SA07280596B1 - Pyridine Amide Compounds and Their Use as Inhibitors of 11- B- Hydroxysteroid Dehydrogenase Type 1 Enzyme - Google Patents

Abstract

Compounds of formula (I) wherein variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are described.

Description

Y — _ Pyridine amide compounds and their use as inhibitors of 11-B-hydroxysteroid dehydrogenase type 1 enzyme Full description: Background of the invention: This relates to The invention contains chemical compounds or pharmaceutically acceptable salts thereof. These compounds have an inhibitory effect on the human enzyme 11-B-hydroxysteroid dehydrogenase type I (11BHSD1), and therefore are considered important in the treatment of pathological conditions, including the metabolic syndrome, and are considered useful in oo Methods of treatment of cl Ql hot blood Jie human. The invention also relates to processes for the manufacture of said compounds; It is related to pharmaceutical formulations containing it and its use in the manufacture of drugs to inhibit enzyme 11811901 in warm-blooded organisms such as humans. Cortisol (glucocorticoids in humans and 5 corticosterone in rodents) are considered antagonistic regulators, that is, they resist the effects of insulin: MF, Strack AM, Akana SF et al. 1993; Front Neuroendocrinol 14, 303-347). It regulates modification 1 of hepatic enzymes that are involved in the formation of glucose and in increasing the supply of enzyme subject matter by the release of glycerol from adipose tissue ( Increased breakdown of fats) and amino acids from muscles (decreased protein degradation and increased its breakdown). Glucocorticoids are also important in the differentiation of pre-adipocytes into Yyaivia

Y — — Mature adipose cells able to store triglycerides (Bujalska IJ et al. 1999; Endocrinology 140, 3188-3196) This may be critical in disease states when associated with glucocorticoids produced by “stress.” Stress Central obesity Central obesity, which in itself is a strong risk factor for type 0 diabetes and high blood pressure Cardiovascular disease les 18 (ares hypertension) : (Bjorntorp P & Rosmond R 2000;

J.

Obesity 24, S80-S85) It is well known (oy) that the activity of ay glucocorticoids is controlled simply by cortisol secretion but is also controlled at the tissue level by intertransversion in active cortisol and noncortisone Active by enzymes: 11-beta hydroxysteroid dehydrogenases, 1 BHSD1 0 (which activates cortisone and enzyme sll) 11BHSDI inactivates cortisol (Sandeep TC & Walker BR 2001 Trends in Endocrinol & Metab. 12, 446 The importance of this mechanism was first demonstrated using treatment with (lic) carbenoxolone, an anti-ulcer that inhibits both enzymes (11811502): (Walker BR et al. 1995; J.

Clean.

Endocrinol.

Metab. 80, 3155-3159) 0 that leads to increased insulin sensitivity indicating that enzyme 11811501 regulates the effects of insulin by reducing the levels of active glucocorticoids in tissues: Walker BR et al. 1995; J.

Clean.

Endocrinol.

Metab. 80, 3155-3159).

And

Cushing's Syndrome An increase in cortisol, which in turn is accompanied by glucose intolerance or obesity

central obesity (caused by stimulation of the synthesis of pre-adipogenic cells in this depot); and misalignment

The level of lipids in the blood, “dyslipidaemia and hypertension, hypertension pall syndrome appear

A number of obvious things happen in parallel with the metabolic syndrome, even though the metabolic syndrome is not generally associated with an increase in blood levels.

Cortisol: in the circulatory system

(Jessop DS et al. 2001; J.

Clean.

Endocrinol.

Metab. 86, 4109-4114) it is expected to increase

The abnormal activity of enzyme 11011501 within the tissues has the same effect. It turns out in obese men that

Although they had the same or lower levels of plasma cortisol than in lean men,

The activity of enzyme 1 in subcutaneous fat was greatly enhanced

J. Clin.

Endocrinol.

Metab. 1418 - 1421). ¢Rask E et al. 2001 In addition to “ly the fat

Central activity associated with the metabolic syndrome has significantly higher levels of subcutaneous lipid activity 11811801

Skin 1997 Lancet 349 ¢ (Bujalska U et al.) (1210-1213). Thus there appears to be a link between compounds 058 and enzyme 11811501 and the metabolic syndrome.

1 The mouse that was mutated in enzyme 11811801 by excluding a specific gene showed weak activation by glucocorticoids effect of gluconeogenic enzymes as a result of fasting or low levels of glucose in plasma as a result of stress or obesity:

(Rask E et al. 2001; J.

Clean.

Endocrinol.

Metab. 1418-1421) explaining the use of enzyme 1 inhibition in reducing plasma glucose and reducing hepatic output in type 2 diabetes mellitus. Furthermore it; This mouse showed an anti-aggregation curve of the Yava lipoprotein

_ M __ has low triglycerides and high HDL cholesterol and elevated apolipoprotein levels: (Morton NM et al. 2001; J.

Biol.

Chem. 276, 41293-41300) the reason for this phenotype is considered to be increased hepatic expression of the enzymes fat catabolism and PPAR. Metabolic Syndrome Blood Lipids The most convincing illustration of the link between metabolic syndrome and enzyme 11811501 comes from recent studies of a transgenic mouse that overexpresses an enzyme (Masuzaki H et al. 2001; Science 294, 2166-2170). 11811901 0 When modified under the control of a lipid-specific promoter, the mouse transgenic with enzyme 71 suffers from elevated corticosterone lipid levels and central obesity17; What is most important is that the high levels of enzyme 1 activity in the fat of these mice is similar to that seen in obese patients. The activity of enzyme 10 was 1180115101 hepatic and corticosterone levels in normal plasma.However, the levels of 00106 in the hepatic portal vein increased ?times and it is believed that this is the reason for the metabolic effects in the liver.Jiver

A——Finally, it is now clear that the full-blown metabolic syndrome can be simulated in mice simply by over-modulating enzyme 11811511 in fat alone at levels similar to those found in an obese man. The enzyme 11011501 is widely distributed in the tissue and bypasses the distribution of the metabolite “glucocorticoids 0”. Thus, it can strongly resist the inhibition of the enzyme 11811501. The effects of glucocorticoids in a number of physiological / pathological functions. There is an enzyme 11811801 in human skeletal muscle. human skeletal muscle, and glucocorticoid resistance to the anabolic effects of insulin on protein transformation and metabolism6 is well documented (Whorwood CB et al. 2001; J.

Clean.

Endocrinol.

Metab. 86, 2296-2308). Therefore, skeletal muscle should be considered a target of Lala for enzyme-dependent therapy. BHSDI-11 also reduces insulin (3h) glucocorticoids and may lead to increased anticholinergic effects. Insulin produced by glucocorticoids modulates pancreatic islets enzyme 1 and carbenoxolone can inhibit the effect of 11-dehydocorticosterone on the release of: (Davani 8 et al. 2000; J.

Biol.

Chem. 275, 34841-34844) 0 Thus, in the treatment of diabetes, Gull reductase 1BHSDI inhibitors can not only act at the tissue level in relation to insulin resistance but also increase insulin secretion itself. Structural growth and bone function are also regulated by the effect of glucocorticoids, and there is an enzyme 11811801 in the cells, Osteoporosis and bone building, and the treatment of healthy volunteers was explained by the

Y — _ carbenoxolone decreased in signs of bone resorption with no change in signs of bone formation: (Say (Cooper MS © al 2000; Bone 27, 375-381) using inhibition of bone 11811501 enzyme activity as a mechanism, 458 in Treatment of osteoporosis. Glucocorticoids may also be involved in eye diseases such as glaucoma. It has been shown that enzyme 1 affects intraocular pressure in humans. It is expected that inhibition of enzyme 11011571 relieves excess intraocular pressure. Glaucoma-associated eyeball: (Rauz 5 et al. 2001; Investigative Opthalmology & Visual Science 42, 2037-2042). Clearly, there is a convincing link between enzyme 11811571 and metabolic syndrome in both rodents and humans. Evidence indicates Indicates that a drug that specifically inhibits enzyme 11811501 0 in obese type 2 diabetics will lower the level of glucose in the blood by reducing glucose formation in the liver; reduce central obesity and improve the phenotype of the causative lipoprotein. To aggregate 0” and lower blood pressure ©1037 and reduce resistance to 0. The effects of insulin in the muscle will be enhanced and the secretion of WA (insulin beta cells) in the islets may also be increased. There are two known definitions of Glad for metabolic syndrome (1) metabolic syndrome The Treatment for Adults Authority (TMA) 2001 definition 77111 states that metabolic syndrome is considered to be present if a patient has three or more of the following symptoms: - The waist measurement was at least 460 inches (VY cm) for men; and AA cm YO) inches

A _ __ for women ¢ - the level of triglycerides in serum (fame) © “serum L (1 mmol/L) was at least; - The Jil HDL cholesterol levels were of 46 mg/dL (Ho.mol/L) in men; and less than 000 mg/dL (9010 mol/L) in women; - the pressure of [YY blood pressure pall] was at least 0 mmHg; And/or - the blood sugar level (Let 1) Al (serum glucose) Blood sugar (mol/L) is at least: (Y) The following definition has been recommended by the WHO advisory body Which does not include causal relationships and is suggested as a sufficient definition to be improved in time: - The patient suffers from at least one of the following conditions: Glucose intolerance or acquired glucose tolerance oe (IGT) diabetes Diabetes and/or insulin resistance with two or more of the following: ¢raised arterial pressure 1 - elevated levels of triglycerides in plasma; - Central obesity - Traces of albumin in the urine - Microalbuminuria. The inventors have found that all compounds defined in the invention or pharmaceutically acceptable salts thereof

And - they are effective inhibitors of enzyme 11811501, and accordingly they are considered important in the treatment of pathological conditions associated with the metabolic syndrome. For example ;" Generally the compounds of the invention have a good oral bioavailability of 0:81 while oo has the potency. It is thus expected that this group of compounds provides superior oral exposure at a low dose and is thus particularly suited for the treatment or prevention of a disease or medical condition that can be treated by inhibition of 11811501. The invention may include superior potency, beneficial physical properties, and/or Favorable toxicity profiles and/or favorable metabolic profiles compared to the 11811511 inhibitors known in the art. 0 General description of the invention: Accordingly, a compound of formula (1) is provided: (RY), 0 NF 0 Le | Ha Ri 0 (1) where: © is a single bond p081; or -0-; or -4-8; or Cua N(R1S)—a kelase Vo is hydrogen , Cy.salkyl or Cyzalkanoyl or RY and 81 in addition to the nitrogen atom to which they are attached form a saturated ring with a number of atoms from 0 to 7;

Ne = - to be: C,-salkynyl, Cs.scycloalkyl, Cs.scycloalkylCi.zalkyl, in addition to the conjugate and conjugate Cs.rcycloalkylCs.salkenyl, C;.scycloalkylCy salkynyl, phenyl, phenylCi.salkyl, heteroaryl , heteroarylC,_salkyl, heterocyclyl, or heterocyclylC; alkyl 0 each of which has an optional substitution by a group; or two” or three groups to be chosen from: Ci.alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C;salkoxy, carboxyCj.jalkyl, C 1-3alkylS(O)p- (where ple is n from Safra, 11, or oY?); and : R¥0C(0)- and 2005 77150-:- Bermah'a-(716)0 087( 07 ,-) 12720011087 (where the 0 is the He for Crsalkyl optional substituted with a number Substitution groups 1; or FY are independently selected from cyano g halos chydroxyl and 1 and 87 are independently selected from Cjalkyl s hydrogen optional substituted by the number of substitution groups 1, −, or ? are independently selected from halo 5 hydroxyl and “absolute ©” cyano carboxy s or form RY RY together in addition to a nitrogen atom to which 1 is attached to a saturated ring with a member number from; to [(V) and is done additionally Selection of the optional heterocyclyl substituent groups and the heterocyclyl group in heterocyclyl Cy.salkyl from “R?! 22100-78(0) (where k is zero or 10 or ?) and -( 82011:00)0 where there are 12 optional substituents with the number of substituent groups 1a or 7 being independently selected from halo <hydroxy s and mucin and trifluoromethyl or 1h

When © is a bond, then L can be a hydrogen. 5 optionally has one or two atoms in the ring and is chosen independently from oxygen 5 “nitrogen and sulfur ¢sulfur and is Ble m for zero; or 5h) 7 and optionally 0 replaces the rings by the number of replacement groups 1; or oY or ? It is selected independently from “RS”. laa of Cs.cycloalkyl and Cs.cycloalkylmethyl atolease ¢hydrogen, forming RPGR? together with the addition of a nitrogen atom to which they are attached to a saturated mono or bicyclic system or a bridged system optionally containing one or (3) additional heteroatoms selected from oxygen “nitrogen” and sulfur 0 optionally combined with a saturated or partially-saturated ring partially 410 or a mono-unsaturated ring where in the resulting ring system there is an optional substitution with the number of substitution groups (6) or oF or © are independently selected from R7 (RY is independently selected from the “maqalqir” < halo, C;.alkyl, cyano, and ¢trifluoromethyl © and 87 are selected independently from: hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R', R°0O-, R'°CO- , R°C(0)0-, R°CONR)-, (R)(R*NC(0)-, (R*)R™)N-, R'S(0)s- where is Ble a about zero to ; And: (R*)R*’)NSO,-, R’SO,NR?)-, (R”)RINC(ON(R’””)-, phenyl and with heteroaryl

Y — \ — [where phenyl and heteroaryl groups optionally combine with <heteroaryl “phenyl or a saturated or partially-saturated ring having the number of © atoms or 1 containing optionally on the number of heteroatoms 10; or "+ or ? is chosen independently from (6p0100; oxygen and sulfur and in the resulting ring system an optional substitution by the number of groups 0 substituting 1 or oY or is chosen independently of : hydroxyl, cyano, trifluoromethyl, trifluoromoxy, halo, Cj.4alkoxy, di-releasing Ci.4alkoxyCialkyl, CisalkoxyCialkyl, amino, N-C, .salkylamino, di-N,N-(C,.alkyl) amino , N-C;_alkylcarbamoyl, di-N,N-(C;.salkyl)carbamoyl, C;.4alkylS(O);-, Ci.4alkylS (0),Ci4alkyl 0 where: is yellow f(YseVy) is in 18 substituents with Crsalkyl has an optional substitution with the number of substitution groups 1; or 1 or ? is chosen independently from ¢cyano s hydroxyl, halo, C;. Independent choose RY Rho R75 from hydrogen and be at 0.1191 Optional substitution with halo sl chydroxyl “ or “ Cjalkoxy or carboxy or ¢ (cyano Ve) © is yellow or 1 or ¢Y where X is either M or -N(R™)(CH) M —O(CHy)g, -S(CHz) or when R12 is for <hydrogen 1 toller or ls: . and is a zero or 1; and

Y is: 1) a dyma ring and c, a phenylene ring, a cadamantdiyl group, or a saturated heterocyclic ring with a number of © to V atoms (bonded by a carbon ring atom containing Heteroatoms 1 or ¥ are selected from oxygen “nitrogen” and sulfur “a-[lebium] oo (where Rys Rx is independently selected from “Cj.alkyl <hydrogen”) “hydroxyl moiety s or Jo moi together in addition to the carbon atom to which they are attached to the Ci.cycloalkdiyl ring and Vv is a 3 or l or “ or ¥ or ¢ or °) and when Vv is greater than 1 the group can optionally be suppressed by -=O or -4-8© or the group Can NRY)- RY is hydrogen or tolloderin; Y 0 (represents X-Y Together a group has the formula: -and [(2(]0)413()414) where: A is bonded to a pyridine group and DCRR; is bonded to a toarboxy group and A is a non-ring system A mono-, double- or homo-cyclic with a number of atoms from 0 to 17 comprising a nitrogen ring atom 0 to which the pyridine ring is attached plus another heterocyclic atom selected from coxygen 5 “nitrogen and sulfur ¢ sulfur Yyivi

7 is -0— or -8-” or alkali where each is hydrogen or “Cysalkyl or ¢C, .salkanoyl be; is zero or 1 over condition when Ble s 05S is about zero and t is zero; The RY is independently selected from: hydroxy, halo, oxo, cyano, trifluoromethyl, C,.;alkoxy, isole for the values C,.3alkenyl, etholalkyl (C13alkylS(O)y-Cua) being « is zero or 3 or oY or 0 ' mole with RYCONR'™), R'R'INC(0)-, R'OC(0)- and (where R' is for Cpaalkyl is optionally substituted by hydroxyl or s halo isoform; 0 is independently selected for C and C of hydrogen and lah : 0 is optionally substituted by <hydroxyl carboxy tweezers «Cjalkoxy or (cyano or LR! yr" J in addition to the nitrogen atom to which they are attached to a ring with a number of atoms from ; to 7; Ble u is about zero or 1 or ?; done independently Choice 183 and R™ of hydrogen and Craalkyl or RM, RS together can form 10 plus the carbon atom to which they are attached to the ¢cycloalkyl ring C37 being 5 is a yellow; or 1 Or ¢Y, or a pharmaceutically acceptable salt thereof, or an ester thereof that is biodegradable in the organism, provided that the compound does not consist of:

- 1 and -

: or {(3S)-1-[5-(adamantan-1 -ylcarbamoyl)pyridin-2-yl]piperidin-3-yl} acetic acid {(3S)-1-[5-(cyclohexylcarbamoyl)-6 -(piperazin-1-yl)pyridin-2-yl]piperidin-3-yl} acetic acid

Or a pharmaceutically acceptable salt thereof, or an ester thereof in the organism subject to water lysis. 0 On the side of DAT a compound of formula (1) is presented as described in the present application above or a pharmaceutically acceptable salt thereof. Where: © is a single bond or -0-¢ or -8-; or -(1108015-), where each is hydrogen 1 and the bitumen or Cy3alkanoyl or form RY and a in addition to the nitrogen atom 0 to which they are attached to a saturated ring having a number of atoms from; to Vv ble RY is Cp ¢alkenyl, C,galkynyl, Cs.rcycloalkyl, C;.7cycloalkylCi.zalkyl, C3cycloalkylCy.jalkenyl, Cs.cycloalkylCs salkynyl, phenyl, phenylCi.;alkyl, heteroaryl, heteroarylC) alkyl, heterocyclyl, or heterocyclylC.salkyl 0 each of which has an optionally substituted by a group; or two or three groups to be chosen from hydroxy, -(15)0 and for the halo, oxo, cyano bitumen , trifluoromethyl, Cjsalkoxy, (where “ ple is about zero or 1; or oY or 0); RBCONRY)-, R*)RPINC(0)-, R¥OC(0)- and (R*)(R*INSO,- where m is an optional substituent of God with the number of substitution groups 1; or 7” ? is selected independently 0 of the hydroxyl and tweezers ¢cyano s and is selected Kg independently of hydrogen and

