaldehyde (0.50 g, 2.69 mmol) and 4-methyl- 1H-1,2,3-triazole (0.38 g, 4.03 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 - 2.40 (m, 3H), 8.30 (d, J=8.53 Hz, 1H), 8.44 - 8.54 (m, 1H), 8.70 (s, 1H) , 9.10 (d, J=1.51 Hz, 1H), 10.15 (s, 1H). LCMS: (Method-D) retention time: 1.119 min, [M+1]: 189.2.

Intermediate 141: 1-(5-formylpyrimidin-2-yl)-1H-1,2,4-triazole-3-carbonitrile O

Intermediate 141 was obtained (0.25 g, 46.70%) as a brown solid using a synthetic procedure similar to that of intermediate 20 starting from 2-chloropyrimidine-5-carbaldehyde (0.50 g , 2.69 mmol) and 1H-1,2,4-triazole-3carbonitrile (0.38 g, 4.03 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.14 - 81.6 (d, J=8.80 Hz, 1H), 9.13 (s, 2H), 10.18 (s, 1H). LCMS (Method-H): retention time 1.27 min, [M+H] 201.2.

Intermediate 142: 1-(5-formylpyrimidin-2-yl)-3-methoxy-1H-pyrazole-4carbonitrile

ABOUT

N

Intermediate 142 was obtained (1.15 g, 93.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 20 starting from 6-bromonicotinaldehyde (1.00 g, 5.42 mmol) and 3-methoxy-1H-pyrazole-4carbonitrile (0.80 g, 6.50 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.07 (s, 3H), 7.95-8.00 (m, 1H), 8.45-8.48 (m, 2H), 9.37 (s, 1H), 10.11 (s, 1H). LCMS (Method-D): retention time 2.21 min, [M+H] 229.0.

Intermediate 143: 3-ethyl-1-(5-formylpyridin-2-yl)-1H-pyrazole-4-carbonitrile

- 155 043056

Intermediate 143A: ((E)-2-(ethoxymethylene)-3-oxo-pentanenitrile O %

Synthesized according to literature procedures (Australian Journal of Chemistry, 44, 1263-1273, 1991).

Intermediate 143B: 3-ethyl-1H-pyrazole-4-carbonitrile

Me

NC. /

H

To a solution of intermediate 143A (5.00 g, 32.60 mmol) in EtOH (50 ml) was added hydrazine hydrate (5.12 ml, 163 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The resulting mixture was diluted with water (40 ml) and extracted with 10% MeOH in DCM (2x50 ml). The combined organic layers were washed with brine (20 ml) and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by Combiflash chromatography (Redisep-40 g, 50% EtOAc/nhexane) to give Intermediate 143B (3.10 g, 78.00%) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 8.16 (s, 1H), 13.4 (br. s, 1H ). LCMS (method-L), retention time 0.75 min, [M+H] 122.1.

Intermediate 143.

Intermediate 143 was prepared (0.22 g, 68.70%) using a synthetic procedure similar to that of intermediate 20, starting from intermediate 143B (0.19 g, 1.61 mmol) and 6- bromonicotinaldehyde (0.25 g, 1.34 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, J=7.6 Hz, 3H), 2.82 (q, J=7.6 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8. 47(dd, J=1.6Hz, J=8.4Hz, 1H), 9.03(s, 1H), 9.43(s, 1H), 10.12(s, 1H). LCMS (Method-L), retention time 1.18 min, [M+H] 227.1.

Intermediate 144: 1-(5-formylpyrimidin-2-yl)-3-methoxy-1H-pyrazole-4carbonitrile

To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (0.25 g, 1.75 mmol) in THF (10 mL) was added 3-methoxy-1H-pyrazole-4-carbonitrile (0.32 g, 2.63 mmol) followed by the addition of K2CO3 (0.36 g, 2.63 mmol) and the resulting reaction mixture was heated at 70°C for 1 h. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with water (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 0-50% EtOAc/n-hexane) to give Intermediate 144 (0.24 g, 60.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.06 (s, 3H), 9.29 (s, 1H), 9.31 (s, 1H), 9.45 (s, 1H), 10.13 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 145: 3-ethyl-1-(5-formylpyrimidin-2-yl)-1H-pyrazole-4-carbonitrile

- 156 043056

Intermediate 145 was prepared (0.23 g, 57.70%) using a synthetic protocol similar to that of intermediate 20, starting from intermediate 143B (0.32 g, 2.63 mmol) and 2 -chloropyrimidine-5-carbaldehyde (0.25 g, 1.75 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.31 (t, J=7.6 Hz, 3H), 2.82 (q, J=3.6 Hz, 2H), 9.34 (s, 2H), 9.49 (s, 1H), 10.14 (s, 1H). LCMS (Method-D): retention time 1.55 min, [M+18+H] 246.1.

Intermediate 146: 3-cyclopropyl-1-(5-formylpyrimidin-2-yl)-1H-pyrazole-4-carbonitrile

Intermediate 146A: 3-cyclopropyl-1H-pyrazole-4-carbonitrile

Synthesized in accordance with the methods described in the literature (international PCT application, 2015052264).

Intermediate 146 was obtained (0.22 g, 51.90%) as an off-white solid using a synthesis protocol similar to that of intermediate 144, starting from 2-chloropyrimidine-5-carbaldehyde (0.25 g, 1.75 mmol) and Intermediate 146A (0.35 g, 2.63 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.99 - 1.06 (m, 2H), 1.12 (dt, J=8.53, 3.01 Hz, 2H), 2.00 - 2.20 (m, 1H), 9.23 - 9.36 (m, 2H), 9.46 (s, 1H), 10.14 (s, 1H). LCMS (Method D): retention time 1.70 min, [M+H] 240.2.

Intermediate 147: 3-(difluoromethoxy)-1-(5-formylpyridin-2-yl)-1H-pyrazole-4carbonitrile

Intermediate 147A: 1-(5-formylpyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazole-4carbonitrile

To a solution of intermediate 142 (0.60 g, 2.63 mmol) in DCM (25 ml) was added BBr ₃ (0.75 ml, 7.89 mmol) at 0°C and the resulting reaction mixture was stirred at 50°C for for 16 hours the resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure and diluted with water (50 ml). The solid was filtered off and dried in vacuo to give intermediate 147A (0.80 g, crude). LCMS (Method L): retention time 1.57 min, [M+H] 294.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 147.

To a stirred solution of intermediate 147A (0.80 g, 2.71 mmol) in DMF (10 mL) was added sodium chlorodifluoroacetate (0.62 g, 4.07 mmol) followed by Cs ₂ CO ₃ (2.65 g, 8.13 mmol) and the resulting reaction mixture was heated at 100° C. for 3 hours. The resulting mixture was cooled to ambient temperature and diluted with water (30 ml). The solid was filtered off and dried in vacuo to give intermediate 12 (0.25 g, 16.41%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33 - 7.86 (m, 1H), 7.93 - 8.13 (m, 1H), 8.33 8.63 (m, 1H), 9.03 (dd, J=17.32, 1.76 Hz, 1H), 9.29 - 9.59 (m, 1H), 10.12 (d, J=9.54 Hz, 1H). LCMS (method-L): retention time 2.20 min, [M+H] 265.2.

- 157 043056

Intermediate 148: 3-(difluoromethyl)-1H-pyrazole-4-carbonitrile

Intermediate 148A: (E)-3-(dimethylamino)acrylonitrile

Me

To a solution of 2-cyanoacetic acid (5.00 g, 58.8 mmol) in 1,4-dioxane (30 ml) was added DMFDMA (8.66 ml, 64.7 mmol) and the resulting reaction mixture was stirred at ambient temperature for over 4 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure to give intermediate 148A (5.90 g, crude). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.73 (s, 6H) 6.89 (s, 1H) 6.93 (s, 1H).

Intermediate 148B: (7)-2-((dimethylamino)methylene)-4,4-difluoro-3-oxobutanenitrile

To a solution of intermediate 148A (2.00 g, 20.81 mmol) in toluene (20 mL) was added TEA (5.80 mL, 41.6 mmol) followed by 2,2-difluoroacetic acid (1.99 g, 20.81 mmol) at 0°C. Then 20% phosgene in toluene (10 ml, 22.89 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting mixture was concentrated to dryness under reduced pressure, diluted with saturated NaHCO ₃ solution (120 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give Intermediate 148B (1.70 g, 46.90%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.35 (s, 6H), 6.31-6.75 (m, 1H), 8.02 (s, 1H). LCMS (Method-O): retention time 0.62 min, [MH] 175.3.

Intermediate 148.

Intermediate 148 was obtained (0.65 g, 32.60%) as a brown solid using a synthetic procedure similar to that of intermediate 143B, starting from intermediate 148B (1.70 g, 9.76 mmol) and hydrazine hydrate (1.53 ml, 48.80 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.72-7.44(m, 1H), 8.63(s, 1H), 9.11-9.87(m, 1H). LCMS (method-L): retention time 1.28 min, [M-H] 141.9.

Intermediate 149-I: (R)-5-(4-((2-chloropyrimidin-5-yl)methyl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one

ABOUT

Me HN^ ^ _N A _C|

Intermediate 149-I was prepared (0.38 g, 80.00%) using a synthetic procedure similar to that of Intermediate 143B, starting from Intermediate 2-I (0.27 g, 1.17 mmol ) and 2-chloropyrimidine-5-carbaldehyde (0.20 g, 1.40 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 - 2.39 (m, 4H), 2.95 (d, J=11.98 Hz, 3H), 3.52 - 3.67 (m, 1H), 4.17 4.39 (m , 1H), 4.46 -4.75 (m, 2H), 4.85 (d, J=10.03 Hz, 1H), 5.31 - 5.50 (m, 2H), 7.67 - 7.81 (m, 1H), 7.92 (d, J=6.60 Hz, 1H), 8.59-8.77 (m, 1H), 8.85 (br. s., 2H), 9.66 - 9.89 (m, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 0.91 min, [M+H] 359.0.

Intermediate 150: 6-(4-formyl-1H-pyrazol-1-yl)-4-morpholinonicotinonitrile

- 158 043056

Intermediate 150A: 4-chloro-6-(4-formyl-1H-pyrazol-1-yl)nicotinonitrile and Intermediate 150B: 6-chloro-4-(4-formyl-III-pyrazol-1-yl)nicotinonitrile

Intermediate 150A and 150B were prepared using a synthetic procedure similar to that of intermediate 15C, starting from 4,6dichloronicotinonitrile (2.50 g, 14.45 mmol) and 1H-pyrazole-4-carbaldehyde (1.26 g, 13.14 mmol). The first eluted compound, designated Intermediate 150A, was obtained (0.60 g, 19.63%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.27 (s, 1H), 8.41 (s, 1H), 9.12 (s, 1H), 9.39 (s, 1H), 9.99 (s, 1H). The second eluted compound, designated Intermediate 150B, was obtained (0.40 g, 13.09%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm (400 MHz, DMSO-d ₆ ) δ ppm 8.33 (s, 1H), 8.50 (s, 1H), 9.05 (s, 1H), 9.43 (s, 1H), 9.99 (s, 1H).

Intermediate 150.

To a solution of intermediate 150A (0.15 g, 0.65 mmol) in THF (10 mL) was added K2CO3 (0.22 mg, 1.61 mmol) followed by morpholine (0.14 g, 1.61 mmol) and the resulting reaction mixture was stirred for 16 hours. The resulting mixture was concentrated to dryness under reduced pressure, diluted with water (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 150 (0.05 g, 37.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.19 - 2.35 (m, 2H), 2.41 (br. s., 2H), 3.49 (s, 2H), 3.77 (d, J=4.52 Hz, 2H), 7.40 (s, 1H), 7.74 (s, 1H), 7.97 (br. s., 1H), 8.47 (s, 1H), 8.61 (s, 1H). LCMS (Method-D): retention time 1.89 min, [M+H] 284.0.

Intermediate 151: 6-(4-formyl-1H-pyrazol-1-yl)-4-(pyrrolidin-1-yl)nicotinonitrile

Intermediate 151 was obtained (0.08 g, 46.40%) as an off-white solid using a synthetic procedure similar to that of intermediate 150, starting from intermediate 150A (0.15 g, 0.65 mmol) and pyrrolidine (0.12 g, 1.61 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (dt, J=6.27, 3.39 Hz, 4H), 3.69 (br. s., 4H), 7.11 (s, 1H), 8.30 (s, 1H), 8.49 (s, 1H), 9.26 (s, 1H), 9.95 (s, 1H). LCMS (Method-I): retention time 1.09 min, [M+1] 268.4.

Intermediate 152: 1-(5-formylpyridin-2-yl)-1H-1,2,3-triazole-4-carbonitrile

Intermediate 152A: methyl 6-azidonicotinate

Sodium azide (3.77 g, 58.0 mmol) was added to a stirred solution of methyl 6-fluoronicotinate (9.00 g, 58.00 mmol) in DMF (30 ml) and the resulting reaction mixture was heated at 70° C. for 2 h. The resulting mixture was diluted with water (300 mL) and the solid precipitated, filtered and dried in vacuo to give Intermediate 152A (6.80 g, 65.80%). 1H NMR (400 MHz,

- 159 043056

DMSO-d6) δ ppm 3.96 (s, 3H), 8.20 (dd, J=9.35, 1.53 Hz, 1H), 8.30 (m, J=0.98 Hz, 1H), 9.89 (t , J=1.25 Hz, 1H).

LCMS (method-L): retention time 0.73 min, [M+H] 179.1.

Intermediate 152B: methyl 6-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)nicotinate

About “Άι » N nAJ ^ν 'Ν

To a stirred solution of intermediate 152A (3.50 g, 19.65 mmol) and prop-2-yn1-ol (3.30 g, 58.90 mmol) in a mixture of DMF (50 mL) and MeOH (12 mL) was added copper (I) iodide (0.37 g, 1.96 mmol) and stirring continued at 90°C for 4 hours. The resulting mixture was cooled to ambient temperature, filtered through Celite® and the filtrate was concentrated under reduced pressure to obtain an intermediate compound 152B (4.50 g, 98.00%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H), 4.64 (d, J=5.32 Hz, 2H), 5.38 (t, J=5.69 Hz, 1H), 8.27 (d, J=8 .56 Hz, 1H), 8.57 (dd, J=8.56, 2.20 Hz, 1H), 8.74 (s, 1H), 9.08 (s, 1H). LCMS (Method-O): retention time 0.71 min, [M+H] 235.1.

Intermediate 152C: methyl 6-(4-formyl-1H-1,2,3-triazol-1-yl)nicotinate

ABOUT

MeO^LL

L L o

N nAJ ^n'N

Manganese dioxide (10.36 g, 119 mmol) was added to a solution of intermediate 152B (4.50 g, 11.91 mmol) in acetone (100 ml) and the resulting reaction mixture was stirred at 60° C. for 16 h. cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with DCM (250 ml) and filtered through Celite®. The filtrate was evaporated under reduced pressure to give intermediate 152C (1.90 g, 68.70%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.98 (s, 3H), 8.36 (dd, J=8.53, 0.76 Hz, 1H), 9.08-9.10 (m, 1H), 9.13 (dd, J= 2.20, 0.73 Hz, 1H), 9.61(s, 1H), 10.15(s, 1H). LCMS: Compound poorly ionized.

Intermediate 152D: methyl 6-(4-cyano-1H-1,2,3-triazol-1-yl)nicotinate

O ^Me0 Vl ^N^N-y_ _CN

N=n

To a stirred solution of intermediate 152C (1.90 g, 5.73 mmol) in a mixture of pyridine (10 ml) and acetic anhydride (10 ml) was added hydroxylamine hydrochloride (0.59 g, 8.59 mmol) and the resulting reaction mixture was heated at 110°C for 2 hours The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with a solution of NaHCO ₃ (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give Intermediate 152D (1.00 g, 76.00%) as a brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.94 (s, 3H), 8.34 (d, J=8.50 Hz, 1H), 8.65 (dd, J=8.56, 2.20 Hz, 1H), 9.12 (d , J=1.77 Hz, 1H), 9.90 (s, 1H). LCMS (Method-L): retention time 1.10 min, [M+H] 230.1.

Intermediate 152E: 1-(5-(hydroxymethyl)pyridin-2-yl)-1H-1,2,3-triazole-4-carbonitrile

Intermediate 152E was obtained (0.45 g, 46.50%) as an off-white solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 152D (1.00 g, 2.79 mmol) and NaBH ₄ (0.53 g, 13.96 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.61 - 4.67 (m, 2H), 5.53 (t, J=5.59 Hz, 1H), 8.06 - 8.17 (m, 2H), 8.58 (m, 1H) , 9.79 (s, 1H). LCMS (method-L): retention time 0.81 min, [M+H] 202.1.

Intermediate 152.

- 160 043056

Intermediate 152 was obtained (0.18 g, 74.60%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 152E (0.42 g, 1.21 mmol) and DessaMartin periodinan (0.51 g, 1.21 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.39 (d, J=8.41 Hz, 1H), 8.60 (dd, J=8.44,

2.16 Hz, 1H), 9.16 (dd, J=2.13, 0.69 Hz, 1H), 9.92 (s, 1H), 10.19 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 153-I and 153-II: 4-methyl-5-(5-methylpiperazin-2-yl)isobenzofuran1(3H)-one.

Intermediate 153A: 5-(5-methylpyrazin-2-yl)isobenzofuran-1(3H)-one

Intermediate 153A was obtained (3.20 g, 49.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 2C, starting from Intermediate 2B (7.46 g, 27.2 mmol) and 2-chloro-5-methylpyrazine (3.50 g, 27.20 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.32 (s, 3H), 2.60 (s, 3H), 5.50 (s, 2H), 7.70 (d, J=7.53 Hz, 1H), 7.81 (d, J = 7.53 Hz, 1H), 8.71 (d, J=1.00 Hz, 1H), 8.77 (d, J=1.51 Hz, 1H). LCMS (Method-D): retention time 1.22 min, [M+H] 241.1.

Intermediate 153-I and 153-II.

Intermediate 153-I and 153-II were prepared using a synthetic procedure similar to that of intermediate 2-I and 2-II, starting from Intermediate 153A (3.20 g, 13.32 mmol). The racemate was separated into two separate enantiomers by the SFC method [Chiralpak AD-H (250x4.6 mm) 5 microns; 0.2% NH4OH in MeOH+ACN (1:1), flow: 1.2 ml/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 3.1 min), designated Intermediate 153-I, was obtained (0.60 g, 25.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96 (d, J=6.36 Hz, 3H), 2.30 (s, 3H), 2.31-2.46 (m, 2H), 2.66-2.74 (m, 1H) , 2.86 (dd, J=11.74, 2.69 Hz, 1H), 2.95 (dd, J=10.88, 2.81 Hz, 1H), 3.91 (dd, J=9 .90, 2.81 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz, 1H ), (2 exchangeable protons were not observed). LCMS (Method-D): retention time 0.56 min, [M+H] 247.2. Chiral purity (Method XXXII): retention time 3.11 min, 97.10% e.i. The second eluted compound (retention time 4.5 min), designated Intermediate 153-II, was obtained (0.55 g, 23.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96 (d, J=6.36 Hz, 3H), 2.30 (s, 3H), 2.31 - 2.46 (m, 2H), 2.66 - 2.74 (m, 1H) , 2.86 (dd, J=11.74, 2.69 Hz, 1H), 2.95 (dd, J=10.88, 2.81 Hz, 1H), 3.91 (dd, J=9 .90, 2.81 Hz, 1H), 5.38 (s, 2H), 7.65 (d, J=8.07 Hz, 1H), 7.77 (d, J=8.07 Hz, 1H ), (2 exchangeable protons were not observed). LCMS (Method-D): retention time 0.38 min, [M+H] 247.2. Chiral purity (Method-XXXII): retention time 4.82 min, 90.00% ee.

Intermediate 154-I: 5-((2R,6S)-1-hydroxy-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one

- 161 043056

Intermediate 154A-I: tert-butyl (3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate

To a stirred solution of intermediate 51-I (0.20 g, 0.81 mmol) in DCM (20 mL) was added TEA (0.17 mL, 1.22 mmol) followed by Boc anhydride (0.23 mL, 0.97 mmol) and stirring was continued at ambient temperature for 2 hours. The resulting mixture was diluted with 10% NaOH solution (40 ml) and extracted with 10% MeOH in DCM (2x250 ml). The combined organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep -24 g, 35% EtOAc/n-hexane) to give Intermediate 154A-I (0.20 g, 71.10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.48 (s, 9H), 2.33 (s, 4H), 2.75-2.83 (m, 2H), 3.82-3.92 (br. s., 1H), 3.94 - 4.01 (m, 2H), 5.42 (s, 2H), 7.68 - 7.73 (m, 1H), 7.80 - 7.86 (m , 1H). LCMS (method-D): retention time 2.42 min, [M+H] 347.2.

Intermediate 154B-I: tert-Butyl (3S,5R)-4-hydroxy-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperazine-1-carboxylate.

ABOUT

About Me °\ JL XX X ^Me | N About Me

Me N. J

BUT £

Me

To a stirred solution of intermediate 154A-I (0.20 g, 0.57 mmol) in DCM (15 ml) and m-CPBA (0.10 g, 0.57 mmol) was added and the resulting reaction mixture was stirred at ambient temperature over 12 hours. The resulting mixture was concentrated to dryness under reduced pressure and the residue was purified by preparative HPLC [YMC Triart (150x4.6 mm) 5 microns; 0.1% NH ₄ OH in water+ACN (1:1), flow: 1.2 ml/min. Temperature: 30° C., UV: 235 nm] to give Intermediate 154B-I (0.06 mg, 26.30%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (d, J=6.02 Hz, 3H), 1.43 (s, 9H), 2.26-2.36 (m, 3H), 2.68 (d, J=2.01 Hz , 2H), 2.72 (br. s., 1H), 3.80 (d, J=10.54 Hz, 2H), 3.93 (br. s., 1H), 5.42 (s, 2H), 7.68 (d, J=8.03 Hz, 1H), 7.79 (d, J=7.53 Hz, 1H), 8.01 (s, 1H). LCMS (Method-D): retention time 2.44 min, [M+H] 363.4.

Intermediate 154-I.

To a stirred solution of intermediate 154B-I (0.03 g, 0.08 mmol) in DCM (5 ml) was added 4M HCl in dioxane (0.04 ml, 0.16 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in diethyl ether (100 ml) and the solid was filtered off and dried in vacuo to give intermediate 154-I (0.02 g, 89.00%). LCMS (Method-P) retention time 0.45 min, [M+H] 263.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 155: 4-formyl-4'-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carbonitrile.

Intermediate 155 was prepared (0.25 g, 25.10%) using a synthetic procedure similar to that of intermediate 6 starting from 2hydroxyisonicotinaldehyde (0.50 g, 4.06 mmol) and 6-bromo- 4-methylnicotinonitrile (0.80 g, 4.06 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.57 (s, 3H) 6.63 - 6.66 (m, 1H), 7.21 (d, J=1.60 Hz, 1H), 8.05 (t, J=5.2 Hz, 2H), 9.03 (s, 1H), 9.95 (s, 1 H), LCMS (method-D): retention time 2.44 min, [MH] 238.0.

- 162 043056

Intermediate 156: 6-(4-formyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4methylnicotinonitrile

Intermediate 156A: methyl 1-(5-cyano-4-methylpyridin-2-yl)-2-oxo-2,3-dihydro-1nimidazole-4-carboxylate

Intermediate 156A was obtained (4.30 g, 79.00%) as a white solid using a synthetic procedure similar to that of intermediate 15C, starting from 6-bromo-4-methylnicotinonitrile (4.16 g , 21.11 mmol) and methyl 2-oxo-2,3dihydro-1H-imidazole-4-carboxylate (3.00 g, 21.11 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.54 (s, 3H), 3.79 (s, 3H), 7.89 (s, 1H), 8.39 (s, 1H), 8.82 (s, 1H), 11.52 (s , 1H). LCMS (Method-O): retention time 0.88 min, [M+1] 259.1.

Intermediate 156B: methyl 1-(5-cyano-4-methylpyridin-2-yl)-3-methyl-2-oxo-2,3dihydro-1H-imidazole-4-carboxylate

Intermediate 156B was obtained (1.15 g, 99.00%) as a burgundy solid using a synthetic procedure similar to that of Intermediate 93B, starting from Intermediate 156A (1.10 g, 4.26 mmol) and iodomethane (2.65 ml, 42.6 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.58 (s, 3H), 3.43 (s, 3H), 3.81 (s, 3H), 8.01 (s, 1H), 8.42 (s, 1H), 8.86 (s , 1H). LCMS (method-O): retention time 1.07 min, [M+1] 273.5.

Intermediate 156C: 6-(4-(hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol1 -yl)-4-methylnicotinonitrile

Intermediate 156C was obtained (0.80 g, 69.00%) as a burgundy solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 156B (1.30 g, 4.77 mmol) and NaBH ₄ (0.90 g, 23.87 mmol), 1H NMR (400 MHz, DMSOb) δ ppm 2.25 (s, 3H), 3.24 (s, 3H), 4.36 (br.s, 2H), 5.25 (br.s, 1H), 7.28 (s, 1H), 8 .45 (s, 1H), 8.79 (s, 1H). LCMS (Method-O): retention time 0.69 min, [M+1] 245.4.

Intermediate 156.

Intermediate 156 was obtained (0.070 g, crude) as a white solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 156C (1.50 g, 6.20 mmol). LCMS (Method-O): retention time 0.92 min, [M+1] 243.5. The compound was carried directly to the next step without further purification or characterization.

Intermediate 157: 6-(3-(difluoromethyl)-4-formyl-1H-pyrazol-1-yl)-4-methylnico- 163 043056 tinonitrile

Intermediate 157A: (3-(difluoromethyl)-1H-pyrazol-4-yl)methanol

Intermediate 157A was prepared (1.40 g, 71.90%) using a synthetic procedure similar to that of intermediate 67A starting from ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate (2.50 g, 13.15 mmol) and DIBAL-H (39.40 ml, 39.40 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.48 (d, J=5.02 Hz, 2H), 4.96 (t, J=5.27 Hz, 1H), 6.77-7.15 (m, 1H), 7.72 (s , 1H), 13.06 (br. s., 1H). LCMS (Method-D): retention time 0.394 min, [M+H] 149.2.

Intermediate 157B: 3-(difluoromethyl)-1H-pyrazole-4-carbaldehyde

Intermediate 157B was prepared (1.00 g, 50.70%) using a synthetic procedure similar to that of Intermediate 152C starting from Intermediate 157A (1.00 g, 6.75 mmol) and manganese dioxide (1.17 g, 13.50 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.01 - 7.38 (m, 1H), 8.62 (s, 1H), 9.94 (s, 1H), 13.94 (br. s., 1H). LCMS (Method-H): retention time 0.54 min, [MH] 145.0. ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm -112.87.

Intermediate 157.

Intermediate 157 was prepared (0.50 g, 43.50%) using a synthetic procedure similar to that of intermediate 6, starting from intermediate 157B (0.25 g, 1.71 mmol) and 6- bromine-4-methylnicotinonitrile (0.34 g, 1.711 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.66 (s, 3H), 7.30-7.41 (m, 1H), 8.12 (s, 1H), 8.99 (s, 1H), 9.50 (s, 1H), 10 .04 (s, 1H). LCMS (Method-D): retention time 1.48 min, [MH] 261.0.

Intermediate 158: 6-(3-cyclopropyl-4-formyl-1H-pyrazol-1-yl)-4-methylnicotinonitrile

Intermediate 158A was prepared (2.60 g, 67.10%) using a synthetic procedure similar to that of intermediate 157A starting from ethyl 3-cyclopropyl-1H-pyrazole-4-carboxylate (5.00 g, 27.7 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.78 - 0.90 (m, 4H), 1.78 - 1.94 (m, 1H), 4.37 (d, J=5.14 Hz, 2H), 4.65 (t, J= 5.26 Hz, 1H), 7.24-7.43 (m, 1H), 12.16 (br. s., 1H). LCMS (method-H): retention time 0.54 min, [M+H] 208.2.

Intermediate 158B: 3-cyclopropyl-1H-pyrazole-4-carbaldehyde

- 164 043056

Intermediate 158B was prepared (1.20 g, 39.30%) using a synthetic procedure similar to that of intermediate 157B, starting from intermediate 158A (2.00 g, 14.48 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.78 - 0.90 (m, 4H), 2.08 - 2.14 (m, 1H), 7.98 - 8.19 (m, 1H), 9.90 (s, 1H), (not 1 exchangeable proton was observed). LCMS (Method-D): retention time 0.57 min, [M+H] 137.1.

Intermediate 158.

Intermediate 158 was prepared (0.03 g, 52.90%) using a synthetic procedure similar to that of intermediate 6, starting from intermediate 158B (0.03 g, 1.83 mmol) and 6- bromine-4-methylnicotinonitrile (0.04 g, 1.836 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 - 1.12 (m, 4H), 2.50 - 2.52 (m, 1H), 2.60 (s, 3H), 7.94 (s, 1H), 8.91 (s, 1H), 9.27 (s, 1H), 10.05 (s, 1H). LCMS (Method-H): retention time 2.72 min, [M+H] 253.1.

Intermediate 159: 1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 159 was prepared (0.10 g, 58.90%) using a synthetic procedure similar to that of intermediate 20 starting from 2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and 4-(trifluoromethyl)-1H-imidazole (0.10 g, 0.77 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.62 (t, J=1.60 Hz, 1H), 8.87 (d, J=1.00 Hz, 1H), 9.36 (s, 2H), 10.16 (s, 1H). LCMS (Method-J): retention time 1.80 min, [M+H] 243.0.

Intermediate 160: 2-(4-formyl-2-methyl-1H-imidazol-1-yl)-4-methoxypyrimidine-5carbonitrile

To a stirred solution of 2-methyl-1H-imidazole-4-carbaldehyde (0.24 g, 2.21 mmol) in ACN (25 mL) was added 2-chloro-4-methoxypyrimidine-5-carbonitrile (0.25 g, 1 .47 mmol) followed by addition of K2CO3 (0.20 g, 1.47 mmol) and stirring continued at ambient temperature for 1 hour. The resulting mixture was diluted with water (30 ml). The solid was filtered off, washed with EtOH (2 ml) and dried in vacuo to give intermediate 160 (0.15 g, crude). LCMS (Method-O): retention time 0.81 min, [M+H] 244.1. The compound was carried directly to the next step without further purification or characterization.

Intermediate 161: 6-(4-formyl-1H-imidazol-1-yl)-4-methoxynicotinonitrile

Intermediate 161 was prepared (0.30 g, 25.00%) using a synthetic procedure similar to that of intermediate 20, starting from 1-nimidazole-4-carbaldehyde (0.50 g, 5.20 mmol) and 6-chloro-4-methoxynicotinonitrile (1.05 g, 6.24 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.13 (s, 3H), 7.81 (s, 1H), 8.83 (s, 2H), 8.95 (d, J=1.19 Hz, 1H), 9.87 (s, 1H ). LCMS (method-L): retention time 0.75 min, [M+H] 229.1.

- 165 043056

Intermediate 162: 3-(4-(trimethylstannyl)pyridin-2-yl)oxazolidin-2-one

Me Me^ I, Me Sn

Intermediate 162A: 3-(4-bromopyridin-2-yl)oxazolidin-2-one

To a stirred solution of 4-bromopyridine-2-amine (5.00 g, 28.90 mmol) in THF (50 mL) was added 2-chloroethyl chloroformate (4.47 mL, 43.30 mmol) and K2CO3 (11.98 g, 87.00 mmol) and the resulting mixture was heated to 70° C. for 10 hours. The resulting mixture was cooled to ambient temperature, concentrated to dryness under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 10-20% EtOAc/n-hexane) to give Intermediate 162A (1.40 g, 20.00%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13 - 4.20 (m, 2H), 4.44 - 4.50 (m, 2H), 7.41 (dd, J=5.27, 1.76 Hz, 1H), 8.29 ( d, J=5.52 Hz, 1H), 8.30 (d, J=1.51 Hz, 1H). LCMS (method-D), retention time 1.86 min, [M+H] 243.

Intermediate 162.

Intermediate 162 was prepared (0.15 g, crude) using a synthetic procedure similar to that of Intermediate 23A, starting from Intermediate 162A (0.15 g, 0.62 mmol). LCMS (Method-O): retention time 1.30 min, [M+1] 328.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 163-I and 163-II: 5-(piperazin-2-yl)isobenzofuran-1(3H)-one. o °

HN^ ^HN ^

Enantiomer-1 (163-1) Enantiomer-ll (163-11)

Intermediate 163A: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran1(3H)-one o

°OS JL o ^Μ θ /^ ^me ΜίΑθ

Synthesized in accordance with the methods described in the literature (international PCT application, 2012037132).

Intermediate 163B: 5-(pyrazin-2-yl)isobenzofuran-1(3H)-one

ABOUT

Intermediate 163B was prepared (3.20 g, 49.00%) using a synthetic procedure similar to that of intermediate 2C, starting from intermediate 163A (20.44 g, 79.00 mmol) and 2- chlorpyrazine (9.00 g, 79.00 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.51 (s, 2H), 8.00 (d, J=8.03 Hz, 1H), 8.35 (dd, J=8.03, 1.51 Hz, 1H), 8.44 (d , J=1.00 Hz, 1H), 8.72 (d, J=2.51 Hz, 1H), 8.81 (dd, J=2.51, 1.51 Hz, 1H), 9.38 (d, J=1.51 Hz, 1H). LCMS (Method D): retention time 1.11 min, [M+H] 213.0.

Intermediate 163-I and 163-II.

Intermediate 163-I and 163-II were prepared using a synthetic procedure similar to

- 166 043056 that of intermediate 2-I and 2-II, and starting from intermediate 163B (5.50 g, 25.90 mmol). The racemate was separated into two separate enantiomers by SFC [Lux Amylose-2 (250x4.6 mm) 5 microns; 0.4% DEA in EtOH, flow: 3.0 g/min. Temperature: 30°C, UV: 230 nm]. The first eluted compound (retention time 1.8 min), designated Intermediate 163-I, was obtained (0.50 g, 16.70%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (d, J=11.55 Hz, 1H), 2.61-2.69 (m, 1H), 2.72-2.86 (m, 2H), 2.92 (d, J= 11.55 Hz, 2H), 3.81 (d, J=8.03 Hz, 1H), 5.38 (s, 2H), 7.58 (d, J=8.03 Hz, 1H), 7 .68 (s, 1H), 7.78 (d, J=8.03 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-D): retention time 0.39 min, [M+H] 219.1. Chiral purity (Method-XVI): retention time 3.11 min, 95.80% e.i. The second eluted compound (retention time 2.40 min) designated as

Intermediate 163-II was obtained (0.70 g, 23.30%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.43 (d, J=11.55 Hz, 1H), 2.61-2.69 (m, 1H), 2.72-2.86 (m, 2H), 2.92 (d, J= 11.55 Hz, 2H), 3.81 (d, J=8.03 Hz, 1H), 5.38 (s, 2H), 7.58 (d, J=8.03 Hz, 1H), 7 .68 (s, 1H), 7.78 (d, J=8.03 Hz, 1H), (2 exchangeable protons not observed). LCMS (Method-D) retention time 0.53 min, [M+H] 219.1. Chiral purity (Method-XVI): retention time 4.82 min, 90.00% e.i.

Intermediate 164-I and 164-II: 4-methyl-5-((2R)-6-methylmorpholin-2-yl)isobenzofuran1(3H)-one

Intermediate 164A-I: 5-((1R)-1-hydroxy-2-((2-hydroxypropyl)amino)ethyl)-4methylisobenzofuran-1(3H)-one

To a stirred solution of intermediate 1-I (10.00 g, 52.60 mmol) in EtOH (150 ml) was added 1-aminopropan-2-ol (11.85 g, 158.0 mmol) and stirring continued at 50° C for 16 hours. The resulting mixture was concentrated under reduced pressure and diluted with diethyl ether (50 ml). The solid was filtered off and dried in vacuo to give intermediate 164A-I (8.00 g, 57.40%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.96 - 1.05 (m, 3H), 1.98 (br. s., 1H), 2.26 (s, 3H), 2.31 - 2.43 (m, 1H), 2.55 - 2.69 (m, 1H), 3.47 (br. s., 1H), 4.46 (br. s., 1H), 4.97 (br. s., 1H), 5.38 ( d, J=2.01 Hz, 2H), 5.42 (br. s., 1H), 7.65 - 7.70 (m, 2H), (2 exchangeable protons not observed). LCMS (Method-O): retention time 0.43 min, [M+H] 266.5.

Intermediate 164-I and 164-II.

A stirred solution of intermediate 164A-I (5.00 g, 18.85 mmol) in 63% HBr (50 ml, 921 mmol) in water was heated at 90° C. for 16 hours. The resulting mixture was cooled to ambient temperature, diluted 10% NaOH solution (100 ml) and extracted with 10% MeOH in DCM (2x250 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. A mixture of diastereomers was separated into individual isomers by SFC [Chiralpak AD-H (250x4.6 mm) 5 microns; 0.2% NH4OH in MeOH, flow: 4.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 6.20 min), designated Intermediate 164-I, was obtained (0.80 g, 32.00%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (d, J=6.02 Hz, 3H), 2.28 (s, 3H), 2.97-3.09 (m, 2H), 3.32 (br. s., 2H), 3.83 (ddd, J=10.42, 6.15, 2.51 Hz, 1H), 4.89 (dd, J=10.29, 2.26 Hz, 1H), 5.40 (d, J=3.51 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), (1 exchangeable proton not observed ). LCMS (method-D) retention time 0.83 min, [M+H] 248.2. Chiral purity (XXXII): retention time 6.00 min, 99.00% e.i. The second eluted compound (7.80 min retention time), designated Intermediate 164-II, was obtained (1.00 g, 40.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (d, J=6.02 Hz, 3H), 2.28 (s, 3H), 2.97-3.09 (m, 2H), 3.32 (br. s., 2H), 3.83 (ddd, J=10.42, 6.15, 2.51 Hz, 1H), 4.89 (dd, J=10.29, 2.26 Hz, 1H), 5.40 (d, J=3.51 Hz, 2H), 7.61 (d, J=8.00 Hz, 1H), 7.68 (d, J=8.00 Hz, 1H), (1 exchangeable proton not observed ). LCMS (Method-D) retention time 0.80 min, [M+H] 248.2. Chiral purity (method-XXXII): retention time 7.62 min, 95.00% ee.

Intermediate 165: 5-(4-((5-Bromopyridin-2-yl)methyl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one.

- 167 043056

Intermediate 165 was prepared (0.18 g, 15.54%) using a synthetic procedure similar to that of intermediate 4 starting from intermediate 2-I (0.19 g, 0.81 mmol) and 5-bromopicolinaldehyde (0.15 g, 0.81 mmol). LCMS (Method-D): retention time 1.416 min, [M+2H] 404.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 166: 2-(1H-1,2,4-triazol-1-yl)pyrimidine-5-carbaldehyde.

Intermediate 166 was prepared (0.30 g, 33.20%) using a synthetic procedure similar to that of intermediate 144, starting from 2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and 4H-1,2,4-triazole (0.266 g, 3.86 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.42 (s, 1H), 9.38 (s, 2H), 9.58 (s, 1H), 10.16 (s, 1H). LCMS (Method-D): retention time 0.43 min, [M+H] 174.2.

Intermediate 167: 1-(5-formylpyridin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 167 was prepared (1.15 g, 52.10%) using a synthetic procedure similar to that of intermediate 20, starting from 6-bromonicotinaldehyde (0.30 g, 1.61 mmol) and 4-methyl- 1H-pyrazole-3-carbonitrile (0.19 g, 1.77 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J=1.00 Hz, 3H), 8.15 (d, J=8.53 Hz, 1H), 8.45 - 8.50 (m, 1H), 8.83 (s , 1H), 9.03-9.07 (m, 1H), 10.14 (s, 1H). LCMS (Method-D): retention time 2.164 min, [M+H] 213.2.

Intermediate 168: 1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 168 was prepared (0.30 g, 40.10%) using a synthetic procedure similar to that of intermediate 144, starting from 2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and 4-methyl-1H-pyrazole-3-carbonitrile (0.41 g, 3.86 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (d, J=1.00 Hz, 3H), 8.85 (d, J=1.00 Hz, 1H), 8.90 (s, 1H), 9.36 (s, 1H), 10.15 (s, 1H). LCMS (Method-D): retention time 1.54 min, [M+H] 214.0.

Intermediate 169: 1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 169 was prepared (0.10 g, 58.90%) using a synthetic procedure similar to that of intermediate 144, starting from 2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and 4-(trifluoromethyl)-1H-imidazole (0.11 g, 0.77 mmol). 1H NMR (400 MHz, DMSO4) δ ppm 8.62 (t, J=1.60 Hz, 1H), 8.87 (d, J=1.00 Hz, 1H), 9.36 (s, 2H), 10.16 (s, 1H). LCMS (Method-J): retention time 1.80 min, [M+H] 243.0.

- 168 043056

Intermediate 170: 1-(5-formylpyridin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 170 was prepared (0.20 g, 58.40%) using a synthetic procedure similar to that of intermediate 20, starting from 6-bromonicotinaldehyde (0.3 g, 1.61 mmol) and 4-methyl- 1H-pyrazole-3-carbonitrile (0.19 g, 1.77 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (d, J=1.00 Hz, 3H), 8.15 (d, J=8.53 Hz, 1H), 8.45-8.50 (m, 1H), 8.83 (s , 1H), 9.03 - 9.07 (m, 1H), 10.14 (s, 1H). LCMS (Method-D): retention time 2.16 min, [M+H] 213.2.

Intermediate 171: 1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 171 was prepared (0.30, 40.10%) using a synthetic procedure similar to that of intermediate 144 starting from 2-chloropyrimidine-5-carbaldehyde (0.50 g, 3.51 mmol) and 4 -methyl-1H-pyrazole-3-carbonitrile (0.413 g, 3.86 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.23 (d, J=1.00 Hz, 3H), 8.85 (d, J=1.00 Hz, 1H), 8.90 (s, 1H), 9.36 (s, 1H), 10.15 (s, 1H). LCMS (Method-D): retention time 1.54 min, [M+H] 214.0.

Intermediate 172: 1-(5-formylpyrimidin-2-yl)-4-methyl-1H-pyrazole-3-carbonitrile

Intermediate 172 was prepared (0.10 g, 58.90%) using a synthetic procedure similar to that of intermediate 144, starting from 2-chloropyrimidine-5-carbaldehyde (0.10 g, 0.70 mmol) and 4-(trifluoromethyl)-1H-imidazole (0.10 g, 0.77 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.62 (t, J=1.6 Hz, 1H), 8.87 (d, J=1.00 Hz, 1H), 9.36 (s, 2H), 10.16 (s, 1H). LCMS (Method-J), retention time 1.80 min, [M+H] 243.0.

Intermediate 173: 6-(1H-1,2,4-triazol-1-yl)nicotinaldehyde.