Cyoalkyl has an optional substitution with the number of substitution groups 1, oY, or ? They are independently selected from: cyano hydroxyl, halo, C.alkoxy, carboxy or together form RY SRY plus 5 nitrogen to which they are linked to a saturated ring having a member number of ; to 7)]; or © when Ble is on a bond RY can also be a hydrogen R? is chosen from Cyaeycloalkyl(CHy)m-, and Ce.pppolycycloalkyl(CHy)m- ( where m is zero or 1; or ? and the rings have an optional substitution of the number of substituent groups 1 or 1 or are chosen independently from and R?jlaal is from ¢hydrogen, C;.4alkyl Cs.scycloalkyl and Cs.cycloalkylmethyl 0 form 12 and 13 together in addition to a nitrogen atom to which they are attached to a saturated monocyclic, bicyclic or bridged system optionally containing one or two additional heterocyclic atoms that are Choice of “nitrogen, oxygen, and sulfur” optionally combined with a saturated, cpartially-saturated Loa, or unsaturated monocyclic ring where in the resulting ring system there is an optional substitution by the number of substitution groups 1; or ? or ?0 are selected independently from R7 (R* is selected independently from cyano, Cjoalkoxy, halo, and ¢trifluoromethyl) and 17 independently from: R°CO-, R°C(0)0-, dot hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, rR', ah

(R”)R’™)NC(O)-, (R”)R”™)N-, 175(0) -( 17001107 where a is zero to ?; phenyl and - ( 27)227110)011)67) rn28 77071150 (0)0 for heteroaryl 0 [where heteroaryl groups.s phenyl cule sana is optionally combined with a 5 “phenyl cheteroaryl or saturated ring or partially-saturated having the number of atoms © or 1 optionally containing the number of heteroatoms 1 or 7 or ¥ to be chosen independently from 011008860 oxygen and sulfur and in the resulting ring system an optional substitution of a number replacement groups 1 or 7; OR © are chosen independently from: Ciaalkyl, hydroxyl, cyano, trifluoromethyl, trifluoromoxy, halo, C, .4alkoxy, Ci.salkoxyCi4alkyl, C; .4alkoxyCi4alkyl, amino, N-C;_salkylamino, di-N,N-( where C;.alkyl ) amino, N-Cjalkylcarbamoyl, di-N,N-(C,.4alkyl)carbamoyl, C;4alkylS(O),-, C;4alkylS (0)C.4alkyl where is “ Ble about zero; (Ys Vg yo be in R® substituted with b to find an optional substitution with the number of substitution groups 1a or oY or la lial independently of tcyano sy hydroxyl, halo, C;.4alkoxy, carboxy (R” and 17 and 187 are independently selected from hydrogen and in Cpsalkyl optionally substituted with (cyano 0 hydroxyl, halo, C,_salkoxy, carboxy Yyiva

© is zero; or 1 or ?; WX is -0) or -8. or -Cun NR) “Li is:

hydrogen, atole 0 or C;.;alkanoyl is: YS

“C3-7cycloalkdiyldila) 1) or a saturated heterocyclic ring with number of atoms from © to V (connected by a carbon ring atom) containing hetero-atoms 1 or ? Selected from oxygen nitrogen and sulfur esulfur or -,[(,005,005] (whereby Rys Ry is independently selected from hydrogen, Cisalkyl, Cjsalkoxy and hydroxyl 0 forming Ry sR together as well as the carbon atom to which the C3-7cycloalkdiyl ring is attached and v is 1; or

1 0 or fr Slav ; or 0 (and when » is greater than 1 the group can optionally be suppressed by - (=O or -48© or the group in N(R?)- 827 is hydrogen or volatile); ) bee X-Y- represents a group with the formula: (R10), LJ [C(R™)(R™)],-0 where: A bonds to a pyridine group and -[ bonds CRP(R™)]- with a tearboxy group and Ble A for a spiro bi- or spiro heterocyclic ring sf having a number of any

Atoms 4 to 1 Includes a nitrogen ring atom to which the pyridine ring is attached plus 0 other heterocyclic atom selected from 0100860 and coxygen and sulfur ¢sulfur done independently Choose RY from: Cialkyl, Cy3alkenyl, Cyalkynyl, hydroxy, halo, oxo, cyano, trifluoromethyl, © 1-3alkoxy, Cy.3alkylS(O),- (where « is a yellow, a 3, or l or 0 : -180 at pg and rmmr (R'(RINC(0)-,),(p001!l8) (where RY is a cysalkyl optionally substituted with <hydroxyl or tcyano ol halo is independently selected "!ac, 1871" from hydrogen and Crsalkyl 4, optional substituting 0 with carboxy «Cisalkoxy chalo < hydroxyl or (cyano) or forms LR SR In addition to the nitrogen atom to which they are attached to a ring with the number of atoms from 4 to 7; u is a zero, 1, or ¢Y hydrogen (RM sR"? and cisalkyl or JE with laa RY plus the carbon atom to which they bond to the cycloalkyl bond Ble yo can form ha, 1, ¢Y, or a pharmaceutically acceptable salt thereof. In this specification the term '11c' includes both straight-chain and branched-chain alkyl groups but references to discrete alkyl groups such as 'propyl' are restricted to the type with

— not just the straight chain. For example, "wallab" includes the "propyl", "isopropyl" and "t-butyl" groups except that references to separate alkyl groups "propyl" Jie are limited to the straight-chain type only and references to Separate, branched alkyls such as isopropyl" " are restricted to the ALL branched type only. A similar terminology applies to the other moieties of so 2° would chtma: “Ci4alkoxyCi.satkyl” would include 1-(C,4alkoxy)propyl, 2-(Cj4alkoxy)ethyl and 3-(Cj.4alkoxy)butyl. The term “halo” refers to “fluoro,” <bromo 5 “chloro, and 1000. When selecting optional substituents from 'one or more groups' 0 it must be understood that this definition includes all substituents selected from one of the given groups or substituents selected from two or more of the given groups. A saturated ring 0 with a ring having a number of atoms from 1 to Ae (eg between Lol or Cg and R* and the nitrogen atom it is attached to) is a monocyclic ring containing an atom 3, X nitrogen only loop. 10 to be "heteroaryl" set unless otherwise specified; is a monocyclic ring containing a number of atoms from * or 11 and at least one atom is independently selected; or two atoms; Or three of “nitrogen, sulfur, esulfur, or oxygen, which, unless otherwise stated, may be attached to a carbon atom. The nitrogen ring atom can be oxidized to form the corresponding N-oxide. Examples and appropriate meanings of the term “heteroaryl” are:

- 071 - thienyl, furyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, triazolyl, pyrimidyl, pyrazinyl, pyridazinyl and pyridyl.

Particularly "heteroaryl" refers to thienyl, fury, thiazolyl, pyridyl, imidazolyl or pyrazolyl. It contains atoms other than 1 to a saturated monocyclic ring with a number of atoms of ; Refers to "heterocyclyl".

is homogeneous from 1 to ? They are selected from coxygen enitrogen and sulfur Examples of heterocyclyl include piperidinyl ¢piperazinyl <morpholinyl and -thiomorpholinyl The polycycloalkyl ring is a ring system in which the Lol The combination of two Lea rings or two rings that contain a co-ring atom (spiro). In particular, the polycycloalkyl ring includes two or three rings; or fours. An example of a polycycloalkyl ring is -adamantdiyl

0 includes “a mono-, double-, or bridging-ring system containing one or two additional hetero-atoms selected from 0150860 oxygen and sulfur”; Unless otherwise specified it includes atoms of; to Ne, and in particular a monocyclic ring contains a number of atoms of ; to 7; and a double ring with a number of atoms from 1 to .04 Examples of mono rings include piperidinyl and .morpholinyl 5 piperazinyl Examples of double rings include:

0 2,3,3a,4,5,6,7,7a-octahydro-1H-indene § decalin 00 Bridged ring systems are ring systems in which there are two or more bonds in common with two or more rings. Examples of gantry ring systems include:

1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, 2-aza-bicyclo[2.2.1]heptane and 7-azabicyclo (2,2,1)heptane, 1- and 2-adamantanyl.

The term "monocyclic saturated; partially-saturated or unsaturated"; Unless

otherwise specified to ring ;- 7. A Bay includes “cyclopropyl” and “cyclobutyl”

-phenyl and “cyclohexenyl 5” cyclohexyl and “cyclopentenyl” and “cyclopentyl s” to a single saturated carbon ring. It is a two-slit ring "Cycycloalkdiyl" ring in the two-slit ring system of the adamantdiyl ring system. The cycloalkane is represented by a ring on a specific side where the cracks are on the . benzene in the phenylene ring moiety represented by .adamantane 0

different ring atoms. Examples of a “saturated heterocyclic with a number of atoms from © to V (carbon ring seed bonded) containing one or two hetero-atoms selected from oxygen s nitrogen and sulfur” include “piperazinyl and ¢ piperidinyl and -morpholinyl 0 denotes "a mono-, double-, or spiro-heterocyclic ring system having a number of atoms from 1 to 17 containing a nitrogen ring atom and through which it is attached to a pyridine ring and in addition to that another heterocyclic is selected from coxygen “nitrogen and sulfur” to a saturated ring system which is a monocyclic system; or bi; or a spiro has the number of atoms of ; to 7. It includes a “mono-, double-, or spiro-heterocyclic ring system having a number of atoms from 1 to 1 containing a yo atom of a nitrogen ring through which it is attached to a pyridine ring and in addition another heterocyclic ring is a choice of oxygen 5 ¢nitrogen and sulfur " contains <piperidinyl , piperazinyl , and -morpholinyl Examples of " include a saturated or partially-saturated ring with the number of © atoms or 7 containing

— saddle number of heteroatoms 1 or SY ¥ is chosen independently from “nitrogen,” “cOXygen,” and “sulfur” on “piperidinyl and -morpholinyl” piperazinyl Examples include “Cj4alkoxy on .propoxy cethoxy s «methoxy CjalkoxyC, "," alkyl examples include : methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 2- propoxyethyl. ,(15)0: and bear: “where « is a zero to” on: methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples include “CialkylS(0),Cy alkyl” where Ble is q for “zero to 1” includes: methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methylthiomethyl, ethylthiomethyl, methylsulphinylmethyl, ethylsulphinylmethyl, mesylmethyl and ethylsulphonylmethyl. “Cyqalkanoyl” db] includes to .acetyl 5 propionyl “N-(C4alkyl)amino” 4 tial includes .ethylamino s methylamino and examples of “N-(C).alkyl)amino” include “N,N- (Cy4alkyl)amino 0 has <N,N dimethylamino and N,N diethylamino and N-ethyl-N-methylamino . Examples of “C,4alkenyl” in cethynyl “N-(Cj4alkyl)carbamoyl” i Vid Ja iy 2 include -propynyl 5 ¢<1-propynyl s in methylaminocarbonyl and -ethylaminocarbonyl Examples include “N,N-(Cj4alkyl),carbamoyl” in -methylethylaminocarbonyl 5 dimethylaminocarbonyl Examples include: “Cs.cycloalkylCy .salkalkyl” 00 on “2-cyclopropylethyl” cyclopropymethyl and:

Y ¢ — — cyclopentylmethyl 5 “cyclobutylmethyl and .cyclohexylmethyl.” Examples: “C;.cycloalkylC;.salkalkenyl” include “2-cyclopropylethenyl, 2-cyclopentylethenyl, and .2- cyclohexylethenyl The “CiacycloalkylCysalkalkynyl” complement includes: “2-cyclopropylethynyl, 2-cyclopentylethynyl and -2-cyclohexylethynyl m.” Examples of “ben” (CH,m-) cycloalkyl include cyclopropymethyl and “2-cyclopropylethyl” and “<cyclobutylmethyl” and “cyclopentylmethyl” and “-cyclohexylmethyl.” Examples include: - (1)0112 LD6200170710: and 1- and 2- and (11-)17:010] 3-2.1[100130 norbornyl bicyclo[2.2.2]octane(CH,)m-, adamantanyl(CH;)p,-.0 The appropriate pharmaceutically acceptable salt according to the compound of the invention is indicated for example in the addition salt The acid of the compound of the invention, which is basic to a sufficient degree, Jie salt, is added with an inorganic acid or an organic acid, for example, such as hydrochloric acid, i.e. <hydrobromic, or sulfuric acid, i.e., phosphoric, or trifluoroacetic, or In addition to this, it is considered a pharmaceutically acceptable salt suitable for the compound of the invention, which is acidic to a sufficient degree, a salt of 0 alkali metal such as potassium sl sodium, or a salt of an earth alkali metal such as calcium or “magnesium” Or an ammonium salt or a salt with an organic base that gives a physiologically acceptable cation Jie salt with “methylamine or dimethylamine, trimethylamine, tert-butylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine

E - For example, an ester is hydrolyzable in a living organism from a compound according to the invention that contains a carboxy or carboxy group, for example, an ester that is pharmaceutically acceptable as it is hydrolyzed in the human or animal body to obtain the parent acid acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include esters from © to alkoxymethyl Cs eg 5 methoxymethyl esters © to alkanoyloxymethyl Cs eg ¢<pivaloyloxymethyl and phthalidyl esters and : to geycloalkoxycarbonyloxyC to alkyl esters © eg: ,3-dioxolen-2-onylmethyl esters 5 ¢1-cyclohexylcarbonyloxyethyl 1 eg -Ci.¢alkoxycarbonyloxyethyl esters y ¢5-methyl-1, 3-dioxolen-2-onylmethyl 0 A hydrolyzable ester in the organism of a compound according to the invention containing hydroxy groups includes inorganic phosphate esters (Lay) phosphate esters Jia inorganic esters including cyclic esters) a-acyloxyalkyl ethers and related compounds that are the in vivo hydrolysis product of ester breakdown to yield the major hydroxy group(s). Vo examples of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy- -methoxy and the choice of hydrolyzable ester in the hydroxy-forming organism includes calkanoyl and benzoyl “acetyl phenyl 5 <benzoyl substituent” and “acetyl phenyl” and “alkoxycarbonyl” (to obtain “(alkyl ~~ carbonate esters) and N-s dialkylcarbamoyl (dialkylaminoethyl)-N-alkylcarbamoyl (to yield Compounds «(carbamates -acetyl carboxy 5 dialkylaminoacetyl 3 0

Some compounds of formula (1) may have chiral centers or geometric isomeric centers (E- and 7- isomers) and it must be understood that the invention includes all of these optical diastereoisomers and geometric geometric ones. The invention relates to any and all tautomeric forms of compounds of formula (1) which have inhibitory activity of enzyme 11811501. It must also be understood that certain compounds of formula (1) can exist in soluble form. In addition to being present in an undissolved form (Jie, hydrated forms), and it must be understood that the invention includes all these forms that are in the form of solubles, which have inhibitory activity 0 enzyme 11811801. In one of the embodiments of the invention a compound is provided for it Formula (1).In an alternative embodiment, pharmaceutically acceptable salts of compounds of formula (1) are presented.When positions on the pyridine ring are generally indicated, the position of ? indicates the position at which a !0-8-group substitution is present, and thus The numbering of the other positions Defined vo values for the various groups are shown as follows. These values may be used where appropriate with any of the definitions; or safeguards; or the forms specified in the present application hereinafter or hereafter; For compounds of formula (1):

1 - - (RY), 0 2 HO Y = : TN Te F 1 0 0 0 In one embodiment, Q is a "bond" or -0 ¢ or -8-; Or -(110815- where *!17 is <hydrogen, i.e., di-alkanoyl release or forms a tabo LR! in addition to the nitrogen atom to which they are attached to a saturated ring with a number of atoms from ; to 1 + 0 is: Cs.cycloalkylC jalkyl, Baboldama grape Ci.alkyl, Cy.alkenyl, Cy salkynyl, Cs.7cycloalkylCy.zalkenyl, Cs cycloalkylC, alkynyl, phenyl, phenylC, alkyl, heteroaryl, heteroarylC,.salkyl, heterocyclyl, or heterocyclylC;.salkyl [each optionally substituted with one, two, or three groups chosen from: hydroxy, halo, oxo, cyano, trifluoromethyl, Cialkoxy, Ci.3alkylS(O ),- 0 (where ng ssa is zero, 3, l, or oY and: R¥OC(0)- and 22777150 (2777(771020) .-220011087 (where 1 is the parenthesis Eh optional substitution Ady substitution groups 3 or YY independently selected from hydroxyl and tweezers; 'cyano and 0 and RY and 87 independently selected from Cpsalkyl g hydrogen 4 optional substitution by number Yava

Substituent groups 11, oY, or independently selected from <halo § hydroxyl, “Cj.3alkoxy, carboxy, enantiomer, or RY JE and 87 plus the nitrogen atom to which they are attached to a ring saturated with a number of atoms of ; to ()] in an embodiment is © Ble for a “single bond” or -0- ; or -8- ; Or -(14087- where o is a hydrogen, C; salkyl or Cyalkanoyl or J tabgo R! together in addition to the nitrogen atom to which they are attached to a saturated ring with a number of atoms from; to 1 RY is: Ci.salkyl, Cy.alkenyl, Cs.salkynyl, Csscycloalkyl, Cs cycloalkylC.salkyl, Cs.cycloalkyl C.zalkenyl, Cs.cycloalkylCs salkynyl, phenyl, heteroaryl, heterocyclyl, or heterocyclylC, .salkyl 0 ([(each has an optionally substituted with a group; or two; or three groups chosen from: Cua hydroxy, halo, oxo, cyano, trifluoromethyl, C,.;alkoxy, C 1 -3alkylS(O),- is : « is a zero or 1 or ¥« or ¥(« sR'CONR®)-, R¥)R™INC(0)-, R*OC(0) - , 8770877150 (where 1 is an optional substitution Crsalkyl with the number of substitution groups 60 or ? is selected independently from 1nz “middelnestel and tweezers” , cyano and vo and 187 and 187 are independently selected from hydrogen and Cig alkyl optionally substituted with the number of substituent groups 1 or oY or independently selected from : hydroxyl, halo, Cjsalkoxy, carboxy and cyano or J 5 and 87 plus atom

0 to which they are attached to a saturated ring having a number of atoms of ; to JY In an embodiment © is ©0; or 8 or daly alone and the RY is: Cs.cycloalkylCisalkyl, Cisalkyl dehydrogenase, Cy.galkenyl, Cy.¢alkynyl, Cs.cycloalkylC, salkenyl or Cs.cycloalkylCy salkynyl, [[( Each has an optionally substituted with one, two, or three groups chosen from: Ci.salkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C,.;alkoxy, C;.3alkylS(O),- (where n is a zero, a 1, a button, or (v . -7150 7p R'CONR®)-, (RP)R*NC(0)-, R¥OC(0)- and (where 1 is a Cpaalkyl optionally substituted with the number of substituent groups of 1; OR ?; OR ? is selected as 0 independently from cyano halo hydroxyl ; RY and R are selected independently from hydrogen and Cp alkyl optionally substituted with the number of groups (0, oY, or ?) are independently selected from <hydroxyl, methylated, Cjsalkoxy +, ll, , , , , , , , , , , , , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, than, than, than, than, than, than, than, than, than, than, than, than , than, than, than , than , than, than ` than `, than `` than the nitrogen 2 attached to a saturated ring having the number of atoms from ; to )]. In another aspect, the invention relates to a compound of formula (I) as shown above wherein Q Vo is a single bond In Jal cals © is NR) In one embodiment RP is -hydrogen on the AT side Lee is 1 and Y is 0:4.