Intermediate 173 was prepared (0.30 g, 49.30%) using a synthetic procedure similar to that of intermediate 138, starting from 6 bromonicotinaldehyde (0.50 g, 2.69 mmol) and 4H-1, 2,4-triazole (0.204 g, 2.96 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.07 (d, J=8.31 Hz, 1H), 8.41 (br. s., 1H), 8.51 (d, J=7.83 Hz, 1H), 9.07 (br. s., 1H), 9.52 (br. s., 1H), 10.15 (br. s., 1H), LCMS (method-O): retention time 0.62 min, [M+H] 175 ,2.

Intermediate 174-I: (R)-5-(4-((6-Bromopyridin-3-yl)methyl)piperazin-2-yl)-4methylisobenzofuran-1(3H)-one

Intermediate 174-I was prepared (0.22 g, 24.50%) using a synthetic procedure similar to that of intermediate 4 starting from intermediate 2-I (0.18 g, 0.77 mmol ) and 5-bromopicolinaldehyde (0.12 g, 0.64 mmol). LCMS (Method-D): retention time 1.02 min, [M+2H] 404.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 175: N-(3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin- 169 043056

4-yl)acetamide

Intermediate 175A: furan-5-yl)piperidine-1-carboxylate

tert-butyl-4-amino-3 - (4-methyl-1 -oxo-1,3-dihydroisobenzo-

Ammonium acetate (0.13 g, 1.74 mmol) was added to a stirred solution of intermediate 4A (0.20 g, 0.58 mmol) in MeOH (20 mL) and stirring was continued at ambient temperature for 12 h. NaCNBH ₄ (0.07 g, 1.16 mmol) was added to the resulting solution and stirring was continued at ambient temperature for 8 hours. The resulting mixture was concentrated to dryness under reduced pressure, diluted with saturated NaHCO ₃ solution (50 ml) and extracted with ethyl acetate (2x40 ml). The combined organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was taken up in diethyl ether (30 ml) and the solid was filtered off and dried in vacuo to give intermediate 175A (0.201 g, 99.10%). LCMS (Method-I): retention time 0.91 min, [MH] 291.5. The compound was carried directly to the next step without further purification or characterization.

Intermediate 175B: tert-Butyl-4-acetamido-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

To a stirred solution of intermediate 175A (0.18 g, 0.52 mmol) in DCM (10 mL) was added TEA (0.22 mL, 1.56 mmol) followed by acetyl chloride (0.06 mL, 0.78 mmol ) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with water (50 ml) and extracted with DCM (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was taken up in diethyl ether (20 ml) and the solid was filtered off and dried in vacuo to give Intermediate 175B (0.20 g, 99.00%) as a yellow solid. LCMS (Method-I): retention time 1.19 min, [M+1] 387.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 175.

Intermediate 175 was obtained (0.160 g, crude) as a yellow solid using a synthetic procedure similar to that of Intermediate 19-I, starting from Intermediate 175B (0.15 g, 0.38 mmol) and TFA (0.300 ml, 3.86 mmol). LCMS (Method-I): retention time 0.38 min, [M+1] 289.6. The compound was carried directly to the next step without further purification or characterization.

Intermediate 176: 1-(6-methyl-4-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole4-carbaldehyde

- 170 043056

Intermediate 176A: 1-(4-amino-6-methylpyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 176 was prepared (2.10 g, 64.70%) using a synthetic procedure similar to that of intermediate 6 starting from 1Hpyrazole-4-carbaldehyde (1.54 g, 16.04 mmol) and 2-bromo-6-methylpyridine-4-amine (3.00 g, 16.04 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.31 (s, 3H), 6.21-6.26 (m, 2H), 6.97 (d, J=2.01 Hz, 1H), 7.62 (s, 1H), 8.19 (s, 1H), 9.15 (s, 1H), 9.94 (s, 1H). LCMS (Method-I): retention time 0.74 min, [M+1] 203.4.

Intermediate 176B: 2-chloroethyl-(2-(4-formyl-1H-pyrazol-1-yl)-6-methylpyridin-4yl)carbamate

Intermediate 176B was prepared (1.10 g, 72.10%) using a synthetic procedure similar to that of intermediate 76A, starting from intermediate 176A (1.00 g, 4.95 mmol) and 2- chloroethyl carbonochloridate (0.70 ml, 6.43 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 3.90-3.93 (m, 2H), 4.41-4.43 (m, 2H), 7.33 (s, 1H), 8.03 (s, 1H), 8.26(s, 1H), 9.24(s, 1H), 9.96(s, 1H), 10.59(s, 1H). LCMS (method-T): retention time 1.14 min, [M+1] 309.2.

Intermediate 176.

Intermediate 176 was prepared (0.60 g, 68.00%) using a synthetic procedure similar to that of intermediate 76B, starting from intermediate 176B (1.00 g, 3.24 mmol) and NaH ( 0.26 g, 6.48 mmol). 1H NMR (400 MHz, DMSOd ₆ ) δ ppm 2.54 (s, 3H), 4.14 (dd, J=9.04, 7.03 Hz, 2H), 4.52 (dd, J=9.04, 7.03 Hz, 2H), 7 .35 (d, J=2.01 Hz, 1H), 8.20 (d, J=1.51 Hz, 1H), 8.29 (s, 1H), 9.28 (s, 1H), 9 .97 (s, 1H). LCMS (Method-I): retention time 0.90 min, [M+1] 273.1.

Intermediate 177: 1-(6-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole-4carbaldehyde

Intermediate 177A: 1-(6-aminopyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 177A was prepared (2.00 g, 51.10%) using a synthetic procedure similar to that of intermediate 6 starting from 1Hpyrazole-4-carbaldehyde (2.00 g, 20.81 mmol) and 6-bromopyridine-2-amine (3.60 g, 20.81 mmol). LCMS (Method-I) retention time 0.72 min, [M+H] 189.4. The compound was carried directly to the next step without further purification or characterization.

- 171 043056

Intermediate 177B: 2-chloroethyl (6-(4-formyl-1H-pyrazol-1-yl)pyridin-2-yl)carbamate

ABOUT %

Intermediate 177B was obtained (0.09 g, 60.00%) as a yellow solid using a synthetic procedure similar to that of intermediate 76A, starting from intermediate 177A (0.05 g, 0.27 mmol) and 2-chloroethylcarbonochloridate (0.04 ml, 0.35 mmol). LCMS (Method-I): retention time 1.06 min, [M+1] 295.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 177.

Intermediate 177B was obtained (0.01 g, 99.90%) as a yellow solid using a synthetic procedure similar to that of Intermediate 76B, starting from Intermediate 177B (0.08 g, 0.27 mmol) and NaH (0.02 g, 0.41 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.20 - 4.41 (m, 2H), 4.43 - 4.68 (m, 2H), 7.69 (dd, J=6.53, 2.01 Hz, 1H), 7.87 - 8.16 (m, 2H), 8.33 (s, 1H), 9.32 (s, 1H), 9.98 (s, 1H). LCMS (Method-I): retention time 0.92 min, [M+1] 259.2.

Intermediate 178: N-(6-(4-formyl-1H-n-nirazol-1-yl)pyridin-2-yl)-N-methylmethanesulfonamide

O ⁿ w e c /

Me^+O O

Intermediate 178A: N-(6-(4-formyl-1H-pyrazol-1-yl)pyridin-2-yl)methanesulfonamide

Intermediate 178A was obtained (0.52 g, 92.00%) as a yellow solid using a synthetic procedure similar to that of intermediate 59 starting from intermediate 177A (0.40 g, 2.13 mmol) and mesyl-Cl (0.23 ml, 2.76 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H), 7.82 (d, J=7.53 Hz, 1H), 8.14 (d, J=9.04 Hz, 1H), 8.25 - 8.32 (m , 1H), 8.37 (s, 1H), 9.40 (s, 1H), 10.00 (s, 1H), (no exchangeable proton observed). LCMS (Method-I): retention time 0.94 min, [M-1] 265.2.

Intermediate 178.

Intermediate 178 was obtained (0.150 g, 71.20%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 93B, starting from intermediate 178A (0.20 g, 0.75 mmol) and iodomethane (1.07 g, 7.51 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.10 (s, 3H), 3.29 (s, 3H), 7.48 (d, J=8.03 Hz, 1H), 7.77 (d, J=8.03 Hz, 1H), 8.08 (t, J=8.03 Hz, 1H), 8.34 (s, 1H), 9.28 (s, 1H), 10.00 (s, 1H). LCMS (Method-I): retention time 0.93 min, [M+1] 281.1.

- 172 043056

Intermediate 179: 1-(4-(1,1-dioxyisothiazolidin-2-yl)-6-methylpyridin-2-yl)-1Hpyrazol-4-carbaldehyde

Intermediate 179A: 3-chloro-N-((3-chloropropyl)sulfonyl)-N-(2-(4-formyl-1Hpyrazol-1-yl)-6-methylpyridin-4-yl)propan-1-sulfonamide

Intermediate 179A was obtained (0.85 g, 53.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 59 starting from intermediate 176A (0.40 g, 1 .97 mmol) and 3-chloropropane 1-sulfonyl chloride (0.70 g, 3.96 mmol). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.17 (t, J=7.28 Hz, 4H), 2.64 (s, 3H), 3.71-3.82 (m, 4H), 3.86-3.96 (m, 4H) , 7.62 (d, J=1.51 Hz, 1H), 7.88 (s, 1H), 8.36 (s, 1H), 9.35 (s, 1H), 10.00 (s, 1H). LCMS (Method-I): retention time 1.69 min, [M+2H] 485.2.

Intermediate 179B: 3-chloro-N-(2-(4-formyl-1H-pyrazol-1-yl)-6-methylpyridin-4yl)propane-1-sulfonamide

To a solution of intermediate 179A (0.85 g, 1.76 mmol) in THF (15 ml) was added NaH (0.141 g, 3.52 mmol) and the resulting reaction mixture was stirred for 4 hours. The resulting mixture was diluted with a saturated solution of NH4Cl solution (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with diethyl ether (30 ml) and dried in vacuo to give intermediate 179B (0.50 g, 83.00%) as a yellow solid. LCMS (Method-I): retention time 1.11 min, [M+H] 343.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 179.

Intermediate 179 was obtained (0.35 g, 79.54%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 76B, starting from intermediate 179B (0.50 g, 1 .46 mmol) and NaH (0.12 g, 2.92 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.40 - 2.49 (m, 3H), 3.60 - 3.69 (m, 3H), 3.83 - 3.92 (m, 3H), 7.00 (d, J=1.51 Hz, 1H), 7.62 (d, J=2.01 Hz, 1H), 8.28 (s, 1H), 9.27 (s, 1H), 9.97 (s, 1H). LCMS (Method-I): retention time 1.13 min, [M+H] 307.2.

Intermediate 180: (1-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)methylmethanesulfonate

Intermediate 180A: methyl 1-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate 173 043056

Intermediate 180A was obtained (1.50 g, 86.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 15C, starting from 4-bromo-2-methoxypyridine (1, 31 g, 6.99 mmol) and methyl 5oxopyrrolidine-3-carboxylate (1.00 g, 6.99 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.71 - 2.90 (m, 2H), 3.69 (s, 3H), 3.84 (s, 3H), 3.97 (dd, J=10.04, 5.52 Hz, 2H) , 4.03 - 4.13 (m, 1H), 7.05 (d, J=2.01 Hz, 1H), 7.36 (dd, J=6.02, 2.01 Hz, 1H), 8.09 (d, J=5.52 Hz, 1H). LCMS (Method-I) retention time 0.90 min, [M+H] 251.4.

Intermediate 180B: 4-(hydroxymethyl)-1-(2-methoxypyridin-4-yl)pyrrolidin-2-one

Intermediate 180B was obtained (0.85 g, 96.00%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 180A (1.00 g, 4 .00 mmol) and NaBH ₄ (0.45 g, 11.99 mmol). 1H NMR (400 MHz, CD3OD) δ ppm 2.48 (dd, J=16.56, 6.02 Hz, 1H), 2.61 - 2.80 (m, 2H), 3.55 - 3.69 (m, 2H), 3.73 ( dd, J=10.04, 5.52 Hz, 1H), 3.91 (s, 3H), 4.00 (dd, J=9.54, 8.03 Hz, 1H), 7.14 (d , J=1.51 Hz, 1H), 7.25-7.47 (m, 1H), 8.06 (d, J=6.02 Hz, 1H), (no exchangeable proton observed). LCMS (Method-I): retention time 0.58 min, [M+H] 223.3.

Intermediate 180.

Intermediate 180B was obtained (0.45 g, 83.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 59 starting from Intermediate 180B (0.40 g, 1.80 mmol) and mesyl chloride (0.17 ml, 2.16 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.44 (dd, J=17.32, 6.78 Hz, 1H), 2.69 - 2.80 (m, 1H), 2.83 - 2.95 (m, 1H), 3.02 - 3.14 (m, 1H), 3.16 - 3.26 (m, 3H), 3.64 (dd, J=10.04, 6.02 Hz, 1H), 3.84 (s, 3H) , 3.98 (dd, J=10.04, 8.03 Hz, 1H), 4.12 - 4.44 (m, 1H), 7.05 (d, J=1.51 Hz, 1H), 7.24 - 7.54 (m, 1H), 8.10 (d, J=5.52 Hz, 1H). LCMS (Method-I): retention time 0.84 min, [M+H] 301.3.

Intermediate 181: (R)-5-(6,6-dimethylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)one

Intermediate 181A-I: (R)-5-(1-hydroxy-2-((2-hydroxy-2-methylpropyl)amino)ethyl)4-methylisobenzofuran-1(3H)-one

Intermediate 181A-I was obtained (1.00, 34.70%) as a pale yellow solid using a synthetic procedure similar to that of Intermediate 164A-I, starting from Intermediate 1-I (1 .00 g, 5.26 mmol) and 1-amino2-methylpropan-2-ol (1.00 g, 11.22 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 0.98 - 1.19 (m, 6H), 2.21 2.32 (s, 3H), 2.60 - 2.67 (m, 2H), 2.70 - 2.75 (m, 2H) , 4.14 - 4.31 (m, 1H), 4.97 - 5.12 (m, 1H), 5.34 - 5.40 (m, 2H), 5.42 - 5.48 (m, 1 H), 7.53-7.80 (m, 2H), (1 exchangeable proton was not observed). LCMS (Method-O): retention time 0.57 min, [M+H] 280.0.

- 174 043056

intermediate connection

181B-I: (R)-5-(2-(benzyl(2-hydroxy-2-methylpropyl)amino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one

Me OH Vp NO

Intermediate 181B-I was obtained (1.30 g, 38.30%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 4, starting from intermediate 181A-I (2, 00 g, 7.16 mmol) and benzaldehyde (0.91 g, 8.59 mmol). LCMS (method-L): retention time 0.78 min, [M+1] 370.

Intermediate 181C-I: (R)-5-(4-benzyl-6,6-dimethylmorpholin-2-yl)-4-methylisobenzofuran-1(3H)-one

Intermediate 181C-I was obtained (0.45 g, 26.90%) as a brown solid using a synthetic procedure similar to that of Intermediate 164-I, starting from Intermediate 181B-I (1, 30 g, 3.52 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H), 1.43 (s, 3H), 1.75-1.86 (m, 1H), 1.88-2.01 (m, 1H), 2.23 (s, 3H), 2.56 - 2.70 (m, 1H), 2.75 - 2.97 (m, 1H), 3.43 - 3.66 (m, 2H), 4.97 - 5.15 ( m, 1H), 5.38 (s, 2H), 7.33-7.35 (m, 5H), 7.61-7.65 (m, 2H). LCMS (Method-O): retention time 1.67 min, [M+1] 352.4.

Intermediate 181-I.

A solution of intermediate 181B-I (0.40 g, 1.14 mmol) in a mixture of MeOH (40 ml) and THF (10 ml) was purged with nitrogen for 2 minutes. 10% Pd/C (0.100 g, 0.09 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h under H ₂ atmosphere. The resulting mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The residue was triturated with diethyl ether (50 ml) and dried in vacuo to give intermediate 181-I (0.350 g, 99.00%) as a pale brown solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.17 (s, 3H), 1.36 (s, 3H), 2.35 (s, 3H), 2.50-2.57 (m, 2H), 2.68-2.71 (m, 1H), 2.95 (dd, J=12.80, 2.26 Hz, 1H), 4.97 (dd, J=10.54, 2.51 Hz, 1H), 5.38 (s, 2H ), 7.50 - 7.80 (m, 2H), (1 exchangeable proton was not observed). LCMS (Method-O): retention time 0.81 min, [M+1] 262.4.

Intermediate 182: 1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-X-methyl-1Hpyrazole-3-carboxamide

Intermediate 182A: ethyl 1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole3-carboxylate

Intermediate 182A was obtained (0.50 g, 21.05%) as a brown solid using a synthetic procedure similar to that of intermediate 6 starting from 6-chloro-4-methoxynicotinonitrile (1.00 g , 5.93 mmol) and ethyl 4-formyl 1H-pyrazole-3-carboxylate (1.49 g, 8.90 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.35 (d, J=7.60 Hz, 3H), 4.18 (s, 3H), 4.43 (q, J=7.20 Hz, 2H), 7.79 (s, 1H), 8.88 (s, 1H), 9.19 (s, 1H), 10.26 (s, 1H). LCMS (method-L): retention time 1.11 min, [M+1] 301.4.

- 175 043056

Intermediate 182B: 1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole-3-carboxylic acid

To a solution of intermediate 182A (0.30 g, 0.99 mmol) in a mixture of water (5 ml) and THF (15 ml) was added LiOH (0.48 g, 1.99 mmol) and the resulting mixture was stirred at ambient temperature within 4 hours the resulting mixture was concentrated in vacuo and diluted with water (30 ml), acidified with 1N HCl solution and was extracted with the addition of ethyl acetate (2x50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 182B (0.30 g, 56.30%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.11 (s, 3H), 7.65 (s, 1H), 8.73 (s, 1H), 9.09 (s, 1H), (1 H no exchangeable protons were observed). LCMS (method-L): retention time 1.03 min, [M+1] 273.1.

Intermediate 182

To a stirred solution of intermediate 182B (0.10 g, 0.37 mmol) in DMF (10 mL) was added HATU (280 mg, 0.74 mmol), methanamine HCl (0.12 g, 1.84 mmol) followed by by adding TEA (0.26 ml, 1.84 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was diluted with water (30 ml) and was extracted with the addition of ethyl acetate (2x25 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 182 (0.20 g, 51.50%) as a brown solid. LCMS (Method-O): retention time 0.87 min, [M+1] 286.4. The compound was carried directly to the next step without further purification or characterization.

Intermediate 183: 1-(5-cyano-4-methoxypyridin-2-yl)-4-formyl-1H-pyrazole-3-carboxamide

Intermediate 183 was obtained (0.30 g, 15.05%) as a brown solid using a synthetic procedure similar to that of intermediate 182 starting from intermediate 182B (0.20 g, 0.74 mmol) and ammonium chloride (0.39 g, 7.35 mmol). LCMS (Method-O): retention time 0.78 min, [M+1] 272. The compound was taken directly to the next step without further purification or characterization.

Intermediate 184: 6-(4-formyl-1H-1,2,3-triazol-1-yl)-4-(methoxy-d ₃ )nicotinonitrile

Intermediate 184A: 6-chloro-4-(methoxy-b ₃ ) nicotinonitrile

To a stirred solution of CD ₃ OD (0.20 ml, 5.78 mmol) and NaH (0.116 g, 2.89 mmol) in THF (10 ml) was added 4,6-dichloronicotinonitrile (1.00 g, 5.78 mmol ) in DMA (20 ml) at 0°C. received re

- 176 043056 the stock mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 0-100% EtOAc/n-hexane)) to give Intermediate 184A (0.25 g, 25.20%) as an off-white solid. 1H NMR (300 MHz, CDCl ₃ ) δ ppm 7.26(s, 1H), 8.48(s, 1H). LCMS (method-L): retention time 1.09 min, [M+1] 173.1.

Intermediate 184B: 6-(4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)-4-(methoxyd ₃ )nicotinonitrile and intermediate 184C: 6-(4-(hydroxymethyl)-1H -1,2,3-triazol-1-yl)-4(methoxy-d ₃ )nicotinonitrile

Intermediate 184B and 184C were prepared using a synthetic procedure similar to that of intermediate 20, starting from intermediate 184A (0.22 g, 1.28 mmol) and intermediate 28A (0.25 g, 2. 56 mmol). The first eluted compound, designated Intermediate 184B, was obtained (0.12 g, 40.00%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.68 (s, 2H), 5.50 (s, 1H), 7.71 (s, 1H), 8.20 (s, 1H), 8.85 (s, 1H). LCMS (Method-O): retention time 0.70 min, [M+1] 235.5. The second eluted compound, designated Intermediate 184C, was obtained (0.06 g, 19.98%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.63 (s, 2H), 5.40 (s, 1H), 7.89 (s, 1H), 8.72 (s, 1H), 8.90 (s, 1H). LCMS (Method-O): retention time 0.70 min, [M+1] 235.5.

Intermediate 184.

Intermediate 184 was obtained (0.05 g, 99.90%) as a brown solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 184B (0.05 g, 0.21 mm) and DessaMartin periodinan (0.18 g, 0.43 mmol). Ή NMR (400 MHz, DMSO-d6) δ ppm 8.01 (s, 1H), 8.98 (s, 1H), 9.61 (s, 1H), 10.15 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 185: 6-(5-methyl-1,2,4-oxadiazol-3-yl)nicotinaldehyde

Intermediate 185A: methyl 6-((((1-aminoethyl)amino)oxy)carbonyl)nicotinate

To a solution of 5-(methoxycarbonyl)picolinic acid (0.60 g, 3.31 mmol) in DCM (30 ml) was added oxalyl chloride (0.580 ml, 6.62 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. the mixture was evaporated under reduced pressure. The residue was redissolved in THF (20 ml) and TEA (2.31 ml, 16.56 mmol) was added followed by (E)-N'-hydroxyacetimidamide (0.37 g, 4.97 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-100% EtOAc/n-hexane)) to give Intermediate 185A (0.18 g, 22.72%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.83 (s, 3H), 3.93 (s, 3H), 6.47 (br.s, 2H), 8.29 (dd, J=0.80, 8.40 Hz, 1H), 8 .42 (dd, J=2.00, 8.00 Hz, 1H), 9.17 (s, 1H). LCMS (method-L): retention time 0.61 min, [M+1] 238.1.

- 177 043056

Intermediate 185B: methyl 6-(3-methyl-1,2,4-oxadiazol-5-yl)nicotinate

To a stirred solution of intermediate 185 (0.15 g, 0.63 mmol) in THF (15 ml) was added 1 M TBAF in THF (1.26 ml, 1.26 mmol) and the resulting reaction mixture was stirred at ambient temperature within 18 hours the resulting mixture was diluted with water (30 ml) and was extracted with the addition of ethyl acetate (2x25 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-12 g, 0-40% EtOAc/n-hexane) to give Intermediate 185B (0.14 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H), 4.01 (s, 3H), 8.26 (dd, J=0.80, 8.40 Hz, 1H), 8.49 (dd, J=2.00, 8.00 Hz, 1H), 9.38 (s, 1H). LCMS (method-L): retention time 0.93 min, [M+1] 220.1.

Intermediate 185C: (6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methanol

Intermediate 185C was obtained (0.10 g, 96.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 60B, starting from Intermediate 185B (0.12 g, 0.55 mmol) and NaBH ₄ (0.04 g, 1.00 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.44 (s, 3H), 4.65 (d, J=5.60, 2H), 5.54 (d, J=5.60 Hz, 1H), 7.98 (d, J=6, 80 Hz, 1H), 8.19 (d, J=8.00 Hz, 1H), 8.74 (s, 1H). LCMS (Method-I) retention time 0.74 min, [MH] 192.2.

Intermediate 185.

Intermediate 185 was obtained (0.10 g, 39.00%) as a brown solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 185C (0.07 g, 0.37 mm) and DessaMartin periodinan (0.31 g, 0.73 mmol). LCMS (method-L): retention time 0.78 min, [M+1] 190.0. The compound was carried directly to the next step without further purification or characterization.

Intermediate 186A and 186B: tert-Butyl-(5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-3-yl)carbamate

Intermediate 186C: tert-butyl-(5-bromopyridin-3-yl)carbamate

To a stirred HCl solution of 5-bromonicotinic acid salt (4.00 g, 19.80 mmol) in toluene (25 mL) was added TEA (13.80 mL, 99 mmol) followed by diphenylphosphoryl azide (6.54 g, 23.76 mmol) and the resulting mixture was heated at 60°C for 2 h. The resulting mixture was heated at 100°C after adding tert-butanol (25 ml) for 18 h. The resulting reaction mixture was evaporated in vacuo, diluted with 10% NaHCO ₃ and was extracted with the addition of ethyl acetate (2x100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 40-80% EtOAc/n-hexane)) to give Intermediate 186C (4.00 g, 74.00%) as a brown solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.49 (s, 9H), 8.17 (s, 1H), 8.29 (d, J=1.60 Hz, 1H), 8.56 (d, J=1.60 Hz, 1H), 9.82 (s, 1H). LCMS (method-L): retention time 1.32 min, [M+2] 274.7.

Intermediate 186D: tert-butyl-(5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5

- 178 043056 yl) pyridin-3-yl) carbamate

To a stirred solution of intermediate 186C (4.00 g, 14.65 mmol) in a mixture of dioxane (100 ml) and water (10 ml) was added intermediate 2B (4.82 g, 17.57 mmol) and Cs ₂ CO ₃ (9.54 g, 29.3 mmol). The resulting reaction mixture was purged with nitrogen for 10 min and Pd(Ph ₃ P) ₄ (0.86 g, 0.73 mmol) was added. The resulting reaction mixture was heated at 100°C for 18 h and cooled to ambient temperature. The resulting mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Redisep-40 g, 0-40% EtOAc/n-hexane)) to give Intermediate 186D (5.00 g, 94.00%) as a light brown solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.49 (s, 9H), 2.22 (s, 3H), 5.47 (s, 2H), 7.47 (d, J=7.60 Hz, 1H), 7.76 (d, J =7.60 Hz, 1H), 7.93(d, J=2.00 Hz, 1H), 8.17(s, 1H), 8.65(s, 1H), (1 H proton exchangeable not observed). LCMS (method-O): retention time 1.12 min, [M+1] 341.5.

Intermediate connection 186A and 186B.

Intermediate 186 was obtained as a brown solid using a synthetic procedure similar to that of intermediate 118A, starting from intermediate 186D (5.00 g, 14.69 mmol). The two diastereomers were separated by SFC [Chiralpak ADH (250x4.6 mm) 5 microns; 0.2% NH4OH in MeOH, flow: 1.2 ml/min, temperature: 27°C, UV: 210 nm]. The first eluted compound (retention time 4.08 min), designated Intermediate 186A: Dia-I, was obtained (0.15 g, 2.96%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.38 (s, 9H), 1.45 - 1.50 (m, 1H), 1.81 - 1.96 (m, 1H), 2.33 (s, 3H), 2.40 - 2, 45 (m, 2H), 2.78 - 2.89 (m, 1H), 2.94 - 3.11 (m, 2H), 3.36 - 3.50 (m, 1H), 5.37 ( s, 2H), 6.73-6.75 (m, 1H), 7.38 (d, J=8.30 Hz, 1H), 7.64 (d, J=8.30 Hz, 1H). (No 1 exchangeable proton was observed). LCMS (Method-O): retention time 0.84 min, [M+1] 347.6. The second eluted compound (retention time 7.99 min), designated Intermediate 186B: Dia-II, was obtained (0.12 g, 2.37%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.45-1.50 (m, 1H), 1.81-1.96 (m, 1H), 2.33 (s, 3H), 2.40-2, 45 (m, 2H), 2.78 - 2.89 (m, 1H), 2.94 - 3.11 (m, 2H), 3.36 - 3.50 (m, 1H), 5.37 ( s, 2H), 6.73-6.75 (m, 1H), 7.38 (d, J=8.30 Hz, 1H), 7.64 (d, J=8.30 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-O): retention time 0.86 min, [M+1] 347.6.

Intermediate 187: (5-(5-cyano-4-methylpyridin-2-yl)-1,2,4-oxadiazol-3yl)methylmethanesulfonate

Intermediate 187A: 5-cyano-4-methylpicolinic acid

Intermediate 187A was obtained (0.70 g, 76.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 182B, starting from methyl 5-cyano-4-methylpicolinate (1, 00 g, 5.68 mmol) and LiOH (0.27 g, 11.35 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.56 (s, 3H), 8.07 (s, 1H), 8.98 (s, 1H), (1 H no exchangeable protons were observed). LCMS: (Method-I) retention time: 0.41 min, [M+1]: 163.3.

- 179 043056

Intermediate 187B: ethyl 5-(5-cyano-4-methylpyridin-2-yl)-1,2,4-oxadiazole-3carboxylate

CN

To a stirred solution of intermediate 187A (0.70 g, 4.32 mmol) in EtOAc (25 mL) was added TEA (2.41 mL, 17.27 mmol), ethyl-(Z)-2-amino-2-( hydroxyimino)acetate (0.07 g, 5.18 mmol) followed by the addition of 1-propanephosphonic anhydride (5.49 g, 8.63 mmol) at 0°C and the resulting reaction mixture was heated at 70°C for 18 hours. The resulting mixture was diluted with water (50 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 35% EtOAc/n-hexane) to give Intermediate 187B (0.50 g, 44.90%). 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.51 (t, J=7.03 Hz, 3H), 2.66-2.77 (s, 3H), 4.59 (q, J=7.36 Hz, 2H), 8.39 (s , 1H), 9.00 (s, 1H). LCMS (Method-I) retention time 1.39 min, [M+H] 259.3.

Intermediate 187C: 6-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)-4-methylnicotinonitrile

Intermediate 187C was obtained (0.25 g, 42.70%) as an off-white solid using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 187B (0.70 g, 2.71 mmol) and NaBH ₄ (0.20 g, 5.42 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.62 (s, 3H), 4.67 (d, J=4.60 Hz, 2H), 5.83 (s, 1H), 8.51 (s, 1H), 9.09 (s, 1H ). LCMS (Method-I) retention time 0.74 min, [MH] 217.0.

Intermediate 187.

Intermediate 187 was obtained (0.15 g, 6.61%) as an off-white solid using a synthetic procedure similar to that of intermediate 59 starting from intermediate 187C (0.25 g, 1.16 mmol) and mesyl chloride (0.09 ml, 1.16 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.37 (s, 3H), 2.73 (s, 3H), 5.01 (s, 2H), 7.95 (s, 1H), 8.76 (d, J=4.80 Hz, 1H ). LCMS (Method-I): retention time 1.08 min, [M+1] 295.2.

Intermediate 188: 1'-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridine]-5-carbaldehyde

Intermediate 188A: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Intermediate 188A was obtained (0.75 g, 60.00%) as a brown solid using a synthetic procedure similar to that of Intermediate 2B starting from 5-bromo-1-methylpyridine-2(1H) -one (0.10 g, 0.53 mmol). LCMS (Method-H): retention time 1.08 min, [M+1] 252.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 188.

Intermediate 188 was obtained (0.25 g, 24.27%) as a brown solid using a synthetic procedure similar to that of Intermediate 2C and using

- 180 043056 Intermediate 188A (0.61 g, 3.27 mmol) and 6-bromonicotinaldehyde as starting compounds. LCMS (Method-O): retention time 0.55 min, [M+1] 215. The compound was taken directly to the next step without further purification or characterization.

Intermediate 189-I, II, III and IV: tert-butyl 3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl)piperidine-1-carboxylate

Intermediate 189A: methyl 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)nicotinate

Intermediate 189A was obtained (1.30 g, 63.00%) as a brown solid using a synthetic procedure similar to that of intermediate 2C, starting from intermediate 2B (2.00 g, 7.30 mmol) and methyl 5-bromonicotinate (1.50 g, 6.90 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.25(s, 3H), 3.99(s, 3H), 5.33(s, 2H), 7.43(d, J=7.60 Hz, 1H), 7.86(d, J = 7.60 Hz, 1H), 8.29 (s, 1H), 8.77 (s, 1H), 9.29 (s, 1H). LCMS (Method-O): retention time 0.68 min, [M+1] 284.1.

Intermediate 189B: methyl 5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-3-carboxylate

Intermediate 189B was obtained (1.30 g, 98.00%) as a brown solid using a synthetic procedure similar to that of intermediate 118A starting from intermediate 189A (1.30 g, 4.59 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.97 - 2.06 (m, 1H), 2.08 - 2.16 (m, 1H), 2.30 (s, 3H), 2.68 - 2.73 (m, 1H), 2, 75 - 2.81 (m, 1H), 2.83 - 2.92 (m, 1H), 2.97 - 3.08 (m, 1H), 3.11 - 3.23 (m, 1H), 3.28 - 3.35 (m, 1H), 3.60 (s, 3H), 5.36 (s, 2H), 7.52 (d, J=8.00 Hz, 1H) 7.62 ( d, J=8.00 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-O): retention time 0.65 min, [M+1] 290.1.

Intermediate 189C: 1-(tert-butyl) 3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidine-1,3-dicarboxylate

Intermediate 189C was prepared (1.00 g, 70.00%) using a synthetic procedure similar to that of Intermediate 154A-I, starting from Intermediate 189B (1.30 g, 4.50 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.97 - 2.06 (m, 1H), 2.08 - 2.16 (m, 1H), 2.30 (s, 3H), 2.68 - 2 .73 (m, 1H), 2.75 - 2.81 (m, 1H), 2.83 - 2.92 (m, 1H), 2.97 - 3.08 (m, 1H), 3.11 - 3.23 (m, 1H), 3.28 - 3.35 (m, 1H), 3.60 (s, 3H), 5.36 (s, 2H), 7.52 (d, J=8 .00 Hz, 1H) 7.62 (d, J=8.00 Hz, 1H), LCMS (method-I): retention time 1.28 min, [M+H] 390.3.

Intermediate 189-I, II, III and IV.

To a stirred solution of intermediate 189C (2.00 g, 5.14 mmol) in THF (20 ml) was added a 2M solution of LiBH ₄ in THF (12.84 ml, 25.70 mmol) and the resulting reaction mixture was heated at 70°C within 18 hours the resulting mixture was cooled to ambient temperature, diluted with 10% solution of NH ₄ Cl (100 ml) and was extracted with the addition of ethyl acetate (2x100 ml). United

- 181 043056 the organic layers were washed with saturated saline (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The racemate was separated into individual enantiomers by the SFC method [Chiralpak ADH (250x4.6 mm) 5 microns; 0.2% NH ₄ OH in MeOH, flow: 1.2 ml/min, temperature: 27° C., UV: 210 nm]. The first eluted compound (retention time 6.12 min), designated Intermediate 189-I, was obtained (0.12 g, 6.50%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H), 1.70-1.79 (m, 1H), 1.77 (br. s., 1H), 1.80 (br. s., 1H), 2.29 (s, 3H) 2.64 - 2.78 (m, 1H), 2.98 (br. s., 1H), 3.39 - 3.47 (m, 3H), 4.00 (br. s ., 1H), 4.20 (br. s., 1H), 4.70 (br. s., 1H), 5.29 - 5.51 (m, 2 H), 7.48 (d, J = 8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (method-O): retention time 1.04 min, [M+1] 362.4. The second eluted compound (retention time 6.37 min), designated as intermediate 189-II, was obtained (0.04 g, 2.16%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.70-1.79 (m, 1H), 1.80-1.86 (m., 2H), 2.32 (s, 3H) 2.64-2 .78 (m, 1H), 2.96 - 2.99 (m., 1H), 3.39 - 3.47 (m, 3H), 3.82-3.90 (m., 1H), 3 .94 4.16 (m., 1H), 4.63 (br. s., 1H), 5.40 - 5.44 (m, 2H), 7.48 (d, J=8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retention time 1.07 min, [M+1] 362.4. The third eluted compound (retention time 7.77 min), designated as intermediate 189-III, was obtained (0.08 g, 4.33%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.77-1.92 (m., 3H), 2.29 (s, 3H) 2.64 - 2.78 (m, 1H), 3.05 - 3 .20 (m, 2H), 3.42-3.52 (m, 2H), 3.80-4.00 (m, 2H), 4.55 (br. s., 1H), 5.4 ( s, 2H), 7.50 (d, J=8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retention time 1.04 min, [M+1] 362.4. The fourth eluted compound (retention time 8.38 min), designated Intermediate 189-IV, was obtained (0.03 g, 1.62%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 1.77 -1.92 (m, 3H), 2.29 (s, 3H) 2.64 - 2.78 (m, 1H), 3.05 3.20 (m, 2H), 3.42-3.52 (m, 2H), 3.80-4.00 (m., 2H), 4.55 (br. s., 1H), 5.4 (s , 2H), 7.50 (d, J=8.30 Hz, 1H), 7.65 (d, J=8.30 Hz, 1H). LCMS (Method-O): retention time 1.07 min, [M+1] 362.4.

Intermediate 190: 3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4ylmethylcarbamate

Intermediate 190A: tert-Butyl 3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)4-((methylcarbamoyl)oxy)piperidine-1-carboxylate

To a stirred solution of intermediate 52A (0.30 g, 0.86 mmol) in THF (25 mL) was added NaH (41.6 mg, 1.73 mmol) followed by CDI (0.21 g, 1.30 mmol ) at 0°C and the resulting mixture was stirred at ambient temperature for 10 minutes. To the resulting reaction mixture was added methylamine hydrochloride (0.23 g, 3.46 mmol) and stirring at ambient temperature was continued for 18 hours. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 0-80% EtOAc/n-hexane)) to give Intermediate 190A (0.15 g, 43.00%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.42 (s, 9H), 2.04 - 2.13 (m, 1H), 2.30 (s, 3H), 2.42 (s, 3H), 2.77 - 3.17 (m , 3H), 3.69 - 3.95 (m, 1H), 3.98 - 4.19 (m, 2H), 5.07 - 5.30 (m, 1H), 5.40 (d, J = 5.02 Hz, 2H), 6.57 - 6.90 (m, 1H), 7.54 (d, J=8.53 Hz, 1H), 7.68 (d, J=8.53 Hz , 1H). LCMS (Method-O): retention time 1.16 min, [M-56] 349.5.

Intermediate 190.

Intermediate 190 was prepared (0.80 g, 0.55 mmol) using a synthetic procedure similar to that of intermediate 38-I, starting from intermediate 190A (0.15 g, 0.37 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.04 - 2.13 (m, 1H), 2.30 (s, 3H), 2.42 (s, 3H), 2.77 - 3.17 (m, 3H), 3.69 - 3, 95 (m, 1H), 3.98 - 4.19 (m, 2H), 5.07 - 5.30 (m, 1h), 5.40 (d, J=5.02 Hz, 2H), 6 .57 - 6.90 (m, 1H), 7.54 (d, J=8.53 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H), (no 1 capable of proton exchange). LCMS (Method-O): retention time 0.44 min, [M+1] 305.5.

- 182 043056

Intermediate 191: 4-(5-formyl-2H-tetrazol-2-yl)-2-methylbenzonitrile o

N-n

CN

Intermediate 191A: ethyl 2-(4-cyano-3-methylphenyl)-2H-tetrazole-5-carboxylate o

CN

To a stirred solution of 4-amino-2-methylbenzonitrile (1.00 g, 7.57 mmol) in EtOH (10 ml) and water (10 ml) at 0°C HCl (4.60 ml, 151 mmol) and sodium nitrite (1.04 g, 15.13 mmol). The resulting reaction mixture was stirred for 20 min at 0°C. to another 50 ml round bottom flask was added EtOH (20 ml), benzenesulphonohydrazide (1.30 g, 7.57 mmol) followed by ethyl 2-oxoacetate (1.545 g, 15.13 mmol) and the mixture was stirred at ambient temperature for 1 hour. The resulting mixture was evaporated under reduced pressure to obtain (ethyl-(E)-2-(2-(phenylsulfonyl)hydrazono)acetate, which was dissolved in pyridine (12.24 ml, 15 mmol) and added to the resulting mixture containing the first reaction set (diazotization) The resulting reaction mixture was stirred at ambient temperature for 18 h. The resulting mixture was concentrated to dryness under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml). washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure The residue was purified by column chromatography (Redisep-24 g, 3555% EtOAc/n-hexane) to give intermediate 191A (0.15 d, 7.71%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.48 (t, J=7.20 Hz, 3H), 2.71 (s, 3H), 4.55 (q, J=6.90 Hz, 2H), 8.0 (d, J=8 .40 Hz, 1H), 8.22 (m, 1H) 8.33 (s, 1H). LCMS (Method-I) retention time 1.60 min, [M+H] 258.1.

Intermediate 191B: 4-(5-(hydroxymethyl)-2H-tetrazol-2-yl)-2-methylbenzonitrile

Intermediate 191B was prepared (0.12 g, 83.00%) using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 191A (0.15 g, 0.58 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.50 (s, 3H), 4.81 (d, J=6.00 Hz, 2H), 5.81 (t, J=6.00 Hz, 1H), 8.09 (s, 2H) 8 .25 (s, 1H). LCMS (Method-I) retention time 0.97 min, [M+H] 216.4.

Intermediate 191.

Intermediate 191 was prepared (0.08 g, 67.30%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 191B (0.12 g, 0.56 mmol) and Dess periodinan -Martin (0.35 g, 0.84 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.66 (s, 3H), 8.11 -8.16 (m, 1H), 8.18 (d, J=2.51 Hz, 1H), 8.35 (s, 1H), 10.27 (s, 1H). LCMS (Method-I): retention time 0.87 min, [M-H] 212.0.

Intermediate 192: 1-(4-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

- 183 043056

Intermediate 192A: 1-(4-aminopyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Intermediate 192A was obtained (0.40 g, 26.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 6 starting from 1H-pyrazole-4-carbaldehyde (0. 80 g, 8.33 mmol) and 2-bromopyridine-4amine (1.44 g, 8.33 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.49 - 6.53 (m, 3H), 7.12 (d, J=2.01 Hz, 1H), 7.93 (d, J=5.52 Hz, 1H), 8.21 (d , J=1.00 Hz, 1H), 9.16 (s, 1H), 9.93 (s, 1H). LCMS (Method-D): retention time 0.73 min, [M+H] 189.1.

Intermediate yl) carbamate (2-(4-formyl-1 H-pyrazol-1 -yl) pyridine-4192B: 2-chloroethyl

Intermediate 192B was obtained (0.20 g, 43.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 76A, starting from intermediate 192A (0.30 g, 1 .60 mmol) and 2 chloroethyl chloroformate (0.27 g, 1.91 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.89 - 3.93 (m, 2H), 4.41 4.45 (m, 2H), 7.47 (dd, J=5.52, 2.01 Hz, 1H), 8.22 (d , J=2.01Hz, 1H), 8.28(s, 1H), 8.36(d, J=6.02Hz, 1H), 9.27(s, 1H), 9.96(s , 1H), 10.66 (s, 1H). LCMS (method-D): retention time 1.92 min, [M+H] 295.

Intermediate 192.

Intermediate 192 was obtained (0.10 g, 56.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 76B, starting from intermediate 192B (0.15 g, 0 .51 mmol) and NaH (0.02 g, 1.018 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.16 (dd, J=8.93, 6.97 Hz, 2H), 4.50-4.55 (m, 2H), 7.52 (dd, J=5.75, 2.08 Hz, 1H), 8.31 (s, 2H), 8.47 (d, J=5.87 Hz, 1H), 9.31 (s, 1H), 9.97 (s, 1H). LCMS (Method D): retention time 1.20 min, [M+H] 259.1.

Example 113-I: 4,4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazine-1 -yl)methyl)thiazol-2-yl)nicotinonitrile.

The compound of Example 113-I was obtained (0.02 g, 32.30%) as a white solid using a synthetic procedure similar to that of Intermediate 23B, starting from Intermediate 55-I (0.20 g, 0.47 mmol) and Intermediate 53 (0.26 g, 0.98 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.20 (s, 3H), 2.25 (s, 3H), 2.50 (s, 3H), 2.60 (br. s, 2H), 2.84 (br. s., 2H) , 2.98 (br. s., 1H), 3.71 - 3.96 (m, 2 H), 4.16 (br. s., 1H), 5.37 (br. s., 2 H ), 7.65 (m, J=8.00 Hz, 1H), 7.79 (d, J=8.00 Hz, 1H), 7.91 (s, 1H), 8.19 (s, 1H ), 8.98 (s, 1H), (1 exchangeable proton was not observed). LCMS/HPLC (Method-S): retention time 1.69 min, [M+H] 460.2, purity: 100%. (Method-R): retention time 1.25 min, [M+H] 460.2, purity: 96.09%.

- 184 043056

Example 114-I: 6-(4-((4-Hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)- 1 H-pyrazol-1 -yl)-4-methylnicotinonitrile

The compound according to Example 114-I was prepared from the compound according to Example 1-I, and using a synthetic procedure similar to that of the starting compounds, Intermediate 72 (0.02 g, 0.919 mmol) and Intermediate 6 (0.02 g , 0.707 mmol). The racemate was separated into individual enantiomers by the SFC method [Luxcellulose-2 (250x21.5 mm) 5 microns; 0.1% DEA in IPA+ACN (10:90), flow: 1.0 g/min. Temperature: 30°C, UV: 235 nm]. The first eluted compound (retention time 7.34 min), designated Example 114-I, was obtained (0.01 g, 3.86%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.93 (s, 3H), 1.62 (d, J=13.2 Hz, 1H), 1.79 (td, J=12.80, 4.3 Hz, 1H), 2.24 (s , 3H), 2.46 - 2.39 (m, 1H), 2.59 - 2.54 (m, 4H), 2.64 - 2.60 (m, 1H), 2.71 (d, J =10.80 Hz, 1H), 3.12 (dd, J=11.20, 3.4 Hz, 1H), 3.58 - 3.50 (m, 2H), 4.34 (br. s. , 1H), 5.45 5.23 (m, 2H), 7.58 (d, J=7.80 Hz, 1H), 7.88-7.75 (m, 2H), 7.97 (s , 1H), 8.52 (s, 1H), 8.83 (s, 1H). HPLC/LCMS (Method-R): retention time 1.14 min, [M+H] 458.2, purity: 100%. (Method-S): retention time 1.46 min, [M+H] 458.2, purity: 100%. Chiral purity (Method-XXVIII): retention time 7.34 min, 100% e.i.

Example 115-I: 4-methyl-6-(4-((2-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)- 1 H-pyrazol-1 -yl) nicotinonitrile

The compound of Example 115-I was prepared (0.01 g, 5.86%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 71-I (0.15 g, 0.61 mmol) and intermediate 6 (0.10 g, 0.47 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.67 (d, J=6.10 Hz, 3H), 2.18 (s, 3H), 2.58 (s, 3H), 2.66 (d, J=10.80 Hz, 1H), 3.08 - 2.86 (m, 3H), 3.17 (d, J=5.10 Hz, 1H), 3.61 (br. s., 2H), 4.31 (br. s., 1H), 5.35 (s, 2H), 7.66 (s, 2H), 7.90 (s, 1H), 7.99 (s, 1H), 8.56 (s, 1H), 8, 84 (s, 1H), (1 exchangeable proton was not observed). LCMS/HPLC (Method-R): retention 1.04 min, [M+H] 443.2, purity: 98.77%. (Method-S): retention time 1.46 min, [M+H] 443.2, purity: 98.63%. Chiral purity (Method-V): retention time 7.99 min, 97.93%e.

Example 116-I: 6-(4-((4-Hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl )-1 H-pyrazol-1 -yl)-4-methylnicotinonitrile

The compound of Example 116-I was prepared (0.01 g, 15.60%) using a synthetic procedure similar to that of the compound of Example 1-I, starting from Intermediate 73-I (0.02 g, 0.92 mmol) and intermediate 6 (0.03 g, 0.14 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.90 (s, 3H), 1.08 (s, 3H), 1.24 (s, 1H), 2.03(t, J=11.10 Hz, 1H), 2.26 (s, 3H ), 2.64 - 2.56 (m, 4H), 2.78 (d, J=10.30 Hz, 1H), 3.29 (d, J=4.20 Hz, 1H), 3.54 - 3.38 (m, 3H), 4.42 (d, J=6.10 Hz, 1H), 5.44 - 5.29 (m, 2H), 7.53 (d, J=8.30 Hz, 1H), 7.63 (d, J=7.80 Hz, 1H), 7.84 (s, 1H), 7.99 (s, 1H), 8.51 (s, 1H), 8, 84(s, 1H). HPLC/LCMS (Method-R): retention time 1.12 min, [M+H] 472.3, purity: 96.20%. (Method-S): retention time 1.82 min, [M+H] 472.3, purity: 94.72%. Chiral purity

- 185 043056 (method-V): retention time 4.17 min, 100% e.i.

Example 117-I: 4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl )methyl)-2-oxooxazol-3(2H)-yl)nicotinonitrile

Example 117-I was prepared (0.02 g, 21.10%) using a synthetic procedure similar to that of Intermediate 15C, starting from Intermediate 75 (0.07 g, 0.204 mmol) and 6 -bromo-4-methylnicotinonitrile (0.05 g, 0.245 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (d, J=6.10 Hz, 3H), 1.24 (s, 1H), 1.95-1.74 (m, 2H), 2.30 (s, 3H), 2.61 - 2.53 (m, 3H), 2.83 (d, J=10.3 Hz, 2H), 2.96 (br. s., 1H), 3.48 (s, 2H), 4.16 (d , J=9.00 Hz, 1H), 5.46 - 5.30 (m, 2H), 7.66 (d, J=7.80 Hz, 1H), 7.74 (s, 1H), 7 .81 (d, J=7.80 Hz, 1H), 8.24 - 8.15 (m, 1H), 8.84 (s, 1H). LCMS/HPLC (Method-R): retention time 0.93 min, [M+H] 460.2, purity: 97.01%. (Method-S): retention time 1.42 min, [M+H] 460.2, purity: 95.11%.

Example 118-I: (R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxo-imidazolidin-1-yl) methyl)-1 H-pyrazol-1 -yl) nicotinonitrile

To a stirred solution of intermediate 131-I (0.05 g, 0.12 mmol) in THF (10 ml) was added TEA (0.03 ml, 0.25 mmol) followed by CDI (0.03 g, 0. 18 mmol) and the resulting reaction mixture was heated at 70°C for 1 h. The resulting mixture was cooled to ambient temperature, diluted with water (20 ml) and was extracted with the addition of ethyl acetate (2x40 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [XBridge C18 (19x150 mm) 5 microns; solvent A: 0.1% TFA; solvent B: acetonitrile; gradient: 10-40% B over 25 min, flow: 15 ml/min, retention time 13.72 min, UV: 240 nm] to give the compound of Example 118-I (0.012 g, 20.41%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.23 (s, 3H), 2.57 (s, 3H), 2.93 (dd, J=8.93, 6.48 Hz, 1H), 3.87 (t, J=8.93 Hz , 1H), 4.13 - 4.34 (m, 2H), 5.06 (t, J=7.09 Hz, 1H), 5.31 - 5.45 (m, 2H), 7.22 ( s, 1H), 7.56 (d, J=8.07 Hz, 1H), 7.71 (d, J=8.07 Hz, 1H), 7.80 (s, 1H), 7.97 ( s, 1H), 8.53(s, 1H), 8.83(s, 1H). LCMS/HPLC (Method-S): retention time 1.60 min, [M+H] 429.1, purity: 96.70%. (Method-R): retention time 1.61 min, [M+H] 429.1, purity: 97.92%. Chiral purity (Method-XVIII): retention time 13.72 min, 95.00% e.i.

Example 119-I: (R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,1-dioxido1,2, 5-thiadiazolidin-2-yl)methyl)-1H-nirazol-1-yl)nicotinonitrile.

To a stirred solution of intermediate 131-I (0.06 g, 0.15 mmol) in pyridine (0.50 ml) was added sulfamide (0.30 g, 0.30 mmol) and the resulting reaction mixture was heated at 125°C in for 16 hours the resulting mixture was cooled to ambient temperature, diluted with water (20 ml) and was extracted with the addition of ethyl acetate (2x50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC [Sunfire OBD-C18 (30x250 mm) 5 microns; solvent A: 10 mM ammonium acetate; solvent B: acetonitrile; gradient: 20-50% B over 12 min, flow: 25 ml/min, retention time 17.55 min, UV: 240 nm] to give Example 119-I (0.02 g, 24 .55%) as a white solid. 1H NMR (400 MHz, DMSOd ₆ ) δ ppm 2.25 (s, 3H), 2.58 (s, 3H), 2.94 (dd, J=9.90, 7.70 Hz, 1H), 3.92-4.08 (m, 2H) , 4.20 (d, J=14.43 Hz, 1H), 5.11 (q, J=7.42 Hz, 1H), 5.30 -5.43 (m, 2H), 7.65 - 7.78 (m, 2H), 7.91 (s, 1H), 7.98 (s, 1H), 8.14 (d, J=7.09 Hz, 1H), 8.65 (s, 1H ), 8.84 (s, 1H), LCMS/HPLC (method-S): retention time 1.42 min, [M+H] 465.1, purity: 100%. (Method-R): retention time 1.41 min, [M+H] 465.1, purity: 100%. [M+H] 465.1, Chiral purity (Method-XVIII): retention time 17.55 min, 97.25% ee.

Example 120-I: 2-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl )methyl)pyridin-2-yl)pyridazin-3 (2Н)-one

Example 120-I was prepared (0.02 g, 11.00%) using a synthetic procedure similar to that of Intermediate 23B, starting from Intermediate 96-I (0.15 g, 0.36 mmol) and Intermediate 102 (0.01 g, 0.36 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02 (d, J=5.90 Hz, 3H), 1.68 - 1.82 (m, 2H), 2.23 (s, 3H), 2.76 (t, J=10.00 Hz , 2H), 2.99 (br. s., 1H), 3.52 - 3.65 (m, 2H), 3.77 (s, 3H), 4.17 (d, J=9.00 Hz , 1H), 5.27 - 5.46 (m, 2H), 7.07 (d, J=9.80 Hz, 1H), 7.65 (d, J=8.10 Hz, 1H), 7 .80 (d, J=8.10 Hz, 1H), 7.89 (dd, J=8.20 Hz, 1.6 Hz, 1H), 8.07 (d, J=8.30 Hz, 1H ), 8.29 (d, J=9.80 Hz, 1H), 8.57 (br. s., 1H), (1 exchangeable proton not observed). LCMS/HPLC (Method-S): retention time 1.17 min, [M+H] 446.2, purity: 100%. (Method-R): retention time 0.60 min, [M+H] 446.2, purity: 99.60%. Chiral purity (Method-XI): retention time 12.50 min, 100% e.i.

Example 121-I: 4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)ethyl) -2H-1,2,3-triazol-2-yl)nicotinonitrile (Dia-I:Ena-I) and Example 121-I: 4-methyl-6-(4-(1-((R)-3- (4methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile (Dia-II:Ena-I) ,

To a stirred solution of intermediate 101 (0.100 g, 0.325 mmol) in ACN (6 mL) was added intermediate 2-I (0.08 g, 0.36 mmol) followed by K ₂ CO ₃ (0.09 g, 0 .65 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 hours. The resulting mixture was diluted with ACN (20 ml) and filtered through celite. The filtrate was evaporated under reduced pressure and the residue was purified by HPLC [Sunfire OBD (250x30 mm) 5 microns; solvent A: 10 mM ammonium acetate; solvent B: acetonitrile, gradient: 30-100% B over 15.5 min, retention time 12.07, UV: 254 nm] to give a racemate which was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Chiralpak OJ -H (250x21mm) 5 microns; 0.2% NH4OH in MeOH+ACN (1:1), flow: 70.0 ml/min. Temperature: 30°C, UV: 290 nm]. The first eluted compound (retention time 5.9 min), designated Example 121-I, was obtained (0.02 g, 12.20%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (d, J=7.00 Hz, 3H), 1.87 (t, J=10.30 Hz, 1H), 2.12-2.20 (m, 1H), 2.26 (s , 3H), 2.61 (s, 3H), 2.75 (d, J=11.00 Hz, 1H), 2.83-2.92 (m, 2H), 2.99 (br. s. , 1H), 4.07 (d, J=7.00 Hz, 2H), 5.37 (s, 2H), 7.61 (d, J=8.00 Hz, 1H), 7.72 (d , J=8.00 Hz, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8.92 (s, 1H), (no exchangeable proton observed). HPLC (Method-P): retention time 7.92 minutes, purity: 97.9%. (Method-Q): retention time 6.98 min, purity: 98.0%. LCMS (Method-D): retention time 1.73 min, [M+H] 444.2. Chiral purity (method-XX): retention time 4.79 min, 99.5% e.i. The second eluted compound (7.70 min retention time), designated Example 121-II, was obtained (0.02 g, 12.90%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.43 (d, J=7.00 Hz, 3H), 1.87 (t, J=10.30 Hz, 1H), 2.12 - 2.20 (m, 1H), 2.26 (s , 3H), 2.61 (s, 3H), 2.75 (d, J=11.00 Hz, 1H), 2.83-2.92 (m, 2H), 2.99 (br. s. , 1H), 4.07 (d, J=7.00 Hz, 2H), 5.37 (s, 2H), 7.61 (d, J=8.00 Hz, 1H), 7.72 (d , J=8.00 Hz, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8.92 (s, 1H), (no exchangeable proton observed). HPLC (Method-P): retention time 7.83 minutes, purity: 98.20%. (Method-Q): retention time 7.02 minutes, purity: 98.8%. LCMS (Method-D): retention time 1.84 min, [M+H] 444.2.

- 187 043056

Chiral purity (method-XX): retention time 6.34 min, 98.60% ee

Example 122-I: 4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1-yl )methyl)- 1H-1,2,4-triazol-1 -yl)nicotinonitrile

Example 122-I was prepared (0.02 g, 28.40%) using a synthetic procedure similar to that of Intermediate 20, starting from Intermediate 97 (0.03 g, 0.09 mmol) and 6-bromo-4-methylnicotinonitrile (0.02 g, 0.110 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 - 1.35 (m, 3H), 2.37 (s, 3H), 2.59 - 2.70 (m, 4H), 3.14 - 3.26 (m, 3H), 3, 93 (s., 3H), 4.78 (br. s., 1H), 5.38-5.56 (m, 2H), 7.80 (d, J=7.80 Hz, 1H), 7 .87 (d, J=7.80 Hz, 1H), 7.93 - 8.00 (m, 1H), 8.92 - 8.99 (m, 1H), 9.59 (s, 1H), (1 exchangeable proton was not observed). LCMS/HPLC (Method-S): retention time 1.86 min, [M+H] 444.2, purity: 96.60%. (Method-R): retention time 1.19 min, [M+H] 444.2, purity: 93.30%. Chiral purity (Method-VIII): retention time 4.64 min, 100% e.i.

Example 123-I: 6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile (Dia-I:Ena-I) and Example 123-II: 6-(4-((2(hydroxymethyl)-5-(4-methyl-1-oxo-1, 3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol1-yl)-4-methylnicotinonitrile (Dia-I:Ena-II)

To a solution of 103 (Diastereomer I) (0.06 g, 0.23 mmol) in ACN (5 mL) was added intermediate 104 (0.08 g, 0.34 mmol) followed by K ₂ CO ₃ (0.13 g, 0.91 mmol) and the resulting reaction mixture was heated at 60°C for 12 h.

The resulting mixture was diluted with ACN (20 ml) and filtered through celite. The filtrate was evaporated under reduced pressure and the residue was purified by HPLC [Intersil ODS (250x20 mm) 5 microns; solvent A: 10 mM ammonium acetate; solvent B: acetonitrile, gradient: 20-100% B over 16 minutes, retention time: 11.8, UV: 220] to give a racemic mixture which was separated into two separate enantiomers by supercritical fluid chromatography (SFC) [Lux amylose- 2 (250x21 mm) 5 microns; 0.2% NH ₄ OH in MeOH+acetonitrile (1:1), flow: 70.0 ml/min. Temperature: 30°C, UV: 240 nm]. The first eluted compound (retention time 6.38), designated Example 123-I, was obtained (0.005 g, 4.60%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 - 1.90 (m, 1H), 2.23 (s, 3H), 2.58 (s, 4H), 2.60 - 2.62 (m, 1H), 2.75 (dd, J=10.79, 2.26 Hz, 1H), 3.13 (dd, J=11.55, 3.01 Hz, 1H), 3.44 - 3.49 (m, 1H), 3.68 - 3.73 (m, 1H), 3.78 - 3.83 (m, 1H), 3.87 (d, J=15.06 Hz, 1H), 4.01 (d, J=8.03 Hz, 1H), 4.70 (t, J=5.27 Hz, 1H), 5.36 (s, 2H), 7.59 - 7.63 (m, 1H), 7.70 (d, J = 8.03 Hz, 1H), 7.83 (s, 1H), 7.98 (s, 1H), 8.53 (s, 1H), 8.82 (s, 1H), (not observed 1 capable to proton exchange). HPLC (Method-P): retention time 9.77 minutes, purity: 98.80%. (Method-Q): retention time 7.95 min, purity: 97.0%. LCMS (Method-D): retention time 1.55 min, [M+H] 459.2. Chiral purity (Method-XIII) retention time 7.20 min, 100% e.i. The second eluted compound (retention time 9.20 min), designated Example 123-II, was obtained (0.005 g, 4.60%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.84 - 1.90 (m, 1H), 2.23 (s, 3H), 2.58 (s, 4H), 2.60 - 2.62 (m, 1H), 2.75 (dd, J=10.79, 2.26Hz, 1H), 3.13(dd, J=11.55, 3.01Hz, 1H), 3.44-3.49(m, 1H), 3.68 - 3.73 (m, 1H), 3.78 - 3.83 (m, 1H), 3.87 (d, J=15.06 Hz, 1H), 4.01 (d, J=8.03 Hz, 1H), 4.70 (t, J=5.27 Hz, 1H), 5.36 (s, 2H), 7.59 - 7.63 (m, 1H), 7.70 (d, J = 8.03 Hz, 1H), 7.83 (s, 1H), 7.98 (s, 1H), 8.53 (s, 1H), 8.82 (s, 1H), (not observed 1 capable to proton exchange). HPLC (Method-P): retention time 9.96 min, purity: 99.30%. (Method-Q): retention time 8.13 minutes, purity: 98.70%. LCMS (Method-D): retention time 1.55 min, [M+H] 459.2. Chiral purity (Method XIII) retention time 10.25 min, 100% e.i.

Compounds according to the examples listed in table. 3 was synthesized according to the procedures for compounds according to examples 1-I - 24-I, 81-I - 84-I and 113-I - 123-I

- 188 043056

Example Structure Name LCMS (M+N) ⁺ HPLC/LC ms Method: RT (min), purity NMR 125-1 0 to Q CN 6-(5-(((35.45)-4hydroxy-3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)thiazol-2yl)-4- methyl nicotinonitrile l. 461.2 S: 1.52, 93.70% R: 1.03, 94.16% Ή NMR (400 MHz, DMSO-c/e) δ ppm 1.60 (br. s., 1 H), 1.92 (br. s., 1 H), 2.15 (t, J= 11.0 Hz, 1 H), 2.24 (s, 3 H), 2.32 (d, J = 14.20 Hz, 1 H), 2.65 (s, 3 H), 2.76 (d, J = 9.40 Hz, 1 H), 2.97 (d, J = 11.80 Hz, 1 N), 3.08 (t, J = 8.80 Hz, 1 N), 3.76 (br. s., 1 N), 3.80 - 3, 96 (m, 2 N), 4.62 (d, J= 5.60 Hz, 1 N), 5.26 - 5.47 (m, 2 N), 7.54 (d, J= 8.00 Hz, 1 H), 7.64 (d, J= 8.00 Hz, 1 H), 7.91 (s, 1 H), 8.18 (s, 1 H), 8.97 (s, 1 N). 126-1 127-1 128-1 \°Υ° ³ \ / ³ \ / f GO \ / GO \ / ^f U fQ f& f^ I _______________________Z ¹ ________________________________ f 5-((25.65)-4-((1-(2methoxypyridin-4yl)- 1//-imidazol-4yl)methyl)-6methylpiperazin-2yl)-4- methylisobenzofuran1(37U)-one 5-((25.65)-4-((1-(2(difluoromethyl)pyridi n-4-yl)- 177-pyrazol4-yl)methyl)-6methylpiperazin-2yl)-4- methylisobenzofuran1(3R)-one 4-methyl-5-((25.65)-6methyl-4-((1-(2- (trifluoromethyl)pyride in-4-yl)- 1H-pyrazole4- yl)methyl)piperazin2-yl)isobenzofuran1(3R)-one 434.2 454.2 472.2 S: 1.20, 98.20% R: 0.78, 99.82% V: 5.73, 100% e.i. S: 1.29, 96.29% R: 0.72, 97.83% S: 1.16, 96.16% R: 0.92, 96.93% IX: 4.77, 100% ee Ή NMR (400 MHz, DMSO-c/ ₆ ) δ ppm 1.03 (d, J= 6.1 Hz, 3 H), 1.78 (br. s., 2 H), 2.27 (s, 3 H), 2.84 (br. s 2 H ), 2.97 (br. s., 1 H), 3.47 (br. s., 2 H), 3.90 (s, 3 H), 4.18 (br. s, 1 H), 5.38 (s, 2 H), 7.19 (d, J= 1.70 Hz, 1 H), 7.38 (dd, J= 2.00, 6.00 Hz, 1 H), 7, 66 (d, J = 7.60 Hz, 1 H), 7.73 - 7.88 (m, 2 H), 8.23 (d, J = 5.60 Hz, 1 H), 8.45 ( s, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-c/b) δ ppm 1.03 (d, J = 6.00 Hz, 3 H), 1.64 - 1.81 (m, 2 H), 2.15 2.32 (br, 3 H), 2.81 (d, J = 11.20 Hz, 2 H), 2.98 (br. s., 1 H), 3.49 (s, 2 H), 4.17 (d, J = 9.30 Hz, 1 H) , 5.28 - 5.47 (m, 2 N), 7.00 (s, 1 N), 7.65 (d, J= 8.00 Hz, 1 N), 7.72 - 7.88 ( t, 2 N), 8.01 (d, J = 5.00 Hz, 1 N), 8.13 (d, J = 1.80 Hz, 1 N), 8.618.82 (t, 2 N), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSOc/b) δ ppm -115.9. Ή NMR (400 MHz, DMSO-c/b) δ ppm 1.04 (d, 7 = 5.60 Hz, ZN), 1.75 (br. s., 2H), 2.15-2.31 (t, 3 H), 2.82 (d, J= 8.30 Hz, 2 H), 2.99 (br. s., 1 H), 3.50 (br. s., 2 H), 4.19 (br. s., 1 H), 5, 25 - 5.49 (m, 2 H), 7.66 (d, J = 8.60 Hz, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 7.86 ( s, 1 H), 8.14 (dd, J = 2.20, 5.60 Hz, 1 H), 8.31 (d, J = 2.00 Hz, 1 H), 8.72 8.88 (m, 2 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSOc/e) δ ppm - 66.70. 129-1 ta - But 1Ye /A X>0 to to F 1 -(difluoromethyl)-4-(4(((3S,5R)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)- 1Нpyrazol-1yl)pyridine-2( 1Н)-one 470.2 S: 1.19, 94.05% R: 0.68, 100% XIV: 2.70, 100% e.i. Ή NMR (400 MHz, DMSO-c/b) δ ppm 1.04 (br. s., 3 H), 1.72 (br. s., 2 H), 2.32 (s, 3 H), 2.80 (br. s., 2H), 2. 85-3.13 (t, 1 H), 3.48 (br. s., 2H), 4.17 (br. s., 1 H), 5.31-5.49 (m, 2 H) , 6.87 (d, J = 2.00 Hz, 1 H), 7.09 (dd, J = 2.00, 8.00 Hz, 1 H), 7.66 (d, J = 7.50 Hz, 1 H), 7.73 - 7.89 (m, 3 H), 7.89 - 8.05 (m, 1 H), 8.54 - 8.66 (m, 1 H), (not 1 exchangeable proton was observed). ¹⁹ F NMR (400 MHz, DMSO-c/b) δ ppm -102.9.

- 189 043056

130-1 0 - ^Me Κ1Ύ \ N% Me CN 1-(5-(((37.57)-3(hydroxymethyl)-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-2yl)-3 - methyl-1Hpyrazole-4carbonitrile 444.2 S: 1.31, 100% R: 0.99, 100% Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.02 (d, J= 6.40 Hz, 3 N), 1.72 - 1.88 (br, 2 N), 2.32 (s, 3 N), 2.55 (s, 3 N) , 2.85 (d, J = 10.80 Hz, 2 H), 2.98 (d, J = 10.50 Hz, 1 H), 3.55 (s, 2 H), 4.16 (d , J = 8.30 Hz, 1 N), 5.38 (d, J = 2.20 Hz, 2 N), 7.66 (d, J = 7.80 Hz, 1 N), 7.81 ( d, J = 8.10 Hz, 1 H), 8.19 (s, 1 H), 8.26 (s, 1 H), 9.02 (s, 1 H), (no exchangeable proton). 131-1 132-1 133-1 134-1 0 Me k-, ί _Ν Χο f ^Xf 0 °bQ ^Me Xu Y NO U-L bQ + Me CN 0 o^O Me HNj oX Me mO< N% Me CN O _H 0^ 1 -(difluoromethyl)-4-(4(((3 S, 57) -3 -methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl) -1Nimidazol-1yl)pyridine-2(1D)-one 6-(4-(((37.47)-4hydroxy-3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)oxazol-2yl)-4- methylnicotinonitrile l 4-methyl-6-(5(((3S, 57)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)oxazol-2yl )nicotinonitrile 5-((27.65)-4-((1-(6(difluoromethyl)pyridi n-3-yl)-1 H-and m idazol4-yl)methyl)-6methylpiperazin-2yl)-4methylisobenzofuran1(3R )-He 470.2 445.2 444.2 454.2 S: 1.08, 100% R: 0.77, 100% V: 2.77, 100% e.i. S: 1.25, 97.81% R: 0.95 95.67% V: 4.37, 100% e.i. S: 1.51, 100% R: 1.19, 98.32% XI: 6.58 96.51% e.i. S: 1.15, 100% R: 0.78, 100% VII: 7.80 100% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.02 (d, J = 6.10 Hz, 3 H), 1.66 - 1.85 (w, 2 H), 2.19 2.33 (w, 3 H), 2.83 (d, J - 11.00 Hz, 2 N), 2.96 (br. s., 1 N), 3.45 (s, 2 N), 4.16 (d, J= 8.6 Hz, 1 N) , 5.29 - 5.45 (m, 2 N), 6.81 - 6.93 (t, 1 N), 6.97 (dd, J= 2.20, 7.80 Hz, 1 N), 7.64 (d, J= 1.20 Hz, 1 N), 7.55-7.72 (t, 1 N), 7.75-7.91 (t, 2 N), 7.99 (d , J = 7.80 Hz, 1 H), 8.47 (s, 1 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSO-J ₆ ) δ ppm -114.90. ^X NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.58 - 1.70 (t, 1 N), 1.88 - 1.97 (t, 1 N), 2.16 (t, J = 11.1 Hz, 1 N), 2.21 - 2 .32 (t, 4 N), 2.55 (t, 3 N), 2.80 (d, J = 11.70 Hz, 1 N), 3.08 (td, J = 3.40, 10, 20 Hz, 2 N), 3.56 (s, 2 N), 3.72 (td, J = 5.20, 9.8 Hz, 1 N), 4.58 (d, J= 5.60 Hz , 1 N), 5.25 - 5.46 (t, 2 N), 7.55 (d, J = 7.80 Hz, 1 N), 7.64 (d, J = 8.10 Hz, 1 H), 8.19 (s, 1 H), 8.26 (s, 1 H), 9.02 (s, 1 H). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.04 (br. s., 3 H), 1.84 (br. s., 2 H), 2.28 (s, 3 H), 2.60 (s, 3 H), 2.84 ( br. s., 2 H), 2.97 (br. s., 1 H), 3.76 (br. s., 2 H), 4.17 (br. s., 1 H), 5, 39 (s, 2 H), 7.38 (s, 1 H), 7.67 (br. s., 1 H), 7.79 (d, J = 7.80 Hz, 1 H), 8, 18 (s, 1 H), 9.02 (s, 1 H), (1 exchangeable proton not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, J= 6.10 Hz, 3 H), 1.82 (br.s., 2 H), 2.32 (s, 3 H), 2.87 (br. s., 2 H), 2.98 (br. s., 1 Η), 3.49 (s, 2 Η), 4.18 (d, .J- 9.00 Hz, 1 Η), 5.38 (s, 2 Η), 7.02 (s, 1 Η), 7.66 (d, J= 7.80 Hz, 1 Η), 7.72 - 7.92 (m, 3 Η), 8.31 (dd , J= , 2.70, 8.60 Hz, 1 Η), 8.38 (d, J = 1.50 Hz, 1 Η), 9.07 (d, J = 2.70 Hz, 1 H) , (1 exchangeable proton was not observed). 135-1 about P „- ^Me 0% (7) -3,4-d imethyl-5 - (4 ((3 - (4-methyl-1 -oxo1, 3- dihydroisobenzofura n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1yl)benzo[b]oxazol2(3R)-one 474.1 S: 1.31, 98.71% R: 1.02, 99.80% XIV: 9.78, 98.00% e.i. Ή NMR (400 MHz, DMSO-^b) δ ppm 1.71 - 1.80 (br. s., 1 H), 1.91 (br. s., 1 H), 2.10 (t, J = 9.66 Hz, 1 H), 2.24 (d, J = 4.16 Hz, 6 N), 2.77 - 3.06 (br, 4 N), 3.41 - 3.52 (br, 2 N), 3.58 (s, 3 N), 4 .06 (d, J = 8.31 Hz, 1 H), 5.38 (s, 2 H), 7.08 (d, J = 8.31 Hz, 1 H), 7.28 (d, J = 8.56 Hz, 1 N), 7.58 7.70 (m, 2 N), 7.76 - 7.83 (t, 2 N).

- 190 043056

136-1 0 °u H (R)-1-(5-((3-(4-methyl1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-2yl)- 1H-pyrazole-3 carbonitrile 415.1 S: 1.70, 98.44% R: 1.36, 99.60% XVIII: 11.56, 98.10% e.i. ^NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.88 (t, J= 10.76 Hz, 1 Η), 2.12 - 2.29 (m, 4 Η), 2.71 2.85 (m, 2 Η), 2.86 - 3, 05 (m, 2 Η), 3.57 - 3.71 (m, 2 Η), 4.10 (d, J = 7.58 Hz, 1 Η), 5.33 - 5.41 (m, 2 Η), 7.27 (d, J= 2.69 Hz, 1 Η), 7.65 (d, J= 7.83 Hz, 1 Η), 7.78 (d, J = 7.83 Hz, 1 Η), 7.95 - 8.07 (m, 2 Η), 8.46 (s, 1 Η), 8.85 (d, J= 2.69 Hz, 1 H), (no 1 capable to proton exchange). — Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.42 0 (7?)-4-ethoxy-6-(4-((3 - S: 1.74 (t, J= 6.97 Hz, 3 N), 1.83 (br, 1 N), 2.14 (br, 1 N), T (4-methyl-1-oxo-1,3- 97.53% 2.26 (s, 3 H), 2.81 (d, J = 10.03 Hz, 2 H), 2.87 - 137-1 ^Me hO 4 ^,N dihydroisobenzofur R: 1.39 3.07 (gp, 2 H), 3.53 (s, 2 H), 4.10 (br. s., 1 H), 4.41 \==/ ° n-5 -yl)piperazine-1 - 459.1 97.64% (q, J = 7.09 Hz, 2 Η), 5.37 (s, 2 Η), 7.57 (s, 1 Η), yl) methyl) - 1H- XVIII: 7.65 (d, .J- 8.56 Hz, 1 Η), 7.76 (d, .J- 7.83 Hz, 1 pyrazole-1- 16.38 Η), 7.85 (s, 1 Η), 8.52 (s, 1 Η), 8.72 (s, 1 H), (not yl) nicotinonitrile. 99.23% e.i. 1 exchangeable proton was observed). — — ^X NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.87 (R)-1 -(5-((3 -(4-methyl- S: 1.18 (t, J = 10.52 Hz, 1 H), 2.13 - 2.19 (m, 1 H), 2.23 0 1-oxo-1,3- 100% (s, 3 Η), 2.78 (dd, J = 17.12, 11.25 Hz, 2 Η), 2.87 °tl ...... dihydroisobenzofur R: 1.00 - 3.04 (m, 2 Η), 3.61 (q, .7= 13.37 Hz, 2 Η), 4.03 - 138-1 ^Me hnCj n-5 -yl)piperazine-1 - 433.1 100% 4.14 (m, 1 Η), 5.35 (s, 2 Η), 7.21 (br. s., 1 Η), 7.65 >-nh ₂ yl)methyl)pyridine-2- XVIII: (d, J = 7.83 Hz, 1 Η), 7.75 - 7.85 (m, 2 Η), 7.89 - about ² silt) - 1H-pyrazole-4- 13.07, 8.01 (m, 2 Η), 8.12 (s, 1 Η), 8.42 (s, 1 Η), 9.11 (s, carboxamide 98.77% e.i. 1 H), (1 exchangeable proton was not observed). 139-1 O °bg y'U pn me Me (5)-5-(4-((2-(2,4dimethyl-1/7imidazol-1yl)pyrimidin-5yl)methyl)piperazin2-yl)-4- methylisobenzofuran1(3//)-one 419.2 S: 1.08, 97.08% R: 0.63, 96.86% XVIII: 14.89, 96.79% e.i. ^X NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.85 - 1.92 (w, 1 H), 2.09 (s, 3 H), 2.12 - 2.20 (w, 1 H), 2.24 (s, 3 H), 2, 60 - 2.71 (br, 3 N), 2.78 (t, J = 9.41 Hz, 2 N), 2.85 - 3.03 (br, 2 N), 3.55 - 3.66 (br, 2 H), 4.08 (d, J= 8.31 Hz, 1 H), 5.36 (d, J= 3.18 Hz, 2 H), 7.54 (d, J= 0 .98 Hz, 1 N), 7.65 (d, J = 7.83 Hz, 1 N), 7.78 (d, J = 7.83 Hz, 1 N), 8.70 - 8.80 ( w, 2 H), (1 exchangeable proton was not observed).

- 191 043056

140-1 ^HN ^ \ Me \ /~~Me CN (7/)-4-isopropoxy-6(4-((3 -(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl-methyl)-1 Yapyrazol-1yl)nicotinonitrile 473.3 S: 1.44, 98.04% R: 1.35, 96.80% XIV: 7.60 99.25% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.39 (c1.7=6.1Hz,7H), 1.80 (t, J= 10.1 Hz, 1 H), 2.26 (s, 3 H), 2.80 (d, J= 11.03 Hz, 2 N), 2.89 (d, J = 11.03 Hz, 1 N), 2.96 - 3.03 (br, 1 N), 3.47 - 3.57 (t, 2 N), 4.07 (d, J= 10.07 Hz, 1 N), 5.06 (dt, J= 12.0, 6.0 Hz, 1 N), 5.37 (s, 2 N ), 7.57 (s, 1 H), 7.64 (d, J = 8.20 Hz, 1 H), 7.76 (d, J = 8.00 Hz, 1 H), 7.85 ( s, 1 H), 8.52 (s, 1 H), 8.72 (s, 1 H), (1 exchangeable proton not observed). 141-1 0 i ^e ΡνΟ ^ν Ύ1 (I)-4-methyl-5-(4-((4methyl-6-(4-methyl-1nimidazol-1yl)pyridin-3 yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 418.1 R: 0.99, 100% S: 1.49, 99.12% V: 6.57 99.43% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.91 (s, 1 H), 2.17 (s, 3 H), 2.21 (s, 3 H), 2.46 (s, 3 H), 2.70 - 2.77 (w, 3 H), 2.85 - 2.88 (w, 1 H), 2.96 3.02 (w, 1 H), 3.52 (d, J= 7.09 Hz, 2 H), 4, 00 4.05 (w, 1 H), 5.36 (s, 2 H), 7.62 (s, 2 H), 7.66 (d, J = 8.07 Hz, 1 H), 7, 80 (d, J = 8.07 Hz, 1 H), 8.21 (s, 1 H), 8.36 (d, J = 1.22 Hz, 1 H), (1 exchangeable proton was not observed ). 142-1 0 "+ ...... _r ^ΠΝχ ^Μθ^Ν^ΝΡ^_ _Μθ % (7/)-4-methyl-5-(4-((2methyl-6-(4-methyl-1nimidazol-1yl)pyridin-3 yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 418.1 R: 1.01, 99.50% S: 1.55, 99.05% V: 6.65 100% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 2.17 (s, 3 H), 2.22 (s, 3 H), 2.54 (s, 3 H), 2.67-2.69 (br, 1 H), 2.70-2, 77 (w, 3 H), 2.85 - 2.92 (w, 1 H), 2.96 - 3.04 (w, 1 H), 3.48 - 3.55 (w, 2 H), 4.02 4.10 (w, 1 H), 5.36 (s, 2 H), 7.45 - 7.52 (w, 1 H), 7.58 - 7.67 (w, 2 H) , 7.77 - 7.84 (w, 2 H), 8.31 8.42 (w, 1 H), (1 exchangeable proton was not observed). 143-1 0 °bp.„ ^Me HN^ θΛ _Ν Λ^.0Μθ Me N^p _N (7/)-4,6'-dimethoxy-5'((3 - (4-methyl-1 -oxo- 1,h- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-[2,2'bipyridine]-5carbonitrile 486.1 R: 1.52, 98.06% S: 1.98, 95.85% V: 8.55, 98.56% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 2.26 (s, 3 H), 2.80 (t, J= 9.90 Hz, 2 H), 2.93 - 3.03 (br, 2 H), 3.57 (d, J= 3 .18 Hz, 2 N), 4.03 (s, 4 N), 4.10 - 4.16 (br, 5 N), 5.36 (d, J= 2.45 Hz, 2 N), 7 .65 (d, J= 7.83 Hz, 1 N), 7.79 (d, J= 8.07 Hz, 1 N), 7.94 (d, J= 7.58 Hz, 1 N), 8.05 (d, J = 7.58 Hz, 1 H), 8.11 (s, 1 H), 8.88 (s, 1 H), (1 exchangeable proton not observed). 144-1 0 ^o XQ ... HN> ΐΧγ,, % (7/)-5-(4-((5-fluoro-6-(4methyl-1 H-imide azol1-yl)pyride in-3 yl)methyl)piperazin2-yl)-4- methylisobenzofuran1(3N)-one 422.1 R: 0.95, 100% S: 1.47, 98.31% XVIII: 14.16, 98.50% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 2.18 (s, 3 H), 2.25 (s, 2 H), 2.31-2.34 (w, 1 H), 2.64 2.70 (w, 2 H), 2.73 - 2.82 (w, 2 H), 2.88 - 2.96 (w, 1 H), 2.97 - 3.03 (w, 1 H), 3.62 (d, J= 3.42 Hz, 2 H), 4.08 - 4.13 (w, 1 H), 5.37 (d, J= 3.42 Hz, 2 H), 7.51 (s, 1 H), 7.66 (s, 1 H), 7.78 (d, J= 8.07 Hz, 1 H), 7.92 - 7.97 (br, 1 H), 8.19 (s, 1 H), 8, 29 (s, 1 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSOdb) δ ppm -130.24. 145-1 0 °CX J ^{Me N} ^^~ ^Me CN (7/)-4-methyl-6-(3 methyl-4-((3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5 -yl) piperazin-1 yl) methyl) -111- pyrazol-1yl)nicotinonitrile 443.2 R: 1.06, 96.45% S: 1.46, 97.52% V: 8.08, 98.28% e.i. T1NMR (400 MHz, DMSO-db) δ ppm 1.83 (t, J= 10.10 Hz, 1 N), 2.17 - 2.07 (br, 1 N), 2.24 (s, 3 N), 2.32 - 2.27 (br , 3 N), 2.56 (s, 3 N), 2.79 (t, J= 10.6 Hz, 2 N), 2.92 - 2.84 (m, 1 N), 3.00 ( d, J = 11.70 Hz, 1 N), 3.51 - 3.39 (t, 2 N), 4.06 (d, J = 7.60 Hz, 1 N), 4.06 (d, J = 7.60 Hz, 1 N), 5.36 (s, 2 N), 7.64 (d, J = 8.10 Hz, 1 N), 7.77 (d, J = 7.80 Hz .1 H), 7.90 (s, 1 H), 8.41-8.78 (s, 1 H), (1 exchangeable proton was not observed).