D, and in one embodiment, "Lez" is methyl, in one embodiment, Q is 0. On the other hand, © is 5. In one embodiment, RY is: 0 for Di 0 1 and for Demigogy Cj.alkylS(O), [each of which has an optionally substituted with a group; or two; or three groups chosen from: hydroxy, halo, oxo, cyano, trifluoromethyl, C,.jalkoxy, Cj.alkylS(O), - (where n is (la, l, l, or (Y) on the Al side, and ag is Cs.scycloalkyl or Cs.scycloalkylCisalkyl, and lmer is 0.0 in Another aspect is that RY is a cycloalkyl Cay optionally substituted with the number of Z, Af, or 7 substituent groups to be chosen independently of Cisalkyl, hydroxy, halo, oxo, cyano, trifluoromethyl and C;.;alkoxy. On the other hand, R! is a Cycycloalkyl. On the other hand, RY is a CycycloalkylCalkyl that has an optional substitution with the number of groups 1 substituting 1 or 7, or it is chosen independently from: Ci .salkyl, hydroxy, halo, oxo, cyano, trifluoromethyl and C,.;alkoxy.

Aj is a wa 040610311010 . In another aspect, RY is a Cpaalkyl substituent optionally with the number of substituent groups 11 or for L or independently selected from: Cj.salkyl, hydroxy, halo, oxo, cyano, trifluoromethyl and Cj_alkoxy. Hal Ht R! is a Craalkyl on the AT side A is an optionally substituted propyl with the number of substituent groups 1 or 7 chosen from: Cisalkyl, hydroxy, halo, oxo , cyano, trifluoromethyl and C,.;alkoxy. on the R side! al is Ble for -propyl 0 On the other hand 5LeR! is for phenylCrsalkyl Optionally substituted with the number of substituent groups 0, ?, or 7 independently selected from: hydroxy, halo, oxo , cyano, trifluoromethyl and C,.alkoxy on one side of Hal is '--phenylCj.zalkyl on the other side is heteroarylCpaalkyl optionally substituted with the number of substituent groups 1 or 7 Vo or Y is chosen independently from : hydroxy, halo, oxo, cyano, trifluoromethyl and cialkoxy. On the other hand R! is -heteroarylC,_;alkyl On the AT side A is phenyl has an optional substitution of the number of substitution groups 1; or 7;

A name or ¥ is chosen independently from : hydroxy, halo, oxo, cyano, trifluoromethyl and C, .salkoxy on the Hal side is A and .phenyl on the HAT side is R' is heteroaryl groups with an optional substitution of number of groups 0 substituting 1; or ?; or 7 to be selected independently from : hydroxy, halo, oxo, cyano, trifluoromethyl and C;_salkoxy On one side HAT is 'heteroaryl' on the other side L-0-18- is 'hydrogen' on one side”; 3 is a Craalkyl 0 on the AT ¢ side 13 is a methyl | chydrogen or .ethyl on the other hand 18 is 'hydrogen' on the other hand; It is 18 Ble for 1[1161df. on the AT side "187 is ethyl on one side"; 1 is a methyl 1 in al models and 7 is a zero. on one side; is ple of 1 or 7.

d m on the AT side m is a zero or 1. on the Poss al side is 1. on the Poss al side is a 7. In one embodiment, © Ble is about 1 and AR is the -# position. 0 In one of the embodiments, R? is chosen from C37 cycloalkyl (C37 cycloalkyl, and polycycloalkyl U) where “ is 1; ?is independently selected from R® as described in the present order above). In another side, choose 12 polycycloalkyl (CHp)m- 5 «C.7 cycloalkyl (CHp)m- remm (where m is 1 or ¥ and the rings have an optional substitution of the number of ye substituent groups 1 or independently selected from 5k where <hydroxyl and 1810 (trifluoromethyl 5) are independently selected in jal ¢ side R? is selected from cycloalkyl Coz polycycloalkyl s excelled in JS of which An optional ROY-independent substitution where RS is chosen from halo < hydroxyl and trifluoromethyl Ve in one side; R* is chosen from Cs.12 polycycloalkyl (CHy)m- 5 Cs 7. cycloalkyl (CHp)m- (where the rings have an optional substitution with the number of substituent groups )6, 7, or © chosen independently from 8) where « is a zero; or 1 or 1 on either side Another a choice of R? rings: Cr.10bicycloalkyl(CH;)m- and Ciotricycloalkyl(CHy)pm-m(101)0112l0.010: has a substitution

Y ¢ — _ optional with the number of substituting groups 3 or for or als Y selected independently from RS (where 111 is a zero or 1 or . In another side select “18 from: Cr. pobicycloalkyl(CHy)m- and adamantyl -m(12©)dehyde0: (where the cycloalkyl, bicycloalkyl and tricycloalkyl rings 0 have an optional substitution with the number of Yo substituent groups 1 or ? and are independently selected from (RY) Where “is a zero, 1a, or 7. on one side; Ble m is about zero or .1 on the other side forming 12 and 83 together in addition to a nitrogen atom to which they are attached to a single ring system with the number of atoms © or 1 or dicyclic with a number of atoms from 1 to 11 or gantry with a number of 0 atoms from 1 to VY and optionally contains an additional number of heteroatoms 1 or 1 be selected from “nitrogen, oxygen, and sulfur which is optionally combined with a mono-saturated aryl ring; partially-saturated wherein the resulting ring system has an optionally substituting number of substitution groups 1 or oY or is Independently selected from .R' in other wails form 2 and 3 Law plus the 350 nitrogen to which they are attached form a monosaturated yo-ring system having a number of © atoms or 1 and optionally containing an additional number of heteroatoms 1 or ¥ is selected from oxygen s cnitrogen and sulfur which is optionally combined with a monosaturated aryl ring; or partially saturated where the resulting ring system has an optional substitution of the number of substitution groups 1 or 7; or selected independently from 187. In another aspect; Together 12 and 83 plus the nitrogen atom to which they are attached form a monosaturated ring system with a number of © atoms or 6;

_Yo--

It optionally contains an additional number of heteroatoms 1 chosen from coxygen y «nitrogen

and sulfur is sulfur and in the resulting ring system is optional substitution by the number of substitution groups 1; or “selected independently from 187.

on one side; R® is independently selected from hydroxyl, 100 R°CO- and R'C(0)O-© where WSR? is shown in the present application above.

on one side; R® is independently selected from hydroxyl, R°0-, R'CO- and R'C(0)O-

where 177 is 1 and the god,© has an optional substitution of 'cralkoxy' or '.carboxy'

In the “al” side, the RO is independently chosen from:

H1

and (RR INC(OINR®)- (2780:1187 ,(870011)87) where is “18 as shown in the present application Lad above. In another aspect + RS is independently selected from: and 2007077100107 -(29011007 ,-(80011087) where “1 is a 0e Craalkyl optionally substituted with Ci.4alkoxy or ¢carboxy 07 wag and rR” are independently selected of hydrogen and mN has an optional substitution of Benz?, bitumen or carboxy in another aspect; R® is independently selected from -2677)0(11 ¢((R7)R*NC(0) - and ye where RY is mode as defined in the present request above. In another aspect, R ® is independently selected from '(R”)R*)INC(0)- and (R *YR*)N- Cua Rial and 189 are made independently of Crzalkyly hydrogen with the optionally substituted Ci4alkoxy- or .carboxy In one embodiment the RE is selected from: methyl, trifluoromethyl , chloro, fluoro, bromo, methoxy, ethoxy, trifluormethoxy, methanesulfonyl, ethanesulfonyl, methylthio, ethylthio, amino, N-methylamino, N- ethylamino, N-propylamino, N,N-dimethylamino, N,N-methylethylamino or N,N-diethylamino.

vy —_ — In one embodiment R® is chosen from hydroxy, halo and trifluoromethyl in another side 0” is in KG optional substitution of phenyl, pyridyl or pyrimidyl in another side » is in RS is an optional substitution of .pyrid-2-yl, pyrid-3-yl or pyrid-4-yl. On the other hand, Ble R® is for carboxy. In one embodiment, 17 of .hydroxy, halo and trifluoromethyl In one embodiment, X is -0-; or -8 or NR) where 82 ble is for hydrogen, C;.salkyl or Cjsalkanoyl in one embodiment Ble X is for -0-. On the other hand, X is an NR) where RZ is an expression as specified in the present Vo above. On the Al side, X is NR where RZ is 'hydrogen' and on the other side, X is -8-. In one embodiment, 7 Ble is about a “C3-Toycloalkdiyl” ring or a saturated heterocyclic ring with a number of atoms from © to V (a carbon atom bonded to the ring) comprising heterocyclic ahd ae So) 10 to be selected from “nitrogen, oxygen, ¢sulfur, or [CRIRY] (where Ry Ry is independently selected from methyl s hydrogen or Ry and 8 together form an additional ring C3-Teycloalkdiyl and 177 is 1 or 7 or » or 4; or 0)

On the other hand 7 is a C3-Tcycloalkdiyl saturated heterocyclic ring comprising ax atoms from © to Vo (a carbon atom bonded in the ring) having a number of heteroatoms 1 or ¥ chosen from .sulphur 5 oxygen s ¢nitrogen On the other hand 7 is a .aC3-Teycloalkdiyl ring . On the other hand 7 is a saturated heterocyclic with a number of © to 1 (bond

a carbon atom in the ring) having the number of heteroatoms 1 or ¥ chosen from “nitrogen oxygen s” and a styloma. - On the other hand, Yd is of the form [CRORY]- (where Ry is independently chosen and with any of

hydrogen 0 and hypothesis” and V is 1 or 1 or 0 or 4 or ©). when 0” is greater than 1 the set -,[(,8.()8)p] can be suppressed by the set -0-; or -8-. or NR) where RP is Crsalkyl sl hydrogen. In another aspect, Y has the formula [CRIB]: (where Ry Ry is independently selected from methyl 5 hydrogen V is 1 or 1 or 0 or of or ( .

1 In one embodiment, X-Y- together represent a group with the formula:

(R19), J [CRN R™)],- where:

Ring A is bonded to a pyridine group and -.[(" 08( '008]- is bonded to a tcarboxy group. A is a mono-, double-, or spiro-heterocyclic system with a number of atoms of to 17 and includes a nitrogen atom and a pyridine ring is attached to it and optionally another heterocyclic atom is selected from coxygen “nitrogen” and sulfur ¢sulfur 0 is independently selected “a from alkyl, hydroxy, halo and trifluoromethyl;

be zero; or 1; 13 and 1814 are independently chosen from Craalkyl shydrogen or JR can be C and C together as well as the carbon atom to which they are attached to ring 1 and 11D0:70(010); where 5 is a yellow or a 3 or a ring

0 in one of all -X-Y- together represents a group with the formula:

[C(R®)(RM)],-

where: ring A is bonded to a pyridine group and [C(RP)R'™))-s is bonded to a tcarboxy group and A is a monomeric heterocyclic system; or bi; It has the number of atoms of ; to 1 and includes

m a nitrogen atom to which a pyridine ring is attached and optionally additionally another hetero-atomic chosen from ¢nitrogen and 0un:e; And sulfur ¢sulfur

Yyaiva

- 0464 where u is a zero; Independently select hydrogen (R's RP and 'methyl' and ples is 0 or 1 or 7. In another side Ry is 'hydrogen 0' in another side it is 7 is » or 4; or © in an embodiment Ble A is a monomeric heterocyclic ring system with a number of atoms from * to + and that includes a nitrogen atom in the ring to which a pyridine ring is attached and optionally additionally a non- A congener selected from coxygen 5 cnitrogen and sulfur On the other hand, A is piperidino, pyrrolidino, azabicyclo[3.1.0]hexane, morpholino or thiomorpholino. On the other hand, A is For .piperidino, morpholino or thiomorpholino on the AT side A is -piperidino on the AT side A is Cua piperidine The group is: 203 -[(2(, ]00807(8)- at position 1. On the other hand, A is a piperidino where the group is: 2(]608(080(1-2001)- at position 4. Ah

1 - - On one side AT is Sued for pyrrolidine (in one embodiment Z is NR) where it is “!8” as specified in the present application on another side it is Z phrase about -1111. In one embodiment, Ble + is about zero. In one embodiment, RY is chosen from: hydroxy, halo, oxo, cyano, trifluoromethyl and alkoxy. On the other hand, alkyr 0, R'® is independently selected from Cy3alkyl, hydroxy, halo and trifluoromethyl. On the AT side, “18” is selected from cisalkyl and alkoxy. uss is a zero or a 10 on one side of the 'al' is a 1 on the other hand the u is a zero. In one embodiment, 113 R™ is independently .methyl | hydrogen On the AT side the RRP is 'hydrogen'

In one embodiment S is zero or a in one embodiment s is zero. On the Al side bles is 1 for -1. A class of compounds according to the present invention has a formula (1) where: 0 is © for -0-; or -8-; or NR) where He RY is about: amaskatalmina or hydrogen, or form CAG and 21 in addition to the nitrogen atom to which they are attached to a saturated ring with a number of atoms of; to ; 1 is: C;_scycloalkyl, Cs.scycloalkylCy alkyl, , except for the two parents Ci.salkyl, Cyalkenyl, Cs.tycloalkylC, salkenyl, Cs.cycloalkylC, salkynyl, phenyl, heteroaryl, heterocyclyl, or heterocyclylC , salkyl [, each of which has an optional set substitution; or two groups; or three to choose from: hydroxy, halo, oxo, cyano, trifluoromethyl, C;salkoxy, C;.3alkylS(O),- (where n is zero, 3, oY, or ( Y : M -27707(1802) (R¥)R*INC(O)-, R¥OC(0)- and -7 27001108 (where 17 is a © alkyl with optional substitution by the number of groups Substituting 1 or 7? is chosen independently of the 'cyano s 'halos chydroxyl and

Independently select 5 g and kg of hydrogen and require an optional substitution with the number of substituent groups 1 or oY or be independently selected from: carboxy and cyano adsorb hydroxyl, halo, or form Ry together in addition to a nitrogen atom to which they are attached to a saturated ring with a number of atoms of ; to 7)]; or m is chosen from cycloalkyl (CHy)m-min and -(1©) polycycloalkyl dam (where m is 1; or ? and the rings have an optional substitution by the number of substituent groups 1; or 9 or ? are selected independently from 85); 3 are selected from: JE hydrogen, C;4alkyl Cs.cycloalkyl and Cs.cycloalkylmethyl 0 1 and 3 together plus the nitrogen atom to which they are attached to a mono-, double- or bridging-ring system optionally containing an additional number of heteroatoms 1 or 7 selected from coxygen 5 enitrogen and sulfur optionally incorporated into the saturated ring; or partially-saturated or a monounsaturated ring where in the resulting ring system there is an optional substitution of the number of substitution groups 1 - 1 or ? Or to be selected independently from (RT) 5 is to be selected independently from: hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R', 170 R'CO-, R'C(0)0-, R'S(0)s- about R'CONRY)-, R7)RNC(0)-, where le a is about zero yiva

to ? . (R*)R”INC(O)N(R®)-, phenyl and -(01177 205 Me 077115 0C(0)-, w1 heteroaryl [where phenyl groups and optionally combine heteroaryl groups b cheteroaryl 5 “phenyl or © ring saturated or partially-saturated having axe atoms or 1 optionally containing heteroaryl number 1; or SY ? is independently selected of oxygen g «nitrogen and sulfur, and in the resulting ring system there is an optional substitution with the number of substituent groups 11, l or al Y, chosen independently from: Ci4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromoxy, halo, C ;_4alkoxy, Ci.4alkoxyCj.salkyl, Cj4alkoxyC, .4alkyl, amino, N-C_4alkylamino, di- N,N-(C, .4alkyl)amino, N-Cj_salkylcarbamoyl, di-N,N-(C ,.4alkyl)carbamoyl, C1.4alkylS(O),-, Ci-4alkylS(O),C,4alkyl where + Ble is about zero; V5 and ?)]; In R® it has a kernel substitution of 1:.,© has an optional substitution with the number of substitution groups 01 or 7; or? 10 is independently selected from hydroxyl, halo, C_salkoxy, carboxy and cyano then independently selected by RY and 7 and 7 from hydrogen and in Cy salkyl is optionally substituted by ¢(hydroxyl, halo, C ;.salkoxy, carboxy or cyano Ble P is less than zero;

A M P —

WX is -0-; or - 8. or - Goa NR) R? is:

hydrogen

Y is:

1) “C3-Tcycloalkdiyl” ring or saturated heterocyclic with number of atoms from © to V (bonded © by a carbon ring atom) containing heteroatoms 1 or ¥ selected from 01050860

oxygen and esulfur or -[(082()8)©] (where Rys Ry is independently selected from

Cpsalkoxy and hydroxyl oleoresin hydrogen, or form M18 and [Le] in addition to an atom

carbon to which they are attached to the C3-Teycloalkdiyl ring and v is a 1- or ? or ©” or © or

; or ©) and when » is greater than ali 1 the group can optionally be suppressed by -0 or -8- 01 or cua N(R)- Ac gana where R? is hydrogen or null;

") -16-7 together represent a group with the formula:

(R19), LJ [C(R*)(R™)]s-

Where:

A is bonded to a pyridine group and -[C(RP)R')]- is bonded to a tcarboxy group and A is 1 single heterocyclic ring system; or a spiro sl binary having the number of atoms of ; to 1 includes an atom

A nitrogen ring to which the pyridine ring is attached plus another heterocyclic atom in the ring

¢sulphur and coxygen s “nitrogen are selected from

RY is independently selected from: Cs, salkynyl, hydroxy, halo, oxo, cyano, trifluoromethyl, Cisalkyl, Craalkoxy, CraalkylS(O),- (where 8 is yellow or SJ)? or (fF RMOCO)- and R'MYR'INSO,- .-(16)0 !078 (where pleR! for Cpsalkyl© has an optional substitution of ¢cyano sl halo sl chydroxyl Independently choose RM 5 ly from hydrogen and 1 nec© 43 Optionally substituting with <halo < hydroxyl dr alkoxy; or (cyano or LR" formation SRT plus a nitrogen atom to which they bond to a ring having a number of atoms from − to 7 −u is yellow or oy or ¢y yo” RI and R™ are independently selected from hydrogen and cralkyl or RY and aR" together with the 33 carbons to which they are attached can form a cycloalkyl gene loop of s being 0, 1, or ?; or a pharmaceutically acceptable salt thereof or Its ester is hydrolyzable in living organisms. ©, Majesty.” © [And every Lie is in Him

optional substitution by group; or two groups; or three to choose from: hydroxy, halo, oxo, cyano, trifluoromethyl, C;salkoxy, C;.3alkylS(O),- (where n is zero, 3, 31, fv, or R? is chosen from -cycloalkyl b and -oil (polycycloalkyl yum) where m 0 is zero, 1, or 7 and the rings have an optional substitution with the number of substitution groups 1; or oY or chosen independently from 5) ¢ choose 13 hydrogen JK ligands together plus the nitrogen atom to which they are attached to a mono-, double-, or bridging ring system optionally containing an additional number of heteroatoms 1 or 1 is selected from coxygen 5 enitrogen 0 and sulfur and optionally incorporated into the saturated ring; partially-saturated or monounsaturated ring where in the resulting ring system there is an optional substitution of the number of substitution groups 1; or 1 or ¥ is independently selected from R7 RS and 7 are independently selected From : hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, R', R°0-, R°CO-, R°C(0)O-, R'CONR')-, (R") R*)NC(0)-, (R”)(R*)N-, RS(O)s- where a is a zero to ?: R”0OC(0)-, 077180 27501007- 07-0018 777- phenyl and heteroaryl Yiva

[Where phenyl groups and heteroaryl groups are optionally combined with “heteroaryl 5” phenyl or a saturated or partially-saturated ring having a number of © atoms or 1 optionally containing a heteroaryl number of 1a or oY or ? It is independently selected from oxygen s ¢nitrogen and sulfur and in the resulting ring system is optional substitution with the number of substitution groups 11 or 1 0 or ? Independently selected from: Ci4alkyl, hydroxyl, cyano, trifluoromethyl, trifluoromoxy, halo, C;4alkoxy, Ci4alkoxyCi.4alkyl, Cj.4alkoxyCi.salkyl, amino, N-C;_4alkylamino, di- N,N-( where is + is zero, 1, and 1)]; is Optionally substituted by Cpsalkyl with the number of substitution groups 1; or l or ? It is independently selected from hydroxyl, halo, C, .salkoxy, carboxy and cyano. The R53 R” agent is independently selected from hydrogen, and in God it is an optional substitution with (hydroxyl, halo, C; .4alkoxy, carboxy or cyano ¢ P58 vo is a 0; 6 is either a -0, -8, or - Gin NR) ly is : hydrogen, C,.;alkyl or C;_salkanoyl. 7 is:

q — 2 — 1) “C3-Teycloalkdiyl” ring or saturated heterocyclic with number of atoms from © to V (bonded by a carbon atom in the ring) containing hetero-atoms 1 or 7 Its choice of nitrogen oxygen and sulfur ¢sulfur or ") represents de sane las X-Y- has the formula: ee [C(RB)(RM)]¢- where: A bonds to a group pyridine and -[("'608”(04]-) bond to a tcarboxy group and Ble A is a mono-, double-, or spiro-heterocyclic system with number of atoms from; to 1 including atom The nitrogen ring to which the pyridine ring is attached plus another heteroatom in ring 0 is selected from oxygen s nitrogen and sulfur 'sulfur' RY is independently selected from : hydroxy, halo, oxo, cyano, trifluoromethyl, C,.;alkoxy, ento the two monikers Cisalkyl, Cyaalkenyl, C13alkylS(O),- (where « is a zero, a 1, or an ?, or a 7 'RDRINCO)- RMCONR™) 00-(00)0 a and -90na) p8(8) ((where LR ! is for Craalkyl optionally substituted with hydroxyl i.e. tweezers or ¢cyano. is done as Separate selection of "Yo!"a from Cpsalkyls hydrogen has an optional substitution of b

name Q 0 _ (hydroxyl, halo, C;.alkoxy, carboxy or cyano) or “C and LR plus an A nitrogen atom bond to form a ring having a number of atoms from ; to 7; being u is a yellow, oy, or ¢Y that is independently selected as a ligand and a ligand of cialkyls hydrogen or can form a ligand and 4Lee 0 plus the carbon atom to which they are attached to the ¢Cy ring .zeycloalkyl 5 is a yellow, 3, or ¢Y or a pharmaceutically acceptable salt thereof or an ester thereof that is hydrolyzable in the organism.?”- Another class of compounds of the present invention has the formula (1) where : © is -5- 0 R! is Cs.7cycloalkylC alkyl or Cs.7cycloalkylC alkyl mmRn; -m(mit) polycycloalkyl DM (where m Bile is about 0 or 1; or 7 and rings have an optional substitution of 1 substitution groups; or At is chosen independently from) ¢ is selected 13 of ¢thydrogen KE vo »and 3 together plus the nitrogen atom to which they are attached to a mono-, double-, or bridging ring system optionally containing an additional number of heteroatoms 1 or ? Selected from coxygen 5 ¢nitrogen and sulfur and optionally combined with the saturated ring; or partially-saturated or monounsaturated ring in which the resulting ring system has a substitution

oy — - optional with the number of replacement groups 1; or ? or? Independently selected from (R” RT RE is independently selected from : hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, rR', R°O-, R°CO-, R°C (0)0-, R'CONR®)-, (R")R**INC(O)-, 977 R°S(0),- Ble a 05S Cuno from 0 to 7; and: R70C(0)-, (R7)R*NSO,-, R'SONR?)-, 707100157 *1 is independently selected; and 187 and 187 of hydrogen and in Craalkyl optionally substituted with: hydroxyl, halo, C;4alkoxy, carboxy or cyano. 0 is WX -0-; or - 8 or - Gn NR The RY is: oligomers or the ligand is hydrogen, the Y is: 1) “C3-7cycloalkdiyl” ring or a saturated heterocyclic with a number of Atoms 0 to V (connected by a carbon atom in the ring) contain heteroatoms 1 or ? Selected from nitrogen oxygen Vo and sulfur ¢sulfur or ") together X-Y- represent a group having the formula: (R19), LJ [C(RB)(R™));- where: A is bonded to a pyridine group and -,[("'608()8]- is bonded to a tcarboxy group and A is

Y — g single heterocyclic system; or binary or spiro with the number of atoms of ; to 1 comprising a nitrogen ring atom to which the pyridine ring is attached plus another heterocyclic atom selected from coxygen 5 “nitrogen and sulfur ¢ RIO is independently selected from: Cialkyl, Cy3alkenyl, Cy3alkynyl, hydroxy, halo, oxo, cyano, trifluoromethyl, Ci.zalkoxy, C,3alkylS(O),- (where « is yellow or PY SY Sl) and 7160 is the standard R'OC(0)- and MR (AR RYCONR'™), (where A is a Cpalkyl optionally substituted with <hydroxyl or fcyano sl halo and 0 is done independently Choosing C and R' from hydrogen and Allah © It has an optional substitution with carboxy “Cjsalkoxy <halo <hydroxyl” or “Ja 0 (cyano io”!) in addition to the 068 atom to which they are attached to a ring with the number of atoms of VE is “is a zero; whose dala bind between cycloalkyl be 5 is yellow or 0 or 31 or a pharmaceutically acceptable salt thereof or an ester thereof that is hydrolyzable in the organism. Another category of compounds according to the present invention has the formula (1), where:

— 7 gm. or w1 is chosen from cycloalkyl (CHp)m-b and polycycloalkyl (CHp)m-dm (where m is zero or 1; or 7 and the rings have an optional substitution with the number of substituent groups 11 or at 8 (selected independently of you) ¢ R® is selected from ¢ hydrogen ROHR? (RUE) together plus the nitrogen atom to which they are attached to a mono-, double-, or bridging ring system optionally containing an additional number of heteroatoms 1 or 7 chosen from oxygen 3 < nitrogen and sulfur and optionally fused to the ring saturated (saturated or partially-saturated Wa \ or ring J for unsaturated monocyclic where in the resulting ring system there is an optional substitution with the number of substitution groups) 0 ¥ is selected as Agua of “R 44.a3R7 9 R® is chosen independent of chalo 5 < hydroxyl and ¢trifluoromethyl P is zero; X is either - Ca NR?) R'? is a hydrogen GT of: “C3-7cycloalkdiylddla) 1) or a saturated heterocyclic ring with number of atoms from © to V (connected by a carbon atom in the ring) containing non-membered atoms congener 1 or ¥ is selected from nitrogen AH

_Ng oxygen and sulfur (¢sulfur or ") -72-7 bea is a group with the formula: (R10), LJ [C(RT)(RM)];- where: 0 A is bonded to a pyridine group and [CRP)RM)- is bonded to a (<dta:e) group; A is a mono-, double-, or spiro-heterocyclic system with number of atoms from − to V comprises a nitrogen ring atom to which the pyridine ring is attached plus another heterocyclic atom selected from 0100860 5 oxygen and sulfur ¢sulfur RY is independently selected from “Cjzalkyl n<malnite" and <halo and trifluoromethyl and ¢) Se is zero u is 0

LRM Po J or Cisalkyl 5 hydrogen can independently select alkali and 14 of and cycloalkyl C37 plus the carbon atom to which they are attached to the ¢Y ring is 5 is a yellow or 3 or of which is hydrolyzable in the organism. ester or a pharmaceutically acceptable salt thereof, or where: (1) another class of compounds according to the present invention has the formula -#« vo -S- © is

Yava

RY is Crealkyl ; Or choose 12 from “C37 cycloalkyl and polycycloalkyl blood and have in each of them where optional substitution 4 RY 1 choose from ¢hydrogen po your choice 1 from trifluoromethyl <halo 5 chydroxyl be © Ble about zero; Together, X-Y- represents a group with the formula: [C(R13)(R™)].- where:

0 A is conjugated to a pyridine group and -7([6 08( '008]-) is bonded to a tcarboxy group A is a mono-membered, bi- heterocyclic or bi-heterocyclic heterocyclic ring system a spiro has a number of atoms from 1 to 1 comprising a nitrogen ring atom to which the pyridine ring is attached plus another heterocyclic atom selected from ¢nitrogen, coxygen and sulfur RP and ¢methyl 5 hydrogen (eR!) are selected separately

Ne, where 8 is a zero, ¢, or 1

_ 4 mL or a pharmaceutically acceptable salt of it | ester of it is hydrolyzable in the organism. 1- In another aspect, a class of compounds according to the present invention has the formula (1b): 0 2 HO Yo = X N S T R1 where (R25 RY, 2, and 77 have any of the previously mentioned definitions In another aspect according to the invention, “suitable compounds according to the invention are illustrated in one or more examples or a pharmaceutically acceptable salt thereof. In another respect the invention relates to a compound selected from: 2-[(3R)-1-[ 5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl Jacetic acid 1-[5¥(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperidine-3-carboxylic acid 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperidine-4-carboxylic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2- yl]-4-piperidyl]acetic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid 1-[5-(cyclohexylcarbamoyl) -6-propylsulfanyl-pyridin-2-yl]pyrrolidine-3 -carboxylic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-y1]-3 -piperidyl] acetic acid 2-[4-[5-(cyclohexylcarbamoy!)-6-propylsulfanyl-pyridin-2-yl]piperazin-1 -yl]acetic acid

- oy — (3R,5S)-4-[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJamino]adamantane- 1-carboxylic acid (3R,58)-4-[[5-(cyclohexylcarbamoyl) -6-propylsulfanyl-pyridin-2-yl]Jamino]adamantane- 1-carboxylic acid 4-[[8-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-methyl- amino]cyclohexane-1-carboxylic acid 2-[(38)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yljpyrrolidin-3-yl acetic acid 3-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxybenzoic acid 3-[5¥(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]sulfanylbenzoic acid 4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]sulfanylbenzoic acid 4-[5-(cyclohexylcarbamoyl) -6-propylsulfanyl-pyridin-2-ylJoxybenzoic acid 2-[4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxyphenyl]acetic acid 3-[4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl -pyridin-2-ylJoxyphenyl]propanoic acid 2-[4+[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yljsulfanylphenoxyJacetic acid 2-[4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2 -yl]oxyphenoxy]acetic acid 2- [4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]oxyphenylpropanoic acid 2-[4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2 -yl]sulfanylphenyl]acetic acid 2- [3¥[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxyphenyl]acetic acid 2-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJsulfanylbenzoic acid 4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxycyclohexane-1 -carboxylic acid

Yiva

- oA — 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperidine-2-carboxylic acid (2S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl ]pyrrolidine-2-carboxylic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4-piperidyl]propanoic acide 4-[[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl -pyridin-2- yllamino]methyl]cyclohexane-1-carboxylic acid 3-[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJamino]propanoic acid 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl- pyridin-2-ylJazepane-4-carboxylic acid 1-[5¥(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-y1]-4-methyl-piperidine-4- carboxylic acid (1S,5R)-3-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- azabicyclo[3.1.0]hexane-6-carboxylic acid 4-[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJamino] cyclohexane-1- carboxylic acid 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4-propan-2-yl-piperidine-4- carboxylic acid 1-[5-(cyclohexylcarbamoyl)-6 -propylsulfanyl-pyridin-2-yl]-3-methyl-piperidine-4- carboxylic acid 2-[1¥[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]-2- methyl-propanoic acid 2-[(3R)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3-yl]acetic acid

- oq — 3-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]propanoic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin- 2-yl]azetidin-3-ylJoxyacetic acid 1-[1e[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]cyclobutane- 1-carboxylic acid 1-[1-[5- (cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]cyclopropane-1-carboxylic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3 -ylJoxyacetic acid 2-[[1+[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]oxy]propanoic acid 2-[[1-[5-(cyclohexylcarbamoyl)-6- propylsulfanyl-pyridin-2-yl]-3-piperidyl]oxy]-2- methyl-propanoic acid 2-[[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl] oxy]acetic acid 1-[5¥ecyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl}-3-methyl-piperidine-3- carboxylic acid 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin -2-yl]-4-piperidyl]-2-methyl- propanoic acid 1-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4-piperidyl]cyclobutane-

I-catboxylic acid 1-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4- piperidyljcyclopropane-1-carboxylic acid

- +. 4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJmorpholine-2-carboxylic acid Z 2-[(3R)-1-[5 (cyclohexylcarbamoyl)-6-cyclohexyl sulfanyl-pyridin-2 -yl]pyrrolidin-3- yl}acetic acid 2-[(3R)-1-[5-(cyclohexylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2-yl}-3- piperidyl]acetic acid 2-[(3S) -1-[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2 -yl]pyrrolidin-3- yl]asatic acid 2-[(3R)-1-[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]pyrrolidin-3- yl]acetic acid 2-[(3R) )-1-[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 1-[1¥5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]- 3- piperidyljcyclopropane-1-carboxylic acid 2-[(3S)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid 2-[(3S)- 1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3- yl]oxyacetic acid 2-[(3R)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl -pyridin-2-yl]pyrrolidin-3-ylJoxyacetic acid

- +1 - 2-[(35)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3-yl]acetic acid (3R)-1-[5-( 2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidine-3- carboxylic acid 2-[(3R)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin -3- yl]acetic acid (25)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidine-2- carboxylic acid (1S,5R)-3-[5-( 2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-y1]-3- azabieyclo[3.1.0]hexane-6-carboxylic acid (3S)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin -2-yl]pyrrolidine-3- carboxylic acid 4-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJmorpholine-2-carboxylic acid 2-[(38)-1-[5-(2) -adamantylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]pyrrolidin-3- ylloxyacetic acid 2-[(3R)-1-[5-(2-adamantylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]pyrrolidin- 3- ylJoxyacetic acid 2-[(35)-1-[5-(2-adamantylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2-yl]pyrrolidin-3- yl]oxyacetic acid 2-[(3R)-1-[ 5-(2-adamantylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2-yl]pyrrolidin-3- ylloxyacetic acid

Yaivia

— for 2-[(3R)-1-[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl]pyrrolidin-3- yl]acetic acid (3R)-1-[ 5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl]pyrrolidine-3- carboxylic acid ‎(3Sp1-[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl] pyrrolidine-3-carboxylic acid (1S,5R)-3-[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl]-3-azabicyclo[3.1.0]hexane- 6-carboxylic acid 2-[(3R)-1-[5-(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin-2-yljpyrrolidin-3- yllasetic acid (3R)-1-[5 -(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin-2-yl]pyrrolidine-3- carboxylic acid ‎(18,5R)-3-[5-(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin- 2-yl]-3- azabicyclo[3.1.0]hexane-6-carboxylic acid 2-[(38)-1-[5-[((2r,55)-5-hydroxy-2-adamantyl) )carbamoyl]-6-propylsulfanyl-pyridin-2- yl]pyrrolidin-3-yl]acetic acid 4-[[[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl ]-6-propylsulfanyl-pyridin-2- ylJamino]methyl]cyclohexane-1-carboxylic acid 4-[[5-[((21,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6 -propylsulfanyl-pyridin-2- yl]atnino]cyclohexane-1-carboxylic acid 4-[[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl- pyridin-2-ylJamino]cyclohexane-1-carboxylic acid Yiva

trampled

2-[(3S)-1-[5-[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid 1-[ 5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2- yl]piperidine-4-carboxylic acid 2-[(3R)-1-[5-[ [(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2- yl]-3-piperidyl]acetic acid : 2-[1-[5-[[(2r,55) )-5-hydroxy-2-adamantyl[carbamoyl]-6-propylsulfanyl-pyridin-2-yl1]-4- piperidyljacetic acid (1R,5S)-3-[5-[[(2r,55)-5-hydroxy -2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2- yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1-[5-[[(2r,5s)-5-hydroxy- 2-adamantyl]|carbamoyl]-6-propylsulfanyl-pyridin-2-y1]-4- methyl-piperidine-4-carboxylic acid 1-[5-[[(2r,5s)-5-hydroxy-2-adamantyl} carbamoyl]-6-propylsulfanyl-pyridin-2- yl]pyrrolidine-3-carboxylic acid 2-[(BR)-1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]- 6-propylsulfanyl-pyridin-2- yl]pyrrolidin-3-ylJacetic acid 3-[1-[5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2 -yl]-3- piperidyl]propanoic acid 2-[1-[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]-2-methyl-propanoic acid 2-[(35)-1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]pyridin- 2-yl]pyrrolidin -3-yl]acetic acid

Oh

- vs — 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]pyridin- 2-yl]-3-piperidyl]acetic acid 2-[(3R)-1-[6-cyclopentylsulfanyl-5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]pyridin- 2-yl]pyrrolidin-3-yljacetic acid (3R}¥ -1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]pyridin-2- yllpyrrolidine-3-carboxylic acid (2S)-1-[6-cyclopentylsulfanyl-5 -[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]pyridin-2- yl]pyrrolidine-2-carboxylic acid (1R,58)-3-[6-cyclopentylsulfanyl-5-[((2r) ,5s)-5-hydroxy-2- adarhantyl)carbamoyl]|pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1-[6-cyclopentylsulfanyl-5-[((2r, 5s)-5-hydroxy-2-adamantyl)carbamoyl]pyridin-2- yl]piperidine-4-carboxylic acid 2-[(3R)-1-[6-cyclohexylsulfanyl-5-[((2r,5s)-5 -hydroxy-2-adamantyl)carbamoyl]pyridin- 2-yl]pyrrolidin-3-yl]acetic acid (2S)v3-[6-cyclohexylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl) )carbamoyl]pyridin-2- yllpyrrolidine-2-carboxylic acid (3R)-1-[6-cyclohexylsulfanyl-5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]pyridin-2- yllpyrrolidine- 3-carboxylic acid 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]pyridin- 2-yl§-3-piperidyl]acetic acid 2-[(3S)-1-[5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl}-6-(3- methylbutylsulfanyl)pyridin-2-yl]-3-piperidyl] acetic acid