- 192 043056

146-1 0 cQ Me\__ N^Me CN (7?)-4-methyl-6-(5methyl-4-((3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-111pyrazol-1yl)nicotinonitrile 443.2 R: 1.09, 100% S: 1.46, 97.73% V: 8.16, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.95 - 1.82 (w, 1 H), 2.14 (d, J = 13.00 Hz, 1 H), 2.25 (s, 3 H), 2.30 (s, 3 H) , 2.56 (s, 3 H), 2.82 (t, J = 10.00 Hz, 2 H), 2.91 (d, J = 14.20 Hz, 1 H), 3.04 (d , J = 11.50 Hz, 1 N), 3.54 - 3.42 (br, 2 N), 4.12 (d, J = 9.00 Hz, 1 N), 5.46 - 5.27 (br, 2 N), 7.66 (d, J= 7.60 Hz, 1 N), 7.77 (d, J= 8.10 Hz, 1 N), 7.90 (s, 1 N) , 8.43 (s, 1 H), 8.78 (s, 1 H), (1 exchangeable proton not observed). (7?)-4-methyl-5-(4-((6- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 2.18 (4-methyl-1H- R: 0.80 (s, 3 H), 2.25 (s, 3 H), 2.35 (t, 2 H), 2.84 (d, J= 0 imidazol-1 -yl) -4- 95.13% 13.40 Hz, 1 H), 3.08 (s, 2 H), 3.16 (br. s., 2 H), 147-1 0 O'- A ^m ® HN^ <N^N^K_ _Me (trifluoromethyl)pyride in-3- 472.1 S: 1.48, 95.42% 3.82 - 3.69 (m, 2 Η), 5.47 - 5.31 (m, 2 Η), 7.76 - 7.70 (m, 1 Η), 7.83 - 7.76 (m, 2 Η), 8.05 (s, 1 Η), A yl)methyl)piperazine- V: 5.82 8.54 (s, 1 Η), 8.81 (s, 1 H), (not observed 1 2-yl)isobenzofuran- 98.48% e.i. capable of proton exchange). ¹⁹ F NMR (400 1(ZN)-on MHz, DMSO-J ₆ ) δ ppm - 59.25, - 60.50, - 61.47. (7?)-5-(4-((2-(4,5- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.93 dimethyl-1H- R: 0.68 - 1.87 (w, 1 H), 2.11 (s, 3 H), 2.20 - 2.13 (w, 1 H), 0 imidazole-1- 94.87% 2.25 (s, 3 H), 2.45 (s, 3 H), 2.79 (t, J=9.70 Hz, 2 148-1 £ XX X AAx NN ^y- _Me yl)pyrimidin-5yl)methyl)piperazine- 2-yl)-4- 419.2 S: 1.17, 95.02% V: 8.32, H), 2.95 - 2.86 (w, 1 H), 3.03 - 2.96 (w, 1 H), 3.64 - 3.53 (w, 2 H), 4.08 (d , J = 9.30 Hz, 1 H), 5.43 5.30 (br, 2 H), 7.65 (d, J = 8.30 Hz, 1 H), 7.78 (d, methylisobenzofuran- 100% e.i. J= 7.80 Hz, 1 N), 8.30 (s, 1 N), 8.77 (s, 2 N), (not 1(ZN)-on 1 exchangeable proton was observed). (7?)-5-(4-((4-methoxy- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.94 6-(4-methyl-1H- R: 0.64 - 1.85 (w, 1 H), 2.17 (s, 4 H), 2.26 (s, 3 H), 2.78 0 imidazole-1- 100% (d, J= 10.30 Hz, 2 N), 2.91 (d, J= 7.80 Hz, 1 N), 149-1 oQ TA ^0Me - hO V yl) pyr idine-3 - yl)methyl)piperazine- 434.2 S: 1.08, 100% 3.01 - 2.95 (br. s. 1 H), 3.52 (s. 2 H), 3.94 (s. 3 H), 4.07 (br. s., 1 H), 5.37 (s, 2 H), 7.29 (s, 1 H), 7.64 2-yl)-4- XII: 2.71, (d, J = 8.10 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J = methylisobenzofuran- 100% e.i. 8.30 Hz, 1 N), 8.21 (s, 1 N), 8.42 (s, 1 N), (not 1(ZN)-on 1 exchangeable proton was observed). 150-1 0 ^ ^N- (7^)-5-(4-((2-(5(difluoromethyl)-4methyl-1 H-imide azol1-yl)pyrimidin-5 yl)methyl)piperazin2-yl)-4- methylisobenzofuran1(3N)-one 455.3 S: 1.23, 97.70% R: 0.95, 99.03% XVIII: 6.04, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 2.37 - 2.33 (w, 3 H), 2.59 - 2.53 (w, 2 H), 2.63 (t, J = 2.10 Hz, 3 H), 3.08 (d , J= 10.50 Hz, 2 H), 3.43 (br. s" 2 H), 3.79 (s, 2 H), 4.73 (br. s" 1 H), 5.42 ( s, 1 H), 5.46 (s, 1 H), 7.14 - 7.00 (m, 1 H), 7.77 (d, J= 8.10 Hz, 1 H), 7.86 (d, J = 7.80 Hz, 1 H), 8.47 (s, 1 H), 8.89 (s, 2 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSO-Je) δ ppm -110.99. 4,6-dimethyl-2-(4- R: 0.95 Ή NMR (400 MHz, DMSO-J6) δ ppm 1.04 (((35.57?)-3-methyl-5- 97.35% (d, J = 5.60 Hz, 3 H), 1.82 (br. s., 2 Η), 2.28 (s, 3 0 (4-methyl-1-oxo-1,3- S: 1.19 Η), 2.76 - 2.66 (m, 6 Η), 2.81 (br. s., 2 H), 2.99 (br. 151-1 Xj] VAAn ¹ hnA N- _n Me An ^N >XMe dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2,3- 459.2 100% XXV: 7.12, 100% e.i. s „ 1 H), 3.78 (s, 2 H), 4.19 (br. s „ 1 H), 5.46 - 5.30 (m, 2 H), 7.67 (d, J = 7.60 Hz, 1 H), 7.80 (d, J = 8.30 Hz, 1 H), 8.24 (s, 1 H), (not observed 1 Me CN triazol-2yl)pyrimidine-5carbonitrile capable of proton exchange).

- 193 043056

152-1 0 3-(3-methyl-5-(4(((3 5.57?) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofura n-5 -yl)piperazin-1 yl)methyl )-111pyrazol-1yl)phenyl)oxazolidi H-2-0H 502.2 S: 1.42, 100% R: 0.90, 100% I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, J = 6.50 Hz, 3 Η), 1.79 - 1.64 (m, 2 Η), 2.32 2.18 (m, 3 Η), 2.43 - 2, 35 (m, 3 H), 2.81 (d, J = 11.00 Hz, 2 H), 2.97 (br. s., 1 H), 3.48 (s, 2 H), 4, 24 - 4.03 (m, 3 H), 4.56 - 4.40 (m, 2 H), 5.38 (s, 2 H), 7.30 (s, 1 H), 7.42 ( s, 1 H), 7.69 - 7.58 (m, 2 H), 7.80 (d, J= 8.00 Hz, 1 H), 7.90 - 7.84 (m, 1 H) , 8.37 (s, 1 H), (1 exchangeable proton not observed). 0 Me ™ _{N 0} 0-U Me ⁴ 153-1 0 χρ. Me ^HN ^^Me (7?)-4-methyl-5-(4-((6(4-methyl-1nimidazol-1yl)pyridazin-3yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 405.4 S: 1.13, 95.04% R: 0.75, 95.90% I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.90 - 2.01 (m, 1 N), 2.20 (s, 3 N), 2.24 (s, 3 N), 2.27 2.34 (t, 2 N), 2.73 - 2.80 (w, 2 N), 2.89 - 3.03 (t, 2 N), 3.85 (d, J = 5.32 Hz, 2 N), 4.05 - 4.10 ( t, 1 N), 5.31 - 5.41 (t, 2 N), 7.65 (d, J = 8.13 Hz, 1 N), 7.74 - 7.80 (t, 2 N) , 7.93 (d, J= 8.93 Hz, 1 H), 8.12 (d, J= 9.05 Hz, 1 H), 8.51 (s, 1 H). 4-methoxy-6-(3 -(((7?)- I! NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00 3 - (4-methyl-1 -oxo- G: 9.96 - 1.06 (m, 1 N), 1.73 - 1.81 (t, 2 N), 2.04 - 2.14 0 1,h- 95.87% (t, 2 N), 2.31 (s, 3 N), 2.34 - 2.40 (t, 3 N), 2.44 T'N'yy nmc L _n ' dihydroisobenzofur F: 8.77 - 2.48 (t, 2 N), 2.53 - 2.62 (w, 1 N), 2.78 - 3.02 154-1 Me n-5-yl)piperazine-1 - 448.2 96.16% (w, 4 H), 3.92 (s, 3 H), 4.03 - 4.10 (w, 1 H), 5.38 ^N ^Y-OMe yl)methyl)pyrrolidine XIII: 3.39, (d, J = 5.77 Hz, 2 N), 6.00 (s, 1 N), 7.65 (d, J = CN -1- 100% e.i. 8.03 Hz, 1 H), 7.80 (d, J = 8.09 Hz, 1 H), 8.26 (s, yl) nicotinonitrile (Diastereomer I) 1 H), 8.55 - 8.56 (w, 1 H). 4-methoxy-6-(3 -(((7?)- I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.79 3 - (4-methyl-1 -oxo- F: 8.09 - 1.86 (w, 2 H), 2.02 - 2.08 (w, 1 H), 2.30 (s, 3 H), 0 1.3- 96.88% 2.34 - 2.39 (t, 4 N), 2.76 - 2.81 (t, 2 N), 2.84 - Q N dihydroisobenzofur G: 10.05 2.93 (w, 5 H), 2.95 - 3.01 (w, 1 H), 3.39 - 3.46 (w, 155-1 Me HN^J W n-5-yl)piperazine-1 - 448.2 96.44% 1 H), 3.92 (s, 3 H), 4.07 (d, J= 9.79 Hz, 1 H), 5.38 <UOMe yl)methyl)pyrrolidine XIII: 4.72, (d, J = 4.14 Hz, 2 N), 6.00 (s, 1 N), 7.65 (d, J = CN -1- 97.82% e.i. 8.09 Hz, 1 H), 7.80 (d, J = 7.91 Hz, 1 H), 8.25 (s, yl) nicotinonitrile (Diastereomer II) 1H). 4-methyl-6-(3 -(((7?)-3 - I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.79 0 (4-methyl-1-oxo-1,3- F: 9.61 - 1.86 (w, 2 H), 2.00 - 2.14 (w, 3 H), 2.30 (s, 3 H), Ij dihydroisobenzofur 96.97% 2.33 (w, 4 H), 2.34 - 2.39 (w, 2 H), 2.53 - 2.61 (w, 156-1 Me oud n-5-yl)piperazin-1 yl)methyl)pyrrolidine 432.2 G: 10.62, 97.28% 1 H), 2.77 - 2.93 (w, 4 H), 2.94 - 3.01 (w, 1 H), 3.35 - 3.46 (w, 2 H), 4.06 (d, J = 7.91 Hz, 1 H), ^^-Me G* KI -1- XIII: 3.05 5.38 (d, J = 5.96 Hz, 2 H), 6.46 (s, 1 H), 7.65 (d, J VIN yl) nicotinonitrile 99.92% e.i. = 7.97 Hz, 1 H), 7.79 (d, J = 7.91 Hz, 1 H), 8.36 (Diastereomer I) (s, 1 H). 4-methyl-6-(3 -(((7?)-3 - F: 9.60 I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.10 (4-methyl-1-oxo-1,3- 97.43% - 1.16 (w, 1 H), 1.79 - 1.87 (w, 1 H), 2.30 (s, 3 H), O dihydroisobenzofur G: 10.59 2.33 (w, 5 H), 2.33 - 2.37 (w, 3 H), 2.53 - 2.61 (w, 157-1 0 Me HN ^N _N n-5-yl)piperazin-1 yl)methyl)pyrrolidine 432.2 97.53% XIII: 3.86, 1 H), 2.77 - 2.93 (w, 4 H), 2.94 - 3.01 (w, 1 H), 3.08 - 3.15 (w, 1 H), 3.35 - 3.46 (w, 2 H), 4.06 (d, NQ Me -1- 95.66% e.i. J= 7.91 Hz, 1 N), 5.38 (d, J= 3.95 Hz, 2 N), 6.46 CN yl) nicotinonitrile (s, 1 H), 7.65 (d, J = 8.16 Hz, 1 H), 7.79 (d, J = (Diastereomer II) 8.03 Hz, 1 N), 8.36 (s, 1 N).

- 194 043056

158-1 159-1 160-1 161-1 0 Ά- ^Me no LfA N^V _M e CN 0 Y i f N^-OMe CN 0 ηΟΎΑ YV-Me CN 0 -H _N U Me _N H SO ₂ Me 4-methyl-6-(4-(((7/)-3(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2oxopyrrolidin-1 yl)nicotinonitrile ( Diastereomer II) 4-methoxy-6-(4-(((7/)3 -(4-methyl-1-oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2oxopyrrolidin-1 yl)nicotinonitrile (Diastereomer I) 4-methyl-6-(5-(((7/)-3(4-methyl-1-oxo -1,3dihydroisobenzofura n-5 -yl)piperazin-1 yl)methyl)-2oxooxazolidin-3 yl)nicotinonitrile (Diastereomer II) 4-methyl-5-((27/, 65)-6methyl-4-((1-(5- (methylsulfonyl)pyridin-2-yl)-1Hpyrazol-4yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 446.2 462.3 448.2 482.2 F: 9.97 95.67% G: 12.43, 96.68% XIII: 4.57, 98.7% e.i. S: 1.22 97.06% R: 0.97, 96.87% XIII: 5.20, 97.50% e.i. Q: 8.61, 94.33% D: 1.67, 99.28% S: 1.26, 95.63%. R: 0.85, 96.50%. XVIII: 17.07, 100% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.12-1.20 (w, 1 H), 1.80 - 1.90 (w, 1 H), 2.00 2.10 (w, 1 H), 2.29 - 2.35 (w , 3 N), 2.45 - 2.58 (br, 2 H), 2.54 - 2.58 (m, 5 H), 2.65 - 2.90 (br, 5 H), 3.70 - 3.80 (w, 1 H), 4.05 - 4.15 (w, 2 H), 5.39 (d, J= 4.65 Hz, 2 H), 7.66 (d, J= 8.13 Hz, 1 H), 7.80 (d, J = 8.31 Hz, 1 H), 8.37 (s, 1 H), 8.78 (s, 1 H). ^NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.85 - 1.93 (w, 1 H), 2.07 - 2.11 (w, 1 H), 2.30 (s, 3 H), 2.37 - 2.45 (w, 2 H ), 2.69 - 2.81 (w, 3 H), 2.84 2.96 (w, 2 H), 2.98 - 3.05 (w, 3 H), 3.47 - 3.57 (w, 2 H), 3.72 - 3.78 (w, 3 H), 4.07 - 4.15 (w, 1 H), 5.38 (d, J = 3.91 Hz, 2 H ), 7.66 (d, J = 7.83 Hz, 1 H), 7.78 (d, J = 8.01 Hz, 1 H), 8.16 (s, 1 H), 8.64 ( s, 1 H). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.99 (s, 1 Η), 2.29 (s, 3 Η), 2.46 - 2.48 (m, 3 Η), 2.59 2.62 (m, 2 Η), 2.71 - 2.75 (m, 3 Η), 2.81 - 2.87 (m, 4 Η), 3.80 - 3.89 (m, 1 Η), 3.90 - 3.96 (m, 1 Η), 4.23 - 4.29 (m, 1 Η), 5.40 (s, 2 Η), 7.66 (d, J= 7.72 Hz, 1 Η), 7.80 (d, J = 8.03 Hz, 1 Η), 8.16 (s, 1 Η), 8.78 (s, 1 Η). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.04 (d, J = 6.10 Hz, 3 H), 1.74 (br. s., 2 H), 2.27 (s, 3 H), 2.82 (d, J = 8, 30 Hz, 2 H), 2.98 (br. s., 1 H), 3.35 (s, 3 H), 3.55 (br. s., 2 H), 4.18 (br. s ., 1 H), 5.46 -5.27 (m, 2 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.80 (d, J = 7.80 Hz, 1 H), 7.87 (s, 1 H), 8.10 (d, J = 8.80 Hz, 1 H), 8.46 (dd, J= 8.80, 2.40 Hz, 1 H ), 8.58 (s, 1 H), 8.93 (d, J = 2.20 Hz, 1 H), (1 exchangeable proton was not observed). 162-1 0 Gu- , Me XJ ^H0 Q-OMe CN 4-(4-(((37/,47/)-4hydroxy-3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piper idin-1 yl)methyl)-1Nimide azol-1-yl)-2methoxybenzonitrile 459.2 S: 1.19, 100% R: 0.97, 100% XXIX: 3.00, 100% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 1.96 (br. s., 1 H), 2.13-2.43 (br. 4 H), 2.74 (br. 1 H), 2.79-3.07 (br. 2 H) , 3.07-3.20 (br. 2 H), 3.82 (br. s., 1 H), 3.94-4.12 (br. 4 H), 4.68 (br. s. , 1 H), 5.36 (br. s., 2 H), 7.46-7.56 (m, 4 H), 7.61-7.79 (m, 2 H), 7.94- 8.13 (m, 1 H), (1 exchangeable proton not observed). 163-1 HO^V Cb CN 6-(4-(((37/,47/)-4hydroxy-3-(4-methyl1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-1Nimide azol-1-yl )-4methylnicotinonitrile 444.5 P: 4.27, 98.40% Q: 5.59, 98.86% Ή NMR (400 MHz, DMSO-Je) δ ppm 1.60 - 1.80 (w, 1 H), 1.92 - 1.97 (w, 1 H), 2.23 - 2.30 (w, 1 H), 2.35 (S, 3 H ), 2.76 - 2.91 (w, 3 H), 2.95 - 3.16 (w, 2 H), 3.44 - 3.61 (w, 2 H), 3.65 - 3, 80 (w, 2 H), 4.51 (s, 1 H), 5.37 (d, J = 6.40 Hz, 2 H), 7.54 (d, J = 8.03 Hz, 1 H ), 7.64 (d, J = 7.91 Hz, 1 H), 7.85 (br. s., 1 H), 8.00 (s, 2 H), 8.55 (br. s. , 1 Η), 8.86 (s, 1 Η).

- 195 043056

164-1 0 °όθ CN 4-methyl-2-(4- (((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)-1nimidazol-1yl)pyrimidine-5carbonitrile 444.3 S: 1.32, 100% R: 0.98 96.43% XX1X:3.45, 93.48% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 1.02 (d, J= 6.10 Hz, 3 N), 1.88-1.71 (br, 2 N), 2.20-2.32 (br, 3 H), 2.67-2 .74 (br, 3 H), 2.76-2.88 (w, 2 H), 2.96 (ddd, J = 9.60, 6.50, 2.70 Hz, 1 H), 3, 52 (s, 2 H), 4.16 (dd, J= 10.00, 2.20 Hz, 1 H), 5.47-5.29 (br, 2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.89 - 7.75 (w, 2 H), 8.56 (d, J = 1.20 Hz, 1 H), 9.22 (s, 1 H) , (1 exchangeable proton was not observed). 165-1 0 °BE ··· « ^e %bo ₂ Me 4-methyl-5-((27?, 65)-6methyl-4-((6'(methylsulfonyl)[2,3'-bipyridine]-5yl)methyl)piperazin2-yl)isobenzofuran- 1(ZN)-on 493.2 S: 1.27, 99.27% R: 0.81, 98.46% XXIX: 9.99, 100% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 1.03 (d, J= 6.40 Hz, 3 H), 1.64-1.88 (br. 2 H), 2.25 (s, 3 H), 2.99 (br. s., 2 H), 2.79 (d, J= 10.30 Hz, 2 H), 3.34 (s, 3 H), 3.64 (s, 2 H), 4.19 (d, J= 9 .50 Hz, 1 N), 5.46 - 5.28 (m, 2 N), 7.66 (d, J= 8.10 Hz, 1 N), 7.81 (d, J= 8.10 Hz, 1 N), 7.93 (dd, J = 8.10, 2.00 Hz, 1 N), 8.09 - 8.25 (t, 2 N), 8.70 (d, J = 1 .70 Hz, 1 H), 8.78 (dd, J = 8.10, 2.20 Hz, 1 H), 9.39-9.49 (t, 1 H). 166-1 O oto b _η 0Χν Me JN \>~ ^0Me CN 4-methoxy-2-(4- (((3 S, 57?) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2,3triazol-2yl )pyrimidine-5carbonitrile 461.3 P: 6.75, 95.94% Q: 8.64, 96.38% V: 5.85 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.02 (d, J = 6.21 Hz, 3 Η), 1.77 - 1.87 (t, 2 Η), 2.26 (s, 3 Η), 2.80 (d, J = 10 .60 Hz, 2 Η), 2.94 - 3.01 (m, 1 Η), 3.77 (s, 2 Η), 4.17 - 4.19 (m, 4 Η), 5.37 ( d, J = 3.01 Hz, 2 H), 7.65 (d, J = 7.97 Hz, 1 H), 7.79 (d, J= 7.97 Hz, 1 H), 8.25 (s, 1 H), 9.15 (s, 1 H), (1 exchangeable proton was not observed). 167-1 O °^X ^N to Me gLL / Rome CN 4-methoxy-2-(2-methyl4-(((35.57?)-3 -methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl) -1nimidazol-1yl)pyrimidine-5carbonitrile 474.3 Q: 9.51, 99.30% P: 5.20, 99.42% Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.73 - 1.84 (t, 3 N), 1.91 (s, 2 N), 2.28 (s, 3 N), 2.54 2.58 (t, 2 N), 2.66 - 2.69 (t, 1 N), 2.72 (s, 1 N), 2.79 - 2.88 (t, 3 N), 2.92 - 2.99 (t, 2 N), 4 .15 (t, 4 N), 4.16 - 5.38 (d, J= 1.51 Hz, 2 N), 7.65 (d, J= 7.84 Hz, 1 N), 7.75 (s, 1 H), 7.80 (d, J = 7.91 Hz, 1 H), 9.09 (s, 1 H).

- 196 043056

168-1 0 P . n (7?)-4-methoxy-6-(4((3 - (4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2,3triazol-2yl)nicotinonitrile 446.2 E: 8.07, 99.40% G: 9.30, 99.10% XIV: 9.58, 99.00% e.i. 'H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.90 (t, J = 10.39 Hz, 1 Η), 2.21 (d, J = 2.93 Hz, 1 Η), 2.27 (s, 3 Η), 2.79 - 2, 94 (m, 3 Η), 2.96 - 3.03 (m, 1 Η), 3.77 (s, 2H), 4.09 (d, 7= 8.07 Hz, 1 Η), 4, 13 (s, 3 Η), 5.38 (d, J = 2.45 Hz, 2 Η), 7.65 (d, J = 8.07 Hz, 1 Η), 7.70 (s, 1 Η ), 7.78 (d, J= 7.83 Hz, 1 H), 8.23 (s, 1 H), 8.83 (s, 1 H), (1 exchangeable proton was not observed). HN^ Nn ^N ^-0Me CN 169-1 0 9......r. ^Me HNb Me N- _n ^N ^~Me CN (7?)-4-methyl-6-(4methyl-5 -((3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2,3triazol-2yl)nicotinonitrile 444.3 S: 1.29, 97.2% R: 1.05, 98.06% XIV: 6.83, 100% e.i. ^NMR (400 MHz, DMSO-t/e) δ ppm 1.91 (t, 7= 10.4 Hz, 1 N), 2.13 - 2.23 (br, 1 N), 2.25 (s, 3 N), 2.42 (s, 3 N) , 2.59 (s, 3 H), 2.78 (d, 7= 11.20 Hz, 2 H), 2.83 - 2.92 (br, 1 H), 2.96 - 3.04 ( w, 1 H), 3.63 - 3.77 (w, 2 H), 4.06 (d, 7= 7.80 Hz, 1 H), 5.36 (s, 2 H), 7.64 (d, 7= 7.80 Hz, 1 N), 7.78 (d, 7= 7.80 Hz, 1 N), 8.03 (s, 1 N), 8.88 (s, 1 N) , (1 exchangeable proton was not observed). 4-methoxy-6-(4- Ή NMR (400 MHz, DMSO-Te) δ ppm 1.04 X (((3 S, 5R) -3-methyl-5- S: 1.49 (d, 7= 6.10 Hz, 3 N), 1.74 (t, 7= 9.80 Hz, 2 N), c D..... (4-methyl-1-oxo-1,3- 100% 2.31 (s, 3 H), 2.33 - 2.48 (w, 3 H), 2.64 - 2.89 (w, 170-1 “θ HN J dihydroisobenzofur R: 1.07 4 H), 2.96 (br. s., 1 H), 3.77 (dd, 7= 11.0, 5.40 Hz, Me N^-OMe n-5 -yl)piperazine-1 - 476.3 99.06% 1 H), 3.97 (s, 3 H), 4.12 (dd, 7= 11.40, 7.70 Hz, 2 CN yl)methyl)-2- XXXI: H), 5.31 - 5.50 (w, 2 H), 7.67 (d, 7 = 8.10 Hz, 1 oxopyrrolidine-1 - 4.36 H), 7.82 (d, 7= 8.10 Hz, 1 H), 8.18 (s, 1 H), 8.66 yl) nicotinonitrile 100% e.i. (s, 1 H), (not observed 1 capable of (Diastereomer I) proton exchange). 6-(4-(((37?,47?)-4- Ή NMR (400 MHz, DMSO-Te) δ ppm 1.55 hydroxy-3 -(4-methyl- R: 9.20 - 1.66 (w, 1 H), 1.91 - 1.98 (w, 1 H), 2.07 - 2.15 O Me 1-oxo-1,3- 99.40% (w, 1 H), 2.25 (s, 4 H), 2.74 - 2.81 (w, 1 H), 2.92 171-1 0 l dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-3-methyl-2- 490.2 Q: 5.03, 98.10%XXVII: - 2.99 (w, 1 H), 3.01 - 3.08 (w, 1 H), 3.30 (s, 3 H), 3.43 (d, 7= 9.04 Hz, 2 H ), 3.71 - 3.80 (w, 1 H), 4.01 (s, 3 H), 4.60 (d, 7= 5.52 Hz, 1 H), 5.36 (d, 7 MeO cn oxo-2,3-dihydro-1H- 5.46 = 8.53 Hz, 2 N), 7.27 (s, 1 N), 7.56 (s, 1 N), 7.63 - imidazol-1 -yl) -4- 100% e.i. 7.66 (w, 1 H), 8.27 (s, 1 H), 8.66 (s, 1 H). methoxynicotinonite ril

- 197 043056

172-1 173-1 0 O^P ^Me yMe MeO CN O Oy) Me -HN A / Ln Me V% Me N 6-(3-isopropyl-4- (((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)-2-oxo-2,3 dihydro-1Nimide azol-1-yl)-4methoxynicotinonite ril 3-methyl-4-(((35.57/)-3methyl-5 -(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1-(2methylpyrimidin-4yl)-1,3-dihydro-2nimidazol-2-one 517.3 449.3 S: 1.88, 98.00% R: 1.35, 98.45% XXX: 6.78, 96.70% e.i. S: 1.29, 98.42% R: 0.78, 97.30% VI: 12.32, 100% e.i. Ή NMR (400 MHz, DMSO-A) δ ppm 1.05 (d, J = 6.40 Hz, 3 N), 1.51 (d, J = 6.80 Hz, 3 N), 1.50 (d, J = 6.60 Hz, 3 N) , 1.67 - 1.79 (t, 2 H), 2.24 (s, 3 H), 2.63 (br. s., 1 H), 2.72 - 2.80 (m, 1 H ), 2.85 (d, J = 10.00 Hz, 1 Η), 2.88 - 2.99 (m, 1 Η), 3.45 (d, J = 14.20 Hz, 1 Η), 4.02 (s, 3 Η), 4.10 (d, J = 9.30 Hz, 1 Η), 4.36 - 4.48 (m, 1 Η), 5.37 (s, 2 Η) , 7.26 (s, 1 Η), 7.67 (d, J = 8.10 Hz, 1 Η), 7.83 (d, J = 7.80 Hz, 1 Η), 8.28 (s , 1 Η), 8.65 (s, 1 Η), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-A) δ ppm 1.04 (d, E = 6.10 Hz, 3 N), 1.84 - 1.64 (br, 2 N), 2.26 (s, 3 N), 2.56 (s, 3 N) , 2.83 (t, J = 8.40 Hz, 2 H), 2.87 - 2.99 (br, 1 H), 3.29 (s, 3 H), 3.40 (s, 2 H ), 4.12 (d, J = 7.80 Hz, 1 H), 5.38 (s, 2 H), 7.27 (s, 1 H), 7.67 (d, J = 8.30 Hz, 1 N), 7.82 (d, J = 8.10 Hz, 1 N), 8.18 (d, J = 5.60 Hz, 1 N), 8.66 (d, J = 5, 60 Hz, 1 N), (1 exchangeable proton was not observed). 174-1 _f ......b F o ^Z P U-tS Z=/ 3-(5-(((35.57/)-3methyl-5-(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-[2,4'bipyridin]-2'yl)oxazolidin-2-one 500.3 S: 1.37, 98.95% R: 0.66, 98.40% XVII: MI 100% e.i. Ή NMR (400 MHz, DMSO-i/b) δ ppm 1.04 (br. s., 3 H), 1.78 (d, J = 13.00 Hz, 2 H), 1.92 (s, 1 H), 2.25 (s, 3 H), 2.80 (br. s., 2 H), 2.99 (br. s., 1 H), 3.61 (br. s., 2 H), 4.07 - 4.30 (m, 3 H), 4.42 4.54 (m, 2 H), 5.29 - 5.47 (m, 2 H), 7.47 - 7.56 (m, 1 H), 7.59 - 7, 75 (m, 1 H), 7.75 - 7.88 (m, 2 H), 7.94 (d, J = 8.10 Hz, 1 H), 8.28 (s, 1 H), 8 .60 (s, 1 H), (1 exchangeable proton was not observed). 175-1 o ohn ^{t e} n ''yy _N Me HN% Nn ^Μ θ ^Me n^A V=/ ^Me CN 6-(4-((3,3-dimethyl-5(4-methyl-1-oxo-1,3 dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-5-methyl2H-1, 2.3 -triazol-2yl)-4- methylnicotinonitrile l (Enantiomer-1) 472.3 S: 1.96, 98.70% R: 1.41, 98.60% VIII: 3.60 100% e.i. Ή NMR (400 MHz, DMSO-A) δ ppm 1.07 (s, 3 H), 1.20-1.41 (w, 3 H), 1.82 (t, J = 9.00 Hz, 1 H), 1.93 (d, J = 9 .80 Hz, 1 N), 2.06 (d, J = 13.20 Hz, 1 N), 2.26 (s, 3 N), 2.45 (s, 3 N), 2.54 - 2 .64 (t, 3 N), 2.79 (d, J = 10.00 Hz, 1 N), 3.68 (s, 2 N), 4.38 (d, J = 9.50 Hz, 1 H), 5.37 (s, 2 H), 7.66 (d, J = 8.60 Hz, 1 H), 7.79 (d, J = 8.10 Hz, 1 H), 8.03 (s, 1 H), 8.88 (s, 1 H), (1 exchangeable proton not observed).

- 198 043056

4-methyl-6-(5-methyl-4- Ή NMR (400 MHz, DMSO-Z) δ ppm 1.02 O (((3 S, 5R) -3-methyl-5- S: 1.69 (d, J= 6.10 Hz, 3 N), 1.73 - 1.90 (m, 2 N), 2.21 - (4-methyl-1-oxo-1,3- 96.05% 2.31 (t, 3 H), 2.59 (s, 3 H), 2.64 (s, 3 H), 2.75 - 176-1 dihydroisobenzofur 458.3 R: 1.09 2.87 (t, 2 H), 2.95 (br. s., 1 H), 3.61-3.74 (t, 2 Me N%Me n-5 -yl)piperazine-1 - 96.40% Η), 4.15 (d, J = 8.10 Hz, 1 Η), 5.31 - 5.43 (m, 2 CN yl)methyl)- 1H-1,2,3- VIII: 10.08 Η), 7.66 (d, J = 8.10 Hz, 1 Η), 7.80 (d, J = 7.80 triazole-1- 100% e.i. Hz, 1 Η), 8.17 (s, 1 Η), 9.01 (s, 1 H), (not yl) nicotinonitrile 1 exchangeable proton was observed). (7?)-4-methyl-5-(4-((1- ΉNMR (400 MHz, DMSO-Tb) δ ppm 2.30 (1-methyl-\H- A:1.41, (s, 3 N), 3.15 - 3.20 (t, 2 N), 3.50 - 3.90 (t, 2 N), pyrrolo[2,3- 98.80% 3.90 -3.40 (t, 5 H), 4.40 (br. s., 2 H), 5.10 (br. s., 177-1 Me 4 b] pyridin-4-yl)-\Hpyrazol-4- 444.2 B: 0.95, 98.40% 1 H), 5.40 - 5.50 (m, 2 H), 7.10 (m, 1 H), 7.52 (d, J= 5.20 Hz, 1 H), 7.64 - 7 .68 (m, 2H), 7.75 (d, J ?A--n yl)methyl)morpholine- = 8.00 Hz, 1 H), 8.0 (s, 1 H), 8.35 (d, J = 8.00 Hz, ^V N \ie 2-yl)isobenzofuran- 1 H), 8.90 (s, 1 H). 1(ZYA)-on — Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 0 4-methyl-5-((27?, 65)-6- A:1.35, (d, J= 6.02 Hz, 3 Η), 1.72 - 1.83 (m, 2 Η) 2.27 (s, methyl-4-(( 1 -(p-tolyl)- 97.80% 3 H) 2.34 (s, 3 H), 2.85 (d, J= 11.55 Hz, 2 H), 2.90 T G I li / Me HN^ %n 1//-imidazole-4- B: 0.79 - 3.00 (m, 1 Η), 3.45 (s, 2 Η), 4.15 (dd, J = 10.04, 178-1 Me yl)methyl)piperazine- 417.3 99.10% 2.01 Hz, 1 Η), 5.38 (s, 2 Η), 7.30 (d, J = 8.53 Hz, Me 2-yl)isobenzofuran- 2 Η), 7.49 - 7.56 (m, 3 Η), 7.65 (d, J= 7.53 Hz, 1 1(3//)-he Η), 7.82 (s, 1 Η), 8.06 - 8.07 (m, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.03 4-methyl-5-((27?, 65)-6- (d, J = 6.02 Hz, 3 Η), 1.72 - 1.83 (t, 2 Η), 2.24 - o methyl-4-((1-(3- A: 0.97 2.31 (t, 6 Η), 2.85 (d, J = 11.55 Hz, 2 Η), 2.90 - °fiii ^Ύ'ΓΠ^ methylpyridin-4-yl)- 96.90% 3.00 (m, 1 Η), 3.45 (s, 2 Η), 4.15 (dd, J = 10.04, 179-1 Me HN J _Μ θ 1//-imidazole-4- 418.2 B: 0.53 2.01 Hz, 1 Η), 5.38 (s, 2 Η), 7.30 (d, J = 8.53 Hz, Me ZX \=N yl)methyl)piperazine- 94.90% 2 H), 7.65 (d, J = 7.53 Hz, 1 H), 7.82 (d, J= 7.53 2-yl)isobenzofuran- Hz, 1 Η), 7.92 (s, 1 Η), 7.52 (d, J= 5.20 Hz, 1 Η), 1(3//)-on 8.61 (s, 1 H), (1 exchangeable proton not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.02 4-methyl-5-((27?, 65)-6- (d, J \u003d 6.02 Hz, 3 Η), 1.69 - 1.85 (t, 2 Η), 2.23 (s, ABOUT methyl-4-((1-(6- A: 1.00 3 H), 2.50 (s, 3 H), 2.85 (br. s., 2 H), 2.95 (d, J = 180-1 methylpyridin-3 -yl)- 98.60% 3.51 Hz, 1 H), 3.43 - 3.50 (m, 2 H), 4.15 (d, J = T Ι Ϊ ) Me HN^Z U-n = 177-imide azole-4- 418.2 B: 0.59 9.54 Hz, 1 H), 5.38 (s, 2 H), 7.39 (d, J = 8.53 Hz, Me /A Q yl)methyl)piperazine- 95.40% 1 H), 7.65 (d, J = 8.03 Hz, 2 H), 7.80 (d, J = 8.03 Me 2-yl)isobenzofuran- Hz, 1 H), 7.98 (s, 1 H), 8.12 - 8.32 (m, 1 H), 8.77 1(377)-he (d, J = 2.51 Hz, 1 H), (1 exchangeable proton not observed). 5-((27?,65)-4-((1-(2,6- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 0.97 dimethylpyridine-4- - 1.07 (t, 3 N), 1.74 - 1.82 (t, 2 N), 2.27 (s, 3 N), silt)- 1H-imidazole-4- A: 0.99 2.46 (s, 6 H), 2.83 (d, J= 10.80 Hz, 2 H), 2.96 (br. 181-1 yl)methyl)-6- 432.3 99.50% s., 1 N), 3.39-3.41 (t, 2 N), 4.15 (d, J= 8.20 Hz, t ι ι Ύ) Me HN^J : \___ methylpiperazine-2- B: 0.79 1 H), 5.38 (br. sn 2 H), 7.44 (s, 1 H), 7.64 - 7.66 θ Ο-θ silt) -4- 94.90% (t, 2 N), 7.80 (d, J= 8.00 Hz, 1 N), 7.95 - 7.97 Me ^Z methylisobenzofuran- (t, 1 H), 8.80 (s, 1 H), (not observed 1 1(3//)-on. capable of proton exchange).

- 199 043056

182-1 O Me oXo F F 5-((2^,65)-4-((1-(2,2difluorobenzo[(1] [ 1,3 ]d ioxol-5-yl )-1 Yaimidazol-4yl)methyl)-6methylpiperazin-2yl)- 4methylisobenzofuran1(3R)-one 483.3 A: 1.48, 97.10% B: 0.92, 97.80% 'H NMR (400 MHz, DMSO-Yab) δ ppm 0.96 - 1.06 (br. 3 H), 1.80 (br. s., 2 H), 2.27 (s., 3 H), 2.80 - 2.90 (br. 3 H ), 3.40 (br. s., 2 H), 4.10 (br. s., 1 H), 5.32 - 5.45 (m, 2 H), 7.50 - 7.60 ( m, 3 H), 7.70 - 7.75 (m, 2 H), 7.85 - 7.90 (m, 2 H), (1 exchangeable proton was not observed). 183-1 0 ι Г>^Л Me HN^y 'll 2 II 7 N _x J ^ CN (7?)-4-methyl-6-(2-((3 (4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyrimidin5-yl)nicotinonitrile 441.2 A: 0.93, 97.97% B: 1.12, 100% XVIII: 23.32, 95.58% e.i. Ή NMR (400 MHz, DMSO-Yab) δ ppm 2.03 (t, J = 10.40 Hz, 1 Η), 2.27 (s, 3 Η), 2.32 (d, J = 3.4 Hz, 1 Η), 2.59 (s, 3 Η), 2.81 - 3.05 (m, 4 Η), 3.84 (s, 2 Η), 4.10 (d, J= 8.60 Hz, 1 Η), 5.37 (s , 2 H), 7.64 (d, J= 7.80 Hz, 1 H), 7.79 (d, J= 7.80 Hz, 1 H), 8.31 (s, 1 H), 9 .06 (s, 1 H), 9.44 (s, 2 H), (1 exchangeable proton was not observed). 184-1 0 ^ΊΓ Me HN^PN~ _n ' N^Me Me ^Z qn (7?)-2,4-dimethyl-6-(4((3 - (4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2,3triazol-2yl)nicotinonitrile 444.2 A: 1.04, 100% B: 1.27, 99.69% XIV: 10.30 98.57% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.84 - 1.97 (w, 1 H), 2.16 - 2.24 (w, 1 H), 2.26 (s, 3 H), 2.59 (s, 3 H), 2, 69 - 2.73 (br, 3 H), 2.82 (d, J = 10.0 Hz, 2 H), 2.88 - 2.95 (br, 1 H), 2.97 - 3.05 (br, 1 H), 3.76 (s, 2 H), 4.10 (d, J = 9.30 Hz, 1 H), 5.31 5.48 (br, 2 H), 7.65 (d, J= 8.10 Hz, 1 H), 7.77 (d, J= 8.10 Hz, 1 H), 7.93 (s, 1 H), 8.18 (s, 1 H) , (1 exchangeable proton was not observed). 185-1 (Y V . (^).3-(2-(4-((3-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-111pyrazol-1yl)pyridin-4yl)oxazolidin- 2nd 475.1 S: 1.35, 100% R: 1.11, 100% XIV: 15.72, 98.00% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.79 (t, J = 10.15 Hz, 1 Η), 2.07 - 2.15 (m, 1 Η), 2.25 (s, 3 Η), 2.77 - 3.01 (m , 3 Η), 3.17 (d, J= 5.14 Hz, 1 Η), 3.46 - 3.56 (m, 2 Η), 4.04 - 4.17 (m, 3 Η), 4C7.4.54 ( _m , 2 Η), 5.36 (s, 2 Η), 7.42 (dd, J = 5.87, 2.20 Hz, 1 Η), 7.63 (d, J = 8.07 Hz, 1 Η), 7.72 - 7.79 (m, 2 Η), 8.16 (d, J= 2.20 Hz, 1 Η), 8.35 (d, J= 5 .87 Hz, 1 H), 8.47 (s, 1 H), (1 exchangeable proton was not observed). 186-1 0 ογτΧ Me ΗΝ^ Me ^{7 X} _CN (7?)-2,4-dimethyl-6-(4((3 -(4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)- 1H-1,2,3triazol-1yl)nicotinonitrile 444.2 C: 6.15, 98.53% G: 6.95, 99.21% V: 11.71, 99.21% e.i. Ή NMR (400 MHz, DMSO-Yab) δ ppm 1.87 (t, J= 10.39 Hz, 1 Η), 2.12 - 2.22 (m, 1 Η), 2.26 (s, 3 Η), 2.62 (s, 3 Η) , 2.69 - 2.75 (m, 3 Η), 2.78 2.92 (m, 3 Η), 2.95 - 3.02 (m, 1 Η), 3.74 (s, 2 Η ), 4.06 (d, J = 7.58 Hz, 1 Η), 5.38 (s, 2 Η), 7.64 (d, J = 8.07 Hz, 1 Η), 7.76 ( d, J = 8.07 Hz, 1 H), 8.10 (s, 1 H), 8.74 (s, 1 H), (1 exchangeable proton was not observed). 187-1 0 °lO,, _N ^Μ θ ^n'C'N (7?)-4-methoxy-2methyl-6-(4-((3-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)- 1H-1,2, 3triazol-1yl)nicotinonitrile 460.3 R: 1.06, 100% S: 1.27, 99.47% V: 10.37 98.87% e.i. ^NMR (400 MHz, DMSO-Je) δ ppm 1.87 - 1.98 (w, 1 H), 2.14 - 2.24 (t, 1 H), 2.27 (s, 3 H), 2.64 - 2.69 (w, 3 H ), 2.85 (t, J = 9.50 Hz, 2 H), 2.92 (d, J = 10.00 Hz, 1 H), 2.97 - 3.05 (br, 1 H), 3.76 (s, 2 H), 4.04 - 4.19 (w, 4 H), 5.31 - 5.46 (w, 2 H), 7.65 (d, J = 7.80 Hz , 1 H), 7.73 (s, 1 H), 7.76 (d, J = 7.80 Hz, 1 H), 8.75 (s, 1 H), (1 exchangeable proton was not observed ).

- 200 043056

188-1 0 °yO, Me ΗΝ^> Ν~ _ν ' ^N ^3~OMe m®cn (7?)-4-methoxy-2methyl-6-(4-((3 -(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2, 3triazol-2yl)nicotinonitrile 460.3 R: 1.02, 100% S: 1.20, 98.54% V: 8.18, 99.14% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.91 (t, J= 10.30 Hz, 1 N), 2.13 - 2.25 (br, 1 N), 2.26 (s, 3 N), 2.64 (s, 3 N) , 2.82 (d, J= 11.20Hz, 2N), 2.90 (t, J= 11.20Hz, 1N), 3.00 (d, J= 12.00Hz, 1N ), 3.76 (s, 2 H), 4.03-4.17 (br, 4 H), 5.27-5.46 (br, 2 H), 7.55 (s, 1 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.19 (s, 1 H), (no 1 capable of proton exchange). 189-1 190-1 191-1 0 Me ΗΝ^ Y^Me MeO CN O ^τίΥιΥΠν Me HN^J Nn Me ^Z Me ^N AoMe CN 0 YA/'n'VN 1 g 1 VN Me HN^J Me _ν Ύ Me CN (7?)-2-methoxy-4methyl-6-(4-((3 -(4methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)-1 Η-1,2 ,3 triazol-1yl)nicotinonitrile 6-(4-((3,3-dimethyl-5(4-methyl-1-oxo-1,3dihydroisobenzofura n-5-yl)piperazin-1 yl)methyl)-2H-1 ,2,3triazol-2-yl)-4methoxynicotinonitril (Enantiomer-1) 4-methyl-6-(5(((35.57?)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1, 3,4oxadiazol-2yl)nicotinonitrile 460.3 474.3 445.2 R: 1.13, 100% S: 1.35, 100% VI: 14.78, 98.24% e.i. R: 1.10, 97.63% S: 1.53, 96.84% XVIII: 17.70, 100% e.i. A: 0.95, 100% B: 1.26, 100% XIV: 8.77, 100% Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.87 - 1.98 (w, 1 H), 2.14 - 2.24 (w, 1 H), 2.28 (s, 3 H), 2.59 (s, 3 H), 2, 85 (t, J = 9.50 Hz, 2 H), 2.91 (br. s., 2 H), 3.78 (br. s., 2 H), 4.11 (s, 4 H) , 5.39 (d, J = 3.70 Hz, 2 H), 7.71 (br. s., 1 Η), 7.80 - 7.74 (m, 1 Η), 7.83 (s , 1 H), 8.85 (s, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.07 (s, 3 Η), 1.32 (s, 3 Η), 1.85 (t, J= 10.40 Hz, 1 Η), 1.93 (d, J= 10.50 Hz, 1 H), 2.04 (br. s., 1 H), 2.29 (s, 3 H), 2.57 (d, J= 10.80 Hz, 1 H), 2.88 (d, J = 10.00 Hz, 1 H), 3.65 - 3.88 (m, 2 H), 4.13 (s, 3 H), 4.42 (d, J= 9.00 Hz, 1 H ), 5.32 - 5.47 (m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7.70 (s, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.21 (s, 1 H), 8.83 (s, 1 H). Ή NMR (400 MHz, DMSO-J ₆ ) δ 1.03 (d, J= 6.40 Hz, 3 H), 1.87 - 2.03 (m, 2 H), 2.30 (s, 3 H), 2.63 (s, 3H), 2.78 - 2.93 (m, 2H), 2.99 (br. s., 1H), 4.00 (s, 2H), 4 .19 (d, J = 7.60 Hz, 1 H), 5.40 (s, 2 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.79 (d, J = 8.10 Hz, 1 H), 8.32 (s, 1 H), 9.11 (s, 1 H), (1 exchangeable proton was not observed). 192-1 0 K^x, N / ^OMe °CX1 g ν-/Ύ Υγ _Ν ^^ _Ν _/-0Ν Μθ HlY Me 4-methoxy-6-(4-(2((35.57?)-3-methyl-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)ethyl)-1 N-pyrazol1 -yl)nicotinonitrile 433.3 R: 0.54, 100% S: 1.26, 94.95% XV: 6.26, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.05 (d, 7= 6.10 Hz, 3 H), 1.24 (s, 1 H), 1.65 - 1.82 (w, 2 H), 2.27 - 2.34 (w , 3 N), 2.56 (d, J= 7.10 Hz, 1 N), 2.59 - 2.65 (t, 3 N), 2.65 - 2.74 (br, 2 N), 2.88 (d, J = 10.30 Hz, 2 Η), 2.96 (br. s., 1 Η), 4.16 (d, J = 9.80 Hz, 1 Η), 5.32 - 5.47 (m, 2 Η), 7.62 - 7.72 (m, 2 Η), 7.78 - 7.90 (m, 2 Η), 8.52 (s, 1 Η), 8 .73 (d, J = 5.60 Hz, 1 H), (1 exchangeable proton was not observed). 193-1 0 Me XJM' HO \__ ^ ^me CN 6-(5-(((37?,47?)-4hydroxy-3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)isoxazol3-yl)-4- methylnicotinonitrile l 445.3 R: 1.17, 100% S: 1.58, 100% XVIII: 5.84, 100% e.i. ^X NMR (400 MHz, DMSO-Te) δ ppm 1.59 - 1.70 (br, 1 H), 1.94 (d, J = 9.50 Hz, 1 H), 2.16 2.41 (br, 5 H), 2.59 (s, 3 N), 2.79 (d, 7= 11.20 Hz, 1 N), 2.95 (d, J= 10.30 Hz, 1 N), 3.09 (t, J= 10.40 Hz , 1 H), 3.64 - 3.77 (br. s., 2 H), 3.86 (br. s., 2 H), 4.61 (d, J= 5.40 Hz, 1 H), 5 .30 - 5.49 (m, 2 Η), 6.99 (s, 1 Η), 7.54 (d, J = 8.10 Hz, 1 Η), 7.64 (d, J = 7, 80 Hz, 1 H), 8.15 (s, 1 H), 9.05 (s, 1 H).

- 201 043056

194-1 o o ^z O. Me HN^b Me ¢+ o s <0 5-((2R,65)-4-((1-(4methoxy-1,3,5 - triaz in-2-yl)-1Hpyrazol-4-yl)methyl)6-methylpiperazin-2yl)-4- methylisobenzofuran1(3N)-one 436.2 R: 0.76, 100% S: 1.09, 100% VIII: 9.06, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 0.93 - 1.11 (w, 3 H), 1.73 (td, J = 10.6, 4.3 Hz, 2 H), 2.26 (s, 3 H), 2.80 (d , J = 10.80 Hz, 2 N), 2.94 3.02 (br, 1 N), 3.45 - 3.58 (br, 2 N), 3.98 - 4.11 (br, 3 H), 4.13 - 4.21 (w, 1 H), 5.31 - 5.47 (w, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7, 79 (d, J = 8.10 Hz, 1 H), 7.95 - 7.86 (br, 1 H), 8.57 (s, 1 H), 8.96 (s, 1 H), ( 1 exchangeable proton was not observed). 6-(4-(((37?,57?)-3- (hydroxymethyl)-4- R: 1.10 Ή NMR (400 MHz, DMSO-J6) δ ppm ABOUT methyl-5 - (4-methyl-1 - 96.00% 1.88 (br. s., 1 H), 1.93-2.08 (br. s., 4 H), 2.27 (br. s., o ^z Yb oxo-1,3- S: 1.47 3 Η), 2.36 (d, J = 10.00 Hz, 1 Η), 2.58 (s, 3 Η), 195-1 Me N. J Me ^z V HC< Ό ^N b“ dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1H- 473.3 95.73% XV: 4.2Z, 100% e.i. 2.72 (d, J= 11.70 Hz, 1 H), 3.09 (d, J= 11.00 Hz, 1 H), 3.18 (d, J= 4.60 Hz, 1 H) , 3.43 - 3.54 (m, 2 Η), 3.58 - 3.73 (m, 2 Η), 4.55 (br. s., 1 H), 5.30 - pyrazol-1-yl)-4- 5.47 (m, 2 H), 7.59 - 7.73 (m, 2 H), 7.84 (s, 1 H), methylnicotinonitrile 7.99 (s, 1 H), 8.52 (s, 1 H), 8.83 (s, 1 H). l 6-(4-(((35.57?)-3- Ή NMR (400 MHz, DMSO-J6) δ ppm methyl-5 - (4-methyl-1 - R: 1.91 1.02 (d, J= 6.10 Hz, 3 Η), 1.64 - 1.81 (m, 2 Η), ABOUT oxo-1,3- 100% 2.27 (s, 3 H), 2.81 (d, J = 9.80 Hz, 2 H), 2.97 (br. O' Λ dihydroisobenzofur S: 2.07 s., 1 H), 3.55 (s, 2 H), 4.17 (d, J= 9.00 Hz, 1 H), 196-1 Me HN^b T, ⁿ n-5 -yl)piperazine-1 - 497.3 100% 5.28 - 5.46 (m, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), Me ^N tb ^F ' yl)methyl)-1H- XXVIII: 7.79 (d, J= 7.80 Hz, 1 H), 7.96 (s, 1 H), 8.24 (s, 1 CN pyrazol-1-yl)-4- 4.19 H), 8.61 (s, 1 H), 9.23 (s, 1 H), (not observed (trifluoromethyl)nicot 96.40% e.i. 1 exchangeable proton). ¹⁹ F NMR (400 inonitrile MHz, DMSO-t/b) δ ppm - 63.47. 4-methyl-6-(4-((3 -(4- ^NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.51 methyl-1-oxo-1,3- S: 1.98 (br. s., 1 H), 1.75 (br. s., 3 H), 2.04 (br. s., 2 H), O dihydroisobenzofur 98.50% 2.24 (s, 3 H), 2.54 - 2.62 (m, 3 H), 2.73 - 3.00 (m, 197-1 su Me bf?N n-5 -yl)piperidin-1 yl)methyl)-1H- 428.1 R: 1.40, 94.37% 2 H), 3.04 - 3.24 (m, 1 H), 3.53 (br. s., 2 H), 5.36 (s, 2 H), 7.49 (d, J = 8 .07 Hz, 1 H), 7.63 (d, J = ^N b”° pyrazole-1- V: 11.03 7.09 Hz, 1 H), 7.87 (br. s., 1 H), 7.99 (s, 1 H), 8.54 CN yl) nicotinonitrile (Enantiomer-1) 97.37% e.i. (br. s., 1H), 8.83 (s, 1H).

- 202 043056

198-1 199-IV 200-Π 0 □to Me HN^> + _N ' 0 °x^Ol Me kJ %N ^OH ty CN 0 °0Ol tt^7'^C ⁿ Me 4' OMe \==/ ^M ® CN (7/)-2-(4-((3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-111pyrazol-1- yl) isonicotinonitri l 6-(4-((3-hydroxy-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-111pyrazol-1-yl)-4- methylnicotinonitrile l (Enantiomer-IV) 6-(4-((3-methoxy-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-111pyrazol-1-yl)-4- methylnicotinonitrile l (Enantiomer-P) 415.1 459.3 458.2 S: 1.20, 100% R: 0.87, 100% S: 1.42, 97.51% R: 1.01, 96.70% XVIII: 19.33, 100% e.i. S: 1.66, 97.24% R: 1.13, 97.40% XVIII: 18.01, 100% e.i. 'H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.83 (t, J = 10.90 Hz, 1 Η), 2.14 (t, J = 9.80 Hz, 1 Η), 2.26 (s, 3 Η), 2.81 (d, J= 8.10 Hz, 2 Η), 2.94 - 2.86 (m, 1 Η), 3.05 - 2.97 (m, 1 Η), 3.59 - 3.45 (m, 2 Η), 4.10 (d, J= 9.30 Hz, 1 Η), 5.45 - 5.30 (m, 2 Η), 7.64 (d, J= 8.10 Hz, 1 Η) , 7.80 - 7.70 (m, 2 Η), 7.83 (s, 1 Η), 8.22 (s, 1 Η), 8.51 (s, 1 Η), 8.68 (d , J = 5.10 Hz, 1H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.70 (br. s., 2 Η), 2.25 (s, 4 Η), 2.58 (s, 3 Η), 2.77 (br. s., 2 Η), 3.57 ( br. s., 3 H), 3.86 (br. s., 1 H), 4.63 (br. s., 1 H), 5.36 (s, 2 H), 7.67 - 7 .52 (m, 2 H), 7.89 (s, 1 H), 7.99 (s, 1 H), 8.57 (s, 1 H), 8.83 (s, 1 H), ( 1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.41-1.30 (w, 1 N), 1.84 (t, J = 10.60 Hz, 1 N), 1.95 (t, J = 10.80 Hz, 1 N), 2, 14 (s, 1 H), 2.24 (s, 3 H), 2.58 (s, 3 H), 2.81 (d, J = 11.70 Hz, 1 H), 3.16 (d , 7= 11.20 Hz, 1 H), 3.24 (d, 7= 6.10 Hz, 1 H), 3.29 (s, 3 H), 3.48 (s, 1 H), 3 .69 - 3.55 (w, 2 H), 5.36 (s, 2 H), 7.48 (d, J = 7.80 Hz, 1 H), 7.62 (d, J = 8, 30 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.54 (s, 1 H), 8.83 (s, 1 H). 201-1 0 Me HN j IL _n A _n 4 _n mA ¹ ' (7/)-5-(4-((2-(3,5dimethyl-4H-1,2,4triazol-4yl)pyrimidin-5yl)methyl)piperazin2-yl)-4methylisobenzofuran1(3H)-one 420.2 S: 0.88, 97.02% R: 0.70, 96.77% Ή NMR (400 MHz, DMSO-7 ₆ ) δ ppm 1.95 - 1.83 (w, 1 H), 2.23 - 2.08 (w, 2 H), 2.32 - 2.24 (w, 6 H), 2.70 (s, 3 H ), 2.80 (t, J= 10.90 Hz, 2 N), 2.92 (t, J= 10.30 Hz, 1 N), 3.07 - 2.98 (m, 1 N), 3.73 - 3.54 (br, 2 H), 4.11 (d, J = 8.30 Hz, 1 H), 5.48 - 5.29 (br, 2 H), 7.66 (d , J = 7.80 Hz, 1 H), 7.79 (d, J= 7.80 Hz, 1 H), 8.86 (s, 2 H).

- 203 043056

202-1 0 Me ΗΝ. J m 'Υ ^Ν . Me Me \A~cn 3-methyl-2-(4(((35.57?)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol- 1yl)isonicotinonitrile l 443.3 S: 1.41, 99.79% R: 0.94, 99.70% XVIII: 8.45, 100% e.i. Ή NMR (400 MHz, DMSO-Je) δ ppm 1.17 (t, J = 7.20 Hz, 3 Η), 2.36 (s, 3 Η), 2.68 (s, 3 Η), 2.99 - 2.87 (m, 2 Η) , 3.15 (br. s., 2 H), 3.64 (br. s., 1 H), 3.76 (br. s., 1 H), 3.84 (s, 1 H), 4.75 (br. s., 1 H), 5.60 - 5.37 (m, 2 H), 7.87 - 7.73 (m, 3 H), 7.90 (d, J = 4 .90 Hz, 1 H), 8.32 (br. s., 1 H), 8.42 (br. s., 1 H), 8.59 (d, J= 4.60 Hz, 1 H) . 203-1 Ο οΧΑ ^ί'ι^^αΑν Me kJ C _N ' ^{F Ν} ΧΑμ _Θ CN 6-(4-((3-fluoro-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)- 1H-1,2,3triazol-1-yl)- 4methylnicotinonitrile l (Enantiomer-1) 447.2 S: 1.66, 100% R: 1.17, 100% XXVIII: 6.53, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.79 - 1.65 (m, 1 Η), 2.24 - 2.03 (m, 3 Η), 2.26 (s, 3 Η), 2.67 - 2.60 (m, 3 Η ), 2.86 (d, J = 10.80 Hz, 1 Η), 3.21 (t, J = 10.80 Hz, 1 Η), 3.31 (d, J = 3.90 Hz, 1 Η), 3.96 - 3.79 (m, 2 Η), 4.95 - 4.68 (m, 1 Η), 5.38 (s, 2 Η), 7.54 (d, J = 8 .10 Hz, 1 Η), 7.65 (d, J = 8.10 Hz, 1 Η), 9.00 (s, 1 Η), 8.85 (s, 1 Η), 8.30 (s , 1H). ¹⁹ F NMR (300 MHz, DMSO-J ₆ ) δ ppm 178.31. 204-1 0 A _v t ϊ ⁿ A+m ^Me HN JL/ To ά°μ CN 6-(4-((3-(1hydroxyethyl)-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)-4- methoxynicotinonite ril (Enantiomer-1) 489.3 S: 1.38, 99.33% R:l.05, 97.87% XXVIII: 5.73, 95.11% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.10 (d, J= 6.0 Hz, 3 H), 1.77 (br. s., 2 H), 2.27 (s, 3 H), 2.74 (s, 3 H), 3.01 (br. s., 1 H), 3.54 (br. s., 3 H), 4.11 (s, 3 H), 4.15 (br. s., 1 H), 4 .54 (br. s., 1 H), 5.39 (s, 2 H), 7.61 (s, 1 H), 7.66 (d, J = 6.40 Hz, 1 H), 7 .80 (d, J = 8.30 Hz, 1 H), 7.87 (s, 1 H), 8.53 (br. s., 1 H), 8.75 (s, 1 H). 205-1 0 ^iAAAYA Me HN^J % _N ' Λ ^Ν ^^M _Θ 6-(4-((3(difluoromethyl)-5-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitrile l (Enantiomer-1) 479.2 S: 1.80, 94.40% R: 1.23, 94.62% X: 4.29, 89.07% ee Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.77 (br. s., 1 H), 2.01 (br. s., 1 H), 2.14 - 2.08 (m, 1 H), 2.27 (s, 3 H), 2.58 (s, 3 H), 2.84 (br. s., 2 H), 2.94 (br. s., 1 H), 3.62 (br. s., 2 H), 4 .24 (br. s., 1 H), 5.49 - 5.30 (m, 2 H), 5.96 (br. s., 1 H), 7.67 (d, J= 7.60 Hz, 1 H), 7.77 (d, J= 8.10 Hz, 1 H), 7.88 (br. s., 1 H), 8.00 (s, 1 H), 8.57 ( br. s., 1 H), 8.84 (s, 1 H). ¹⁹ F NMR (300 MHz, DMSO-J ₆ ) δ ppm 126.20, -126.07.

- 204 043056

206-1 /°у° f \ / .o/ f 4-methyl-5-((27/, 65)-6methyl-4-((1-(5methylpyrazin-2-yl)1H-pyrazol-4yl)methyl)piperazin2-yl)isobenzofuran- 1(ZN)-on 419.3 R: 0.63, 94.20% S: 1.40, 95.10% VIII: 5.80, 100% e.i. 'H NMR (400 MHz, DMSO-7 ₆ ) δ ppm 1.03 (d, 7=6.10 Hz, 3 H), 1.73 (br. s., 2H), 2.31-2.18 (m, 3 Η), 2.56 - 2.52 ( m, 4 Η), 2.81 (d, J = 10.30 Hz, 2 Η), 2.98 (br. s., 1 Η), 3.53 (s, 2 Η), 4.16 ( br. s., 1 H), 5.37 (d, J = 2.00 Hz, 2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.88 - 7.74 (m, 2 H), 8.40 (s, 1 H), 8.45 (s, 1 H), 9.05 (d, J= 1.50 Hz, 1 H). 207-1 0 D+t Me + _N Me H %0Me 5-((27/.65)-4-((1-(6methoxypyrimidin-4yl)-1 H-pyrazol-4yl)methyl)-6methylpiperazin-2yl)-4methylisobenzofuran1(3H)-one 435.2 S: 1.34, 99.14% R: 0.73, 100% XXV: 13.93, 98.14% e.i. Ή NMR (400 MHz, DMSO-Je) δ ppm 1.02 (d, J= 6.10 Hz, 3 Η), 1.80-1.61 (m, 2 Η), 2.26 (s, 3 Η), 2.79 (d, J= 10 .30 Hz, 2 Η), 2.96 (br. s., 1 Η), 3.18 (d, J= 5.40 Hz, 1 Η), 3.51 (s, 2 Η), 3, 99 (s, 3 Η), 4.15 (d, J = 8.60 Hz, 1 Η), 5.47 - 5.29 (m, 2 Η), 7.16 (d, J = 1.00 Hz, 1 Η), 7.65 (d, J= 8.10 Hz, 1 Η), 7.79 (d, J = 8.10 Hz, 1 Η), 7.88 - 7.81 (m, 1 H), 8.49 (s, 1 H), 8.71 (d, 7=1.00 Hz, 1 H). 208-1 0 ® ^e "Η OMe 5-((27/.65)-4-((1-(2methoxypyrimide in-5yl)-1H-pyrazol-4yl)methyl)-6methylpiperazin-2yl)-4methylisobenzofuran1(3H)-one 435.3 S: 1.07, 95.74% R: 0.55, 98.67% XIV: 5.56, 100% e.i. Ή NMR (400 MHz, DMSO-7 ₆ ) δ ppm 1.03 (d, 7= 5.60 Hz, 3 Η), 1.73 (d, 7= 10.30 Hz, 2 Η), 2.27 (s, 3 Η), 2.82 (d, 7= 10.30 Hz, 2 H), 2.98 (br. s., 1 H), 3.48 (s, 2 H), 3.97 (s, 3 H), 4.18 (br. s., 1 H), 5.47 - 5.28 (m, 2 H), 7.66 (d, 7= 7.80 Hz, 1 H), 7.72 (s, 1 H), 7, 80 (d, 7= 8.10 Hz, 1 H), 8.42 (s, 1 H), 9.05 (s, 2 H), (1 exchangeable proton not observed). 209-1 0 Me \N TO Me 4-methyl-5-((27/,65)-6methyl-4-((1-(2methylpyrimidin-5yl)-1 H-pyrazol-4yl)methyl)piperazin2-yl)isobenzofuran- 1(ZN)-on 419.2 S: 0.98, 93.79% R: 0.50, 98.28% XXVI: 9.79, 100% e.i. Ή NMR (400 MHz, DMSO-Te) δ ppm 1.04 (d, 7= 6.10 Hz, ZN), 1.72 (br. s., 2H), 2.33-2.14 (m, 3 Η), 2.70 - 2.60 ( m, 3 H), 2.82 (d, 7= 8.60 Hz, 2 H), 2.98 (br. s., 1 H), 3.49 (s, 2 H), 4.16 ( br. s., 1 H), 5.45 - 5.30 (m, 2 H), 7.66 (d, 7= 8.10 Hz, 1 H), 7.76 (s, 1 H), 7.80 (d,7= 8.10 Hz, 1 H), 8.53 (s, 1 H), 9.22 - 9.09 (m, 2 H), (1 exchangeable proton not observed) . 210-1 O ο^Ύ^Ί] ^τΌΎ ^v '° Me HN^ +/ Me mO O'* CN 4-methyl-6-(3(((35.57/)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)isoxazol5-yl )nicotinonitrile 444.2 R: 1.50, 94.28% S: 1.13, 95.39% Ή NMR (400 MHz, DMSO-Te) δ ppm 1.04 (d, 7= 6.10 Hz, ZN), 1.94-1.80 (br, 2H), 2.27 (s, 3 H), 2.64 - 2.54 (br, 4 H), 2.82 (d, 7= 10.30 Hz, 2 H), 3.00 (br. s., 1 H), 3.72 (s, 2 H), 4.19 (d, 7 = 8.10 Hz, 1 N), 5.38 (s, 2 N), 7.23 (s, 1 N), 7.66 (d, 7= 8.10 Hz, 1 N), 7.80 (d, 7= 7.80 Hz, 1 H), 8.14 (s, 1 H), 9.04 (s, 1 H). 211-1 0 /XX/ \ ^N ^\—, Me )— ⁷ ΖΓΧ HO % X %XMe CN 6-(4-((3-hydroxy-4(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)pyrrolidin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitrile l (Diastereomer I: Enantiomer-1) 430.2 R: 0.99, 100% S: 1.25, 100% XVIII: 16.83, 99.40% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 2.26 (s, 3 N), 2.58 (s, 3 N), 2.84 - 3.03 (m, 2 N), 3.19 (dd, 7= 10.10, 5.70 Hz , 1 N), 3.51 - 3.63 (t, 1 N), 3.70 (s, 2 N), 4.38 - 4.48 (t, 1 N), 4.51 (d, 7 = 4.90 Hz, 1 N), 5.36 (s, 2 N), 7.54 (d, 7= 7.80 Hz, 1 N), 7.59 (d, 7= 8.10 Hz, 1 H), 7.91 (s, 1 H), 7.99 (s, 1 H), 8.59 (s, 1 H), 8.85 (s, 1 H). (No 1 exchangeable proton was observed).

- 205 043056

212-Π Oh οζ Xv | | N- Me A—/ F O-X }-Z^\ = )=/ Ξ <d 6-(4-((3-fluoro-4-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)pyrrolidin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitrile l (Diastereomer I: Enantiomer-P) 432.2 R: 1.12, 94.07% S: 1.80, 93.34% VIII: 4.92, 99.73% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 2.30 (s, 3 H), 2.59 (s, 3 H), 2.93-3.02 (m, 1 H), 3.05 (br. s., 1 H), 3.24 - 3.29 (t, 1 N), 3.39 (d, J= 6.10 Hz, 1 N), 3.69 (s, 2 N), 3.74 (d, J= 5.60 Hz , 1 N), 3.78 - 3.88 (t, 1 N), 5.40 (s, 2 N), 7.53 (d, J = 8.30 Hz, 1 N), 7.69 ( d, J= 7.80 Hz, 1 H), 7.92 (s, 1 H), 8.01 (s, 1 H), 8.60 (s, 1 H), 8.86 (s, 1 N). ¹⁹ F NMR (400 MHz, DMSO-J ₆ ) δ ppm -164.03. 6-(4-((3-(2- 'H NMR (400 MHz, DMSO-76) δ ppm hydroxypropane-2- 1.14 (d, J= 3.90 Hz, 6 H), 1.71 (t, J= 10.40 Hz, 1 213-1 0 o ^z Me HN^J Tme HO^Me ^nXm . CN yl)-5-(4-methyl-1oxo-1,3dihydroisobenzofura n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitri 487.3 R: 1.18, 93.00% S: 1.61, 93.00% XXV: 6.47, 100% e.i. Η), 1.82 (t, J= 10.50 Hz, 1 Η), 2.26 (s, 3 Η), 2.58 (s, 3 Η), 2.73 - 2.85 (m, 2 H), 2.92 (d, J= 10.00 Hz, 1 H), 3.51 (d, J= 13.90 Hz, 1 H), 3.59 (d, J= 13.70 Hz , 1 H), 4.15 (d, J= 7.60 Hz, 1 H), 4.40 (br. s., 1 H), 5.37 (s, 2 H), 7.66 (d , J= 7.80 Hz, 1 H), 7.82 (d, J = 7.80 Hz, 1 H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8 .53(s, 1H), 8.83(s, 1H). (He l 1 exchangeable proton was observed). (Enantiomer-1) 214-1 0 o ^z χχ Me HN^X Me b ^N X3~Me CN 4-methyl-6-(5- (((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)isoxazol3 -yl)nicotinonitrile 444.2 R: 1.16, 97.73% S: 1.56, 97.61% XVIII: 5.63, 100% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 1.03 (d, 7=6.10 Hz, ZN), 1.86 (dt, J= 13.60, 10.5 Hz, 2 N), 2.28 (s, 3 N), 2.55 - 2.65 (t, 4 N), 2.83 (d, J = 10.80 Hz, 2 N), 2.93 - 3.04 (t, 1 N), 3.86 (s, 2 N ), 4.17 (d, J= 8.10 Hz, 1 H), 5.39 (s, 2 H), 6.98 (s, 1 H), 7.65 (d, J= 7.80 Hz, 1 N), 7.73 - 7.83 (t, 1 N), 8.15 (s, 1 N), 9.05 (s, 1 N). ^X NMR (400 MHz, DMSO-Ts) δ ppm 1.87 (A)-4-methyl-5-(4-((2- A: 1.07 - 1.96 (t, 1 N), 2.12-2.17 (t, 1 N), 2.24 (s, 3 N), 0 (4-methyl-1H- 99.60% 2.75 - 2.85 (t, 2 N), 2.94 (d, J = 12.96 Hz, 1 N), 215-1 »™+%-Va 4 imidazol-1yl)pyrimidin-5yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 416.20 B: 1.32, 98.32% XVIII: 16.98 98.00% e.i. 3.02 (d, J = 11.98 Hz, 1 N), 3.54 - 3.65 (t, 2 N), 4.12 (d, J = 8.80 Hz, 1 N), 5, 31 - 5.43 (t, 2 N), 7.62 - 7.69 (t, 2 N), 7.77 (d, J = 7.83 Hz, 1 N), 8.44 (d, J = 1.22 Hz, 1 H), 8.75 (s, 2 H), (1 exchangeable proton not observed).

- 206 043056

216-1 i to (A)-1 -(5 -((3 -(4-methyl1-oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)pyrimidin2-yl)-1 H-imide azole-4carbonitrile 405.20 E: 7.08, 97.55% G: 8.03, 98.45% XIV: 7.18, 98.01% e.i. Ή NMR (400 MHz, DMSO-c/b) δ ppm 1.87-1.96 (m, 1 H), 2.12-2.17 (m, 1 H), 2.18 (s, 3 H), 2.24 (s, 3 H), 2, 75 - 2.85 (m, 2 N), 2.94 (d, J = 12.96 Hz, 1 N), 3.02 (d, J = 11.98 Hz, 1 N), 3.54 3 .65 (m, 2 H), 4.12 (d, J = 8.80 Hz, 1 H), 5.31 5.43 (m, 2 H), 7.62 - 7.69 (m, 2 H), 7.77 (d, J = 7.83 Hz, 1 H), 8.44 (d, J = 1.22 Hz, 1 H), 8.75 (s, 2 H), (not observed 1 exchangeable proton). (J?)-1-(5-((3-(4-methyl- 'H NMR (400 MHz, DMSO-c/b) δ ppm 1.92 1-oxo-1,3- S: 1.14 (t, J = 10.64 Hz, 1 N), 2.15 - 2.22 (m, 1 N), 2.25 O ΥΊ dihydroisobenzofur 98.53% (s, 3 N), 2.80 (t, J= 9.05 Hz, 2 N), 2.87 - 2.96 (w, 217-1 ABOUT n-5 -yl)piperazin-1 yl)methyl)pyrimidine- 417.5 R: 1.34, 99.21% 1 N), 2.96 - 3.05 (m, 1 N), 3.58 - 3.74 (m, 2 N), 4.11 (d, J = 8.80 Hz, 1 N), 5.28 - 5.43 (m, 2 N), 2-yl)-1H-1,2,4- XVIII: 7.65 (d, J = 8.07 Hz, 1 N), 7.78 (d, J = Hz, 1 triazole-3- 24.93, Η), 8.94 (s, 2 Η), 9.78 (s, 1 H), (not observed carbonitrile 100% e.i. 1 exchangeable proton). 218-1 O sl Μθ ΗΝ^ τ (L)-3-cyclopropyl-1 (5-((3-(4-methyl-1oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyrimidin2-yl)-1H-pyrazole-4carbonitrile 456.5 S: 1.08, 99.41% R: 1.32, 99.66% XVIII: 19.26, 98.54% e.i. Ή NMR (400 MHz, DMSO-c/e) δ ppm 1.03 - 0.88 (m, 2 N), 1.17 - 1.04 (m, 2 N), 1.87 (t, J = 10.3 Hz, 1 N), 2.11 - 2 .02 (m, 1 N), 2.20 - 2.11 (w, 1 N), 2.24 (s, 3 N), 2.77 (t, J = 12.00 Hz, 2 N), 2.94 - 2.84 (m, 1 H), 3.07 - 2.96 (m, 1 H), 3.74 - 3.50 (m, 2 H), 4.07 (d, J = 8.10 Hz, 1 N), 5.48 - 5.24 (t, 2 N), 7.64 (d, J = 8.10 Hz, 1 N), 7.77 (d, J = 8, 10 Hz, 1 H), 8.81 (s, 2 H), 9.32 (s, 1 H). (No 1 exchangeable proton was observed). (to- Ή NMR (400 MHz, DMSO-c/b) δ ppm (difluoro methoxy) -1 - S: 1.29 1.16 (t, J= 7.20 Hz, 3 H), 2.32 (s, 3 H), 2.93 (dd, O Ά (5-((3-(4-methyl-1- 99.02% J= 12.20, 7.1 Hz, 2 H), 3.03 (br. s., 2 H), 3.42 (br. 219-1 O Me N^/ oxo-1,3- dihydroisobenzofur 481.3 R: 1.60, 99.41% s., 2 H), 3.78 (br. s., 2 H), 4.73 (br. s., 1 H), 5.43 (d, J= 14.20 Hz, 1 H), 7.58 (t, J= 53.50 Hz, 1 H), v° n-5 -yl)piperazine-1 - XVIII: 7.80 - 7.67 (m, 1 H), 7.90 - 7.81 (m, 1 H), 8.06 (dd, yl)methyl)pyridine-2- 7.03, J= 8.40, 2.10 Hz, 1 H), 8.50 (d, J = 1.70 Hz, 1 H), yl)-1 H-pyrazole-4- 100% e.i. 9.40(s, 1H). ¹⁹ F NMR (300 MHz, DMSO-c/ ₆ ) δ carbonitrile ppm - 84.69. Ή NMR (400 MHz, DMSO-c/b) δ 2.33 (s, ABOUT (R)-6-(4-((3 -(4-methyl- S: 0.96 3 Η), 2.60 (br. s., 1 Η), 3.16 (br. s., 2 Η), 3.21 (br. Ό ύΑ 1-oxo-1,3- 99.62% s., 1 H), 3.48 - 3.34 (m, 2 H), 3.60 - 3.54 (m, 4 H), 220-1 Me ΗΝ^ to' Η dihydroisobenzofur n-5-yl)piperazin-1 - 500.2 R: 1.27, 97.76% 3.80 - 3.74 (m, 4 H), 3.83 (br.s., 2 H), 4.74 (d, J= 10.80 Hz, 1 H), 5.52 - 5, 39(m, 2H), 7.38(s, 1H), h yl)methyl)-1H- XIV: 10.79, 7.75 (d, J = 8.10 Hz, 1 H), 7.84 (d, J = 7.80 Hz,1 0 ^CN pyrazol-1-yl)-4- 99.64% e.i. H), 8.60 (s, 1 H), 7.87 (s, 1 H), 8.63 (s, 1 H), (not morpholinonicotinon 1 exchangeable proton was observed). itril 221-1 ίκΟ+ζΧ n%/ Me (R)-3-methyl-1-(5-((3(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyrimidin2-yl)-1H-pyrazol- 4carbonitrile 430.20 G:ll,37, 97.70% F: 10.57, 97.50% XVIII: 18.61 98.90% e.i. Ή NMR (400 MHz, DMSO-c/e) δ ppm 1.91 (s, 1 H), 2.15-2.23 (m, 1 H), 2.24 (s, 3 H), 2.41 (s, 3 H), 2.72-2, 85 (m, 2 N), 2.94 (d, J = 10.52 Hz, 1 N), 3.01 (d, J = 9.54 Hz, 1 N), 3.57 - 3.71 ( m, 2 N), 4.11 (d, J = 9.54 Hz, 1 N), 5.29 - 5.43 (m, 2 N), 7.66 (d, J = 8.07 Hz, 1 H), 7.78 (d, J = 7.83 Hz, 1 H), 8.83 (s, 2 H), 9.34 (s, 1 H). (No 1 exchangeable proton was observed).

- 207 043056

222-1 223-1 224-1 225-1 226-1 227-1 0 7 A-Me ⁿ \u003d n 0 C ¹ hnO ^N AQ ^N h V-CN OMe 0 Vo-xt 0 ^N 4 A-CN n \u003d n 0 ^N 4 A-cn ^N T Me ^o x. „ _r Me HN ^ ^N h A-cn Νΐ/ OMe (A)-4-methyl-5-(4-((6(4-methyl-1H-1,2,3triazol-1yl)pyridin-3yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one (7 /) -3 -methoxy-1 - (5 ((3 - (4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-2yl)-1 H-pyrazole-4carbonitrile (7/)-4-methyl-5-(4-((2(4-methyl-1nimidazol-1yl)pyrimidin-5yl)methyl)morpholin2-yl)isobenzofuran1(3H)-one (7/)-1 -(5-((3 -(4-methyl1-oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-2yl)-1H-1,2,3-triazole4-carbonitrile (7/)-3-ethyl-1-(5-((3-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-2yl)-1H-pyrazole -4carbonitrile (7/)-3 -methoxy-1 -(5 ((3 -(4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyrimidin2-yl)-1H-pyrazole-4carbonitrile 405.00 445.10 406.3 416.2 443.2 446.2 B: 1.42, 100% A: 1.18, 100% XIV: 7.16, 98.10% e.i. B: 1.81, 100% A: 1.48, 100% XIV: 7.96, 98.66% e.i. C: 7.89, 98.69% G: 8.99, 98.54% XVIII: 20.31, 100% e.i. B: 1.24, 100% A: 0.99, 100% XIV: 7.96, 97.30% e.i. B: 1.67, 100% A: 1.25, 98.15% XIV: 7.78, 99.0% e.i. B: 1.17, 95.59% A: 0.97, 94.45% XVIII: 18.87, 97.5% e.i. 'H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.93 (br. s., 1 H), 2.15-2.22 (br, 1 H), 2.24 (s, 3H) 2.37 (s, 3 H), 2.80 (t , J= 12.47 Hz, 2 H), 2.96 (br. s., 1 H), 3.03 (br. s., 1 H), 3.57 - 3.71 (m, 2 H ), 4.17 (br. s., 1 H), 5.28 - 5.43 (m, 2 H), 7.67 (d, J= 7.34 Hz, 1 H), 7.78 ( d, J= 8.07 Hz, 1 H), 8.01 - 8.14 (m, 2 H), 8.49 (s, 1 H), 8.56 (s, 1 H). (He observed 1 exchangeable proton). ^X NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.85 (t, J = 10.52 Hz, 1 Η), 2.09 - 2.20 (m, 1 Η), 2.22 (s, 3 Η) 2.71 - 2.81 (m, 2 Η), 2.92 (d, J = 10.03 Hz, 1 Η), 2.96 - 3.03 (m, 1 Η), 3.51 - 3.66 (m, 2 Η), 4 .04 (m, 4 Η), 4.08 (d, J = 9.29 Hz, 1 Η), 5.36 (d, J = 1.22 Hz, 2 Η), 7.65 (d, J = 8.07 Hz, 1 Η), 7.73 - 7.83 (m, 1 Η), 7.95 - 8.02 (m, 1 Η), 8.39 (d, J = 1.96 Hz , 1 H), 9.21 (s, 1 H). (He observed 1 exchangeable proton). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.95 - 2.04 (w, 1 H), 2.17 (s, 3 H), 2.22 (s, 3 H), 2.23 2.36 (w, 1 H), 2.70 (d, J= 9.60 Hz, 1 H), 2.90 (d, J= 12.00 Hz, 1 H), 3.57 (s, 2 H), 3.65 - 3.77 (w , 1 N), 3.97 (d, J= 7.20 Hz, 1 N), 4.82 (d, J= 7.58 Hz, 1 N), 5.26 - 5.45 (br, 2 H), 7.61-7.68 (w, 3 H), 8.47 (dd, J= 8.31, 2.20 Hz, 1 H), 8.78 (s, 2 H). Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.95 - 1.84 (w, 1 H), 2.21-2.14 (w, 1 H), 2.24 (s, 3 H), 2.78 (t, J = 9.80 Hz , 2 H), 2.92 (d, J = 9.80 Hz, 1 H), 2.99 (s, 1 H), 3.61-3.73 (br, 2 H), 4.10 ( d, J = 10.50 Hz, 1 H), 5.43 - 5.29 (br, 2 H), 7.65 (d, J = 7.80 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.21 8.08 (br, 2 H), 8.57 (s, 1 H), 9.78 (s, 1 H), (no 1 capable of proton exchange). ^X NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.30 (t, J = 7.60 Hz, 3 Η), 1.85 (t, J = 10.30 Hz, 1 Η), 2.10 - 2.20 (m, 1 Η), 2, 22 (s, 3 Η), 2.70-2.85 (m, 4 Η), 2.94 - 2.85 (m, 1 Η), 3.06 - 2.95 (m, 1 Η), 3.60 (q, J= 13.50 Hz, 2 Η), 4.08 (d, J= 10.00 Hz, 1 Η), 5.24 -5.48 (m, 2 Η), 7, 64 (d, J = 7.80 Hz, 1 H), 7.77 (d, J= 8.10 Hz, 1 H), 7.90 (d, J= 8.30 Hz, 1 H), 7 .99 (dd, J= 8.40, 2.1 Hz, 1 Η), 8.41 (d, J = 2.00 Hz, 1 Η), 9.27 (s, 1 H), (not observed 1 exchangeable proton). ^X NMR (400 MHz, DMSO-t/ ₆ ) δ ppm 1.87 (t, J = 10.50 Hz, 1 N), 2.11-2.20 (br, 2 N), 2.212.30 (br, 3 N), 2.77 (t, J = 12 .30 Hz, 2 N), 2.84 2.94 (br, 1 N), 2.95 -3.06 (m, 1 N), 3.53 -3.74 (t, 2 N), 4 .03 (s, 3 N), 4.07 (d, J= 7.50 Hz, 1 N), 5.27 -5.50 (t, 2 N), 7.64 (d, J= 8, 00 Hz, 1 H), 7.78 (d, J = 8.00 Hz, 1 H), 8.80 (s, 2 H), 9.30 (s, 1 H).