Yyiva

- qo — (BR)-1-[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-(3- methylbutylsulfanyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid (IR,5S)-3-[5-[((21,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-(3- methylbutylsulfanyl)pyridin-2-yl]-3-azabicyclo[3,1. 0]hexane-6-carboxylic acid 2-[(3S)-1-[6-benzylsulfanyl-5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl]pyridin-2- yl]-3 -piperidyl]acetic acid 2-[(3S)-1-[5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl]-6-phenethylsulfanyl-pyridin- 2-yl]-3-piperidyl ]acetic acid 2-[(3S)-1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]-6-propoxy-pyridin-2-yl]-3- piperidyl]acetic acid 2-[1-[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propoxy-pyridin-2-yl]-3- piperidyl]-2-methyl-propanoic acid (1R,58,6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)pyridin-2-yl)-3-azabicyclo[3.1.0] hexane-6-carboxylic acid (1S,5R)-3-[6-cyclohexylsulfanyl-5-(3-pyridin-3-ylpyrrolidine-1-carbonyl)pyridin-2-yl]- 3-azabicyclo[3.1.0Thexane-6 -carboxylic acid 2-[(3S)-1-[6-propylsulfanyl-5-(3-pyridin-3-ylpyrrolidine-1-carbonyl)pyridin-2-yl]-3- piperidyl]jacetic acid 2-[(3S) )-1-[6-propylsulfanyl-5-(3-pyridin-2-ylpyrrolidine-1-carbonyl)pyridin-2-yl]-3-

piperidyl]acetic acid 2-[(3S)-1-[5-(piperidine-1-carbonyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid

2-[(3S)-1-[6-propylsulfanyl-5-(3-pyrazin-2-ylpyrrolidine-1-carbonyl)pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1 -[5-(4,4-difluoropiperidine- 1-carbonyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl}acetic acid 2-[(8S)-1-[6-propylsulfanyl-5-[ 3-(trifluoromethyl)piperidine- 1-carbonyl]pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[6-propylsulfanyl-5-[4-(trifluoromethyl)piperidine-1- carbonyl|pyridin-2-yl}-3- piperidyl]acetic acid 2-[(3S)-1-[5-(4-carbamoylpiperidine-1-carbonyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexyl-cyclopropyl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1- [5-(cyclohexyl-(cyclopropylmethyl)carbamoyl)-6-propylsulfanyl-pyridin-2- yl]-3-piperidyl]acetic acid 2-[(38)-1-[5-(cyclohexyl-ethyl-carbamoyl)-6 -propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexyl-propan-2-yl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl] -3-

piperidyljacetic acid 2-[(3S)-1-[5-[(4-hydroxycyclohexyl)carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[ 6-propylsulfanyl-5-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1- carbonyl]pyridin-2-yl]-3-piperidyl]acetic acid

2-[(3S)-1-[5-[((21,55)-5-methylsulfonyl-2-adamantyl)carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid 2- [(3S)-1-[6-cyclopentylsulfanyl-5-(3-pyridin-3-ylpyrrolidine-1-carbonyl)pyridin-2-yl]- 3-piperidyl]acetic acid 2-[(3R)-1-[ 5-(cyclohexylcarbamoyl)-6-phenethylsulfanyl-pyridin-2-y1]-3- piperidyl]jacetic acid2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-phenethylsulfanyl-pyridin-2- yl]-3 -piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(2-pyridin-3-ylethylsulfanyl)pyridin-2-y1]-3- piperidyl]acetic acid 2-[(38) )-1-[5-(cyclohexylcarbamoyl)-6-(2-pyrazin-2-ylethylsulfanyl)pyridin-2-yl]-3- piperidyl]acetic acid 2-[(35)-1-[5-(cyclohexylcarbamoyl) pyridin-2-yl]-3-piperidyl]acetic acid 2-[(3S)-1-[5-(2-adamantylcarbamoyl)pyridin-2-yl]-3-piperidyl]acetic acid 2-[(35)- 1-[5-(cyclohexylcarbamoyl)-6-[2-(4-fluorophenyl)ethoxy]pyridin-2-yl]-3- piperrdyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)- 6-(3-methylbutoxy)pyridin-2-yl]-3-piperidyl acetic acid 2-[(35)-1-[5-(cyclohexylcarbamoyl)-6-(3-phenylpropoxy)pyridin-2-yl]-3 - piperidyl]acetic acid 2-[(38)-1-[5-(cyclohexylcarbamoyl)-6-(2-pyridin-3-ylethoxy)pyridin-2-yl]-3- piperidylJacetic acid 2-[(3S)- 1-[5-(cyclohexylcarbamoyl)-6-methoxy-pyridin-2-yl]-3-piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propoxy-pyridin-2- yl]-3-piperidyl]acetic acid

Yiva

- A — 2-[(35)-1-[5-(cyclohexylcarbamoyl)-6-(1-piperidyl)pyridin-2-yl]-3-piperidyl]acetic acid 2-[(3S)-1-[6 -[2-(4-chlorophenyl)ethylamino]-5-(cyclohexylcarbamoyl)pyridin-2-yl1]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-[3 -(4-fluorophenyl)pyrrolidin-1-yl]pyridin-2-yl]- 3-piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(3,4-dihydro- 1 H-isoquinolin-2-yl)pyridin-2-yl]- 3-piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(3,4-dihydro-1H-isoquinolin) -2-yl)pyridin-2-yl]- 3-piperidyl]acetic acid 2-[(38)-1-[5-(cyclohexylcarbamoyl)-6-(4-phenylpiperazin-1-yl)pyridin-2-yl ]-3- piperidyl]acetic acid 2-[(35)-1-[5-(cyclohexylcarbamoyl)-6-[4-(4-fluorobenzoyl)piperazin-1-yl]pyridin-2-yl]- 3-piperidyl ]acetic acid 2-[(3S)-1-[6-(4-acetylpiperazin-1-yl)-5-(cyclohexylcarbamoyl)pyridin-2-yl]-3- piperrdyljacetic acid 2-[(35)-1- [5-(cyclohexylcarbamoyl)-6-(4-ethylsulfonylpiperazin-1-yl)pyridin-2-yl]-3-

piperidyl]acetic acid 2-[(35)-1-[6-[4-(benzenesulfonyl)piperazin-1-yl]-5-(cyclohexylcarbamoyl)pyridin-2-yl]- 3-piperidyl]acetic acid

2-[(38)-1-[5-(cyclohexylcarbamoyl)-6-(4-phenylmethoxycarbonylpiperazin-1-

yDpyridin-2-yl]-3-piperidyl]acetic acid

2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylamino-pyridin-2-yl]-3-piperidyl acetic acid

2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(phenethylamino)pyridin-2-yl]-3-piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)- 6-(methyl-phenethyl-amino)pyridin-2-yl]-3- piperidyl]acetic acid 2-[(8S)-1-[5-(cyclohexylcarbamoy!)-6-(methyl-propyl-amino)pyridin- 2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-pyrrolidin-1-yl-pyridin-2-yl]-3-piperidyl]acetic acid 2- [(35)-1-[5-(cyclohexylcarbamoyl)-6-morpholin-4-yl-pyridin-2-yl]-3-piperidyl]acetic acid\ + 2-[(3S)-1-[5-( cyclohexyl-methyl-carbamoyl)-6-propylamino-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexyl-methyl-carbamoyl)-6-(methyl-propyl) -amino)pyridin-2-yl]-3- piperidyl]acetic acid 2-[(38)-1-[5-(cyclohexylcarbamoyl)-6-methyl-pyridin-2-yl]-3-piperidyl]acetic acid 2 -[(3S)-1-[5-(1-adamantylcarbamoyl)-6-methyl-pyridin-2-yl]-3-piperidyl]acetic acid

2-[(3S)-1-[5-(2-adamantylcarbamoyl)-6-methyl-pyridin-2-yl]-3-piperidyl]acetic acid

2-[(35)-1-[5-(2-adamantylcarbamoyl)-6-butyl-pyridin-2-yl]-3-piperidyl]acetic acid

3-[5-(2-adamantylcarbamoyl)-6-butyl-pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-

carboxylic acid

2-[(35)-1-[6-butyl-5-(cyclohexylcarbamoyl)pyridin-2-yl]-3-piperidyl acetic acid

2-[(35)-1-[5-(cyclohexylcarbamoy!)-6-cyclopropyl-pyridin-2-yl]-3 -piperidyl]acetic acid yivsa

a. 2-[(3S)-1-[5-(2-adamantylcarbamoyl)-6-cyclopropyl-pyridin-2-yl]-3-piperidyl]acetic acid 2-[(35)-1 -[6-cyclopropyl-5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3R)- 1-[5-(cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetic acid 2-[(3S)-1-[5-(cyclohexyl-methyl) -carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyljacetic acid [(35)-1-{5-[((2r,55)-5-methoxyadamantan-2-yl)( methyl)carbamoyl]-6- (propylthio)pyridin-2-yl} piperidin-3-yl]acetic acid [(38)-1-{5-[((2r,5s)-5-hydroxyadamantan- 2-yl)(methyl)carbamoyl]-6- (propylthio)pyridin-2-yl} piperidin-3-yl]acetic acid {(38)-1-[5-(adamantan-1-ylcarbamoyl) -6-(propylthio)pyridin-2-yl]piperidin-3-yl } acetic acid {(38)e1-[6-(propylthio)-5-(tetrahydro-2 H-pyran-4-ylcarbamoyl) )pyridin-2-yl]piperidin-3- yl}acetic acid [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio) pyridin-2- yl} piperidin-3-yl]acetic acid 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- adamantyl]carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetic acid 2-[(35)-1-[6-cyclohexylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2 - adamantyl]carbamoyl]pyridin-2-yl]-3-piperidyl]acetic acid

- vy - 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- adamantyl]carbamoyl]pyridin-2-yl]pyrrolidin-3-yl ]acetic acid 2-[(35)-1-[6-cyclopentylsulfanyl-5-[[(2r,55)-5-(difluoromethoxy)-2- adamantyl]carbamoyl]pyridin-2-yl]-3-piperidyl] acetic acid 2-[(8S)-1-[5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl] acetic acid 2-[(3S)-1-[5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsulfanyl- pyridin-2-yl]pyrrolidin-3-yl ]acetic acid 2-[(3S)-1-[5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propoxy-pyridin- 2-yli-3-piperidyl] acetic acid (3R)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]pyridin-2-yl]pyrrolidine-3-carboxylic acid (1R, 5S)-3-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6 -carboxylic acid 2-[(3R)-1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3- yl]acetic acid 1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2- yl]pyrrolidine-3-carboxylic acid (8)- 2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2-yl)piperidin-3-

yDatetic acid and (R)-2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2- yDpiperidin-3-yl)acetic acid

And salts from it are pharmaceutically acceptable.

YY — _ In another aspect, the invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof which includes [where 7 is -X-Y-COOH and other various combinations]; unless otherwise specified That, as shown in the formula [(1) on any of the processes from a) to »(: (i ° reaction of a compound of formula ) 0 with a compound of formula: (Y) (RY), 9 Ls 9 2 2 1c (3) 2 b Reaction of a compound of formula (¢ ) with a compound of formula (°): (RY), 0 R2 STN + _ z- ON 0 8 1c (5) 0 where X is a leaving group; OR 01 = reaction of a compound of formula ( 1) with a compound of formula: (V) (R9), 0 ~R ?SY 1 RF and HSS 2 A H

(7) (6) where Ble *X is about a leaving group or d Reaction of a compound of formula (A) with a compound of formula (4): RY, 1 z 0 oy 1 3 = N xX” R 27 (9) 8 © where TX is a leaving group; or “) Reaction of a compound of formula (Ye.) with a compound of formula (11): RY, | 2 rr [ 3 = xm" N Q R Z H (11) (10) where 7X is a teaving group and then if necessary or desired: 1) 01 a compound of formula (1) is converted to another compound of formula (1) ' (7) removing any ¢protecting groups

‘resolving enantiomers’ (Y)

(?) A pharmaceutically acceptable salt composition or an ester thereof that is hydrolyzable in the organism.

Examples of processes for converting a compound of formula (1) to another compound of known formula (1) include:

well for those skilled in the art on internal conversions of functional groups such as hydrolysis; and/or hydrogenation and/or chydrogenolysis and/or

cooxidation 5 | or “reduction” and/or more functional operations by

Standard reactions such as the catalytic coupling of an amide or a metal or

Nuclear displacement reactions.

Those interactions for the preceding operations (A through E) are as follows:

dichloromethane or N,N-dimethylformamide Jie process {: typically carried out in a suitable solvent 0 using a suitable reactant eg acyl halide either by formation in place of eg or through the addition of a coupling element oxalyl chloride, such as a suitable reagent, for example, EDAC 5 HOBT, is active as an ester, to form suitable combinating agents (or synthesis agents) and optionally in the presence of a suitable base, such as

triethylamine or N,N-di-iso-propylamine 00 for example. The reaction typically takes place at ambient temperature or an elevated temperature between 0-0°C. Process B): It is typically carried out in a suitable solvent such as dichloromethane or THF for example using a strong base (Jia) strong base: (sodium hydride or lithium or potassium hexamethyldisylazides) and an alkylating agent

Yava

- from

suitable agent (such as alkyl iodide) and the reaction is typical at ambient temperature.

Suitable examples of leaving groups (X) are in:

chloro, bromo, iodo, mesylate, tosylate or triflate. Other combinations are known in art.

Process C): Typically carried out in a suitable solvent eg acetonitrile, butyronitrile or methanol Jie © eg; Typically, by adding a suitable base, Jie suitable base:

Potassium carbonate or sodium hydroxide, for example. The reaction typically takes place at a degree

high temperature using microwave or conventional heating

cheating as JU at temperatures between 10 - 001 C. In certain cases it is done

reactions at ambient temperature. Appropriate examples of leaving groups (X) are shown in:

Cad chloro, bromo, iodo, mesylate, tosylate or triflate ~~ 0 Other groups in Art. Process d): may be carried out in a suitable solvent such as <butyronitrile sl «acetonitrile or (DMF.) or THF for example; typically with the addition of a suitable free base such as potassium carbonate or e.g. Example .sodium hexamethyldisilylazide The reaction is typical at ambient temperature or at a high temperature between a VAC

0 (This is achieved by conventional heating or microwave irradiation. Suitable examples of leaving (X") groups are fluoro and oleoresin.

Other groups are known in art. Process e): It can be carried out in a suitable solvent <butyronitrile sl «acetonitrile (ie) or (DMF or THF for example) and typically by adding a suitable base potassium carbonate Jie or

yn — eg sodium hexamethyldisilylazide and the reaction typically takes place at ambient temperature or at a temperature as high as 080 Fo C (achieved by conventional heating or microwave irradiation ). Suitable examples of leaving (X™) groups are chloro s fluoro Other groups are known in Art.0 The commercial availability of intermediates for the synthesis of compounds of formula (1) will be assessed; they may be known in the art or prepared by known procedures and/or procedures described above (a-e). It will be estimated that the sequence in which the processes take place will be determined by the type of compound of formula (1) being synthesized. For example, it will be Jol is a compound of formula (VY) with suitable (Nu) nucleophilic reactants that 0 lead to the displacement of (X*5 X') leaving groups to generate compounds of types p (11) or (£1) is very useful in the synthesis of compounds of formula (1) (R%), F (RY),

Xt Nd X2 Nu NT x2 Xt NG Nu (12) (13) (14) (chloro or fluoro (typically) leaving groups and 72 are X! when 1 by amide processes or alternatively a group that can be converted to an amide is W and that can be hydrolyzed to an acid that can then be converted to an ester known in the art (eg ¢) amide and the nature of 17 and the nature of the position of any of the X25 X!

RY substitution groups, the reaction conditions of that solvent, and the temperature of any additional catalysts (eg palladium and copper ligands (ligands) can influence the arrangement of the XC-displaced groups, 32 Correspondingly the order of dle i required to be performed to obtain the desired compounds.It will be estimated that examples of pyridine© compounds with suitable substitutions at positions ;6 are known in the art and can also be used as starting points for the synthesis of compounds of type (1). It will be estimated that when © is an H the required compounds can be accessed by intermediate compounds of type (V0) according to the operations described 0 above. iol Xs" ON (15) The possibility of introducing specific substituent groups from several substituent groups into compounds of the present invention; and into intermediates for their preparation by standard aromatic substitution reactions 1 or can be induced by Modification of conventional functional groups either prior to or immediately after the above-mentioned processes and so on may be included in the processes which are an image of the invention. These interactions and modifications include; For example, enter

a substitution group by an aromatic substitution reaction; substitution group reduction; the alkylation of substituent groups; The chemical agents and reaction conditions for these procedures are well known in the chemical art. Specific examples of aromatic substitution reactions include nitro moiety using concentrated nitric acid, acyl moiety using acyl halide and Lewis acid (eg aluminum trichloride) under friedel crafts conditions for example: and alkyl group using alkyl halide and lewis acid (eg aluminum trichloride) under conditions crafts 016061; introduction of 00p1810 group. Specific examples of modifications include reduction of a nitro group to an amino group for example by hydrogenation catalytic hydrogenation by means of a nickel catalyst or treatment by iron in the presence of 0 hydrochloric acid with heating; and oxidation of alkylthio ie sana to .alkylsulphonyl sl alkylsulfinyl it will be estimated that in Some of the reactions mentioned in this order may be necessary/desirable to protect any sensitive groups in the compounds.The situations in which protection is necessary or desirable and the appropriate methods of protection are known to those skilled in the art.These groups may be used Conventional protector according to the standard method (for clarification see: T.W.Green Protective Groups in Organic Synthesis, JohnWiley and Sons, 1991 Vo., etc.) This group is involved in some of the interactions mentioned in this application. An acyl group, for example, is a suitable protecting group for the Jie alkylamino sf amino group, an alkanoyl group as an “acetyl” group, or an alkoxycarbonyl group as a “methoxycarbonyl” ethoxycarbonyl 0 0 or “t-butoxycarbonyl” group 0 arylmethoxycarbonyl group as a group

- 18 ah) The conditions of benzoyl as the aroyl group or the “benzyloxycarbonyl” protecting group of the previous protecting groups necessarily differ with the choice of the protecting group. Thus, for example, an aroyl or an alkoxycarbonyl group or an alkanoyl group such as an acyl group can remove a hydroxy metal group such as a suitable base by means of a suitable base hydrolysis, for example by hydrolysis

Jie acyl alternatively, the sodium or lithium alkali metal hydroxide group can be removed, for example; By treatment with a suitable acid such as t-butoxycarbonyl acid of group ic gana ctrifluoroacetic or phosphoric or csulphuric or sulfuric <hydrochloric for example; By hydrogenation, Jue Je cbenzyloxycarbonyl is like the arylmethoxycarbonyl group

Jie lewis on carbon; Or by treatment with palladium Jie acid over a hydrogenation catalyst with an alternative protective group, phthaloyl, eg yal group. (trifluoroacetate) boron tris 00

Jie alkylamine can be removed by treatment with Ally primary amino suitable for the .hydrazine group or with chydroxylamine: suitable for the protecting group acyl group considered for example. or benzoyl group as aroyl group or cacetyl group as alkanoyl group as protective hydroxy group Ah) as group 060271. _ Arylmethyl group 0 conditions will necessarily differ to choose the mentioned Wy protecting groups for deprotection conditions or the alkanoyl Jie acyl group. Thus, for example, a group can be removed

Jie suitable base by means of suitable base hydrolysis by hydrolysis Mia aroyl group alternatively sodium or lithium hydroxide as alkali metal 3% hydroxide hydrogenation can be removed for example by hydrogenation benzyl Jie arylmethyl group 0 group on carbon palladium Jie catalyst over catalyst

A. — - is an esterifying entry set for example | For example, a protective group suitable for the “carboxy” group, and for example, the “methyl group” or the ethyl group can be removed by hydrolysis by the sodium or Sa hydroxide base, for example, the removal of the t- group butyl, for example, by treatment with an acid; For example, Jie organic acid, trifluoroacetic acid or ©, for example, the benzyl group can be removed by hydrogenation over a palladium (fie) catalyst on carbon. The groups can be removed Protection at any suitable stage in the synthesis reaction using conventional methods well known in chemical art. As stated before, the known compounds of the present invention have inhibitory activity of enzyme 11811501 activity |0 and these properties can be evaluated using the following experiment. Experiments Conversion of cortisone to active steroid cortisol via oxo-reductase activity 11811901 can be measured using a competitive homogeneous time-based fluorescence experiment (HTRF) (CisBio International, R&D, Administration and Europe Office, In Vitro Technologies HTRF® / Bioassays BP 84175, 30204 Bagnols/Céze Cedex, France.