- 208 043056

B: 1.24 'H NMR (400 MHz, DMSO-J ₆ ) δ ppm 9.34 (R)-3-ethyl-1-(5-((3-(4- 99.34% (s, 1 Η), 8.83 (s, 2 Η), 7.78 (d, J = 8.10 Hz, 1 Η), methyl-1-oxo-1,3- A: 1.04, 7.65 (d, J = 8.10 Hz, 1 Η), 5.47 - 5.26 (m, 2 Η), 228-1 1 dihydroisobenzofur 100% 4.11 (d, J = 9.30 Hz, 1 Η), 3.73 - 3.52 (m, 2 Η), n-5 -yl)piperazine-1 - 444.3 XVIII: 3.06 - 2.97 (m, 1 Η), 2.96 - 2.87 (m, 1 Η), 2.85 - Ύ yl)methyl)pyrimidine- 18.45, 2.71 (m, 4 Η), 2.24 (s, 3 Η), 2.22 - 2.12 (m, 1 Η), Me ^Z 2-yl)-1Н-pyrazole-4- 98.08% e.i. 1.90 (t, J = 10.30 Hz, 1 Η), 1.29 (t, J = 7.60 Hz, 3 carbonitrile H). (He observed 1 exchangeable proton). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.90 (R)-3 -(d iftoromethyl)- (t, J= 9.80 Hz, 1 Η), 2.09 - 2.22 (m, 1 Η), 2.24 (s, O 1 - (5 - ((3 - (4-methyl-1 - B: 1.25 3 H), 2.79 (t, J = 11.00 Hz, 2 H), 2.92 (d, J = 9.80 jfl___ oxo-1,3- 95.14% Hz, 1 Η), 2.96 -3.05 (m, 1 Η), 3.59 -3.76 (m, 2 Η), 229-1 dihydroisobenzofur 466.3 A: 1.02, 4.09 (d, J = 8.80 Hz, 1 Η), 5.21-5.48 (m, 2 Η), ^Ν h V CN X n-5 -yl)piperazine-1 - 96.07% 7.23-7.49 (t, J = 52.80 Hz, 1 H), 7.65 (d, J = 7.80 F yl)methyl)pyrimidine- XIV: 10.12, Hz, 1 H), 7.78 (d, J= 8.10 Hz, 1H), 8.90 (s, 2 H), 2-yl)-1Н-pyrazole-4- 98.00% e.i. 9.62 (s, 1 H), (not observed 1 capable of carbonitrile proton exchange), 1 ⁹ F NMR (400 MHz, DMSOde) δ ppm -114.59. (7?)-4-methyl-2-(4-((3 - B: 1.05 Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.91 ABOUT (4-methyl-1-oxo-1,3- 98.55% (s, 1 Η), 2.27 (s, 4 Η), 2.70 (s, 3 Η), 2.86 (br. s., 2 o ^z ζθ dihydroisobenzofur A: 0.76 H), 2.99 (s, 1 H), 3.08 (br. s., 1 H), 3.56 (br. s., 2 230-1 ίγ n-5 -yl)piperazine-1 - 430.2 97.72% H), 4.23 (br. s., 1 H), 5.22 -5.50 (m, 2 H), 7.68 (d, Μθ Χν yl)methyl)-1H- XVIII: J= 8.30 Hz, 1 H), 7.76 (d, J = 8.30 Hz, 1 H), 7.89 Me pyrazole-1- 18.27 (s, 1 H), 8.59 (s, 1 H), (9.20 (s, 1 H), (not yl)pyrimidine-5carbonitrile 99.00% e.i. 1 exchangeable proton was observed). (7?)-2-(4-((3 -(4-methyl- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.97 1-oxo-1,3- B: 1.45 -2.01 (m, 4 N), 2.34 (s, 4 N), 3.05 (d, J= 10.30 Hz, ABOUT dihydroisobenzofur 99.72% 2 H), 3.17 (s, 2 H), 3.40 (br. s., 1 H), 3.67 (br. s., 5 231-1 o ^z Ο τ n-5 -yl)piperazine-1 - A: 1.09, H), 4.72 (br.s., 1 H), 5.45 (d, J = 12.70 Hz, 2 H), Me HN^JU _N - yl)methyl)-1H- 484.3 100% 7.03(s, 1H), 7.69-7.76(m, 1H), 7.79(s, 1H), Χό pyrazol-1-yl)-5- XVIII: 7.85 (d, J= 7.80 Hz, 1 H), 8.41 (s, 1 H), 8.53 (s, 1 CN (pyrrolidine-1- 15.10, H), 8.88 (s, 1 H), 9.33 (s, 1 H). yl) isonicotinonitri l 100% e.i.

- 209 043056

232-1 0 A AZ+me Λ 4-methyl-6-(4-((3 -(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)-4oxopiperidin-1 yl)methyl)-1Hpyrazol-1yl)nicotinonitrile 442.2 R: 1.34, 62.00% S: 1.86, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.15 (s, 3 Η), 2.35 (d, J= 14.43 Hz, 1 Η), 2.58 (s, 3 Η), 2.62 - 2.71 (m, 2 Η) , 2.73 - 2.89 (m, 1 H), 3.20 (br. s., 2 H), 3.75 (s, 2 H), 4.27 (dd, J= 11.37, 5.50 Hz, 1 H), 5.30 - 5.44 (m, 2 H), 7.42 (d, J= 8.07 Hz, 1 H), 7.62 (d, J = 7, 58 Hz, 1 H), 7.93 (s, 1 H), 7.99 (s, 1 H), 8.62 (s, 1 H), 8.84 (s, 1 H). 233-1 C% X (I)-b-(3(difluoromethyl)-4-((3(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)- 4methylnicotinonitrile l 479.1 R: 1.59, 99.30% S: 1.94, 98.00% XVIII: 10.70, 100% e.i. ^NMR (400 MHz, DMSO-t/b) δ ppm 1.89 (br. s., 1 H), 2.19 (br. s., 1 H), 2.24 (s, 3 H), 2.60 (s, 3 H), 2.76 - 2.89 (m, 2 H), 2.94 (br. s., 1 H), 3.03 (br. s., 1 H), 3.51 - 3.67 (m, 2 H), 4.12 (br. s., 1 H), 5.36 (d, J= 3.18 Hz, 2 H), 7.08 - 7.39 (m, 1 H), 7.66 (d, J= 7.58 Hz, 1 H), 7.77 (d, J= 7.83 Hz, 1 H), 8.02 (s, 1 H), 8.66 (s, 1 H), 8, 89(s, 1H). (He observed 1 exchangeable proton). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm -114.2. 234-1 ο to Me ΗΝ^ ^ _ν Α _ν ,Ν α _ν > (R)-5-(4-((2-(1H-1, 2,4triazol-1yl)pyrimidin-5yl)methyl)piperazin2-yl)-4methylisobenzofuran1(3H)-one 392.1 R: 0.93, 97.00% S: 1.06, 93.50% XIV: 7.53, 100% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.86 - 1.95 (w, 1 H), 2.13 - 2.22 (w, 1 H), 2.25 (s, 3 H), 2.64 - 2.84 (w, 2 H ), 2.86 - 3.05 (w, 2 H), 3.65 (d, J= 8.07 Hz, 2 H), 4.09 (d, J= 8.31 Hz, 1 H), 5.36 (d, J= 4.40 Hz, 2 N), 7.65 (d, J= 7.83 Hz, 1 N), 7.78 (d, J= 7.58 Hz, 1 N) , 8.32 (s, 1 H), 8.87 (s, 2 H), 9.43 (s, 1 H). (No 1 exchangeable proton was observed). 235-1 ο _F F (^).5.(4-((6-(4 (difluoromethyl)-1nimidazol-1yl)pyridin-3 yl)methyl)piperazin2-yl)-4methylisobenzofuran1(3H)-one 440.1 R: 1.19, 95.40% S: 1.45, 98.40% XIV: 6.79, 88.00% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.79 - 1.90 (w, 1 H), 2.09 - 2.19 (w, 1 H), 2.23 (s, 3 H), 2.72 - 2.80 (w, 2 H ), 2.86 - 2.93 (w, 1 H), 2.94 - 3.03 (w, 1 H), 3.49 - 3.53 (w, 2 H), 4.07 (d, J= 7.58 Hz, 1 N), 5.36 (s, 2 N), 6.82 - 7.14 (br, 1 N), 7.64 (d, J= 7.83 Hz, 1 N ), 7.78 (d, J= 8.07 Hz, 1 H), 7.86 (d, J= 8.07 Hz, 1 H), 7.97 (dd, J= 8.31, 2, 20 Hz, 1 H), 8.29 (s, 1 H), 8.44 (d, J= 1.71 Hz, 1 H), 8.62 (s, 1 H). (No 1 exchangeable proton was observed). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm - 112.0.

- 210 043056

236-1 O to Me HN^J k _N A _N ^F _F (7/)-4-methyl-5-(4-((2(4-(trifluoromethyl)1H-imidazol-1yl)pyrimidin-5yl)methyl)piperazin2-yl)isobenzofuran1(3H)-one 459.1 A: 1.34, 96.60% B: 1.65, 97.40% XIV: 6.82, 97.00% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.94 (br. s., 1 H), 2.21 (br. s., 1 H), 2.25 (s, 3 H), 2.82 (br. s., 2 H), 2 .91 - 3.08 (t, 2 N), 3.66 (d, J = 5.87 Hz, 2 N), 4.13 (br. s., 1 N), 5.37 (d, J = 6.36 Hz, 2 N), 7.67 (d, 7 = 8.31 Hz, 1 N), 7.78 (d, 7 = 8.07 Hz, 1 N), 8.52 (s, 1 H), 8.76 (s, 1 H), 8.86 (s, 2 H). (No 1 exchangeable proton was observed). ¹⁹ F NMR (400 MHz, DMSO-Tb) δ ppm - 61.7. 237-1 ^N ^~Meλ (//)-6-(3cyclopropyl-4-((3-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitrile l 469.1 R: 1.57, 97.90% S: 2.03, 98.00% XVII: 8.49, 100% e.i. Ή NMR (400 MHz, DMSO-76) δ ppm 0.89 - 0.99 (br, 4 N), 1.84 (t, 7= 10.03 Hz, 1 N), 2.05 - 2.19 (w, 2 H), 2.25 (s, 3 H), 2.54 (s, 3 H), 2.76 - 2.95 (w, 3 N), 3.01 (d, 7= 12.23 Hz, 1 N), 3.54 (d, 7= 9.78 Hz, 2 N), 4.08 (d, 7= 8.07 Hz, 1 H), 5.36 (s, 2 H), 7.64 (d, 7 = 8.07 Hz, 1 H), 7.74 7.83 (br, 2 H), 8.39 (s, 1 H), 8.76 (s, 1 H). (No 1 exchangeable proton was observed). 238-1 * toL 00° o G-methyl-5-(((35, 57/)3 -methyl-5 -(4-methyl-1 oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-[2,3' bipyridine]-6'(GN)-one 445.2 R: 0.46, 100% S: 1.02, 96.10% Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.15 - 1.24 (w, 3 H), 2.20 - 2.24 (w, 4 H), 2.52 - 2.55 (w, 2 H), 2.96 (br. s. , 3 H), 3.54 (s, 3 H), 3.68 (br. s., 2 H), 5.54-5.31 (br. 2 H), 6.50 (d, 7= 9.30 Hz, 1 H), 7.79 (s, 4 H), 8.16 (dd, 7= 9.40, 2.60 Hz, 1 H), (8.53 (d, 7= 2 .70 Hz, 2 N) (No 1 exchangeable proton observed). 239-1 240-1 241-1 0 to. / O^^ipN H _N y Ο _N - ^N ^V ^Me 4 0 o^toll^ N o Me HN^ N 'Y-Me CN (7/)-4-methyl-6-(4-((3 (1-oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1yl)nicotinonitrile 4-methyl-6-(4-(((67/)-2methyl-6-(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5- yl)morpholino)methyl) -1 H-pyrazol-1yl)nicotinonitrile (Diastereomer I) (7/)-3-methyl-1-(6-((3(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyridin-3 yl)-1 n-pyrazole-4carbonitrile 415.2 444.2 429.1 R: 0.93, 95.50% S: 1.23, 95.40% R: 1.16, 100% S:l.78, 94.30% XVIII: 14.40, 98.00% e.i. R: 0.94, 98.10% S: 1.18, 94.30% Ή NMR (400 MHz, DMSO-7 ₆ ) δ ppm 1.83-1.97 (w, 1 H), 2.06-2.18 (w, 1 H), 2.58 (s, 3 H), 2.75-2.92 (w, 3 H ), 3.00 (d, 7= 10.5 Hz, 1 H), 3.53 (s, 2 H), 3.96 (d, 7= 8.6 Hz, 1 H), 5.37 (s , 2 H), 7.61 (d, 7= 8.10 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, 7= 7.80 Hz, 1 H), 7 .84 (s, 1 H), 7.98 (s, 1 H), 8.53 (s, 1 H), 8.83 (s, 1 H). (No 1 exchangeable proton was observed). Ή NMR (400 MHz, DMS0-7,) δ ppm 1.17 (d, 7 = 6.10 Hz, 3 H), 1.86 (br. s., 2 Η), 2.24 (s, 3 Η), 2.58 (s, 3 Η), 2.88 (d, 7= 11.50 Hz, 2 H), 3.56 (br. s., 2 H), 3.84 (br. s., 1 H), 4.87 (d, 7 = 10.00 Hz, 1 H), 5.49 - 5.26 (m, 2 H), 7.61 (d, 7= 8.10 Hz, 1 H), 7.68 (d, 7= 7 .80 Hz, 1 H), 7.87 (s, 1 H), 7.99 (s, 1 H), 8.55 (br. s., 1 H), 8.83 (s, 1 H) . Ή NMR (400 MHz, DMSO-Tb) δ ppm 2.34 (s, 3 H), 2.41 (s, 3 H), 2.60 (d, 7= 13.00 Hz, 2 H), 3.09 (d, 7= 12.50 Hz, 2 H), 3.42 (br. s., 2 H), 3.89 (br. s., 2 H), 4.78 (br. s., 1 H), 5.54 - 5.34 (m, 2 H), 7.67 (d, 7= 8.30 Hz, 1 H), 7.76 (d, 7= 8.10 Hz, 1 H), 7.85 (d, 7= 8 .10 Hz, 1 H), 8.24 (dd, 7= 8.60, 2.4 Hz, 1 H), 9.01 (d, 7= 2.20 Hz, 2 H), 9.29 ( s, 1H).

- 211 043056

242-1 φ Ξ Ύωχ υ^° ο (/?)-4-methyl-1 -(5-((3 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)pyridin-2yl)-1 H- pyrazole-3 carbonitrile 429.1 R: 1.54, 97.80% S: 1.89, 95.10% XVIII: 14.07, 100% e.i. ^NMR (400 MHz, DMSO-Y) δ ppm 1.85 (t, J = 9.66 Hz, 1 Η), 2.11 - 2.19 (m, 1 Η), 2.23 (d, J = 4.16 Hz, 6 Η), 2, 71 - 2.82 (m, 2 Η), 2.90 (t, J = 11.37 Hz, 1 Η), 2.99 (d, J = 11.00 Hz, 1 Η), 3.54 - 3.68 (m, 2 Η), 4.08 (d, J = 7.34 Hz, 1 Η), 5.36 (s, 2 Η), 7.64 (d, J = 8.07 Hz, 1 Η), 7.78 (d, J= 8.07 Hz, 1 Η), 7.91 - 7.96 (m, 1 Η), 7.98 - 8.03 (m, 1 Η), 8 .43 (s, 1 H), 8.69 (s, 1 H). (He observed 1 exchangeable proton). 243-1 ο ' Ι^Ν^γ^Ν Me ΗΝ^ Me (7?) -4-methyl-1 - (5- ((3 (4-methyl-1 -oxo-1,3 dihydroisobenzofur n-5 -yl) piperazin-1 yl) methyl) pyrimidin2-yl) -1 H- pyrazole-3 carbonitrile 431.0 R: 1.00, 98.90% S: 1.24, 99.30% XVIII: 9.09, 100% e.i. Ή NMR (400 MHz, DMSO-Y) δ ppm 1.97 - 1.82 (w, 1 H), 2.13 - 2.21 (w, 1 H), 2.22 - 2.29 (w, 6 H), 2.80 (t, J= 11.60 Hz, 2 N), 2.88 - 2.96 (br, 1 N), 2.97 - 3.05 (br, 1 N), 3.55 - 3.74 (br, 2 N) , 4.10 (d, J = 8.60 Hz, 1 H), 5.26 - 5.48 (br, 2 H), 7.65 (d, J = 8.10 Hz, 1 H), 7 .78 (d, J= 8.10 Hz, 1 H), 8.72 (d, J= 0.70 Hz, 1 H), 8.86 (s, 2 H), (no exchangeable proton). 244-Π 245-1 0 °^СХ ^MeHN ^Me + tb λ 0 Yxb N^VA 4-methyl-6-(4-((2methyl-5 -(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1yl)nicotinonitrile (Enantiomer-P) 6-(3 -(d iftoromethyl)-4(((37?,47?)-4-hydroxy- 3 - (4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-1Hpyrazol-1-yl)-4methylnicotinonitri l 443.2 494.2 R: 1.35, 100% S: 1.73, 100% XVIII: 9.09, 100% e.i. R: 1.18, 100% S: 1.71, 98.90% XXVI: 4.36, 100% e.i. ^Χ ΗΠΜΡ (400 MHz, DMSO-J ₆ ) δ ppm 1.32 (d, J = 6.10 Hz, 3 Η), 2.30 - 2.33 (m, 3 Η), 2.58 (s, 3 Η), 2.79 (br. s., 1 H), 3.06 - 3.15 (m, 3 H), 3.89 (d, J= 14.40 Hz, 2 H), 3.99 (d, J= 14.90 Hz, 1 H ), 4.70 (d, J= 8.80 Hz, 1 H), 5.50 - 5.39 (m, 2 H), 7.66 (d, J= 8.10 Hz, 1 H), 7.83 (d, J= 8.10 Hz, 1 H), 7.91 (s, 1 H), 8.00 (s, 1 H), 8.65 (s, 1 H), 8.84 (s, 1 H), (1 exchangeable proton was not observed). 'H NMR (400 MHz, DMSO-Ts) δ ppm 1.64 (d, J= 9.30 Hz, 1 H), 1.92 (br. s., 1 H), 2.00 2.12 (m, 1 H), 2.23 (s, 4 Η), 2.55 (s, 3 Η), 2.58 2.66 (m, 1 Η), 2.72 (d, J= 11.70 Hz, 1 Η), 2.95 (d, 7 \u003d 10.30 Hz, 1 Η), 3.01 - 3.14 (m, 1 Η), 3.46 - 3.67 (m, 2 Η), 3.75 (br. s., 1 Η) , 4.60 (d, J= 5.40 Hz, 1 Η), 5.48 - 5.24 (m, 2 Η), 7.54 (d, J= 7.60 Hz, 1 Η), 7 .63 (d, J = 8.30 Hz, 1 Η), 8.02 (s, 1 Η), 8.65 (s, 1 Η), 8.90 (s, 1 H). ¹⁹ F NMR (400 MHz, DMSO-Tb) δ ppm - 114.00

- 212 043056

246-1 HO £ \___. *Άθ A 6-(4-(((35.57D-4hydroxy-3-methyl-5 (4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2H-1,2 ,3triazol-2-yl)-4methylnicotinonitrile 460.3 R: 0.76, 97.20% S: 1.30, 93.30% XXV: 15.22, 98.00% e.i. 'H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.20 - 1.11 (w, 3 H), 2.26 (s, 3 H), 2.30 - 2.33 (w, 1 H) 2.55 - 2.66 (w, 4 H) , 2.74 (s, 1 H), 2.80 (br. s., 1 H), 4.25 (br. s., 3 H), 5.31-5.49 (m, 2 H) , 7.72 (d, J= 8.10 Hz, 1 H), 7.80 (d, J= 7.80 Hz, 1 H), 7.96 - 8.22 (m, 2 H), 8 .33 (s, 1 H), 8.92 - 9.05 (m, 1 H), (1 exchangeable proton was not observed). 247-1 Me Mx/hL ξ Y ii I Me 0 4'-methyl-4-(((35.57?)3 -methyl-5 -(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2-oxo-2H[1,2'-bipyridine]-5'carbonitrile 470.2 R: 1.18, 96.30% S: 1.52, 100% XIV: 3.45, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.04 (d, J= 6.10 Hz, 3 H), 2.32 - 2.25 (w, 3 H), 2.58 (s, 3 H), 2.75 - 2.72 (w , 1 H), 2.79 (d, J= 11.50 Hz, 2 H), 2.90 (s, 1 H), 3.01 (br. s., 1 H), 3.42 (s , 2 Η), 4.20 (d, J= 10.30 Hz, 1 Η), 5.39 (s, 2 Η), 6.51 6.39 (m, 2 Η), 7.67 (d , J= 7.80 Hz, 1 H), 7.82 (d, J= 8.10 Hz, 1 H), 7.91 (d, J= 7.30 Hz, 1 H), 8.01 ( s, 1 H), 8.99 (s, 1 H), (1 exchangeable proton was not observed). 248-1 O Άι Me % _N - HN \ _O Ame ZV _Me CN Ν-(1-((1-(5-cyano-4methylpyridin-2-yl)1H-pyrazol-4yl)methyl)-3-(4-methyl1-oxo-1,3dihydroisobenzofura n-5-yl)piperidin-4yl )acetamide (Diastereomer II Enantiomer-1) 485.3 S: 1.28, 100% R: 0.94, 100% XXV: 4.99, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.56 (s, 3 H), 1.65 - 1.57 (w, 1 H), 1.98 - 1.79 (w, 2 H), 2.18 (t, J = 11.70 Hz , 1 H), 2.24 (s, 3 H), 2.56 (s, 3 H), 2.98 - 2.85 (br, 2 H), 3.22 - 3.13 (br, 2 H), 4.13 - 4.04 (w, 1 H), 4.17 (d, J = 4.60 Hz, 1 H), 5.42 - 5.23 (w, 2 H), 7, 39 (d, J= 7.80 Hz, 1 H), 7.57 (d, J= 7.80 Hz, 1 H), 7.69 (d, J= 8.80 Hz, 1 H), 7 .83 (s, 1 H), 7.95 (s, 1 H), 8.50 (s, 1 H), 8.80 (s, 1 H). 249-1 Oh Me ΗΝ^Χ % _Ν ' Ye ζ^Ο 3-(6-(4-(((35.5R)-3methyl-5-(4-methyl-1 oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol-1yl)pyridine -2yl)oxazolidin-2-one 489.3 S: 1.41, 93.18% R: 1.01, 94.16% VIII: 5.38, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, E = 6.10 Hz, 3 H), 1.72-1.75 (br. 2 H), 2.31 (s, 3 H), 2.80 (br. s., 2 H), 2.98 (br. s., 1 H), 3.50 3.48 (m., 2 H), 4.17 (d, J= 9.80 Hz, 1 H), 4, 39 4.23 (m, 2 Η), 4.61 - 4.39 (m, 2 Η), 5.38 (s, 2 Η), 7.59 (dd, J = 7.10, 1.70 Hz, 1 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.74 (s, 1 H), 7.81 (d, J = 8.10 Hz, 1 H), 8.09 - 7.91 (m, 2 H), 8.47 (s, 1 H), (1 exchangeable proton was not observed).

- 213 043056

250-1 O । ΠΎ>° QCN 6-(4-(((3R,4R)-4hydroxy-3 -(4-methyl1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-1 yl)methyl)-3-methyl-2oxo-2,3 -dihydro-1Nimide azol-1-yl)-4methylnicotinonitrile 474.4 S: 1.44, 100% R: 0.95, 100% VIII: 5.92, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.25 (s, 2 Η), 1.69 - 1.54 (m, 1 Η), 2.03 - 1.87 (m, 1 Η), 2.11 (t, J= 11.40 Hz , 1 Η), 2.31 - 2.16 (m, 4 Η), 2.78 (d, J = 11.00 Hz, 1 Η), 2.97 (d, J = 12.50 Hz, 1 Η), 3.05 (td, 7 = 10.40, 3.40 Hz, 1 Η), 3.29 (s, 3 Η), 3.50 - 3.36 (m, 2 Η), 3, 81 - 3.70 (m, 1 Η), 4.60 (d, J= 5.40 Hz, 1 Η), 5.45 - 5.24 (m, 2 Η), 7.26 (s, 1 Η), 7.55 (d, J = 7.80 Hz, 1 Η), 7.64 (d, J= 7.80 Hz, 1 Η), 8.44 (s, 1 Η), 8.76 (s, 1 H), (1 exchangeable proton was not observed). 251-1 ABOUT Me HN^y Y' b-ΓΊ 3-(2-methyl-6-(4- (((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)-1Hpyrazol-1yl)pyridin-4yl)oxazolidin- 2nd 503.2 S: 1.39, 100% R: 0.95, 100% XV: 4.95, 100% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.04 (d, J = 4.40 Hz, 3 H), 1.73 (br. s., 2 H), 2.27 (s, 3 H), 2.48 (s, 4 H), 2.81 (d, J = 9.00 Hz, 2 H), 2.98 (br. s., 1 H), 3.52 (br. s., 2 H), 4.26 - 4.03 (m, 3 H), 4.57 - 4.44 (m, 2 H), 5.38 (s, 2 H), 7.27 (d, J= 1.70 Hz, 1 H), 7, 66 (d, J= 8.10 Hz, 1 H), 7.72 (s, 1 H), 7.80 (d, J= 8.10 Hz, 1 H), 8.06 (s, 1 H ), 8.45 (s, 1H). 252-1 0 toO/, Me ΗΝ0 % _N ' Me Me—N _O X° ^u Me T4-methyl-M-(6-(4(((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl) -111pyrazol-1yl)pyridin-2yl)methanesu l f onami d 511.3 S: 1.42, 97.31% R: 1.00, 97.44% XV: 3.94, 98.52% e.i. Ή NMR (400 MHz, DMSO-7 ₆ ) δ ppm 1.03 (d, J = 6.10 Hz, 3 H), 1.73 (br. s., 2 H), 2.26 (s, 3 H), 2.74 (s, 1 H), 2.82 (d, J = 9.80 Hz, 2 H), 2.97 (br. s., 1 H), 3.26 - 3.22 (m, 3 H), 3.38 (s, 3 H), 3.55 - 3.46 (m, 2 H), 4.17 (d, J= 8.60 Hz, 1 H), 5.44 - 5.29 (m, 2 H), 7 .33 (d, J= 7.80 Hz, 1 H), 7.70 - 7.60 (m, 2 H), 7.76 (s, 1 H), 7.81 (d, 7= 8, 10 Hz, 1 H), 8.04 -7.95 (m, 1 H), 8.44 (s, 1 H). 253-1 to 5-((2I,65)-4-((1-(4(1,1- dioxydoisothiazolide in-2-yl)-6methylpyridin-2-yl)1H-pyrazol-4yl)methyl)-6methylpiperazin-2yl)-4- methylisobenzofuran1(3N)-one 537.3 S: 1.41, 96.07% R: 0.99, 97.18% XVII: 8.82, 100% e.i. 'H NMR (400 MHz, DMSO-Tb) δ ppm 1.03 (d, J = 6.40 Hz, 3 Η), 1.24-1.20 (s, 2 Η), 1.71 (t, J = 10.10 Hz, 2 Η), 2, 48 - 2.40 (m, 6 Η), 2.80 (d, J = 10.80 Hz, 2 Η), 2.97 (br. s., 1 H), 3.56 - 3.44 ( m, 2 H), 3.64 (t, J = 7.20 Hz, 2 H), 3.86 (t, J = 6.60 Hz, 2 H), 4.16 (d, J= 8, 80 Hz, 1 H), 5.38 (s, 2 H), 6.87 (d, J= 1.70 Hz, 1 H), 7.52 (d, J = 1.70 Hz, 1 H) , 7.64 (d, J = 8.10 Hz, 1 H), 7.70 (s, 1 H), 7.80 (d, J = 8.10 Hz, 1 H), 8.42 (s , 1 H), (1 exchangeable proton was not observed).

- 214 043056

254-1 0 Me ΗΝ^/ ¹ + _Ν ^Ζ Me GU \ %OMe 1 -(2-methoxypyridin4-yl)-4-(((35.57/)-3methyl-5 -(4-methyl-1 oxo-1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)pyrrolidin-2-one (Diastereomer I) 451.3 S: 1.23, 100% R: 0.47, 100% XXV: 7.16, 97.00% e.i. Ή NMR (400 MHz, DMSO-X) δ ppm 1.09 (d, J = 4.40 Hz, 3 Η), 1.73 (q, J = 10.60 Hz, 2 Η), 2.31 (s, 3 Η), 2.43 - 2, 32 (m, 3 Η), 2.75 - 2.59 (m, 2 Η), 2.81 (t, J= 11.50 Hz, 2 Η), 2.96 (br. s., 1 H ), 3.55 (dd, J= 9.80, 5.60 Hz, 1 H), 3.87 - 3.77 (m, 3 H), 3.92 (dd, J = 9.70, 7 .70 Hz, 1 H), 4.15 (d, J = 8.60 Hz, 1 H), 5.48 - 5.30 (m, 2 H), 7.05 (d, J = 1.50 Hz, 1 H), 7.36 (dd, J= 6.00, 1.80 Hz, 1 H), 7.66 (d, J= 7.80 Hz, 1 H), 7.82 (d, J= 7.80 Hz, 1 H), 8.08 (d, J= 5.90 Hz, 1 H), (1 exchangeable proton was not observed). 255-1 O TI 1 YN Me HN^> + _N 'OMe (7/)-4-methoxy-6-(4((3 -(4-methyl-1 -oxo1,3- dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)- 1H-1,2,3triazol-1yl)nicotinonitrile 446.2 G: 12.33, 99.40% E: 10.51, 98.80% XVIII: 20.06, 100% e.i. ¹ II NMR (400 MHz, DMSO-Jr,) δ ppm 1.84 - 1.94 (m, 1 Η), 2.13 - 2.22 (m, 1 Η), 2.26 (s, 3 Η), 2.78 - 2.92 (m, 3 Η ), 2.93 - 3.01 (m, 1 Η), 3.74 (s, 2 Η), 4.03 - 4.09 (m, 1 Η), 4.16 (s, 3 Η), 5.37 (s, 2 H), 7.64 (d, J= 8.03 Hz, 1 H), 7.76 (d, J= 8.03 Hz, 1 H), 7.88 (s, 1 H), 8.77 (s, 1 H), 8.88 (s, 1 H), (1 exchangeable proton was not observed). 256-Π O °^Cl^ Me θΧ^ ¹¹ Lu _M . CN 6-(4-((2,2-dimethyl-6(4-methyl-1-oxo-1,3dihydroisobenzofur n-5- yl)morpholino)methyl) -1 H-pyrazol-1 -yl)-4methylnicotinonitrile (Enantiomer-P) 458.0 G: 14.03, 95.39% C: 12.55, 95.71% XIII: 3.82, 95.27% e.i. ^NMR (300 MHz, DMSO-t/b) δ ppm 1.20 (s, 3 H), 1.41 (s, 3 H), 1.67 - 1.77 (w, 1 H), 1.87 1.93 (w, 1 H), 2.26 (s, 3H), 2.60(s, 3H), 2.692.72(br, 1H), 2.93-2.96(br, 1H), 3.42-3.67(br , 2 H), 5.08 (d, J= 8.69 Hz, 1 H), 5.38 (s, 2 H), 7.64 (q, J= 7.93 Hz, 2 H), 7 .87 (d, J= 2.40 Hz 1 N), 7.99 (s, 1 N), 8.55 (d, J= 2.40 Hz 1 N), 8.84 (s, 1 N) . 257-1 0 /X1^ .,..,. ^NHACQM . CN N-(1-((1-(5-cyano-4methylpyridin-2-yl)1H-pyrazol-4yl)methyl)- 5-(4-methyl1-oxo-1,3dihydroisobenzofura n-5-yl)piper idin- 3 yl)acetamide (Enantiomer-1) 485.1 R: 1.08, 100% S: 1.43, 100% XXI: 2.38, 100% e.i. Ή NMR (400 MHz, DMSO-db) δ ppm 1.47 - 1.37 (w, 1 H), 1.79 (s, 3 H), 1.88 (d, J= 12.00 Hz, 1 H), 1.98 (t, J= 10 .90 Hz, 1 H), 2.26 (s, 3 H), 2.59 (s, 3 H), 2.86 (d, J= 11.00 Hz, 1 H), 3.02 (br s., 1 H), 3.21 (s, 1 H), 3.61 (s, 2 H), 3.93 (s, 1 H), 5.38 (s, 2 H), 7, 42 (d, J= 8.10 Hz, 1 H), 7.66 (d, J= 8.30 Hz, 1 H), 7.81 (d, J= 7.60 Hz, 1 H), 7 .87 (s, 1 H), 8.00 (s, 1 H), 8.55 (s, 1 H), 8.84 (s, 1 H), (1 exchangeable proton not observed).

- 215 043056

258-1 0 o ^z χχ γ^γ^Ν^ Me 1 J cXnh Me Y^ ^N 2^Me CN 1-((1-(5-cyano-4methylpyridin-2-yl)1H-pyrazol-4yl)methyl)-3 -(4-methyl1-oxo-1,3dihydroisobenzofur n-5-yl)piperidin-4ylmethylcarbamate (Enantiomer- 1) 501.5 R: 1.10, 95.00% S: 1.55, 96.00% XXII: 6.23, 94.05% e.i. 'H NMR (400 MHz, DMSO-Tb) δ ppm 1.66 (d, J = 11.70 Hz, 1 N), 2.20 - 1.99 (m, 2 N), 2.33 2.23 (t, 4 N), 2.42 (d, J = 4.60 Hz, 3 N), 2.58 (s, 3 N), 2.84 (d, J= 9.50 Hz, 1 N), 2.97 (d, J= 11.00 Hz , 1 H), 3.50 -3.68 (t, 2 H), 5.00 - 4.75 (t, 1 H), 5.36 (s, 2 H), 6.73 (d, J = 4.40 Hz, 1 H), 7.52 (d, J = 7.80 Hz, 1 H), 7.64 (d, J = 8.10 Hz, 1 H), 7.87 (s, 1 H), 7.99 (s, 1 H), 8.54 (s, 1 H), 8.83 (s, 1 H), (1 exchangeable proton not observed). 4-methyl-6-(3- 'H NMR (400 MHz, DMSO-c/r,) δ ppm 1.12 259-1 0 ABOUT Me HN^X Me G'o N=/ Xxme CN (((3 S, 5R) -3 -methyl-5 (4-methyl-1 -oxo-1,3dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl) -1,2,4- 445.2 R: 1.05, 100% S: 1.35, 99.10% - 0.93 (t, 3 N), 1.94 (dt, J= 17.20, 10.40 Hz, 2 N), 2.23 -2.34 (t, 3 N), 2.68 - 2.60 (t, 3 N), 2.88 (t, J= 12.00 Hz, 2 N), 3.05 - 2.93 (t, 1 N), 3.84 (s, 2 N) , 4.17 (d, J = 8.10 Hz, 1 N), 5.47 - 5.32 (t, 2 N), 7.66 (d, J = 7.80 Hz, 1 N), 7 .80 (d, J= 8.10 Hz, oxadiazole-5- 1 H), 8.40 (s, 1 H), 8.74 (br. s., 1 H), 9.15 (s, 1 H). yl) nicotinonitrile (7?)-1-(5-cyano-4- I! NMR (400 MHz, DMSO-Tb) δ ppm 1.95 260-1 0 o ^z Me HN^J CONHMe T> ^N ^N ^^~0Me CN methoxypyridin-2yl)-X-methyl-4-((3-(4methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazole-3carboxamide 502.2 R: 0.94, 100% S: 1.22, 98.74% XIV: 9.16, 98.74% e.i. (br. s., 1 H), 2.21 (br. s., 1 H), 2.27 (s, 4 H), 2.96 2.77 (t, 6 H), 3.04 ( br. s., 1 H), 3.76 (br. s., 2 H), 4.14 (s, 3 H), 5.42-5.33 (m, 2 H), 7.67 ( d, J= 7.30 Hz, 1 H), 7.73 (s, 1 H), 7.77 (d, J= 8.30 Hz, 1 H), 8.60 (s, 1 H), 8.78 (s, 1 H), 9.17 (br. s., 1 H), (1 exchangeable proton not observed). 6-(4-((3- I! NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.64 (hydroxymethyl)-5-(4- - 1.45 (t, 1 N), 1.78 (d, J = 12.20 Hz, 1 N), 2.14 methyl-1-oxo-1,3- R: 1.08 (br. s., 1 H), 2.28 (s, 3 H), 2.59 - 2.54 (t, 1 H), 261-II O dihydroisobenzofur 100% 2.61 (s, 3 H), 3.1 l (d, J = 7.60 Hz, 1 H), 3.37-3.28 o ^z XX n-5 -yl)piperidine-1 - 458.2 S: 1.44 (t, 2 N), 3.56 - 3.46 (t, 1 N), 3.37-3.43 (t, 2 N), Me LJ Specification tx CN yl)methyl)-1H- 100% 4.39 (br. s., 2 H), 4.88 (br. s., 1 H), 5.41 (s, 2 H), ΌΗ pyrazol-1-yl)-4methylnicotinonitrile (Diastereomer II: Enantiomer-P) XXVII: 4.90, 100% e.i. 7.53 (d, J= 8.10 Hz, 1 Η), 7.73 (d, J= 8.10 Hz, 1 Η), 8.06 (s, 2 Η), 9.01 - 8, 86 (m, 2 Η).

- 216 043056

262-1 0 Me HN^J conh ₂ (7?)-1-(5-cyano-4methoxypyridin-2yl)-4-((3 -(4-methyl-1 oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-1Hpyrazol- 3carboxamide 488.2 R: 0.86, 100% S: 1.13, 100% XIV: 9.31, 100% e.i. Ή NMR (400 MHz, DMSO-J6) δ ppm 2.34 (s, 4 H), 2.93 (dd, J= 12.20, 6.40 Hz, 1 H), 3.11 (d, J= 11.70 Hz, 2 H), 3. 97 (br. s., 2H), 4.13 (s, 3 Η), 4.74 (br. s., 1 Η), 5.57-5.28 (m, 2 Η), 7.56 (br. s., 1 H), 7.72 (d, J = 8.10 Hz, 1 H), 7.83 (d, J = 7.80 Hz, 1 H), 7.89 (s, 1 H), 8.11 (br. s., 1 H), 8.65 (br. s., 1 H), 8.79 (s, 1 H), 8.87 (br. s., 1 H), 9.37 (br. s., 1 H), (1 exchangeable proton not observed). 4 c -OMe N (7?)-4-(methoxy-b3)-6- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.91 263-1 O ABOUT Me HN^J ,N o HA Cl ~OCD ₃ 1 (4-((3-(4-methyl-1oxo-1,3- dihydroisobenzofur n-5 -yl)piperazin-1 yl)methyl)- 1H-1,2,3- 449.2 R: 0.95, 100%, S: 1.3, 98.70% (s, 1 H), 2.27 (s, 3 H), 2.45 (br. s., 1 H), 2.86 (br. s., 3 H), 3.00 (br. s ., 1 H), 3.76 (s, 2 H), 4.12 (br. s., 1 H), 5.44 - 5.31 (m, 2 H), 7.66 (d, J = 8.10 Hz, 1 H), 7.76 (d, J= 8.30 Hz, 1 H), 7.88 (s, 1 H), 8.78 (s, 1 H), 8.88 (s, 1 H), (not observed 1 triazole-1- capable of proton exchange). yl) nicotinonitrile — ¹ NMR(400MHz,OM8O-b/b)b ppm 1.99 264-1 About £ (7?)-4-methyl-5-(4-((6- (3-methyl-1,2,4- oxadiazole-5- 406.2 R: 0.85, 98.08% S: 1.07, 100% (br. S., 1 H), 2.25 (s, 4 H), 2.45 (s, 3 H), 2.81 (t, J = 12.80 Hz, 2 H), 3.11 -2.95 (br.s., 2H), 3.63-3.78 - (br.s., 2H), 4.20 (br.s., 1H), 5.44 - 5.30 (br.s., 2 H), Me HN^> 4 A N % 1 11.N H Me yl) pyridin-3 yl) methyl) piperazine- 7.68 (d, J= 7.60 Hz, 1 N), 7.78 (d, J= 8.10 Hz, 1 H), 8.03 (dd, J= 8.10, 2.00 Hz, 1 H), 8.20 (d, J= 2-yl)isobenzofuran- 8.10 Hz, 1 N), 8.75 (d, J = 1.50 Hz, 1 N), (not 1(ZN)-on 1 exchangeable proton was observed). 265-1 ABOUT WITH) ABOUT Me Me YN ⁿ ~n /Z V-me CN 2-methyl-4-(5(((35.57?)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur n-5-yl)piperazin-1 yl)methyl)-2Htetrazol- 2- 444.2 R: 1.23, 97.88% S: 1.63, 100% VIII: 4.75, 98.84% e.i. Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, J = 5.90 Hz, 3 Η), 2.00 - 1.78 (m, 2 Η), 2.32 2.21 (m, 3 Η), 2.66 - 2, 56 (m, 3 Η), 3.05 - 2.79 (m, 3 Η), 4.04 - 3.86 (m, 2 Η), 4.17 (d, J = 2.7 Hz, 1 Η), 5.39 (s, 2 Η), 7.66 (d, J = 7.80 Hz, 1 Η), 7.79 (d, J = 8.10 Hz, 1 Η), 8.15 - 7.99 (m, 2 Η), 8.23 (s, 1 H), (not observed 1 exchangeable yl)benzonitrile proton).

Intermediate 193: 6-(5-formylisoxazol-3-yl)-4-methoxynicotinonitrile

Intermediate 193A: methyl 5-cyano-4-methoxypicolinate

Intermediate 193A was obtained (6.00 g, 52.60%) as an off-white solid using a synthetic procedure similar to that of Intermediate 16A starting from 6-chloro-4-methoxynicotinonitrile (10.00 g , 59.30 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3H), 4.11 (s, 3H), 7.82 (s, 1H), 8.94 (s, 1H). LCMS (Method-I): retention time 0.79 min, [M+H] 192.9.

Intermediate 193B: 6-(hydroxymethyl)-4-methoxynicotinonitrile

- 217 043056

To a stirred solution of methyl 5-cyano-4-methoxypicolinate (3.00 g, 15.61 mmol) in a mixture of THF (50 ml) and EtOH (50 ml) was added calcium chloride (4.33 g, 39.00 mmol) followed by the addition of NaBH4 (2.36 g, 62.40 mmol) and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The resulting mixture was concentrated to dryness under reduced pressure, diluted with saturated NaHCO ₃ solution (100 ml) and extracted by adding ethyl acetate (3x100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give Intermediate 193B (1.80 g, 70.20%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.02 (s, 3H), 4.60 (d, J=3.00 Hz, 2H), 5.72 (t, J=3.50 Hz, 1H), 7.30 (s, 1H), 8.71 (s, 1H). LCMS (Method-I): retention time 0.56 min, [M+H] 164.9.

Intermediate 193C: 6-formyl-4-methoxynicotinonitrile

Intermediate 193C was obtained (1.70 g, 96.00%) as an off-white solid using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 193B (1.80 g, 10.96 mmol) and DessaMartin periodinan (6.98 g, 16.45 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.12 (s, 3H), 7.70 (s, 1H), 9.06 (s, 1H), 9.99 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 193D: (E)-6-((hydroxyimino)methyl)-4-methoxynicotinonitrile

Intermediate 193D was obtained (0.90 g, 78.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 110B, starting from intermediate 193C (1.05 g, 6.48 mmol) and hydroxylamine hydrochloride (0.54 g, 7.77 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.04 (s, 3H), 7.50 (s, 1H), 8.11 (s, 1H), 8.81 (s, 1H), 12.14 (s, 1H). LCMS (Method-I): retention time 0.73 min, [M+H] 177.9.