Cortisol bulk — HTREF kit: Cat No. 62CORPEC). Evaluation of the compounds described in the present application was evaluated using 11811501 human full-length Hiss-tagged N-terminal enzyme of baculovirus (*1). enzyme anv. was made from the product of cell lysate dissolved in disinfectant; Using a Yava brass chelate column

AY - - copper chelate column Inhibitors 1 reduce the conversion of cortisone to cortisol which was determined by an increase in the signal in the previous experiment. The compounds to be tested were dissolved in dimethyl sulphoxide (DMSO) to 10 mM and further diluted in a buffer containing DMSO 71 to 10 times 0 final experimental concentration. Then the diluted compounds were placed in opaque dishes with a YA™ eye (Matrix, HudsonNH, USA). The experiment was carried out in a total volume of yo μl consisting of cortisone: 001 Sigma. , Poole, Dorset, UK) 53 mol) 5 glucose-6-phosphate : 1 “Roche Diagnostics) mM); 001 “Sigma, Poole, Dorset NADPH micromolar); YY.o (Roche Diagnostics) glucose-6-phosphate dehydrogenases 0 µg/ml); and 1 sigma, Poole, Dorset (mMolar EDTA); and buffer cell solution “(K;HPO/KH,PO4) 0 mM) pH number ©./a; recombination product 11811571 [using a suitable dilution to obtain a lifetime experiment - an example of a suitable dilution would be 1 in 001 dilution of the crude enzyme [stock enzyme plus compound ve test. The experimental dishes were incubated for 1 min at TVC, after which time the reaction was stopped by the addition of 01 μL of 605 mM glycerrhetinic acid plus conjugated cortisol (XL665 or D2) and After that, 01 microliter of anti-cortisol cryptate was added, and the dishes were sealed and incubated for 7 hours at room temperature. The fluorescence was measured at 175 nano jie and 1170 nano jie and 119 nm was calculated: 170 oy.

A Y — _ This data was used to calculate the ICs for each compound: (Origin 7.5, Microcal software, Northampton MA, USA). The Journal of Biological Chemistry, Vol. 26, No 25, pp16653 — 16658 1 * The compounds of the present invention typically show an ICs value of less than 00 micromolar; Preferably less than 0 * micromolar. For example, the following results were obtained: 6 mlar) compounds: {(35)-1-[5-(adamantan-1-ylcarbamoyl)pyridin-2-yl]piperidin-3-yl} 26116 acid; and {(38)-1-[5-(cyclohexylcarbamoyl)-6-(piperazin-1-yl)pyridin-2-yl]piperidin-3-yl } acetic acid achieved the inhibition of ©7 of the enzyme at less than or equal to 71 μM and therefore not preferred according to the invention. The bioavailability of the compounds according to the invention can be tested as follows:

Determination of Bioavailability in PK Studies Compounds are administered intravenously at [Je Y (kg) and orally at ~mg/kg (5 mL/kg) on 19 / of 11030 in the form of a sorrensons buffer solution of pH 0..0 and 001 blood samples pall were taken before the dose was administered; After dose B (6.Yo, .0), 10 “, FooY, +, 1) and Y, 1 hour for each of the two routes of administration, plasma prepared by centrifugation, and plasma samples were analyzed as shown. Below. PK parameters (disposal p206:d1e; volume of distribution, bioavailability, cabsorbed fraction, etc.) were calculated by standard PK methods using PK software. Suitable for Bioanalysis of Plasma Samples (WinNon-Lin): The instructions described apply to manual preparation of plasma samples after a single compound or administration of yo tablets of Compound | To test each of the 2 PK types used in the ais) for a .DMPK and a description of the analysis by open access (LC-MS/MS) 0 manual methods - (LC-MS) Contents 1- Materials

— mm - “ - General Extraction Method * - List of Example Samples Using Generic Open Access Batch Submission — ¢ and system checks. 0 — Approval Scale for Batch Acceptance -1° Material: Solvent DMSO acetonitrile 3 cmethanol solvents Water: purified grade or HPLC with 1 ml shallow 176 le dishes or eppendorf tubes 97 wells leds depth ¥ ml with lids 0 placebo due)blank Plasma "-generic extraction method The compound(s) are dissolved to 1 mg/mL using DMSO taking into account salt factors if any are present. Crude may be used DMSO (raw materials) for obtaining measurement and quality samples: 1 - “1” single compound analysis IY - “preparation of measurement and quality samples:

Ao - - - 1 Standard solutions are prepared as follows: Crude dilution | volume of methanol | raw size | Standard plasma concentration 1 mg/mL 4.. = Ma M 011...bb 59.408 90.208 Yeo on +.0 “Vo 0.28 V0.1 Yeon v0 ..0 Yeon Ove © . Ne] v0 Ye. eae Yoo Youu ..0 Y 00 Ove ..0 «0 0.10 .2 Y.

Yoo “0 «YO Ore Yeo 0 b Ye 10 Ow v0 '0 Yoo 0 Yee ..0 - Oo. In a dish containing 16 wells, transfer 1 mL of “shallow well” – 1 μL of each standard solution to the wells of the dish. 4 – Add 50 μL of blank plasma to each of these eyes. iva

QC samples at each concentration). 1- Add 50 µL of placebo plasma to each of these eyes. Transfer 00 µl of each PK sample to a 1 lie 16 mL plate - add µl of methanol (-compound) to all of the PK© samples 4- Ensure that the All dosage formulations thoroughly by vortex mixing Dilute both intravenous (IV) and oral (PO) oral dose formulations to an expected concentration of 0.1 µg/g. mL in methanol (eg formulation prepared to an expected concentration of fase 1 mL diluted to 1:000 to obtain a solution of 01 μg/mL). equal 00 μl of plasma to the dish.Add ∼μl of the diluted intravenous formulation to the eyes; repeat for the oral formulation and remain in the eyes.1- Precipitate the proteins. proteins by adding 100 μl of acetonitrile containing an internal standard relevant to the experiment (at 1 μm faba ml) to all vo “PK 5” QC and formula samples -0 Swirl the vortex mix the plate before centrifuging at 400 818 g for 10 minutes. 001 Jul -6 μL of supernatant to eyes in 47 ¥ ml dish (see next dish diagram). Care should be taken not to disturb the pellet

- Add about 0.6 ml of +10 imethanol 0 water to the last well.

- For analysis on quad systems 016a: add 4080 μL of water

HPLC score to each sample. Mix gently.

standard ml of standard solutions faba nano 000001 μl of crude 001 add -11 μl of water. Add a sample of Standard 9000 to a plate? Fill and add solutions ©

to the other eye (see plate map).

This is to adjust the compound (referred to in the dish diagram) with tuning solutions

-08 For analysis on platform systems: add 100 microliters of water

(HPLC) to each sample. Mix gently.

0 91-Manually tune all compounds using compound solutions prepared to ne ng/ml (add Yoo μl of Onan ng/ml standard solutions solutions to 0000 μL of water)

Cassette dose Analysis of the dose of the cauliflower 0- Preparation of samples for measurement preparation and collection: - 71

1 Required to dilute raw methanol Note: To give tablet doses; The amount of 0 can be set

mg/ml according to the number of compounds present

vial required to stock vial mg/mL of crude 1 μL of 001 add -1

- Add required amount of methanol to obtain a total volume of de 1

AA — _— *- Perform more steps to analyze a single compound (steps from NY 11 above). ;- in case the PK samples exceed the upper limit of quantitation (ULOQ)© - prepare the Alia titer curve and QC samples as indicated above (steps from 1 to 1 (0 + - Transfer less than 00 μl (ex: Yo μl) from 016 samples that exceed 00.1 Amna. 1 - Add a comparison sample of plasma to those samples For a final plasma volume of 050 µl plasma Note the dilution 0 Jal — A 0 µl of remaining PK samples 0 4 - Prepare all formula samples and extract all samples as described above (Steps V1 = A) Note: Higher concentrations can be reviewed to generate a calibration courve though care should be taken to avoid saturating the HPLC column or MS equipment For this reason it is recommended to dilute PK 6 samples in case of low sensitivity (upper limit for titer determination). 11.00 is greater than 01 ng/mL. The following methods should be applied when any of the sequential operations are used.

- In - according to another form of the invention, a pharmaceutical composition is provided that includes a compound having the formulas (TAY) or an acceptable salt (cia) or one of the examples; or a terminally acceptable salt as previously defined in combination with a pharmaceutically acceptable diluent or carrier.

The formulation may be in a form suitable for oral use (eg JU tablets, ctablets, lozenges, hard or soft capsules, caqueous or oily suspensions, and lozenges). cemulsions, dispersible powders, cgranules, syrups, or elixirs, or suitable for topical use (for example, creams or ointments Or gels, aqueous or oily solutions, or suspensions “(suspensions 0) or suitable for administration by inhalation, for example, in the form of a powder that is divided into powder or liquid aerosol or suitable for administration by insufflation (eg as a divided powder) or suitable for parenteral administration (eg as a sterile aqueous solution aqueous or sterile oily for intravenous vo or subcutaneous administration or cintramuscular or intramuscular dosing or suppository for rectal administration. (rectal general;

Compositions in coral form are preferred. The compositions according to the invention can be obtained by conventional procedures using conventional pharmaceutical excipients; Well known in the arts. Subsequently; © Compositions for oral use may include, for example, one or more coloring and/or sweetening agents

9.0 - Sweetening and or flavoring and/or preservative agents Suitable excipients that are pharmaceutically acceptable for tablet formulation include, for example, inert diluents such as lactose or sodium carbonate. or “calcium phosphate 0” “calcium carbonate” or granulating or disintegrating agents such as “corn starch”; algenic acid; Binding agents such as starch, lubricating agents, “magnesium stearate Jie agents” or stale of stearic acid, preservatives such as “ethyl” or “propyl p-hydroxybenzoate” and antioxidants “Jie canti oxidants” ascorbic tablet formulations may be uncoated or coated either to modify its disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract or to improve the stability of it and/or Leda in either case; 0 using conventional encapsulating agents and procedures well known in the art. Compositions suitable for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate I «calcium carbonate Or kaolin or hard gelatin capsules where the active ingredient is mixed with water or oil such as (cw) vo ad nut (peanut) or liquid paraffin (cliquid paraffin) or olive oil. aqueous suspensions on active ingredient in a fine powder Lae finely powdered with one or more suspension agents Jia <hydroxypropylmethylcellulose y “methylcellulose 3 ” sodium carboxymethylcellulose “sodium alginate 5 and polyvinyl-pyrrolidone tragacanth gum tragacanth and acacia 0 finger; Dispersing or wetting agents such as lecithin

91 - or thickening products of alkylene oxide with fatty acids fatty acids (for example, polyoxethylene stearate; or thickening products of ethylene oxide with long chain aliphatic alcohols cong chain for example cheptadecaethyleneoxycetanol or condensation products of ethylene oxide with partial esters © derived from fatty acids and Jie hexitol: “polyoxyethylene sorbitol monooleate or products Condensation of ethylene oxide plus long chain aliphatic alcohols e.g.: <heptadecaethyleneoxycetanol or condensation products of ethylene oxide plus partial esters derived from hexitol s fatty acids acids such as: “polyoxyethylene sorbitol monooleate 0 0 condensation products from ethylene oxide in addition to partial esters derived from chexitol anhydrides j fatty acids, for example polyethylene sorbitan monooleate. Aqueous suspensions may also include one or more preservatives (such as cethyl or propyl p hydroxybenzoate), anti-oxidants (such as 0% ascorbic acid), coloring agents, or “flavoring agents” / or sweetening agents (¢sucrose Jie) sweetening agents | Uninterrupted (aspartame sl) Oily suspensions can be formulated by suspending the active ingredient in vegetable oil (such as carachis oil, colive olive oil, sesame oil, or Coconut oil or mineral oil (Jaze Cu) (eg paraffin 0 londonna). Load oily suspensions may also include an agent

ay - - Jia thickening agent beeswax and hard paraffin or -cetyl alcohol Jie sweetening agents described above can be added. And flavoring agents, to obtain palatable oral coral preparations, these compositions can be preserved by adding an anti-oxidant such as 0e-ascorbic acid.

Generally includes dispersible powders and granules suitable for preparing a Sle suspension by adding water to the active ingredient in addition to a dispersing or wetting agent or a suspending agent and a one case

or more.

0 And then give examples of appropriate dispersing or wetting agents and suspending agents with those mentioned previously. Additional excipients can also exist such as sweetening agents, flavoring agents and coloring agents. Lad Pharmaceutical compositions according to the invention can exist in the form of oil-in-water emulsions. maybe

Vo also that the oily phase is a vegetable oil “oil p 76861801” Jie “olive oil” or peanut “arachis oil” or mineral oil “mineral oil” such as liquid paraffin liquid paraffin or a mixture thereof. Suitable emulsifying agents could be, for example, Jia naturally-occurring gums, gum acacia, or tragacanth, or naturally occurring phosphatides such as

070 Detroitic or clecithin or esters or partial esters derived from fatty acids

- and - fatty acids and (Ae) hexitol anhydrides, for example (sorbitan monooleate) and condensation products from the aforementioned partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Lad can be Emulsions may include sweetening agents 0, flavoring agents, and preservative agents ©. Syrups and elixirs can be formulated with sweetening agents such as “glycerol or” propylene, glycol, sorbitol, aspartame, or 5010:0858 and may also include a demulcent or preservative and 0 flavoring agent [5] or Coloring agent. Pharmaceutical compositions may also be in the form of a sterile injectable suspension that is aqueous or coily and can be formulated according to known procedures using one or more dispersing or wetting agents The sterile injectable formulation may also be in the form of a sterile injectable solution or suspension in a non-toxic diluent or solvent accepted by non-enteric route; For example, solved at “1 4:01 PM” 3-5:18. Compositions for administration by inhalation 0 may be in the form of a conventional pressurized aerosol positioned to dispense the active ingredient as either an aerosol containing solid or liquid droplets divided into particles. Jie conventional aerosol propellants can use volatile fluorinated hydrocarbons or hydrocarbons and the aerosol device is placed in a conventional manner to dispense a measurable amount of the active ingredient. 0 For more information, the reader can refer to: lighter

Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. Treatment and specific route of administration eg © A formulation intended for oral administration to eg humans will comprise 05 mg to ? gram of the active agent complex with an appropriate and adequate amount of the excipients which may vary from about * to about 7 AA by weight of the total formulation. The dale form unit dose will contain from about 1 mg to about 5000 mg of the active ingredient. For further information on routes of administration and dosage regimens the reader may refer to: Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; 01 Chairman of Editorial Board), Pergamon Press 1990. The inventors have found that the compounds identified in the invention ; or a pharmaceutically acceptable salt of which are considered to be effective inhibitors of the enzyme ceffective 11811801 inhibitors and thus have importance in the treatment of pathological conditions associated with the metabolic syndrome. 0 It must be understood that when the term metabolic syndrome is used in this application; This usage relates to the metabolic syndrome as defined in (1) and/or (Y) or any other known definition of this syndrome. Synonyms for “metabolic syndrome” used in art include reaven's <syndrome and cinsulin resistance syndrome and cinsulin resistance syndrome 72. It should be understood that when the term “metabolic syndrome” is used it also refers to Aelia reaven's;

X and cinsulin syndrome 0

— Moe-

According to another form of the invention Mall, a compound of formula (1) is provided; or a pharmaceutically acceptable salt thereof; or examples; or a pharmaceutically acceptable salt of a terminator as previously defined for use in a method for the prophylactic or therapeutic treatment of warm-blooded human jie.

Thus, according to this version of the invention, a compound of formula (1) was provided; or a pharmaceutically acceptable salt thereof;

0 or examples; or a pharmaceutically acceptable salt of the terminator as previously defined as a drug.

In accordance with another aspect of the invention, the use of a compound of formula (1; or a pharmaceutically acceptable salt thereof; or of the examples; or a pharmaceutically acceptable salt terminated as previously defined is provided for use in the manufacture of a drug used to produce an inhibitory effect of enzyme 11811901 in A warm-blooded being Jie human.

01 when the production of an enzyme 11811571 inhibitory effect is appropriately indicated; this refers to an alternative treatment so when production of a metabolic syndrome inhibited effect or cobesity elevation of enzyme 11811501 is indicated this indicates diabetes treatment 0:256:8; Or obesity, or chyperlipidaemia, or high blood glucose, hyperlipidaemia, blood lipids, <hypertension, blood, or hyperinsulinemia, or high levels of insulin in the blood, 1, specifically diabetic and obese patients. Alternatively, when it is indicated to produce an inhibitory effect of costeoporosis or osteoporosis “glaucoma” this refers to the treatment of old glaucoma (11BHSDI) or “cognitive disorders” or “dementia” or “dementia” or “ctuberculosis” or Tuberculosis

.depression

alternatively; When it is indicated that 811801 11 produces an inhibitory effect, it is due to the treatment of cognitive disorders, such as improving a person's cognitive ability; JU) by improving verbal fluency, verbal memory or logical memory, or for the treatment of mild cognitive disorders 0 See, for example, International Patent No. 17/087411 and the references contained therein and: Proceedings of national academy of sciences (pnas), 2001, 98 (8), 4717-4721. When indicated to produce an inhibitory effect 11811801 is due to ge and/or delaying the onset of delaying the onset and/or reducing the risk of atherosclerosis — see for example: J.