Intermediate 193E: 6-(5-(hydroxymethyl)isoxazol-3-yl)-4-methoxynicotinonitrile

Intermediate 193E was obtained (0.15 g, 25.50%) as an off-white solid using a synthetic procedure similar to that of intermediate 110C, starting from intermediate 193D (0.77 g, 3.75 mmol) and prop-2-yn-1-ol (0.14 g, 2.54 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.12 (s, 3H), 4.66 (d, J=5.00 Hz, 2H), 5.77 (t, J=5.00 Hz, 1H), 6.97 (s, 1H), 7.79 (s, 1H), 8.95 (s, 1H). LCMS (Method-I): retention time 0.84 min, [M+H] 232.0.

Intermediate 193.

Intermediate 193 was obtained (0.17 g, 90.00%) as an off-white solid using a synthetic procedure similar to that of intermediate 9 starting from intermediate 193E (0.19 g, 0.82 mmol) and DessaMartin periodinan (0.52 g, 1.23 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.12 (s, 3H), 7.94 (s, 1H), 8.16 (s, 1H), 9.00 (s, 1H), 9.99 (s, 1H). LCMS: Compound poorly ionized.

Intermediate 194: 2-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2H-1,2,3triazole-4-carbaldehyde

- 218 043056

Intermediate 194A: 1-(difluoromethyl)-4-(4-(hydroxymethyl)-2H-1,2,3-triazol-2yl)pyridin-2(III)-one

Intermediate 194A was obtained (0.20 g, 61.70%) as an off-white solid using a synthetic procedure similar to that of intermediate 42 starting from intermediate 28A (0.13 g, 1.33 mmol) and Intermediate 58A (0.30 g, 1.33 mmol). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 4.62 (d, J=5.52 Hz, 2H), 5.42 (s, 1H), 7.14 (d, J=2.01 Hz, 1H), 7.16 - 7.21 (m , 1H), 7.85-8.04 (m, 1H), 8.07 (d, J=7.53 Hz, 1H), 8.91 (s, 1H). ¹⁹ F NMR (400 MHz, DMSO-d6) δ ppm - 101.0. LCMS (Method-D): retention time 0.54 min, [M+H] 243.0.

Intermediate 194.

Intermediate 194 was prepared (0.08 g, 40.40%) using a synthetic procedure similar to that of intermediate 9 starting from intermediate 194A (0.20 g, 0.82 mmol) and Dess periodinan -Martin (0.70 g, 1.65 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.16 - 7.23 (m, 1H), 7.24 - 7.27 (m, 1H), 7.70 - 8.07 (m, 1H), 8.12 - 8.18 (m, 1H ), 9.76 (s, 1H), 10.13 (s, 1H). LCMS (Method-J): retention time 0.98 min, [M+H] 241.0.

Intermediate 195: 1-(2-(difluoromethyl)pyrimidin-4-yl)-1H-imidazole-4-carbaldehyde

Intermediate 195A: 4-chloropyrimidine-2-carbaldehyde

To a stirred solution of 4-chloropyrimidine-2-carbonitrile (0.25 g, 1.79 mmol) in THF (5 ml) was added 1 M DIBAL-H in heptane (1.79 ml, 1.79 mmol) at -78°C and the resulting reaction mixture was stirred at ambient temperature for 3 hours. The resulting mixture was diluted with a saturated solution of NH ₄ Cl (20 ml) and was extracted by adding 10% Meon in DCM (2x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give intermediate 195A (0.100 g, crude). LCMS (method-D): retention time 0.42 min [M+H] 143.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 195B: 4-chloro-2-(difluoromethyl)pyrimidine

Intermediate 195B was prepared (0.80 g, 36.70%) using a synthetic procedure similar to that of intermediate 4B, starting from pro- 219 043056 Intermediate 195A (1.70 g, 11.93 mmol ) and DAST (3.15 ml, 23.85 mmol). 1H NMR (300 MHz,

CDCl ₃ ) δ ppm 6.44 - 6.80 (m, 1H), 7.49 (d, J=5.40 Hz, 1H), 8.76 (d, J=5.40 Hz, 1H). ¹⁹ F NMR (400 MHz,

DMSO-d ₆ ) δ ppm -118.95. The compound is poorly ionized.

Intermediate 195.

To a stirred solution of intermediate 195B (0.01 g, 0.06 mmol) in 1,4-dioxane (5 mL) was added K ₂ CO ₃ (0.02 g, 0.122 mmol) followed by 1H-imidazole-4- carbaldehyde (0.01 g, 0.09 mmol) and the resulting reaction mixture was stirred at 80° C. for 12 hours. The resulting mixture was cooled to ambient temperature, filtered through Celite® and washed with ethyl acetate (10 ml). The filtrate was evaporated under reduced pressure to give intermediate 195 (0.005 g, 36.70%). LCMS (Method-D): retention time 0.92 min, [M+H] 225.2. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.54 - 6.81 (m, 1H), 7.51 (m, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.58 (d, J = 1.2 Hz , 1H), 9.02 (d, J=5.6 Hz, 1H), 10.01 (s, 1H). ¹⁹ F NMR (400 MHz, DMSO-d ₆ ) δ ppm -119.25.

Intermediate 196: 4-(5-formyl-2H-tetrazol-2-yl)-2-methoxybenzonitrile o

^N UN nn

OME

CN

Intermediate 196A: ethyl 2-(4-cyano-3-methoxyphenyl)-2H-tetrazole-5-carboxylate

About ^Me

II ' N N ' ^^OMe CN

Intermediate 196A was obtained (0.15 g, 7.71%) as a brown solid using a synthetic procedure similar to that of Intermediate 191A starting from 4-amino-2-methoxybenzonitrile (1.00 g , 6.75 mmol). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.48 - 1.52 (t, J = 6.80 Hz, 3H), 4.09 (s, 3H), 4.56 - 4.62 (m, 2H), 7.79 (d, J = 8.40 Hz, 1H), 7.85 (d, J=1.60 Hz, 1H), 7.91-7.94 (m, 1H). LCMS (Method-I) retention time 1.60 min, [M+H] 274.2.

Intermediate 196B: 4-(5-(hydroxymethyl)-2H-tetrazol-2-yl)-2-methoxybenzonitrile

Intermediate 196B was prepared (0.06 g, 54.50%) using a synthetic procedure similar to that of intermediate 60B, starting from intermediate 196A (0.13 g, 0.48 mmol) and NaBH ₄ (0.07 g, 1.90 mmol). 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 4.07 (s, 3H), 4.82 (d, J=7.20 Hz, 2H), 5.84 (t, J=8.00 Hz, 1H), 7.80-7.86 (m , 2H), 8.06 (m, 1H). LCMS (Method-I) retention time 1.52 min, [M+H] 232.2.

Intermediate 196.

Intermediate 196 was prepared (0.95 g, crude) using a synthetic procedure similar to that of Intermediate 9 starting from Intermediate 196B (0.10 g, 0.43 mmol) and Dess-Martin periodinan (0.37 g, 0.86 mmol). LCMS (Method-I): retention time 1.29 min, [M-H] 228.2. The compound was carried directly to the next step without further purification or characterization.

Intermediate 197: (1-(5-cyano-4-methoxypyridin-2-yl)-3-methyl-2-oxoimidazolidin-4-yl)methylmethanesulfonate

- 220 043056

Intermediate 197A: 6-(4-(hydroxymethyl)-3-methyl-2-oxoimidazolidin-1-yl)-4methoxynicotinonitrile

A solution of intermediate 93C (0.50 g, 1.92 mmol) in ethyl acetate (20 ml) was purged with nitrogen for 2 minutes. 10% Pd/C (0.10 g, 0.96 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 hours under H2 atmosphere. The resulting mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give Intermediate 197A (0.25 g, 47.10%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.83 (s, 3H), 3.46 - 3.53 (m, 1H), 3.62 - 3.73 (m, 2H), 3.79 (dd, J=10.79, 5.27 Hz, 1H), 3.93 (s, 3H), 3.97 - 4.04 (m, 1H), 4.98 (t, J = 5.52 Hz, 1H), 8.06 (s, 1H ), 8.54 (s, 1H). LCMS (Method-D): retention time 1.22 min, [M+H] 263.2.

Intermediate 197.

Intermediate 197 was obtained (0.24 g, 81.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 59, starting from intermediate 197A (0.20 g, 0 .76 mmol) and mesyl chloride (0.07 ml, 0.91 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.87 (s, 3H), 3.24 (s, 3H), 3.80 (dd, J=10.79, 4.77 Hz, 1H), 3.94 (s, 3H), 4.02 - 4.09 (m, 1H), 4.10-4.16 (m, 1H), 4.36 (dd, J=11.04, 3.51 Hz, 1H), 4.50 (dd, J =11.04, 3.01 Hz, 1H), 8.04 (s, 1H), 8.56 (s, 1H). LCMS (Method-D): retention time 1.69 min, [M+H] 340.9.

Intermediate 198: 1-methyl-5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl )-1,3-dihydro-2H-imidazol-2-one TFA salt

Intermediate 198A: 1-(tert-butyl)-4-methyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-1,4-dicarboxylate

K ₂ CO 3 (4.86 g, _4.86 g, 35.20 mmol) followed by the addition of BOC2O (8.17 ml, 35.2 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 14 h. The resulting mixture was diluted with MeCN (50 ml) and K ₂ CO ₃ (14.55 g, 105.00 mmol), iodomethane (6.58 ml, 105.00 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for an additional 14 hours. The resulting mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure conditions. The residue was purified by column chromatography (Redisep-40 g, 10-20% EtOAc/n-hexane) to give Intermediate 198A (3.70 g, 41.10%) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.53 (s, 9H), 3.30 (s, 3H), 3.79 (s, 3H), 7.40 (s, 1H). LCMS (method-O): retention time 1.17 min, [M-55] 201.2.

Intermediate 198B: methyl 3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate TFA salt

To a stirred solution of intermediate 198A (3.70 g, 14.44 mmol) in DCM (20 mL) at 0°C was added TFA (10 mL, 130 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours The resulting mixture was concentrated under reduced pressure.

The residue was dissolved in diethyl ether (50 ml) and the solid was filtered off and dried in vacuo to give intermediate 198B (0.22 g, 98.00%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm

3.30 (s, 3H), 3.37 (s, 3H), 5.33 (br. s., 1H), 7.38 (s, 1H), 10.96 (br. s., 1H) . LCMS (Method-O): retention time 0.16 min, [M+H] 156.9.

Intermediate 198C: methyl 3-methyl-2-oxo-1-trityl-2,3-dihydro-1H-imidazole-4carboxylate

Intermediate 198C was obtained (2.90 g, 56.80%) as a white solid using a synthetic procedure similar to that of intermediate 75A, starting from intermediate 198B (2.00 g, 12.81 mmol) and trityl chloride (4.29 g, 15.37 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (s, 3H), 3.69 (s, 3H), 7.11-7.40 (m, 16H). LCMS (Method-D): retention time 3.28 min, [M+H] 399.2.

Intermediate 198D: 4-(hydroxymethyl)-3-methyl-1-trityl-1,3-dihydro-2H-imidazol2-one

To a stirred solution of Intermediate 198C (5.00 g, 12.55 mmol) in THF (40 ml) was added a 2M solution of LiBH4 in THF (18.82 ml, 37.6 mmol) at 0°C and the resulting reaction mixture was stirred at ambient temperature for 14 hours. The resulting mixture was diluted with water (50 ml) and was extracted with the addition of ethyl acetate (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep40 g, 50-80% EtOAc/n-hexane) to give Intermediate 198D (3.30 g, 71.00%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.06 (s, 3H), 4.21 (d, J=6.80, 2H), 5.03 (t, J=14.00, 1H), 6.07 (s, 1H), 7. 09-7.17 (m, 6 H), 7.22-7.37 (m, 9 H). LCMS (Method-D): retention time 2.42 min, [M+H] 371.2.

Intermediate 198E: (3-methyl-2-oxo-1-trityl-2,3-dihydro-1H-imidazole-4-yl)methylmethanesulfonate

Intermediate 198E was prepared (1.40 g, 99.17%) using a synthetic procedure similar to that of intermediate 59 starting from intermediate 198D (2.00 g, 5.40 mmol) and mesyl- Cl (0.50 ml, 6.48 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.04-3.13 (s, 3H), 3.16-3.28 (s, 3H), 4.38 (s, 2H), 6.67 (s, 1H), 7.20-7, 38 (m, 15 H). LCMS: Compound poorly ionized.

Intermediate 198F-I: 3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl )methyl)-1-trityl-1,3-dihydro-2H-imidazol-2-one

- 222 043056

To a stirred solution of intermediate 51-I (0.50 g, 2.02 mmol) in MeCN (40 ml) was added intermediate 198E (0.70 g, 1.56 mmol), sodium iodide (0.234 g, 1.561 mmol) , K ₂ CO ₃ (0.647 g, 4.68 mmol) followed by the addition of 4-methyl-1H-imidazole (0.18 g, 2.21 mmol) and the resulting mixture was heated at 65°C for 4 h. cooled to ambient temperature, filtered through Celite® and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 5-10% MeOH/CHCl ₃ ) to give intermediate 198F-I (0.30 g, 32.10%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.98-1.11(m, 3H), 2.16-2.28(m, 3H), 2.34-2.47(m, 1H), 2.54-2.62(m, 2H ), 2.63 - 2.79 (m, 3H), 2.87 (br. s., 1H), 3.09 (s, 3H), 3.17 - 3.30 (m, 1H), 4 .04 (d, J = 14.00, 1H), 5.42 (s, 2H), 6.06 (s, 1H), 7.10-7.32 (m, 15 H), 7.67 ( d, J=10.80, 1H), 7.80 (d, J=10.40, 1H). LCMS (method-O): retention time 1.87 min, [M+H] 599.3.

Intermediate 198-I.

Intermediate 198-I was prepared (0.55 g, 93.20%) using a synthetic procedure similar to that of intermediate 198B, starting from intermediate 198F-I (1.00 g, 1.67 mmol ) and TFA (5 ml, 64.90 mmol). 1H NMR (400 MHz, DMSOd6) δ ppm 1.28 (d, J = 3.00, 3H), 2.17 - 2.45 (m, 3H), 2.96 - 3.26 (m, 5 H), 3.27 - 3.44 ( m, 5H), 4.70 (br.s., 1H), 5.39-5.53 (m, 2H), 6.32 (s, 1H), 7.29-7.33 (m, 1H), 7.79 - 7.91 (m, 2H), 8.49 - 8.84 (m, 1H), (1 exchangeable proton was not observed). LCMS (Method-O): retention time 0.57 min, [M+H] 357.1.

Example 266-I: 3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1 -(2-methylpyridin-4-yl)-1,3-dihydro-2H-imidazol-2-one

Example 266-I was prepared (0.02 g, 18.73%) using a synthetic procedure similar to that of Intermediate 15C, starting from Intermediate 198-I (0.08 g, 0.23 mmol) and 4-bromo-2-methylpyridine (0.05 g, 0.27 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (d, J = 4.90 Hz, 3H), 1.75 (br. s., 2H), 2.27 (s, 3H), 2.46 (s, 3H), 2.87 ( br. s., 2H), 2.98 (br. s., 1H), 3.28 (s, 2H), 3.33 (s, 3H), 4.18 (br. s., 1H), 5.52 - 5.29 (m, 2H), 7.18 (s, 1H), 7.78 - 7.54 (m, 3H), 7.82 (d, J=8.10 Hz, 1H) , 8.40 (d, J=5.40 Hz, 1H), (1 exchangeable proton not observed). LCMS/HPLC (Method-R): retention time 0.83 min, [M+H] 448.3, purity: 97.78%. (Method-S): retention time 1.34 min, [M+H] 448.3, purity: 97.09%. Chiral purity (Method-XVIII): retention time 13.72 min, 95.00% e.i.

Compounds according to the examples listed in table. 4 were synthesized according to the procedures for compounds according to examples 1-I-24-I, 81-I-84-I, 113-I-123-I and 266-I. Namo Shivay

Example Structure Name LCMS (M+N) ⁺ hplc/lcm s Method: RT (min.), purity NMR 267-1 o N, T T 1 VN Me HN^J oy ^Μ θ θ ^Μ θ CN 6-(5-((3,3-dimethyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)-1,3,4oxadiazol-2-yl) -4methylnicotinoniter silt (Enantiomer-1) 459.3 R: 1.20, 100% S: 1.62, 100% Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.07 (s, 3 H), 1.30 (s, 3 H), 1.89 - 1.99 (w, 1 H), 2.06 (d, J = 10.00 Hz, 1 H) , 2.31 (s, 3 H), 2.63 (s, 4 H), 2.95 (d, J= 10.00 Hz, 1 H), 3.99 (s, 2 H), 4, 40 (d, J= 8.10 Hz, 1 H), 5.39 (s, 2 H), 7.66 (d, J= 8.10 Hz, 1 H), 7.78 (d, J= 8.10 Hz, 1 H), 8.32 (s, 1 H), 9.12 (s, 1 H), (no exchangeable proton observed).

- 223 043056

268-1 o y Af °> Me Me Me / A A- / ^Me ON 6-(5-((3,3-dimethyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)isoxazol- 3-yl)-4- methylnicotinonitrile yl (Enantiomer-1) 458.2 R: 1.46, 100% S: 1.98, 100% XV: 8.87, 100% e.i. Ή NMR (400 MHz, DMSO-t/ ₆ ) δ ppm (s, 3 H), 1.32 (s, 3 H), 1.88 (t, J= 10.60 Hz, 1 H), 1.97 (d, J= 10.30 Hz, 1 H) , 2.26 - 2.33 (m, 3 Η), 2.54 2.65 (m, 4 Η), 2.88 (d, J = 9.50 Hz, 1 Η), 3.84 (s , 2 Η), 4.40 (d, J= 8.10 Hz, 1 Η), 5.37 (s, 2 Η), 6.96 (s, 1 Η), 7.64 (d, J = 8.10 Hz, 1 Η), 7.77 (d, J = 8.10 Hz, 1 Η), 8.14 (s, 1 Η), 9.04 (s, 1 H), (not observed 1 capable of proton exchange). 269-1 A Me HN^> Μθ c/L A/ ^0Me ON 4-methoxy-6-(5(((35.57?)-3-methyl-5(4-methyl-1-oxo-1,3dihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)isoxazol- 3- yl) nicotinonitrile 460.3 R: 1.30, 96.82% S: 1.67, 96.12% VIII: 6.79, 100% e.i. Ή NMR (400 MHz, DMSO-t/b) δ ppm 1.03 (d, 7= 6.10 Hz, 3 H), 1.74-1.94 (br. 2 H), 2.29 (s, 3 H), 2.83 (br. s., 2 H), 2.99 (br. s., 1 Η), 3.86 (s, 2 Η), 4.12 (s, 3 Η), 4.18 (d, J = 7.60 Hz, 1 Η), 5.39 (s, 2 Η), 7.01 (s, 1 Η), 7.66 (d, J = 8.10 Hz, 1 Η), 7.89 - 7.72 - 7, 89 (m, 2 H), 8.94 (s, 1 H), (1 exchangeable proton was not observed). 270-1 0 A Me /=\ t>° Xf F 1 -(difluoromethyl)-4(4-(((35.57?)-3-methyl5 -(4-methyl-1-oxo1,zdihydroisobenzofur an-5-yl)piperazin-1 yl)methyl)-2 //-1,2,3triazol-2yl)pyridine-2( 1Н)one. 471.1 R: 1.10, 100% S: 1.55, 100% XXIX: 3.35, 100% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 8.24 (s, 1 H), 8.02 (d, J= 7.80 Hz, 1 H), 7.88 (s, 1 H), 7.80 (d, J= 8.10 Hz, 1 H), 7.66 (d, J = 7.80 Hz, 1 H), 7.10 (dd, J = 7.90, 2.30 Hz, 1 H), 6.88 (d, J = 2.20 Hz, 1 H), 5.47 - 5.27 (w, 2 H), 4.18 (d, J = 8.30 Hz, 1 H), 3.76 (s, 2 H), 2.98 (br. s., 1 Η), 2.81 (d, J = 9.80 Hz, 2 Η), 2.33 (s, 3 Η), 1.83 (d, J = 9, 00 Hz, 2 Η), 1.03 (d, J = 6.10 Hz, 3 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSO-Tb) δ ppm - 103.0. 271-1 N^N N—\ OMe)—NH 0ΗΜθ oZ 5-((27?,65)-4-((1-(2(difluoromethyl)pyrim idin-4-yl)-1nimidazol-4yl)methyl)-6methylpiperazin-2- yl)-4methylisobenzofuran -1(3H)-one 455.3 S: 1.31, 100% R: 0.98, 100% VIII: 3.83, 100% e.i. Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.02 (d, J= 6.10 Hz, 3 H), 1.80 (q, J= 10.00 Hz, 2 H), 2.31-2.18 (w, 3 H), 2. 91-2.69 (br. 2 H), 2.96 (br. s., 1 H), 3.51 (s, 2 H), 4.16 (d, J = 9.00 Hz, 1 H ), 5.49 - 5.26 (w, 2 H), 6.97 (s, 1 H), 7.64 (d, J = 7.80 Hz, 1 H), 7.79 (d, J = 7.80 Hz, 1 H), 7.91 (s, 1 H), 8.08 (d, J= 5.60 Hz, 1 H), 8.65 (s, 1 H), 9.05 (d, J = 5.60 Hz, 1 H), (1 exchangeable proton was not observed). ¹⁹ F NMR (400 MHz, DMSO7b) δ ppm - 119.33

- 224 043056

4-(5-(((37/,47/)-4- Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.68 hydroxy-3 -(4-methyl- - 1.56 (m, 1 N), 1.99 - 1.85 (t, 2 N), 2.31 - 2.19 ABOUT S: 1.60 (t, 4 N), 2.41 - 2.31 (t, 1 N), 2.85 (d, J = 10.80 1-oxo-1,3- 272-1 100% Hz, 1 N), 2.98 (d, J = 10.80 Hz, 1 N), 3.13 - 3.04 dihydroisobenzofur ⁿ °v 461.2 R: 1.22 (t, 1 H), 3.17 (s, 1 H), 3.72 (br. s., 1 H), 3.98 (s, Ο-OMe an-5-yl)piperidine- 100% 3 H), 4.59 (d, J= 5.40 Hz, 1 H), 5.47 - 5.28 (m, 2 CN 1 -yl)methyl)-2H- Η), 7.54 (d, J= 7.80 Hz, 1 Η), 7.63 (d, J= 8.10 Hz, 1 Η), 7.80 (d, J= 8.30 Hz, 1 H), 7.85 (s, 1 H), 8.04 tetrazol-2-yl)-2- methoxybenzonitrile (d, 7=8.60 Hz, 1 Η). Ή NMR (400 MHz, DMSO-Tb) δ ppm 2.02 6-(5-((3- (t, J= 10.50 Hz, 1 H), 2.33 - 2.15 (m, 4 H), 2.63 (difluoromethyl)-5-(4- S: 1.67 (s, 3 H), 2.88 (br. s., 1 H), 2.95 (d, J= 10.80 Hz, 1 ABOUT methyl-1-oxo-1,3- 100% H), 3.02 (d, J = 9.00 Hz, 1 H), 3.31 (br. s., 1 H), 273-1 1 1 1 G N dihydroisobenzofur R: 1.27 4.10 (s, 2 H), 4.24 (d, J= 9.80 Hz, 1 H), 5.45 - 5.37 Me HN.J O-+ an-5 -yl)piperazine-1 - 481.2 100% (m, 2 H), 5.96 (d, J = 4.40 Hz, 1 H), 7.68 (d, J = ^{ff Ν} Ο~ ^Μ θ yl)methyl)-1,3,4- 8.10 Hz, 1 H), 7.78 (d, J = 8.10 Hz, 1 H), 8.33 (s, CN oxadiazol-2-yl)-4- 1H), 9.12(s, 1H) methyl nicotinonitrile silt (Enantiomer-1) 4-methoxy-6-(3- Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.02 methyl-4-(((3S, 57/)-3 - R: 8.11 (d, J= 6.53 Hz, 3 Η), 1.75 - 1.84 (m, 2 Η), 2.28 (s, ABOUT methyl-5-(4-methyl-1 - 99.10% 3 Η), 2.60 - 2.66 (m, 2 Η), 2.82 (d, J= 10.54 Hz, 2 274-1 ^oYA oxo-1,3- Q: 7.37 Η), 2.86 - 2.93 (m, 4 Η), 3.78 (dd, J= 10.79, 5.27 Me HN^k dihydroisobenzofur 99.30% Hz, 1 Η), 3.85 - 3.92 (m, 1 Η), 3.94 (s, 3 Η), 4.02 Me _K AL \ to °Me an-5 -yl)piperazine-1 - 491.2 XXXIII: - 4.14 (m, 2 Η), 5.40 (s, 2 Η), 7.67 (d, J= 8.03 Hz, yl)methyl)-2- 14.00 1 H), 7.82 (d, J= 8.03 Hz, 1 H), 8.06 (s, 1 H), 8.56 oxoimidazolidine- 100% e.i. (s, 1 Η) (Not observed 1 capable of 1- proton exchange). yl) nicotinonitrile (Diastereomer I) 1-(2- Ή NMR (400 MHz, DMSO-Tb) δ ppm 1.06 methoxypyridine-4- R: 1.00 (br. s., 3 H), 2.27 (s, 3 H), 2.85 (br. s., 3 H), 2.95 yl)-3-methyl-4- 96.14% (br. s., 3 H), 3.28 (s, 2 H), 3.32 (s, 3 H), 3.86 (s, 3 0 Me (((35.57/)-3-methyl-5- S: 1.50 H), 4.14 (br. s., 1 H), 5.38 (s, 2 H), 7.19 (s, 1 H), 275-1 bob Me HN\O (4-methyl-1-oxo-1,3- 464.3 97.76% 7.34 (d, J= 1.70 Hz, 1 H), 7.50 (dd, J= 5.90, 2.00 dihydroisobenzofur Hz, 1 H), 7.68 (d, J = 7.30 Hz, 1 H), 7.82 (d, J = Me/V \/ome an-5 -yl)piperazine-1 - 7.80 Hz, 1 H), 8.14 (d, J = 5.90 Hz, 1 H). yl)methyl)-1,3- dihydro-2H- imidazole-2-one 1-(2- Ή NMR (400 MHz, DMSO-7 ₆ ) δ ppm (difluoromethyl)pyride 1.05 (d, J = 5.10 Hz, 3 H), 1.72 (br. s., 2 H), 2.27 in-4-yl)-3 -methyl-4- R: 1.14 (s, 3 H), 2.86 (br. s., 2 H), 2.96 (br. s., 1 H), 3.33 0 ^Me (((35.57/)-3-methyl-5- 98.10% (s, 3 H), 3.30 (s, 3 H), 4.14 (br. s., 1 H), 5.46 - 5.27 276-1 Oh, ' Me HN^> (4-methyl-1-oxo-1,3- 484.3 S: 1.52 (m, 2 H), 6.95 (s, 1 H), 7.33 (s, 1 H), 7.68 (d, J = MeX/ dihydroisobenzofur 96.63% 8.10 Hz, 1 H), 7.82 (d, J= 8.10 Hz, 1 H), 8.00 (d, _w'f an-5 -yl)piperazine-1 - XV: 8.55 J = 4.60 Hz, 1 H), 8.29 (s, 1 H), 8.65 (d, J = 5.60 yl)methyl)-1,3- 100% e.i. Hz, 1H) dihydro-2H- imidazole-2-one

Intermediate 199-I: 4-methyl-5-((2R,6S)-6-methylpiperazin-2-yl)isobeshofuran1(3H)-one-3,3-d2 TFA salt

- 225 043056

O ^Ο 0θζ tfa

DDII ¹ HN^J

Me

Intermediate 199A-I: tert-butyl (3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl-3-d)piperazine-1-carboxylate

ABOUT

Me

To a stirred solution of intermediate 51-I (1.50 g, 4.33 mmol) in THF (150 ml) was added 1 M LiHMDS in THF (21.65 ml, 21.65 mmol) and the resulting mixture was stirred at ambient temperature for within 30 min. D ₂ O (5.09 ml, 281 mmol) was added to the resulting reaction mixture and stirring at ambient temperature was continued for 15 minutes. The resulting mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-40 g, 60-80% EtOAc/n-hexane) to give Intermediate I99A-I (1.00 g, 33.20%) as a white solid. 1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.05 (s, 3H), 1.42 (s, 9H), 2.32 (s, 3H), 2.42 (br s, 1H), 2.70-2.88 (m, 2H), 3.91 - 4.04 (m, 3H), 5.37 - 5.44 (m, 1H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d, J = 7.90 Hz, 1H), (1 exchangeable proton was not observed). LCMS (Method-D): retention time 2.46 min, [M+H] 348.2.

Intermediate 199B-I and 199C-I: tert-butyl (3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl-3,3-d2)piperazine- 1-carboxylate

Me

199B-I: mono-D to di-D isotope ratio 28:72 199C-I: mono-D to di-D isotope ratio 17:83.

Intermediate 199B-I was obtained (0.40 g, 39.80%) as a white solid using a synthetic procedure similar to that of Intermediate 199A-I, starting from Intermediate I99A-I (1, 00 g, 2.89 mmol) and 1M LiHMDS (14.39 ml, 14.39 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.05 (s, 3H), 1.42 (s, 9H), 2.32 (s, 3H), 2.42 (br s, 1H), 2.70-2.88 (m, 2H) , 3.91 - 4.04 (m, 3H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d, J=7.90 Hz, 1H), (not observed 1 capable of proton exchange). LCMS (Method-D): retention time 2.47 min, [M+H] 349.2. The isotope ratio of mono-D and di-D (28:72) was determined by 1H NMR.

Intermediate 199C-I was obtained (0.20 g, 19.88%) as a white solid using a synthetic procedure similar to that of Intermediate 199A starting from Intermediate I99B-I (0.40 g , 1.15 mmol) and 1M LiHMDS (5.76 ml, 5.76 mmol). 1H NMR (300 MHz, DMSO4) δ ppm 1.05 (s, 3H), 1.42 (s, 9H), 2.32 (s, 3H), 2.42 (br., s, 1H), 2.70-2.88 (m, 2H), 3.91 -4.04 (m, 3H), 7.69 (d, J=7.90 Hz, 1H), 7.82 (d, J=7.90 Hz, 1H), (not 1 exchangeable proton was observed). LCMS (Method-D): retention time 2.47 min, [M+H] 349.2. The isotope ratio of mono-D and di-D (17:83) was determined by 1H NMR.

Intermediate 199-I.

Intermediate 199-I was obtained (0.18 g, 87.00%) as a pale yellow solid using a synthetic procedure similar to that of intermediate 198B, starting from intermediate 199C-I (0. 20 g, 0.57 mmol) and TFA (0.88 ml, 11.48 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.29 (d, J=6.00 Hz, 3H), 2.38 (s, 3H), 3.0 - 3.20 (m, 2H), 3.55 - 3.68 (m, 3H) , 4.86 (br., s., 1H), 7.88-7.82 (m, 2H), (2 exchangeable protons not observed). LCMS (Method-J): retention time 0.40 min, [M+H] 249.2.

Intermediate 200-I: 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3dihydroisobenzofuran-5-yl-3-d) niperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

- 226 043056

To a stirred solution of the compound according to example 83-I (0.10 g, 0.22 mmol) in THF (10 ml) at -50°C was added 1M LiHMDS in THF (1.13 ml, 1.13 mmol) and the resulting mixture stirred at the same temperature for 10 minutes. D ₂ O (2.0 ml, 113 mmol) was added to the resulting reaction mixture and stirring at -50° C. was continued for 10 minutes. The resulting mixture was diluted with water (15 ml) and extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Redisep-24 g, 34% MeOH/DCM) to give Intermediate 200-I (0.045 g, 40.00%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=5.60 Hz, 3H), 1.75 (m, 2H), 2.27 (s, 3H), 2.38 - 2.41 (m, 2H), 2.71 (s, 3H), 2.75 - 2.86 (m, 2H), 3.76 (s, 2H), 4.05 - 4.29 (m, 1H), 5.34 - 5.37 (m , 1H), 7.50 (d, J=8.00 Hz, 1H), 7.80 (d, J=8.00 Hz, 1H), 8.07 - 8.26 (m, 2H), 8 .87 - 9.03 (m, 1H). LCMS (Method-D): retention time 1.15 min, [M+H] 445.0. The isotopic ratio of mono-D AND CI-D (27:73) was determined by ¹ H NMR.

Example 277-I: 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl3,3-d2 )piperazin-1-yl)methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile

The compound of Example 277-I was obtained (0.01 g, 14.80%) as a white solid using a synthetic procedure similar to that of Intermediate 96-I, starting from Intermediate 199-I (0 05 g, 0.188 mmol) and Intermediate 28 (0.04 g, 0.188 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=5.60 Hz, 3H), 1.75 1.88 (m, 2H), 2.26 (s, 3H), 2.61 (s, 3H), 2.74 - 2.86 (m, 2H), 2.92-3.04 (m, 1H), 3.76 (s, 2H), 4.14-4.18 (m, 1H), 7.65 (d, J=7.60Hz, 1H), 7.79(d, J=8.10Hz, 1H), 8.11(s, 1H), 8.20(s, 1H), 8.92(s, 1H), (1 exchangeable proton was not observed). HPLC (Method-P): retention time 7.71 minutes, purity: 98.20%, (Method-Q): retention time 5.65 minutes, purity: 98.17%. LCMS (Method D): retention time 1.93 min, [M+H] 446.2. The isotopic ratio of mono-D AND di-D (17:83) was determined by 1H NMR.

Alternative procedure for the connection according to example 277-I.

The compound of Example 277-I was obtained (0.001 g, 2.82%) as a white solid using a synthetic procedure similar to that of Intermediate 199A-I, starting from Intermediate 200-I (0.04 g, 0.101 mmol) and 1M LiHMDS (0.50 ml, 0.50 mmol). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.02 (d, J=5.60 Hz, 3H), 1.75 - 1.88 (m, 2H), 2.26 (s, 3H), 2.61 (s, 3H), 2.74 - 2.86 (m, 2H), 2.92 - 3.04 (m, 1H), 3.76 (s, 2H), 4.14 - 4.18 (m, 1H), 7.65 (d , J=7.60 Hz, 1H), 7.79 (d, J=8.10 Hz, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.92 (s , 1H), (1 exchangeable proton was not observed). HPLC (Method-P): retention time 7.49 minutes, purity: 92.50%, (Method-Q): retention time 6.54 minutes, purity: 93.04%. LCMS (Method-D): retention time 1.84 min, [M+H] 446.2. Chiral purity (VSH method): retention time 4.99 min, 100% e.i. The isotope ratio of mono-D AND CI-D (5:95) was determined by 1H NMR.

Compounds according to the examples listed in table. 5 was synthesized according to the procedures for compounds according to examples 1-I - 24-I, 81-I - 84-I, 113-I - 123-I, 266-I and 277-I

- 227 043056

Example 278-1 279-1 280-1 281-1 Structure o A) ύΙηΟ V * Am, CN O Me HN^YY' AA ^me CN ^D Me HN^ OY Ye AL ^N k/~Me CN ^D Me HN^ Ye /D OMe CN Name 4-methyl-6-(4-(((35.5R)-3 methyl-5-(4-methyl-1-oxo1,zdihydroisobenzofuran5-yl-3,3-b2)piperazin-1 yl)methyl)-1 H-pyrazol-1 yl)nicotinonitrile (Isotope ratio of mono-D and di-D: 17:83) 4-methyl-6-(4-(((35.5R)-3 methyl-5 -(4-methyl-1-oxo1,3dihydroisobenzofuran5-yl-3,3-b2)piperazin-1 yl)methyl)-1 Η-1,2,3 triazol-1yl)nicotinonitrile (isotopic ratio of mono-D and di-D: 17:83) 4-methyl-6-(5-(((35,5R)-3 methyl-5 -(4-methyl-1 -oxo1,3dihydroisobenzofuran5 -yl-3,3 -b2)piperazin-1 yl)methyl)-1 ,3,4oxadiazol-2yl)nicotinonitrile (isotopic ratio of mono-D and di-D: 22:78) 4-methoxy-6-(5 -(((35.5R)3 -methyl-5 -(4-methyl-1 oxo-1,3 dihydroisobenzofuran5 -yl-3,3 -b2)piperazin-1 yl)methyl) isoxazol-3 yl)nicotinonitrile (isotope ratio of mono-D and di-D: 22:78) LCMS (M+N) ⁺ 445.2 446.2 447.2 462.2 HPLC/ LCMS Method: RT (min), purity P: 4.83, 96.00% Q: 6.29, 97.80% P: 8.22, 97.00% Q: 9.50, 96.30% T: 5.26, 94.27% S:12.13, 95.10% P: 4.53, 90.04% R: 5.64, 90.00% NMR ΉNMR (400 MHz, DMSO-J ₆ ) δ ppm 1.00 (d, J = 6.00 Hz, 3 H), 1.69 (br., s., 2 H), 2.12 (s, 3 H), 2.56 (s, 3 H) , 2.77 (d, J= 9.50 Hz, 2 H), 2.94 (s, 1 H), 3.50 (s, 2 H), 4.13 (d, J= 8.50 Hz , 1 H), 7.62 (d, J = 7.50 Hz, 1 H), 7.70 7.89 (m, 2 H), 7.96 (s, 1 H), 8.50 (s , 1 H), 8.81 (s, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSOY) δ ppm 1.01 (d, J = 6.00 Hz, 3 Η), 1.66 - 1.87 (m, 2 Η), 2.25 (s, 3 Η), 2.56 (s, 3 Η) , 2.82 (t, J= 8.80 Hz, 2 Η), 2.95 (br., s., 1 H), 3.73 (s, 2 H), 4.14 (d, J = 7.50 Hz, 1 H), 7.64 (d, J = 8.00 Hz, 1 H), 7.78 (d, J= 8.00 Hz, 1 H), 8.27 (s, 1 H), 8.76 (s, 1 H), 8.98 (s, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, J= 6.50 Hz, 3 Η), 1.84 - 2.08 (m, 2 Η), 2.28 (s, 3 Η), 2.80 - 3.94 (m , 3 Η), 3.99 (s, 3 Η), 4.18 (d, J = 8.00 Hz, 3 Η), 7.50 (d, J = 8.00 Hz, 1 Η), 7 .85 (d, J= 8.00 Hz, 1 Η), 8.33 (s, 1 Η), 9.12 (s, 1 H), (1 exchangeable proton was not observed). Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.03 (d, J = 6.50 Hz, 3 Η), 1.75 - 1.85 (m, 2 Η), 2.25 (s, 3 Η), 2.81 - 2.90 (m , 2 Η), 2.95 - 3.0 (m, 1 Η), 3.85 (s, 2 Η), 4.01 - 4.23 (m, 4 Η), 7.01 (s, 1 Η), 7.66 (d, J= 8.00 Hz, 1 Η), 7.73 - 7.85 (m, 2 Η), 8.94 (s, 1 I), (not observed 1 capable of proton exchange).

biological analyses.

The pharmacological properties of the compounds of the present invention can be confirmed using a variety of biological assays. The following examples of biological assays were carried out with the compounds of the present invention.

If more than one data point was obtained in the case of any particular test of a particular compound, they were presented in the table as an average value.

Thallium excretion analysis.

Solutions and reagents: Thallium excretion assay was performed using the FluxOR kit (F10017, Life Technologies). Loading buffer, assay buffer and stimulation buffer were prepared using the kit components. HBSS (Hank's Balanced Salt Solution, cat. no. 14025-092) was purchased separately from Life Technologies.

- 228 043056

To prepare 10 ml of loading buffer: 10 µl of FluxOR dye (reconstituted in DMSO) was first added to 100 µl of PowerLoad concentrate and this mixture, together with 100 µl of Probenicid (100x), was then added to 9.79 ml of HBSS. An assay buffer (10 ml) was prepared by adding 2 ml chloride-free FluxOR buffer (5x), 100 μl Probenicid (100x) and 0.2 ml Ouabain (13.77 mmol) in 7.7 ml deionized water. Stimulation buffer consisted of 15 mM Tl ₂ SO ₄ , 0.75 mM K ₂ SO ₄ in chloride-free FluxOR buffer (diluted to 1x with deionized water). The final concentration of Tl ₂ SO ₄ and K ₂ SO ₄ in the assay plate was 3 and 0.15 mM, respectively.

Cell plating and induction: The stable CHO cell line T-Rex hROMK (human Kir1.1) was maintained in Ham's F12 medium supplemented with 10% FBS, 1% penicillin/streptomycin mixture, 500 µg/mL Zeocin, and 10 µg/mL blasticidin at 37 °C in 5% CO2 thermostat. The day before the experiment, the cells were separated by incubation with a solution of ethylenediaminetetraacetic acid (15040-066, Life Technologies) for 10 min at 37°C, followed by the addition of growth medium. The cell suspension was centrifuged at 1200 rpm for 5 min. After removing the supernatant, the cells were resuspended in fresh growth medium and the cell concentration was determined using a hemocytometer. Then, 0.5 μg/ml doxycycline was added to the cell suspension to induce hROMK channel expression, and 50 μl (10,000 cells/well) of the cell suspension was added to each well with poly-D-lysine coated on a 384-well black plate with optical transparent bottom (6007718, Perkin Elmer). The assay plate was stored at 37° C. in a 5% CO2 incubator.

Assay Protocol: On the day of the experiment, the medium was removed and loading buffer (30 μl/well) was added to the assay plate. Cells were incubated in loading buffer for 30 min at 37°C. The loading buffer was then replaced with assay buffer (30 μl/well) followed by the addition of test compounds or controls. Cells were incubated with the compounds for 30 minutes and then the plate was mounted on a FlexStation (Molecular Devices) to read fluorescence at excitation and emission wavelengths of 488 and 525 nm, respectively. Each well was read for 90 s at 2 s intervals and after 20 s of baseline recording, stimulation buffer was added. The final concentration of DMSO was 0.5 or 1% in the assay plate. Positive and negative controls were set by adding DMSO or 3 μM standard ROMK inhibitor to the wells instead of the test compound, respectively.

Data Analysis: The slope (over a period of 15 s) of the increase in fluorescence after the addition of the stimulation buffer was exported from SoftMax Pro to specialized software, where it was converted to % inhibition. A 10-point concentration-response curve was used to evaluate the IC ₅₀ value of the test compounds.

The data in the table. 6 are represented by two significant figures.

- 229 043056

Table 6

- 230 043056

- 231 043056

157-1 12 158-1 36 159-1 16 160-1 130 161-1 170 162-1 260 163-1 29 164-1 31 165-1 67 166-1 thirty 167-1 26 168-1 20 169-1 23 170-1 39 171-1 27 172-1 160 173-1 55 174-1 220 175-1 31 176-1 120 177-1 500 178-1 220 179-1 360 180-1 77 181-1 150 182-1 260 183-1 180 184-1 thirty 185-1 100 186-1 18 187-1 43 188-1 37 189-1 25 190-1 17 191-1 29 192-1 16 193-1 44 194-1 60 195-1 66

196-1 35 197-1 15 198-1 83 199-IV 16 200-Π 64 201-1 190 202-1 140 203-1 43 204-1 220 205-1 71 206-1 82 207-1 53 208-1 190 209-1 100 210-1 41 211-1 thirty 212-Π 97 213-1 1200 214-1 6.6 215-1 AND 216-1 25 217-1 24 218-1 33 219-1 21 220-1 29 221-1 22 222-1 60 223-1 18 224-1 27 225-1 19 226-1 14 227-1 28 228-1 14 229-1 21 230-1 32 231-1 240 232-1 480 233-1 22 234-1 78

- 232 043056

235-1 83 236-1 75 237-1 69 238-1 470 239-1 63 240-1 42 241-1 41 242-1 10 243-1 13 244-P 17 245-1 18 246-1 870 247-1 330 248-1 1500 249-1 120 250-1 27 251-1 61 252-1 72 253-1 400 254-1 1600 255-1 33 256-P 57 257-1 1400 258-1 250 259-1 53 260-1 430 261-II 27 262-1 120 263-1 23 264-1 580 265-1 22 266-1 36 267-1 16 268-1 20 269-1 24 270-1 580 271-1 100 272-1 65 273-1 720

274-1 58 275-1 42 276-1 35 277-1 38

Manual patch-clamp analysis of ROMK.

Cell culture conditions: thallium excretion assay cells. Channel expression was maintained under conditions similar to those for hROMK and was induced by adding 0.6 μg/ml doxycycline 16-24 h prior to experiments. On the day of the experiment, cells were separated using ethylenediaminetetraacetic acid, resuspended in growth medium, and plated on coverslips 15 min before use.

Electrophysiology: A coverslip covered with cells was placed in an experimental chamber perfused with a bath solution consisting of (in mM): 135 NaCl, 5 KCl, 2 CaCl ₂ , 1 MgCl ₂ , 10 HEPES, 5 glucose (pH 7.4). For the formation of gigacontacts, patch pipettes with a resistance of 2 to 5 megaohms were used, when filled with a solution containing (in mM): 135 KCl, 1 EGTA, 1 MgCl ₂ , 10 HEPES, 2 Na ₂ ATP (pH 7.3). Cells were terminated at -75 mV in whole cell configuration using an Axopatch 200b or Multiclamp 700b amplifier (Molecular Devices) controlled by pClamp software (Molecular Devices). The current was recorded by applying a voltage drop of up to -120 mV every 10 s. Each compound was added at 4-6 concentrations for 3-8 minutes in a sequential manner, starting with the lowest concentration. At the end of the experiment, the cells were perfused with a bath solution containing 2 mM Ba ²⁺ in order to isolate the contribution of the hROMK current.

Data Analysis: Raw current values (5 records for each control, compound concentration, and Ba ²⁺ treatment group) were exported from Clampfit to Microsoft Excel, where the current remaining after Ba ²⁺ application was subtracted from the raw current to obtain a specific current. for hROMK. These hROMK current values (mean of 5 records for each group) were then imported into a specialized template to generate a concentration-response curve, which was subsequently adjusted to a four-parameter equation to calculate the IC50 value of the test compound.

The data in the table. 7 are represented by two significant figures.

Table 7

Patent Example Number IC50 EP ROMK (nM) 1-1 AND 2-1 5.7 3-1 44 14-1 51 16-1 AND 22-1 25 23-1 4.9 37-1 22 59-1 4.8 61-1 40 65-1 9.8 66-1 4.7 67-1 29 82-1 7.9 83-1 6.8 84-1 57 87-SH 57 90-1 74 92-1 23 94-1 14 96-1 12 97-1 43 255-1 9.1 263-1 23 267-1 17

Patent Example Number IC50 EP ROMK (nM) 98-1 23 99-1 29 100-1 25 101-1 34 102-1 17 103-1 29 105-1 AND 106-1 10 107-1 18 108-1 21 109-1 54 110-1 16 111-1 62 121-1 740 126-1 17 127-1 14 130-1 20 139-1 thirty 148-1 19 151-1 64 164-1 thirty 165-1 39

Patent Example Number IC50 EP ROMK (nM) 166-1 13 167-1 18 168-1 29 171-1 26 173-1 21 175-1 17 184-1 10 187-1 25 188-1 18 189-1 17 190-1 13 191-1 21 193-1 20 195-1 79 207-1 18 210-1 20 216-1 14 221-1 13 228-1 20 230-1 19 240-1 34 244-P 22

Manual patch-clamp analysis hERG.

Electrophysiological analysis of hERG: Experimental compounds were evaluated for hERG activity on HEK293 cells stably expressing hERG channels using the patch clamp technique.

Cover slips seeded with cells expressing hERG were placed in the experimental chamber and perfused with a solution consisting of (in mM): 140 NaCl, 4 KCl, 1.8 CaCl ₂ , 1 MgCl ₂ , 10 glucose, 10 HEPES (pH 7.4 , NaOH) at room temperature. Borosilicate patch pipettes had a tip resistance of 2-4 MΩ when filled with an internal solution containing: 130 KCl, 1 MgCl ₂ , 1 CaCl ₂ , 10 EGTA, 10 HEPES, 5 ATP-K2 (pH 7.2, KOH). Cells were closed at -80 mV in whole cell configuration using an Axopatch 200B patch clamp amplifier (Axon instruments, Union City, CA) controlled by pClamp software (Axon instruments). When forming gigacontacts to record trace currents, the following voltage protocol (0.05 Hz) was successively applied: a depolarization stage from -80 to +20 mV for 2 s followed by a hyperpolarization stage up to -65 mV (3 s) for induction trace currents. The compounds were added after stabilization of the trace current. First, trace currents were recorded in the presence of only the extracellular solution (control), and then in the extracellular solution containing compounds in increasing concentrations. The compound at each concentration was added for 2–5 min. Percent inhibition at each concentration was calculated as the reduction in peak trace current relative to the peak trace current recorded in the presence of the control solution. Data analysis was carried out in a specialized template. The percentage of inhibition at various concentrations was transferred to a concentration-response curve, subsequently adjusted to a four-parameter equation to calculate the IC ₅₀ hERG value.

Several compounds of the present invention have been tested in the hERG assay. Preferred compounds had a low inhibitory effect on hERG or had a high IC50 value.

Patent Example Number % inhibition. EP hERG with 1 µM 1-1 26 2-1 19 3-1 26 6-1 38 9-1 47 11-1 40 14-1 1.7 15-1 5.8 16-1 7.3 21-1 8.5 22-1 6.0 23-1 12 25-1 8.7 26-1 20 27-1 AND 28-1 15 32-1 6.2 35-1 20 37-1 6.2 40-1 54 46-1 43 47-1 49

Patent Example Number % inhibition. EP hERG with 1 µM 48-1 78 49-1 27 51-1 43 52-1 72 57-1 26 59-1 15 63-1 23 64-1 45 65-1 21 66-1 0 67-1 7.1 70-1 8.4 81-1 7.7 82-1 7.1 83-1 AND 84-1 6.7 85-1 AND 86-1 8.8 87-SH 4.9 88-SH 8.3 89-SH 14 90-1 2.6

Table 8

Patent Example Number % inhibition. EP hERG with 1 µM 91-1 0 92-1 5.2 93-1 23 94-1 4.3 95-1 13 96-1 9.6 98-1 9.3 99-1 9.6 100-1 3.6 101-1 h, o 102-1 5.6 103-1 14 104-1 3.4 105-1 9.7 106-1 0.98 107-1 13 108-1 8.7 109-1 3.6 110-1 9.2 111-1 5.1 112-1 22 114-1 4.2

- 235 -

Claims (21)

1. Compound having the structure of formula (I) I ^x N—L ¹ ν-γ ' A”' ^(R ^d ) _n (I) where the compound of formula (I) is - 237 043056 or a pharmaceutically acceptable salt thereof, wherein R ¹ is each R ^1a is independently -CH3; L ¹ represents -C(R)2-, -C(O)- or -C(R) ₂ -C(R)2-, where R independently represents H, OH or C _1-3 -alkyl; where R is not -OH if it is attached to a carbon atom that is attached to a nitrogen atom; ring B is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, oxazolyl, pyridazinyl, pyrrolidinyl or imidazolidinyl; R ² is phenyl, pyridinyl, benzo[d]oxazolonyl, pyrazolyl, pyrazinyl, pyrazolo[1,5-a]pyrimidinyl, thiazolyl, thiophenyl, 1,2,3-triazolyl, imidazolyl, pyrrolo[2,3-b] pyridinyl, 1,2,4-triazolyl, pyridazinyl, pyrimidinyl, oxadiazolyl or pyrrolopyridinyl, each having 0-3 R ^2a substituents; R ^2a is independently =O, CN, halo, C1-4alkyl, C1-4fluoroalkyl, C1-4alkoxy, C1.4deuteroalkoxy, C1-4fluoroalkoxy, C3-6cycloalkyl, C(=O )N(R ^4b R ^4b ), SO2R ^e , NR ^4b SO ₂ R ^4b or oxazolidinyl, morpholinyl, pyrrolidinyl or dioxydoisothiazolidinyl, wherein oxazolidinyl, morpholinyl, pyrrolidinyl and dioxydoisothiazolidinyl optionally contain an oxo substituent and are optionally substituted with R ^2b ; R ^2b is C _1-3 -alkyl; R ^3a is H; R ^3b is H, or C _1-3 alkyl; R ⁴ is H, C1-3 alkyl, CO2R ^4a , C(O)R ^4a , SO2R ^4a or OH; R ^4a is C _1-3 -αkyl; R ^4b is independently H or C _1-3 alkyl; R ⁵ is independently H, F, OH, C _1-3 alkyl, NR ^5b R ^5b or OR ^5c , or 2 R ⁵ are ═O; where if one R ⁵ is F, OH or NR ^5b R ^5b then the other R ⁵ is not OH or NR ^5b R ^5b ; R ^5b is independently H, C(O)R ^a or SO2R ^a ; R ^5c is independently H, or C(O)NR ^b R ^b ; R ⁶ is independently H, OH, F, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3hydroxyalkyl, C1-3hydroxydeuteroalkyl or NR ^6b R ^6b ; where if one R ⁶ on one carbon atom is F, OH or NR ^6b R ^6b , then the other R ⁶ on the same carbon atom is not OH or NR6b _R 6b _; R ^6b is independently H, C(O)R ^a or SO ₂ R ^a ; R ^a is independently H, C _1-3 alkyl; R ^b is independently H, C _1-3 alkyl; each Rd is independently C _1-3 alkyl, C _1-3 fluoroalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, halogen, =O, or C(O)NR ^e R ^e ; - 238 043056 each Re ^is independently H or C ₁ . ₃ -alkyl; n is 0, 1, or 2. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, isoxazolyl, or pyridazinyl. 3. The compound according to claims 1, 2 or its pharmaceutically acceptable salt, where R ² is phenyl, pyridinyl, benzo[d]oxazol-2(3H)-onyl, pyrazolyl, pyrimidinyl, imidazolyl, triazolyl, oxadiazolyl, pyrazinyl, thiophenyl, pyrazolo[1,5-a]pyrimidinyl or benzo[d]oxazole -2(3H)-onyl, each substituted with 0-3 R ^2a ; And R ^2a is ═O, CN, halogen, SO ₂ C _1-3 -alkyl, oxazolidin-2-one, substituted with 0-1 R ^2b ; R ^2b is C ₁ . ₃ -alkyl. 4. The compound according to claims 1 to 3 or a pharmaceutically acceptable salt thereof, where ring B is pyridinyl, triazolyl, thiazolyl, oxadiazolyl, imidazolyl or pyrazolyl; And R ² is phenyl, pyridinyl, pyrimidinyl, benzo[d]oxazol-2(3H)-onyl, imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each substituted with 0-3 R ^2a . 5. The compound according to claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein L ¹ is -C(R) ₂ -; where R independently represents hydrogen, OH or C ₁ _ ₃ -alkyl; And R ⁶ is independently H, C ₁ _ ₃ alkyl or C ₁ _ ₃ fluoroalkyl. 6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino )methyl)-1Hpyrazol-1-yl)nicotinonitrile; (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl ) nicotinonitrile; (R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin2-yl)benzo[d]oxazol- 2(3H)-he; 5-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1Hpyrazol-1-yl)- 3-methylbenzo[d]oxazol-2(3H)-one; 6-(4-((4,4-difluoro-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1Hpyrazol-1-yl)- 4-methylnicotinonitrile; (R)-6-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl )-4-methylnicotinonitrile; (R)-4-methyl-5-(4-((1-(2-methylthiazol-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran1(3H)-one; (R)-4-cyclopropyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)- 1 H-pyrazol-1 -yl)nicotinonitrile; (R)-4-methyl-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H- pyrazol-1-yl)nicotinonitrile; (R)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxomorpholino)methyl)- 1 H-pyrazol-1 -yl)nicotinonitrile; (R)-4-methoxy-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl ) nicotinonitrile; (R)-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol-2yl)nicotinonitrile; (R)-4-methyl-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4oxadiazole -2-yl)nicotinonitrile; (R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1nimidazol-1-yl ) nicotinonitrile; (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H- pyrazol-1-yl)nicotinonitrile; (R)-4-methoxy-5'-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxo-oxazolidin-3-yl)methyl)-[2 ,2'-bipyridine]-5-carbonitrile; 6-(4-(1-hydroxy-2-((R)-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1Hpyrazol-1-yl)- 4-methylnicotinonitrile (diastereomer-I and II); (R)-3-methyl-5-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2yl)benzo[d]oxazol- 2(3H)-one; (R)-3-methyl-5-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholin-4-carbonyl)thiazol2-yl)benzo[d]oxazole -2(3H)-one; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)thiazol-2-yl)1H-imidazol- 4-carbonitrile; (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H1,2,3 -triazol-2-yl)nicotinonitrile; - 239 043056 (R) -4-methyl-6- (4- ((3 - (4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5-yl) piperazin-1 -yl) methyl) -1H1, 2,3-triazol-1-yl)nicotinonitrile; methyl-(R)-4-((1-(5-cyano-4-methylpyridin-2-yl)-III-pyrazol-4-yl)methyl)-2-(4-methyl-1-oxo-1, 3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate; (S)-4-methyl-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl) nicotinonitrile; (R)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)benzo [d]oxazol-2(3H)-one; (R)-6-(5-methoxy-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)- 4-methylnicotinonitrile; (R)-4-methoxy-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1nimidazol-1-yl)nicotinonitrile; (R)-6-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1yl)nicotinonitrile; (R)-3-methyl-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-imidazol-1-yl)benzo [d]oxazol-2(3H)-one; (R)-4-methyl-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1,3,4-oxadiazol-2 -yl) nicotinonitrile; (R)-4-methyl-6-(4-(2-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)ethyl)-1H-pyrazol-1-yl ) nicotinonitrile; (R)-4-methoxy-6-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)thiazol-2yl)nicotinonitrile; (R)-4-methyl-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholin-4-carbonyl)thiazol2-yl)nicotinonitrile; (R)-4-methoxy-6-(5-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholin-4-carbonyl)thiazol-2-yl)nicotinonitrile; (R)-4-methoxy-5'-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-[2,2'-bipyridine] -5 - carbonitrile; (R)-4-methyl-5 -(4-((2-(4-methyl-1 H-imidazol-1 -yl)thiazol-5-yl)methyl)morpholin-2-yl)isobenzofuran1(3H)- He; (R)-1-(5-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)pyridin-2-yl)-1nimidazole-4-carbonitrile; (R)-4-methyl-5-(4-((1-(thiophen-3-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)one; (R)-4-methyl-5-(4-((1-(pyrazin-2-yl)-1 H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)one; (R)-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1yl)benzonitrile; (R)-4-methyl-5 -(4-(( 1 -(6-methylpyrazin-2-yl)-1 H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran1(3Н)-one ; (R)-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1yl)nicotinonitrile; (R)-3-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1yl)benzonitrile; (R)-4-methyl-5-(4-((1-(pyridin-4-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)one; (R)-4-methyl-5-(4-((1-(4-(methylsulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran-1(3H)-one ; (R)-2-methyl-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1Hpyrazol-1-yl)benzonitrile; (R)-3-methyl-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1Hpyrazol-1-yl)benzonitrile; (R)-5-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1yl)picolinonitrile; (R)-2-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1Hpyrazol-1-yl)benzonitrile; (R)-4-methyl-5-(4-((1-(pyrazolo[1,5-a]pyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)morpholin-2-yl)isobenzofuran -1 (3H) -one; (R)-3-methoxy-4-(4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1Hpyrazol-1-yl)benzonitrile; (R)-4-methyl-6-(3-methyl-4-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)- 1 H-pyrazol-1 -yl)nicotinonitrile; - 240 043056 (R)-4-methyl-6-(3-((2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazole-1 - yl) nicotinonitrile; (S)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl ) nicotinonitrile; (R)-5-(5-methoxy-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl )-3-methylbenzo[d]oxazol-2(3H)-one; (R)-7-fluoro-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H -pyrazol-1-yl)benzo[d]oxazol-2(3H)-one; (R)-7-methoxy-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1H- pyrazol-1-yl)benzo[d]oxazol-2(3H)-one; (R)-3,7-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol- 1-yl)benzo[d]oxazol-2(3H)-one; (R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl )benzo[d]oxazol-2(3H)-one; (R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl ) nicotinonitrile; (R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H1,2,3 -triazol-1-yl)benzo[d]oxazol-2(3H)-one; (R)-6-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2 -yl) nicotinonitrile; (R)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-[2,2'bipyridine] -5-carbonitrile; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)1H-pyrazol- 4-carbonitrile; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)1H-imidazol- 4-carbonitrile; (R)-4-methyl-5 -(4-((6-(4-methyl-1 H-imidazol-1 -yl)pyridin-3 -yl)methyl)piperazin-2-yl)isobenzofuran-1(3Н )-He; (R)-4-methyl-5-(4-((6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl) isobenzofuran-1(3H)-one; (R)-6-(4-((4-Acetyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 Hpyrazol-1- yl)-4-methylnicotinonitrile; (R)-4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-(methylsulfonyl)piperazin-1-yl)methyl) -1H-pyrazol-1-yl)nicotinonitrile; (R)-4-methyl-6-(4-((4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H -pyrazol-1-yl)nicotinonitrile; (R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H- pyrazol-1-yl)benzo[d]oxazol-2(3H)-one; (R)-3-methyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-1H- 1,2,3-triazol-1-yl)benzo[d]oxazol-2(3H)-one; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofurαn-5-yl)-5-oxonineperαzin-1-yl)methyl)niridin-2-yl)- 1H-1,2,4-triazole-3-carbonitrile; (R)-4-methoxy-5'-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1-yl)methyl)-[2,2 '-bipyridine]-5-carbonitrile; (R)-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-((6-(3-methyl-1H-1,2,4-triazol-1-yl )pyridin-3-yl)methyl)piperazin-2-one; (R)-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-((6-(4-methyl-1H-imidazol-1-yl)-pyridin3-yl)methyl )piperazine-2-one; (R)-4-methyl-6-(4-((4-methyl-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-5-oxopiperazin-1 yl)methyl) -1H-pyrazol-1-yl)nicotinonitrile; (R)-4-methoxy-6-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3yl)methyl)-1H-imidazol- 1-yl)nicotinonitrile; (R)-6-(5-methoxy-4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3yl)methyl)-1H-pyrazole- 1-yl)-4-methylnicotinonitrile; (R)-3-methyl-5-(4-((5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxooxazolidin-3-yl)methyl)-1H- pyrazol-1-yl)benzo[d]oxazol-2(3H)-one; 6-(4-(((3R,5R)-3-(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)- 1H-1 ,2,3-triazol-1-yl)-4-methylnicotinonitrile; 2,4-dimethyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl) methyl)-2H-1,2,3-triazol-2-yl)nicotinonitrile; - 241 043056 4-Methoxy-2-methyl-6-(4-(((3S,5R)-3 -methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)-1H-1,2,3-triazol-1 -yl)nicotinonitrile; 6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl )-4-methylnicotinonitrile, (enantiomer-III); 6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)- 1H-1,2,3 -triazol-1 -yl)-4-methylnicotinonitrile, (enantiomer-III); 6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl )-4-methoxynicotinonitrile, (enantiomer-III); 6- (4- ((3 - (hydroxymethyl-d ₂ ) -5- (4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5-yl) piperazin-1 -yl) methyl) -1H-pyrazol- 1 -yl)-4-methylnicotinonitrile, (enantiomer-I); 1-(5-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)pyridine-2- yl)-3-methyl-1H-pyrazole-4-carbonitrile; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1 H- pyrazol-1-yl)-2,4-dimethylnicotinonitrile; 2-methoxy-6-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -1H-pyrazol-1-yl)nicotinonitrile; 5-((2R,6S)-4-((2-(4,5-dimethyl-III-imidazol-1-yl)pyrimidin-5-yl)methyl)-6-methylpiperazin-2-yl)4-methylisobenzofuran -1 (3H) -one; 4,6-dimethyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl) methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile; 4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-ul)piperazin-1yl)methyl)-1 H-pyrazol-1-yl)pyrimidine-5-carbonitrile; 4-methoxy-6-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -1H-imidazol-1-yl)nicotinonitrile; 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1H -imidazol-1-yl)nicotinonitrile; 4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-2H -1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile; 2-methoxy-4-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -1H-imidazol-1-yl)benzonitrile; 4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-methylpyridin-4-yl)-1H-pyrazol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; 4-methoxy-2-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -1 H-imidazol-1 -yl)pyrimidine-5-carbonitrile; 2-(4-(((3R,5R)-3-(hydroxymethyl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2H- 1,2,3-triazol-2-yl)-4-methylpyrimidine-5-carbonitrile; 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1H -pyrazol-1-yl)nicotinonitrile; 4-methyl-6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-ul)piperazin-1yl)methyl)- 1H -1,2,3-triazol-1 -yl)nicotinonitrile; 4-methoxy-6-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -2H-1,2,3-triazol-2-yl)nicotinonitrile; 3-methyl-1-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)pyrimidine- 2-yl)-1H-pyrazole-4-carbonitrile; 5-(4-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-2H-1 ,2,3-triazol-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-2H-1 ,2,3-triazol-2-yl)-4-methoxynicotinonitrile; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazole -1-yl)-4-methoxynicotinonitrile; 4,4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl) thiazol-2-yl)nicotinonitrile; 6-(4-((4-hydroxy-4-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1 -yl)-4-methylnicotinonitrile; 4-methyl-6-(4-((2-methyl-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol-1- yl) nicotinonitrile; 6-(4-((4-hydroxy-3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1yl)methyl)-1H-pyrazole-1 -yl)-4-methylnicotinonitrile; 4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-2 -oxooxazol-3(2H)yl)nicotinonitrile; (R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoimidazolidin-1yl)methyl)-1H-pyrazole- 1-yl)nicotinonitrile; - 242 043056 (R)-4-methyl-6-(4-((4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1,1-dioxido-1,2, 5-thiadiazolidin-2-yl)methyl)-1H-pyrazol-1-yl)nicotinonitrile; 2-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)pyridine- 2-yl)pyridazin-3(2H)-one; 4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H1,2 ,3-triazol-2-yl)nicotinonitrile (diastereomer-1:enantiomer-1); 4-methyl-6-(4-(1-((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)ethyl)-2H- 1,2,3-triazol-2-yl)nicotinonitrile (diastereomer-P:enantiomer-1); 4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-ul)piperazin-1yl)methyl)- 1H -1,2,4-triazol-1 -yl)nicotinonitrile; 6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl )-4-methylnicotinonitrile (diastereomer-1:enantiomer-1); 6-(4-((2-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1-yl )-4-methylnicotinonitrile (diastereomer-1:enantiomer-P); 6-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)thiazol-2- yl)-4-methylnicotinonitrile; 5-((2R,6S)-4-((1-(2-methoxypyridin-4-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4-methylisobenzofuran-1 (3H)-he; 5-((2R,6S)-4-((1-(2-(difluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)4-methylisobenzofuran -1 (3H) -one; 4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazol-4-yl)methyl)piperazin-2- yl)isobenzofuran-1(3H)-one; 1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1H-pyrazol-1-yl)pyridin-2(1H)-one; 1-(5-(((3R,5R)-3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)pyridine-2- yl)-3-methyl-1H-pyrazole-4-carbonitrile; 1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1H-imidazol-1-yl)pyridin-2(1H)-one; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)oxazol-2- yl)-4-methylnicotinonitrile; 4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)oxazol- 2-yl)nicotinonitrile; 5-((2R,6S)-4-((1-(6-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2yl)-4-methylisobenzofuran- 1 (3H)-he; (R)-3,4-dimethyl-5-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol- 1-yl)benzo[d]oxazol-2(3H)-one; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)1 H-pyrazole -3 - carbonitrile; (R)-4-ethoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl ) nicotinonitrile; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)1H-pyrazol- 4-carboxamide; W)-5-(4-((2-(2,4-dimethyl-III-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1 (3N) -He; (R)-4-isopropoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazol- 1 -yl) nicotinonitrile; (R)-4-methyl-5-(4-((4-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran -1 (3H) -one; (R)-4-methyl-5-(4-((2-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran -1 (3H) -one; (R)-4,6'-dimethoxy-5'-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)[2,2' -bipyridine]-5-carbonitrile; (R)-5-(4-((5-fluoro-6-(4-methyl-III-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1 (3H)-he; (R)-4-methyl-6-(3-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H -pyrazol-1-yl)nicotinonitrile; (R)-4-methyl-6-(5-methyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H -pyrazol-1-yl)nicotinonitrile; (R)-4-methyl-5-(4-((6-(4-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)pyridin-3-yl)methyl)piperazin2-yl)isobenzofuran -1 (3H) -one; (R)-5-(4-((2-(4,5-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1 (3H )-He; - 243 043056 (R)-5-(4-((4-methoxy-6-(4-methyl-1 H-imidazol-1 -yl)pyridin-3-yl)methyl)piperazin-2-yl)-4 -methylisobenzofuran-1(3H)-one; (R)-5-(4-((2-(5-(difluoromethyl)-4-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)4-methylisobenzofuran- 1 (3H)-he; 4 ,6-dimethyl-2-(4-(((3 S,5R)-3 -methyl-5-(4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5 -yl)piperazin-1 yl) methyl)-2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile; 3-(3-methyl-5-(4-(((3 S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl )methyl)-1H-pyrazol-1-yl)phenyl)oxazolidin-2-one; (R)-4-methyl-5 -(4-((6-(4-methyl-1 H-imidazol-1 -yl)pyridazin-3 -yl)methyl)piperazin-2-yl)isobenzofuran-1(3Н )-He; 4-methoxy-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl) nicotinonitrile (diastereomer-I); 4-methoxy-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl) nicotinonitrile (diastereomer-II); 4-methyl-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl) nicotinonitrile (diastereomer-I); 4-methyl-6-(3-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl) nicotinonitrile (diastereomer-II); 4-methyl-6-(4-(((R)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2oxopyrrolidin-1-yl ) nicotinonitrile (diastereomer-II); 4-methoxy-6-(4-(((R)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2oxopyrrolidin-1-yl ) nicotinonitrile (diastereomer-I); 4-methyl-6-(5-(((R)-3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2-oxooxazolidin-3 -yl) nicotinonitrile (diastereomer-II); 4-methyl-5-((2R,6S)-6-methyl-4-((1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-2- yl)isobenzofuran-1(3H)-one; 4-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-imidazole -1-yl)-2-methoxybenzonitrile; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-imidazole -1-yl)-4-methylnicotinonitrile; 4-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1H -imidazol-1-yl)pyrimidine-5-carbonitrile; 4-methyl-5-((2R,6S)-6-methyl-4-((6'-(methylsulfonyl)-[2,3'-bipyridin]-5-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; 4-methoxy-2-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -2H-1,2,3-triazol-2-yl)pyrimidine-5-carbonitrile; 4-methoxy-2-(2-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)-1H-imidazol-1-yl)pyrimidine-5-carbonitrile; (R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H1,2,3 -triazol-2-yl)nicotinonitrile; (R)-4-methyl-6-(4-methyl-5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H -1,2,3-triazol-2-yl)nicotinonitrile; 4-methoxy-6-(4-(((3 S,5R)-3-methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) -2-oxopyrrolidin-1-yl)nicotinonitrile (diastereomer-I); 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-3-methyl -2-oxo-2,3-dihydro-1H-imidazol-1 -yl)-4-methoxynicotinonitrile; 6-(3-isopropyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin- 1 -yl)methyl)-2-oxo-2,3-dihydro-1H-imidazol-1 -yl)-4-methoxynicotinonitrile; 3-methyl-4-(((3 S,5R)-3 -methyl-5-(4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5 -yl)piperazin-1 -yl)methyl)-1 -(2-methylpyrimidin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 3-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)[2,4 '-bipyridine]-2'-yl)oxazolidin-2-one; 6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-5methyl-2H-1,2 ,3-triazol-2-yl)-4-methylnicotinonitrile (enantiomer-I); 4-methyl-6-(5-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 - yl)methyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile; (R)-4-methyl-5 -(4-((1-(1-methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)- 1 H-pyrazol-4-yl)methyl )morpholin2-yl)isobenzofuran-1(3H)-one; 4-methyl-5-((2R,6S)-6-methyl-4-((1-(p-tolyl)-1H-imidazol-4-yl)methyl)piperazin-2-yl)isobenzofuran-1(3Н )-He; 4-methyl-5-((2R,6S)-6-methyl-4-((1-(3-methylpyridin-4-yl)-1H-imidazol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; - 244 043056 4-methyl-5-((2R,6S)-6-methyl-4-((1-(6-methylpyridin-3-yl)-III-imidazol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; 5-((2R,6S)-4-((1-(2,6-dimethylpyridin-4-yl)-III-imidazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4methylisobenzofuran-1 (3H)-he; 5-((2R,6S)-4-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazine -2-yl)-4-methylisobenzofuran-1 (3H)-one; (R)-4-methyl-6-(2-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-5-yl) nicotinonitrile; (R)-2,4-dimethyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)2H-1, 2,3-triazol-2-yl)nicotinonitrile; (R)-3-(2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol1-yl) pyridin-4-yl)oxazolidin-2-one; (R)-2,4-dimethyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-1, 2,3-triazol-1-yl)nicotinonitrile; (R) -4-methoxy-2-methyl-6- (4- ((3 - (4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) - 1H- 1,2,3-triazol-1-yl)nicotinonitrile; (R)-4-methoxy-2-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-2H- 1,2,3-triazol-2-yl)nicotinonitrile; (R) -2-methoxy-4-methyl-6- (4- ((3 - (4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5 -yl) piperazin-1 yl) methyl) - 1H- 1,2,3-triazol-1-yl)nicotinonitrile; 6-(4-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-2H1,2,3-triazole -2-yl)-4-methoxynicotinonitrile (enantiomer-I); 4-Methoxy-6-(4-(2-((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl) ethyl)-1H-pyrazol-1-yl)nicotinonitrile; 6-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)isoxazol-3- yl)-4-methylnicotinonitrile; 5-((2R,6S)-4-((1-(4-methoxy-1,3,5-triazin-2-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2- yl)-4methylisobenzofuran-1(3H)-one; 6-(4-(((3R,5R)-3-(hydroxymethyl)-4-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile; 6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol- 1-yl)-4-(trifluoromethyl)nicotinonitrile; 4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1 Hpyrazol-1-yl)nicotinonitrile ( enantiomer-I); (R)-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1yl)isonicotinonitrile ; 6-(4-((3-hydroxy-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1Hpyrazol-1-yl)-4- methylnicotinonitrile (enantiomer-GU); 6-(4-((3-methoxy-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1Hpyrazol-1-yl)-4- methylnicotinonitrile (enantiomer-GG); (R)-5-(4-((2-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4 -methylisobenzofuran-1(3H)-one; 3-methyl-2-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-1H -pyrazol-1-yl)isonicotinonitrile; 6-(4-((3-fluoro-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)- 1H-1,2,3triazol-1 -yl)-4-methylnicotinonitrile (enantiomer-G); 6-(4-((3-(1-hydroxyethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazole-1 -yl)-4-methoxynicotinonitrile (enantiomer-G); 6-(4-((3-(difluoromethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol-1-yl) -4-methylnicotinonitrile (enantiomer-G); 4-methyl-5-((2R,6S)-6-methyl-4-((1-(5-methylpyrazin-2-yl)-1H-pyrazol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; 5-((2R,6S)-4-((1-(6-methoxypyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4methylisobenzofuran-1 (3H )-He; 5-((2R,6S)-4-((1-(2-methoxypyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)-6-methylpiperazin-2-yl)-4methylisobenzofuran-1 (3H )-He; 4-methyl-5-((2R,6S)-6-methyl-4-((1-(2-methylpyrimidin-5-yl)-1H-pyrazol-4-yl)methyl)piperazin-2yl)isobenzofuran-1 (3H)-he; 4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)isoxazol- 5-yl)nicotinonitrile; 6-(4-((3-hydroxy-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidin-1-yl)methyl)-1Hpyrazol-1-yl)-4- methylnicotinonitrile (diastereomer-G:enantiomer-G); - 245 043056 6-(4-((3-fluoro-4-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)pyrrolidin-1-yl)methyl)-1 Hpyrazol-1-yl)-4 -methylnicotinonitrile (diastereomer-canantiomer-P); 6-(4-((3 -(2-hydroxypropan-2-yl)-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)-1H- pyrazol-1-yl)-4-methylnicotinonitrile (enantiomer-I); 4-methyl-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)isoxazol- 3-yl)nicotinonitrile; (R)-4-methyl-5 -(4-((2-(4-methyl-1 H-imidazol-1 -yl)pyrimidin-5-yl)methyl)piperazin-2-yl)isobenzofuran-1 (3H )-He; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2yl)-1H-imidazol-4 -carbonitrile; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydro-isobenzofuran-5-yl)nunerazin-1-yl)methyl)nirimidin-2yl)- 1H-1,2 ,4-triazole-3-carbonitrile; (R)-3-cyclopropyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-3 -(difluoromethoxy)-1 -(5-((3 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl)pyridin-2-yl )-1H-pyrazole-4-carbonitrile; (R)-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazol-1 yl)- 4-morpholinonicotinonitrile; (R)-3-methyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-4-methyl-5-(4-((6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl) isobenzofuran-1(3H)-one; (R)-3-methoxy-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-4-methyl-5 -(4-((2-(4-methyl-1 H-imidazol-1 -yl)pyrimidin-5-yl)methyl)morpholin-2-yl)isobenzofuran-1 (3H )-He; (R)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl)1H-1, 2,3-triazole-4-carbonitrile; (R)-3-ethyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-3-methoxy-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-3-ethyl-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2-yl) -1H-pyrazole-4-carbonitrile; (R)-3-(difluoromethyl)-1-(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyrimidin-2- yl)-1H-pyrazole-4-carbonitrile; (R)-4-methyl-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1Hpyrazol-1-yl )pyrimidine-5-carbonitrile; (R)-2-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1 H-pyrazol-1 yl)- 5-(pyrrolidin-1-yl)isonicotinonitrile; 4-methyl-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-oxo-piperidin-1-yl)methyl)1H-pyrazol-1-yl ) nicotinonitrile; (R)-6-(3-(difluoromethyl)-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazole -1-yl)-4-methylnicotinonitrile; (R)-5-(4-((2-(1H-1,2,4-triazol-1-yl)pyrimidin-5-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran1(3H)- He; (R)-5-(4-((6-(4(difluoromethyl)-1H-imidazol-1-yl)pyridin-3-yl)methyl)piperazin-2-yl)-4-methylisobenzofuran-1 (3H) -He; (R)-4-methyl-5 -(4-((2-(4-(trifluoromethyl)-1 H-imidazol-1 -yl)pyrimidin-5 -yl)methyl)piperazin-2yl)isobenzofuran-1 (3H )-He; (R)-6-(3-cyclopropyl-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1 -yl)-4-methylnicotinonitrile; 1'-methyl-5-(((3 S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)- [2,3'-bipyridine]-6'( 1 'H)-one; (R)-4-methyl-6-(4-((3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H-pyrazol-1yl)nicotinonitrile; 4-methyl-6-(4-(((6R)-2-methyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)1H-pyrazole-1- yl) nicotinonitrile (diastereomer-I); (R)-3-methyl-1-(6-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-3-yl) -1 H-pyrazole-4-carbonitrile; (R)-4-methyl-1 -(5-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)pyridin-2-yl) -1 H-pyrazole-3-carbonitrile; - 246 043056 (R) -4-methyl-1 - (5- ((3 - (4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5-yl) piperazin-1 -yl) methyl) pyrimidin-2 -yl)-1 H-pyrazole-3-carbonitrile; 4-methyl-6-(4-((2-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H-pyrazol-1- yl) nicotinonitrile (enantiomer-II); 6-(3 -(difluoromethyl)-4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl) methyl)-1H-pyrazol-1-yl)-4-methylnicotinonitrile; 6-(4-(((3S,5R)-4-hydroxu-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofurαn-5-yl)nunerazin-1yl)methyl)-2Н -1,2,3-triazol-2-yl)-4-methylnicotinonitrile; 4'-methyl-4-(((3 S,5R)-3 -methyl-5-(4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 -yl)methyl)- 2-oxo-2H-[1,2'-bipyridine]-5'-carbonitrile; N-(1-((1 -(5-cyano-4-methylpyridin-2-yl)-1 H-pyrazol-4-yl)methyl)-3-(4-methyl-1-oxo-1,3- dihydroisobenzofuran-5-yl)piperidin-4-yl)acetamide (diastereomer-P:enantiomer-!); 3 -(6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl) -1H-pyrazol-1-yl)pyridin-2-yl)oxazolidin-2-one; 6-(4-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-3-methyl -2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methylnicotinonitrile; 3 -(2-methyl-6-(4-(((3 S,5R)-3 -methyl-5 -(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl )methyl)-1H-pyrazol-1-yl)pyridin-4-yl)oxazolidin-2-one; N-methyl-N-(6-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl )-1H-pyrazol-1-yl)pyridin-2-yl)methanesulfonamide; 5-((2R,6S)-4-((1-(4-(1,1-dioxyisothiazolidin-2-yl)-6-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)- 6-methylpiperazin-2-yl)-4-methylisobenzofuran-1(3H)-one; 1 -(2-methoxypyridin-4-yl)-4-(((3 S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5yl)piperazin-1- yl)methyl)pyrrolidin-2-one (diastereomer-I); (R)-4-methoxy-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1H1,2,3 -triazol-1 -yl)nicotinonitrile; 6-(4-((2,2-dimethyl-6-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)morpholino)methyl)-1H-pyrazol-1-yl)-4- methylnicotinonitrile (enantiomer-II); N-(1-((1-(5-cyano-4-methylpyridin-2-yl)-1H-pyrazol-4-yl)methyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran -5-yl)piperidin-3-yl)acetamide (enantiomer-I); 1 -((1 -(5-cyano-4-methylpyridin-2-yl)-1 H-pyrazol-4-yl)methyl)-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5 -yl)piperidin-4-yl methyl carbamate (enantiomer-I); 4-methyl-6-(3-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofurαn-5-ul)nunerαzin-1yl)methyl)-1 ,2,4-oxadiazol-5-yl)nicotinonitrile; (R)-1 -(5-cyano-4-methoxypyridin-2-yl)-N-methyl-4-((3-(4-methyl-1-oxo-1,3-d ihydroisobenzofuran5-yl)piperazin- 1 -yl)methyl)-1 H-pyrazole-3-carboxamide; 6-(4-((3-(hydroxymethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-1H-pyrazol-1-yl )-4-methylnicotinonitrile (diastereomer-P:enantiomer-P); (R)-1-(5-cyano-4-methoxypyridin-2-yl)-4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl )methyl)-1 H-pyrazole-3-carboxamide; (R)-4-(methoxy-d ₃ )-6-(4-((3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1H -1,2,3-triazol-1 -yl)nicotinonitrile; (R)-4-methyl-5 -(4-((6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)methyl)piperazin-2-yl)isobenzofuran- 1 (3H)-he; 2-methyl-4-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1yl)methyl)-2H -tetrazol-2-yl)benzonitrile; 3-methyl-4-(((3 S,5R)-3 -methyl-5-(4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5 -yl)piperazin-1 -yl)methyl)-1 -(2-methylpyridin-4-yl)-1,3-dihydro-2H-imidazol-2-one; 6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)-1,3,4oxadiazol-2 -yl)-4-methylnicotinonitrile (enantiomer-I); 6-(5-((3,3-dimethyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)isoxazol-3-yl)-4 -methylnicotinonitrile (enantiomer-I); 4-methoxy-6-(5-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1 yl)methyl) isoxazol-3-yl)nicotinonitrile; 1-(difluoromethyl)-4-(4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl) methyl)-2H-1,2,3-triazol-2-yl)pyridin-2(1 H)-one; 5-((2R,6S)-4-((1-(2-(difluoromethyl)pyrimidin-4-yl)-1H-imidazol-4-yl)methyl)-6-methylpiperazin-2yl)-4-methylisobenzofuran- 1 (3H)-he; 4-(5-(((3R,4R)-4-hydroxy-3-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-1-yl)methyl)-2H-tetrazole -2-yl)-2-methoxybenzonitrile; 6-(5-((3-(difluoromethyl)-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1-yl)methyl)1,3,4-oxadiazol- 2-yl)-4-methylnicotinonitrile (enantiomer-I); - 247 043056 4-methoxy-6-(3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazin-1- yl)methyl)-2-oxoimidazolidin-1-yl)nicotinonitrile (diastereomer-I); 1-(2-methoxypyridin-4-yl)-3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl )piperazin-1-yl)methyl)-1,3-dihydro-2H-imidazol-2-one; 1-(2-(difluoromethyl)pyridin-4-yl)-3-methyl-4-(((3S,5R)-3-methyl-5-(4-methyl-1-oxo-1,3-dihydroisobenzofuran- 5-yl)piperazin-1-yl)methyl)-1,3-dihydro-2H-imidazol-2-one; And 4-methoxy-6-(5 -(((3S,5R)-3-methyl-5 -(4-methyl-1 -oxo-1,3-dihydroisobenzofuran-5-yl-3,3d ₂ )piperazine-1 -yl)methyl)isoxazol-3-yl)nicotinonitrile. 7. Connection, where the connection is or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 7, where the compound is or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, where the compound is 11. A compound, wherein the compound is or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 11, where the compound is - 248 043056 13. A compound, where the compound is or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 13, where the compound is 15. A compound, where the compound is or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 15, where the compound is 17. A compound, where the compound is or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 17, where the compound is - 249 043056 19. A pharmaceutical composition containing a therapeutically effective amount of one or more compounds according to claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 20. The use of a therapeutically effective amount of a compound according to claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the treatment of a cardiovascular disease. 21. Use according to claim 20, wherein said disease is selected from hypertension, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, acute decompensated heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension , pulmonary arterial hypertension, heart failure, nephrotic syndrome and acute renal failure. 22. The use of a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, to stimulate diuresis or natriuresis.