Experimental Medicine, 2005, 202(4), 517527 0 Alternatively; When it is indicated to produce an inhibitory effect of 11811501 it is due to the treatment of Alzheimer's and/or neurodegenerative disorders according to another feature of this form of the invention; A method has been provided to produce an inhibitory effect of enzyme 1 11 in a warm-blooded organism such as humans in need of this treatment, which includes administering to the said organism an effective amount of a compound of formula (1); Or a pharmaceutically acceptable salt for it. In addition to its uses in therapeutic medicine; Compounds of formula (1) and acceptable salts Ly of them are also useful as hunting tools for the development and specification of in vitro and in vivo all test systems to evaluate the effects of enzyme inhibitors 11811501 in laboratory organisms Jie cats and dogs; rabbits” and monkeys; chilly and rats as part of the search for a new dale treatment.

— and - The 118115701 enzyme inhibition mentioned herein may be used as a monotherapy or may comprise in addition to the subject matter of the present invention one or more other substances and/or other treatments. This combination therapy can be worked on by simultaneous administration; or successive administration; or the separate administration of the separate components of the treatment. Concomitant therapy may be in a single tablet or in separate tablets Abadia © For example, the co-administration of other substances with inhibitors 11811501 and in particular those of the present invention which includes the following classes of therapy: 1)insulin and its analogues ¢insulin” agonists hd) the hormone insulin and include sulphonylureas (eg glibenclamide (glipizide ys 0) food glucose regulators (eg nateglinide 5 crepaglinide) dipeptidyl inhibitors peptidase IV inhibitors ¢ (DPP-IV ¥) agents that make insulin sensitive and include PPARy cofactors (eg pioglitazone ¢ (rosiglitazone 3); Jalse suppresses hepatic glucose output ¢ (metformin Jie) hepatic glucose output ro 0 agents designed to reduce the absorption of glucose from the intestine testine (such as ¢ (acarbose 1) agents designed to treat complications of high blood glucose for a period of long; Jie 0/0 aldose reductase inhibitors Other antidiabetic agents include phosotyrosine phosphatase 0 inhibitors, cglucose 6-phosphatase inhibitors, cglucagon receptor antagonists, and enzyme activators. glucokinase and phosphorylase enzyme inhibitors 0©p0a and enzyme inhibitors

M - glutamine 5 « fructose 1,6 bisphosphastase enzyme inhibitors: fructose -6-phosphate amidotransferase. Jalse (A anti-obesity ¢) orlistat 5 sibutramine (fis) anti-obesity agents Blood lipids Jie HMG-CoA reductase inhibitors 0 statins such as pravastatin and PPARa agonists Jie fibrates gemfibrozil and bile acid blockers ¢ (cholestyramine) bile acid and cholesterol absorption inhibitors (plant stanols p101 and synthetic inhibitors 58) and inhibitors of ileal bile acid absorption (IBATI) and fig inhibitors of cholesterol transport ester, nicotinic acid and niacin analogues), slow release formulations 0 anti-hypertensive Jalsa Jie hypertension pall m ¢(inderal 5 “atenolol Jie) and ACE inhibitors (such as lisinopril, nifedipine Ji) calcium antagonists, vascular angiotensin receptor antagonists (candesartan Jia), coc antagonists, diuretic agents (benzthiazide 5 furosemide Jie) agents (1 35S modifiers) blood Jie haemostasis inhibitors of clot formation cantithrombotics and stimulants for fibrinolysis and anti-platelet agents cantiplatelet agents and thrombin antagonists and inhibitors of factor Xa and inhibitors factor 7118); antiplatelet agents (aspirin Js, 1©: p100mm1a); 0 anticoagulants (such as heparin and its low molecular weight analogues)

¢warfarin y «(hirudin

Anti-inflammatory agents (VY) such as non-steroidal anti-inflammatory drugs (VY).

non-steroidal steroids (such as aspirin) and steroidal anti-inflammatory agents

(fis) anti-inflammatory Adsmaddinah").

-(SGLT (inhibitors of kidney by the kidneys glucose agents that prevent reabsorption) 0 11 of the other mentioned also use practical features; method; use and manufacture | any in the composition fishing medicine alternative and preferred models of the compounds of the invention current situation mentioned in this application. Detailed description: 0 Examples:

The invention will now be illustrated by the following examples where; Unless otherwise specified:

(1) The temperatures are given in degrees Celsius (C); operations were carried out at room temperature or

ambient temperature; which is at a temperature ranging from 18 to diego YO atmosphere

m inert gas Jie inert gas normalized;

(7) Evaporation of solvent was done using a rotary evaporator

at low pressure) and 1 p ... Pascal; -250,01 mm Hg (at a bath temperature of up to

“Vee —

ta El 0 silica gel flash chromatography medium ((

(£) General following TLC series reactions and reaction times are for illustrative purposes only;

(©) The outputs are just described and are not necessarily those obtained by creating a process

© ennobled; Processes were repeated if more material was required;

(1) When finished, the NMR data (11!) is in the form of delta values for protons

Diagnostic protons, which are expressed in parts per million for

detramethylsilane (TMS) Set at Yoo or £0 MHz (unless otherwise specified)

using perdeuterio dimethyl sulfoxide (DMSO-ds) as solvent 5017©01; unless specified otherwise; The peaks of the multiples are thus shown: os is singular; double d; “dd is a double of doubles; dt

double of triple; dm is a multiple of multiples; ot triple" 7 is a multiple of; wide;

(V) Chemical symbols have their usual meanings: 51 units and symbols are used;

(A) Solvent ratios are shown by volume: volume terms (vol/vol)

(4) Mass spectra (MS) was measured by electron energy of 71 eV in chemical ionisation (CI) mode using a direct exposure probe.

Ionization demonstrated by electron impact (EI) and fast atom ejection

bombardment (FAB) or electrospray (ESP) values of fmM/z are indicated and can

Use the following abbreviations or in the processing part described in the present application above:

- 1.1 -

diethyl ether: 0 dimethylformamide: DMF dichloromethane: DCM

2-dimethoxyethane : DME methanol : MeOH ethanol : EtOH

HO: water

trifluoroacetic acid: TFA

Tetrahydrofuran: THF dimethylsulfoxide: DMSO 0

1-hydroxybenzotriazole: HOBt

1-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride : EDCI (EDAC)

Diisopropylethylamine: DIPEA

diethyl azodicarboxylate : DEAD ethyl acetate : EtOAc 0

— \ 0 Y —_ sodium bicarbonate NaHCO; potassium phosphate : K3PO4 magnesium sulfate : MgSO, portable polymer : PS 2,2'-bis(diphenylphosphino)-1,1'binaphthyl : BINAP © 1,1°-bis(diphenylphosphino)ferrocene : Dppf dibenzylidineacetone : dba polymer ‏ Loaded on the carbonyldiimidazole: PS-CDI: (1) Example No. 2-[(3R)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl]acetic acid m 0 0 p art (intermediate compound 6-chloro-N-cyclohexyl-2-propylsulfanyl-pyridine-3-carboxamide then mix 010/( methyl-(r)-3-piperidine acetate hydrochloride 5 0 mmol) 1.07 cabin 07 Fakhsh

aslo gram; 1.07 mmol) and 16:60 (0 7.5 080.08 aha mmol) butyronitrile y in a microwave tube and stirred at 178 °C for 2 hours. The mixture changed from a slightly soluble white mixture to an orange solution The reaction was stopped and most of the butyronitrile was evaporated at reduced pressure. Water was added and the product extracted at M8:08 (40 mL © twice); and it was washed with brine (V+) brine brine ml); and dried on ,121850; filtered and evaporated at low pressure to obtain an orange oil that was pre-tampered on celite and purified by flash column chromatography “8i0;) 0 to obtain the compound mentioned in the title as it was in the form of a light yellow oil with crystals to obtain a solid 0 with a white color 0.44 (55 7 grams). Yo)THF ml); 01 (ml) water was added, followed by YAY (mg). The reaction mixture was stirred at room temperature for three hours. The solution was acidified with 2171101 between pH number ; 5© and the product was recovered in EtOAc (£1 mL twice). vo The Jue solution was brine (de V+) brine, dried at 148504, and the organic phase was evaporated at low pressure to obtain a white ingot (OYA (49 7). 1.30 mm 1.26 (311 rd) 1.11 'H NMR (400.13 111126 DMSO-dg) 60.95 (3H¢ t)¢ 1.77 st (1H¢) 1.73 - 1.69 nM (1H¢ m)¢ 1.43 (111 m) )¢ 1.59 (2H¢ t)¢ 1.65 - 1.72 2H¢ (3H¢ m)¢ 1.83 - 1.85 (111 m)¢ 2.12 - 2.25 (211 m)s 2.71 - 2.77 (1H¢ m)¢ 2.86 - 3.02 (1H 0 7.61 has (1H¢ 6.47 has (3H m)¢ 3.63 - 3.67 (1H¢ m)« 4.20 (1H¢ d) 4.29 (1H (1H™ d) 7.79 a

- 1.6

MS m/e 0 and starting material oF The following examples were prepared in a manner similar to Example No. (1); Using a suitable intermediate compound: aminoester from MS m/e "HNMR § name Jaa compound MH"

A Y -5a -1 | (1H NMR (400.13 MHz | 406 (cyclohexylcarbam”) CDCI13) 0.95 BH | 1-6o 0 (1.11 - 1.37 (6H propylsulfanyl- 0 (1.46 - 1.57 2H 0 3- 8 "m) 1.65 - 1.78 (SH carboxylic acid Po «m)1.92- 1.97 2H «m):2.03 - 2.07 (1H «m)«2.50 - 2.57 (1H «m)3.02 - 3.12 GH 3.88 - 3.95 » q:3.42 (1H) « m)¢ 4.03 (1H m)«(1H « m)«4.36 - 4.41 (1H ¢ 6.49 (1H): 06.33 (1H d)c 7.73 (1H«d) 406|1H NMR (300.072 1-[5- v

CDCI3) 0.95 MHz (cyclohexylcarbam 1.14 (111 m)c1.01 3H Or srsulfanyl-0d (2Hem) | pyridin-2- 1.22 - 1.19 lps «d)1.23 (1H ia or 1.31-1.41 m)«(2H o LJ N : « 1.56 - 1.52 m)«(1H 0 » 1.72- 1.62 1.65 - 1.73 « m)«(4H 1.76 - 1.80 « m)«(1H 1.92 - 1.97 « m)«(1H 2.00-2.01 ¢ m)«(3H 2.55 - 2.62 « m)«(1H 3.03 -3.09 « m) «(1H ¢ 5)¢ 3.91 (1H: m)«(4H «m)4.13 - 4.18 (2H « 7.74 (1H m)«6.40 (2H d)

- 1.1 = 420 1H NMR (300.072 2-[1-[5- 1 : : « CDCI3) 0.95 (3H:MHz (cyclohexylcarbam.0oyl)-6- 01.16 - 1.33 (TH) | propvisulfanyl- oe cm) 1.34- 1.41 2H | pyridin-2-yl}-4- ~ N: 1.62 - 1.71 « Vol. 0906 | acid 1.77 - 1.81 « m)«(4H 1.91-1.96« m)«(2H rfc 2.24 2H m)«(2H «m):2.83 - 2.90 2H ¢ 3.92 (1H: t):3.06 2H 1H 1)-6-propylsulfanyl- 0 0 1.50 - 1.59 « lm 1.40 (7H | pyridin-2-y1]-3- or (1.62 - 1.69 (4Hem) “(2H piperidyljacetic acid NN 1.82 - 1.98) text 3Him) 2 : 2.20 - 00:2.01 - 2.07 (1H o 02.75 (1H: m).2.25 (2H 3.91 “m)2.92-3.13 GH “4.15 - 421) 211 83 6.50 » 00 6.32 (1Hem) 007.73 ) 111 3 392 1111111 (400.13 MHz | [1-]5- 1 (cyclohexylcarbamoy 1.09 « t)« CDCI3) 0.95 (3H 1)-6-propylsulfanyl- 1.64 - 1.70 » m).- 1.40 (7H | pyridin-2- yl}pyrrolidine-3- «1.88 - 1.97 (20 1 carboxylic acid 0 0 3.04 - « m)« 2.23 (2Hem) 6 3.42 - 3.46 003.18 GH 7 v 4 »3.54 - 3.60 (1H: 3 rak'ah 3.91 " 03.69 (Q111) 6.55 0015.98 (111 3) 07.72 (111 3)

- VV - (HNMR (400.13 MHz | 2-[(3S)-1-[5- 7 (cyclohexylcarbamoy 420 « )«DMSO-d6) 0.95 (3H 1)-6-propylsulfanyl- 1.15 - «m)«1.05 - 1.18 (1H | pyridin-2-yl}-3- 1.41 - 1.49 « m)e1.35 (SH piperidyl]acetic acid 0 «1.55 - 1.90 (10H: 1 °° or cm): 2.12 - 2.26 ( 2H«m) yo \ 2.85-¢m)2.71 - 2.77 (1H 3.63 - 3.66 » m):3.01 BH « d)« 4.20 (1H m)«(1H tf 6.47 (1H: (4.29) (1H 17. 79 (1H:d).7.61 (1H 1.1 (1H «1H NMR (300.072 MHz | 2-[4-[5- A 421 (cyclohexylcarbamoy « CDCI3) 0.83 - (1H 1)-6-propylsulfanyl- 0 0 ) pyridin-2- 2a yl]piperazin-1- NTN 1.25 ¢m)«1.19 - 1.24 (6H yljacetic acid ~~ N « 1.28 - 1.35 (1H¢ s)«(1H m 1.65 « 10 ): 1.33 (2Hm) «d)c 1.91 (1H¢ m)«(1H p 3.14 )211 2H 3.66 - » 103.53 - 3.57 2H «3.80 (3H: m)«3.70 (1H 6.25 ps 3.87 (2Hum) ¢ 6.49 - 6.50 (1H: d)«(1H d) 7.68 (1Him) 472 'H NMR (400.13 MHz (3R,55)-4-[[5- q (cyclohexylcarbamoy) « 1)«DMSO-d¢) 0.98 (3H 1)-6-propylsulfanyl- ._ 0 0 1.20 - ¢m)¢1.11 - 1.19 (1H|pyridin-2-HOLL yl]Jamino]adamantane ° 1 155 - 1.64 31h (4H | 0 5 «1.68 — 1.82 (10H: 1 «m)¢ 1.95 - 2.00 (1Hm) 2.96 » 002.08 2.13 (4H¢ 3.60 - 3.70 (1H« t)«(2H 'm)« 4.02 -4.15 (1H¢m) Shelf 6.94 (1H: d)«6.34 (1H s) Traction 7.60 (1H: d)<7.48 (1H s)«11.85 (1H

- 118m 472 "HNMR (400.13 MHz (3R,5S)-4-[[5- Ye (cyclohexylcarbamoy « t)«DMSO-dg) 0.96 BH 1)-6-propylsulfanyl- o oo 1.18 —«m)«1.08 - 1.16 (1H | pyridin-2- OAL ylJamino]adamantane «1.46 QHem)1.36 (4H | 7 -carboxylic acid 7 ¢ m): 1.53 -1.62 (311.0( 1.92 » m)«1.68 — 1.75 (6H «1.95 2.10 411 1 3.58 - 10 2.95 (211) 4.05 - 4.07 » 003.70 (1H of 1634 (1H: 3 « d) 7.48 (1H: 6.96) s) 12.14 (1H: d).7.66 (1H 434) (HNMR (400.13 MHz | 4) -[[5-111 (cyclohexylcarbamoy « 1)« DMSO-d¢) 0.99 (3H )-6-propylsulfanyl- Q 0 0 1.24 - 1001.11 - 1.17 (1H|pyridin-2-yl}-methyl-") or ]cyclohexane- +" 1.43 - 1.53 00001.34 (4H | -carboxylic acid 5 0.57 - 1.67 (THe 1 « 1.79 (2H t)« 1.72 2Hum) ls 2.00 - 2.03 (2H.d) 2.87 «m)2.18 — 2.28 (1H «2.95 - 2.99 211 3 4.50 « d): 3.65 (1H:m) 7.62 « d)« 6.31 (1H: s)«(1H « dy 7.68 (1H 3 s)12.03 (1H 4406 | HNMR (400.13 MHz) PO. > 1 VY cyclohexylcarbamoy

HPL + 1)«DMSO-dg)0.96 (3H1)-6-propylsulfanyl-0O

CR 1 122-m)1.09-12(1H | pyridin-2- Cy or = yl]pyrrolidin-3- YR 2.62 1.58 - 1.85 « m).1.35 (4H yl]acetic acid N min. «m): 2.12- 2.2 (1H: m)«(8H 2.52-¢m)«2.31-2.45 (2H 0k 2.98 (2H:m)«2.64 (1H 3.34 - 3.41 » 9 (1H Sun 3.5-3.8) (311 3 ) 7.62 (1He 610 (1H s).« 12.2 (1H: 5). 7.68 (1H)

- 1.84 415 |1111 3 3 -]5- -

DMSO0-d6) 0.58 <MHz (cyclohexylcarbam 1.06 - 1.38 (me 3H)(t) ¢ 1.51 - 1.63 (m«7H) pyridin-2- 0 1.65 - 1.86 (me1H) ylJoxybenzoic acid for -3.60 211: 2.54 (t.4H) N ¢ 6.82 (d¢ 11173.74 (m 7.57 « 1H): 7.43 (d:1H) 117.65 (s¢ TH)«(t 2117.78 - 7.87 (m 12.57 - « 1H):8.13 ( d 11113.46 (m 431 | IH NMR (300.073 3-[5-0]

DMSO0-d6) 0.71MHz | (cyclohexylcarbam. 1.04 - 1.42 (mA) H(t) 149-184 (mH) | -2stphtum 00 © N 3.57 - « 2H]. 2.57 (t5H) Yijsulfanylbenzoic ¢ 7.00 (d¢ 1113.72 (m 7.61) « 1H): 7.58 (d<1H) « 1H)« 7.80 (1 1H)«(t « 8.06 m) 1H):8.03 (d 12.73 « 1H): 8.16 (d<1H) 1H):- 13.56 (m 431 | 1H NMR (300.073 4-[5-vo]

DMSO0-d6) 0.71MHz | (cyclohexylcarbam (105-138 (me SEU | poongrsulfanyl- « 1.50 - 1.62 (m7H) pyridin-2- .. 1.65 - 1.84 (m:1H) yllsulfanylbenzoic per m 3.66 » 211 (2.61 (t4H) N 1107.03 )1 ¢ 7.65 (1 (d 8.17 « 2H): 7.99 (d2H) 1H)« 13.26 (s < 1H)«(d

— \ \ . — 415 «HNMR (300.073 MHz | 4-[5- 1 (cyclohexylcarbamoy ' 3H)DMSO-d6) 0.60 (t 1)-6-propylsulfanyl- 1.50 - « 7TH)1.06 - 1.39 (m | pyridin-2- 0 1.64 - 1.87 1H)1.63 (m | Yoxybenzoic acid 1 3.58 2112.56 (t« 4H)«(m >> H 0 NS 6.82 (d¢ 1H): - 3.73 (m N « 7.84 (ds 2H)« 7.25 ( d«1H) « 8.13 ( 2H): 8.00 (d<1H) 1H) 429 111 NMR (300.072 MHz | 2-[4-[5- VY (cyclohexylcarbamoy 1.14 « 3H).CDCI3) 0.73 (t 1)-6 -propylsulfanyl- 1.55 - 1.81 « 7H)«- 1.50 (m | pyridin-2- «1.95 - 2.07 (m« 3H)«(m Vlloxyphenyljacetic oo : 0) «3.66 (s« 2H): 2.75 1 a YW (5 + 2H): 275 (12H) 0 « 1H) 3.91 - 4.07 (m2H) N 111 6.62 (d« 1H)<6.33 (d « 2H)« 7.31 (d« 2H):7.08 (d 1H)7.92 (d 443) « lH NMR (300.073 MHz | 3-[4-[5- YA (cyclohexylcarbamoy « 3H)DMSO-d6) 0.64 (t | J) 6 propylsulfanyl- 1.50 - « 71101.01 - 1.38 (m | pyridin-2- 1.65-1.89 .T (m | YJoxyphenyljpropan 0 oic acid o o 2.57 « 2H): 2.51 (t« 4H)«(m a Pe 0 Ns 3.58 - « 2H): 2.82 (t« 2H)«(t N «6.70 (d¢ 1113.75 (m ¢ 7.27 (d« 2H)« 7.04 (d<1H) « 8.08 (4 1H)« 7.79 (d<2H) 1H) 461 «lHNMR (300.072 MHz | 2-[4-[5- V4 (cyclohexylcarbamoy 1.18 + 3H).CDCI3) 0.91 0 1)-6-propylsulfanyl- oN . 1.68 - 1.81 « 711(- 1.67 (m | pyridin-2- “01 oo 1.93 - 2.08 (m« 2H)(m ylJsulfanylphenoxy]a Ns cetic acid N 3.88 - « 2H): 2.91 (t:2H) « 2H) : 4.69 (6 1H)«4.10 (m 6.45 « 1H)«4.88 - 5.49 (m 6.95 « 1H): 6.64 (1 7.67 « 2H)« 7.50 (1 001 1H)«(d

- 11110 - 445 1111111 (300.072 MHz | 2-[4-[5-0.(cyclohexylcarbamoy o 1.12 « 3H)« CDCI3) 0.77 (t 1)-6-propylsulfanyl- A 1 . 1.56 - 1.68 « TH)«- 1.52 (m pyridin-2- “CL or ylJoxyphenoxy]acetic “Ns ¢« 1.69 - 1.80 lentils 1H)«(m acid \ « 2H)¢ 1.93 - 2.08 (m<«2H ( 3.91-4.07 « 2H)2.77 (t 6.38 « 2H)« 4.67 (s« 1H)«(m 6.94 « 1H): 6.60 (d« 1H)«(d 7.92 « 7.06 (211 d« 2H)«) d 1H)«(d 443 «HNMR (300.072 MHz | 2-[4-[5- YY (cyclohexylcarbamoy 1.14 - + 3H).CDCI3) 0.71 (t 1)-6-propylsulfanyl- O40 0 0 « 3H)« 1.53 : 7101.50 (m | pyridin-2- 'a oy 1.67 - 1101.57 - 1.67 m 1) Yloxyphenyl]propan 600 oic acid ¢ 1.94 - 2.08 (m« 2111.80 (m ¢ 3.77 (q¢ 2H): 2.73 (t) :2H) « 1H): 3.92 - 4.07 (m<1H) « 1H: 6.62 (1 1H)«6.33 (d « 2H).7.34 (d 2H):7.08 (d 1H).7.92 (d 445 «1H NMR (300.072 MHz | 2-[4-[5- YY - 3H) (cyclohexylcarbamoy 1.13 - « 3H)« CDCI3) 0.88 (t 1)-6-propylsulfanyl-BH .0 1.91-2.08 « 10H)«1.81 (m pyridin-2-©“ oy 3.64 « 2H). 1H): 6.68)1 (d « 2H): 7.51 (de 2H): 7.31 (d 1H). 7.64 (d 429 « 1H NMR (400.132 MHz | 2-[3-[5- YY(cyclohexylcarbamoy 1.14 « 3H) «CDCI3) 0.71 (t 1)-6-propylsulfanyl- 1.56 - 1.66 « TH)¢- 1.49 (m | pyridin-2- ylJoxyphenyl]acetic +1.68- 1.80 (me IH)(m |; 4 m « 2H)« 1.95 - 2.06 (m<2H) 3 2 or 0 © N's 211 3.65 and 6) 0 N 1H ) 1H)

431 | (HNMR (300.072 MHz | 2-[5- Ye (cyclohexylcarbamoy 1.13 + 3H)CDCI3) 0.81 (t 1)-6-propylsulfanyl- 0 0 1.57 - 1.69 « TH)«- 1.51 (m | pyridin-2- or ( 1.67 - 1.81 ( 1H)«(m yl]sulfanylbenzoic acid 3 « 2H)« 1.94 - 2.08 (m« 2H) 3.90 - 4.08 + 1 » 1H)« 6.29 (d« 1H)«) m. -d6) 0.98 (t I)-6-propylsulfanyl- 0 0 0 2.20 » 20111.06 - 2.15 (m | pyridin-2- SOLO ylloxycyclohexane-1- N § «2.99 (t 1H)” - 2.33 (m carboxylic acid « IH) ( 3.57 - 3.74 (m:2H) 6.44 « 1H)« (4.88 - 5.03 (m 7.99 « 111) 7.68 (d« 1H)«(d « 11.98 - 12.22 (m« 1H)«(d 1H) 1 406 (HNMR (400.13 MHz | I-[5-YX

HPL (cyclohexylcarbam cw |¢«HDMSO-d6) 0.94 GH oyl)-6- f 0 0 = «m)¢1.08 — 1.13 (1H propylsulfanyl-2 free 1.7 pyridin-2- NON Ns min, | 2021-1-33 4H yl]piperidine-2- N «m)«1.41 - 1.47 (1H carboxylic acid «m)«1.52 - 1.67 (4H «m)1.68 — 1.80 (4H « 2.91 (2H: d)«2.24 (2H «m)¢ 3.09 - 3.17 (2H) «m)<3.60 — 3.66 2H «5.02 (1H¢ s)«4.11 (1H 7.59 « d)« 6.42 (1H:s)d). 7.78 (111 1

392 | 1HNMR (400.13 MHz | (25)-1-[5-7

HPL (cyclohexylcarbam

CR | CDCI3) 1.00 - 1.05 BH | 416. 0 0 = | SMTLY 1.22-1.31 a( | propylsulfanyl- or hs MSMS PERE 00 «m)«1.59 —- 1.64 (1H carboxylic acid 0 «m):1.67 - 1.77 GH «m)1.97 - 2.04 2H «m)2.10 -2.19 GH 2.99 - 3.06 « 5):2.47 (1H 3.16 - 3.23 :; )¢ 4.65 (1H.m)«(1H « m):6.20 - 6.23 (1H « 7.84 (1H: d)«6.51 (1H d) 434 | (1H NMR (400.13 MHz | 2-[1-[5- Ya

HPL (cyclohexylcarbam

CR | «: DMSO-d6) 0.95 GH | They see = 1.12-1.18 « d)¢1.03 (3H propylsulfanyl- min, | 120-123 emu mo pve 1.26 3H¢m)«2H | acid AA “m):1.57 - 1.63 (4H of N “m):1.68 — 1.73 (4H of “m):1.75 - 1.80 (2H 2.81 2.89 « 1)2.18 (1H ¢ £)¢ 2.93 (2H¢ m)«(2H «m):3.61 —3.67 (1H « 4.44 (1H: d)«4.40 (1H 7.61 « d)« 6.51 (1H:s) d)« 7.80 (1H.d)«( 1h

Yyiva

- 1116 - ¢434 | 111 11118 (400.13 MHz rl Yq

HPL | DMSO-d6) 0.94 - 0.99 prostate

CR | (1L1-122(AHem)(SH tr = Rs 1.23 - 1.40 (6Hm) | ylJamino]methyl]cycl 20 > 1.71 - 001.53 - 1.69 (4H 0206-1 - A 1.91 (2H: m).1.81 (6H 0 LA wear 2.10 - 2.16 (1H:d) : 5 3.16 » 02.94 - 2.96 (2H . 3.55 - 3.65 111 3 churn 7.15 (1 6.14 (1Hem) 7.69 « d) 7.47 (1He 3 s) 12.20 (1H.d)«(1H 366 | {HNMR (400.13 MHz | 3-[[5- 2

HPL | 0450-40 095 GH | |g mmoonsuttons

CR | 1.25 - m)1.09- 1.15 (1H | pyridin-2- 221 | 155-165 m)120 (5H | YLlaminolpropanoic p min. | «1.70 - 1.77 (4H.m)”(4H free ¢ « 3.52 (2H¢ t)« 2.96 W KER (Ns211) r 3.58 - 3.70 (1Het) C N « d) 7.49 (1H: d):6.16 (1H °° d)7.71 (1H 420); ‎ |HNMR (400.13 MHz | 1-[5-vy

HPL | 1.16.:CDCI3) 0.95 3H A

CR | 131-141 RS 1.26 3H | pyridin-2-ylJazepane- 26 1.52 - 1.74 (THe m)«2H 4-carboxylic acid ) min. | ns 1.82 -1.96 (Hum). Tull 2.40 - “m)2.10- 2.17 (1H 2 ( 1H) 3.00-3.11 » 002.46 (1H (3.35 - 3.45) (1H 3 s 3.55 -3.65 (1Hem) 3.88 - “m) :3.70 - 3.85 (2H «6.14 (1H.m)3.96 (1H 7.71 (1He (1 6.44 (1Hed) d)) h1

_ \ \ c — ¢420 | «HNMR (400.13 MHz | 1-]5-YY

HPL | 1.10 (DMSO-d6) 0.96 (0.96) 3H SSb

CR | a(1.22 - 1.33 0116932 | pyridin-2-yl]4- = 1.71 - « m)<1.56 - 1.65 (3H methyl-piperidine-4- 27>t 2.00 rf m):1.77 (4H | carboxylic) acid or ¢3.15-3.22 (2H 0.2.91 (2H Ns 4.00 « m): 3.62 - 3.65 (1H.m) .7.61 «d)« 6.50 (1H.d)«(2H d)« 7.80 ( 1H.8 404|{HNMR (400.13MHz|(1S,5R)-3-[5-vy]

HPL | DMSO-d6) 0.95 - 1.00 (3H ey A 0 0

CR | 124m) 1.10 117 (1H) | poridin 2-yl}-3. Free = t)e 1.40 )111 (1.28 (4H azabicyclo[3.1.0]hexa ys Nig 4 2.19 m):1.58 - 1.78 (7H ne-6-carboxylic acid og 4 3.50 0.2.97) (2H. 3 3.79 » (3.65 (1H: d).

HPL | 1.15 t)}.DMSO-d6) 0.97 3H en otto”o

CtR | LS 124 -1.30 (6H:m)«2H | pyridin-2-oo

Ss, | 157-0037 - 144 1| ylaminolcyclohexan on sleep | 170-178 41-6 ¢-1-carboxylic acid : { 2.15 « m }: 1.95 - 2.03 (4H.m) 02.97 2He m)e- 2.25 (1H ¢ 3.71-3.77 (1H: 5): 3.64 (1H) «7.48 (1H d)« 6.14 (1Hem) 0( 7.63 (1H.d) 1448 | 1HNMR (300.072 MHz | 1-[5- Yo

HPL | 0.96 «d]. CDCI3) 0.87 (6H rast”

CR 1 (114-139 (FH GH | pyridin-2-yl]-4- oo C-ames [POPE LO min. 1.92 - «m):1.69 - 1.76 (SH | carboxylic acid) ; 2.08 (2H 1001.96 (2H AC "4 « 3.05 (2H: t)¢ 2.78 (2Hed) lm 3.92 - 4.00 (1H) 6.21 - 6.29 « d)«4.20 (2H 7.72 « d)« 6.40 (1H« d) (1H d)(1H i.e

- 101 - 420; 111115 (300.072 MHz 1-[5-a HPL | «m).CDCI3)0.90 - 1.16 (6H ri r CtR | 1.52-¢m)1.20-1.38 (6H pyridin-2-yl]- 3- Free = 1.85-1.91 cm)1.68(SH | methyl-piperidine-4- 0 J N 8 2:00 cm): 3.04 - 3.11 , liters m).(4H | Carboxylic acid 1 3.55 - 3.70 (3H: d):3.26 (1H 6.34 (Q211) 4.00 - 3.88 p 7.72 for 1 6.40 (1H: 0 d)”(1H 448 | “IH NMR (300.073 MHz) 2-[1-[5- vv]

HPL | 1.09 « t)DMSO-d6) 0.95 (3H Se alto

CtR | 124-5) L14 GH: Receive | pyridin-2-yl]-3- = 1.55 - 1.63 <m)¢1.53 (6H piperidyl]-2-methyl- tars 1.79 - 1.71 rs | Propanoic acid transpiration 3.05 - « m)2.64 - 2.87 (3H oy N ¢ §)¢ 3.62 (1H: m):3.12 (1H 5 « d)¢ 4.43 (1H: 04.33 (1H « d)¢ 7.58 (1H d)«6.42 (1H s)e 12.20 (1H. d)<7.74 (1H «406 | <1HNMR (300.073 MHz | 2-[(3R)-1-[5-YA

HPL | 1.06 « t)DMSO-d6) 0.94 (3H Ar

CtR | 1.22- 1.34 RH 1.18 021 | pyridin-2- = «m): 1.55 - 1.78 (8H: m):«(4H 1 yl]pyrrolidin-3- 27 2.40 » m)2.12 - 2.19 (1H yljacetic acid } oA x 2.55 - 2.62 (1H) ¢ 31 AC N 8 03.09 (1H« t):2.96 2H 3.53 - » 003.39 - 3.43 (1H « d) ¢ 6.09 (1H: m):3.68 (3H «7.68 (1H« d)«7.60 - 7.62 (1H d) ) «434 | «1HNMR (300.073 MHz 3-[1-[5- v4

HPL | 1.11 «(DMSO-d6) 0.96 3H AT

CtR | 1.37 - 1.30 hes 130 (6H 1 pyridin-2-yl}-3- = r 1.55 - 1.64 (4H.m)«(4H | piperidyl]propanoic 20 228m) 1.69-1795H | 4 A ns 2.59 - 2.67 (1H: t)«(2H NNTs 3.60 «m)2.91 - 3.02 (3H 5 4.27 (14.19 (1H: s)«(1H 7.57 - » d)« 6.48 111 3 07.72 (111 7-0) 5)¢12.00 (1h

- 101 - 408; «1H NMR (400.13 MHz 2-[1-[5- 1

Ch i (cyclohexylcarbamoy

HPL 1.10 « t.DMSO-d6) 0.96 (3H 1)-6-propylsulfanyl-0°

C tR 1 24 - 1 28 + m)¢- 1 20 (1H pyridin-2-yl]azetidin- 0 0 or = for 1.26 - 1.31 (3H m)«(2H | 3-ylJoxyacetic acid Toy N y 2.37 1.72 - «m.1.58 - 3H min. zv 111 3 « d)¢ 7.60 (111 d)«6.04 (1H 0775 (1H «460 | «1HNMR (400.13 MHz) 1 1-{1-[5-0(cyclohexylcarbamoy)

HPL « t)« DMSO-d6) 0.96 (3H I)-6-propylsulfanyl-oo 0 0

CR | 122. (1.10 - 1.19 (1H | pyridin-2-yI]-3- or = piperidyl]cyclobutane on 2.97 | 135-145 (1.34 to 50) | 4 -carboxylic acid min. «1.56 - 1.64 (311 m) «(1H «m)¢ 1.72 - 1.83 (9H:m) 2.27 - (2.09 - 2H 2.67 - 2.90 » 0-0 3.04 - 3.11 (1H.m)«3H »4.30) 111 (3.66 (1H) 648) 111 (14.53 (111.) rmd 7.60 - 7.62 (1110( s) 12.20 (1H« d)«7.74 (1H 446 | 1H NMR) (400.13 MHz) 1 ms ear £Y 0: cyclohexylcarbamoy

HPL | DMSO-dé6)0.79 - 0.83 I)-6-propylsulfanyl-o0

CtR 1.04 « t)« 0.96 311 1 pyridin-2-yl]-3- or 1 - 1.25 - 1.50 « m)«- 1.20 (3H | piperidyl]cyclopropan NTN 4 oo (1.53 - 1.78 (10H:m)(6H) e-1-carboxylic acid stack 2.73 - - 3.04 (4H¢m) 4.39 - 4.45¢s)3.65 (1H « d)« 6.50 111: 1 7.79 07.60 7.62 (1H s)« 12.21 (111 1)

- 118 - 422; «1H NMR (400.13 MHz 2-[1-[5- gy

HPL | 1.12 t)DMSO-d6) 0.97 3H l a le: . 0

CHR | m) 127 @Hem)-121 (1H | puridin-2- HM = 1.68 - (1.59 - 1.66 3H | ylIpyrrolidin-3- Oo 8 2:42 176-182 cm) 1.74 2H | Ylloxyacetic acid cm) . 2.04 - 2.13 (2H: 3 lo 3.45 (1H 3.00 (2H 3.66 « m):3.53 - 3.57 3H 4.31 : f 4.06 2H.s)(1H 7.63 « d): 6.14 (111 3 d). 7.69 (1H.3 ¢450 | 1HNMR (400.13 MHz) 2-[[1-[5-£4

HPL | DMSO-d6) 0.95 - 1.00 (3H sult.

CtR | 1.16 cm): 1.09 - 1.12 test | pyridin-2-yl]-3- 2 63 1.40 - 1.45 ls 1.43 (7TH piperidylJoxyJpropan . ] wong | em) 1.58 - 1.68 (4H m) (1H 016 1 = lH 1.94 - cm)1.71 - 1.79 (SH Oy z 2.91 - 3.05 + (2.02 (1H N « m): 3.20 - 3.40) 3114 3 «4.09 - 4.17 (2H: 13.65 (1H 7.60 « m): 6.47 - 6.53 (1H«m) ) 12.50 « d) 7.74 (1H: d)(1H 1111 464; | 1111018 (400.13 MHz | 2-{[1-[5-m] HPL | 001450-46 0.97 3H re Alice CR | 115 (1.09 - 1.18 (1H | pyridin-2-y1}-3- pud) | «1.37 (6H m)1.28 4H ad oreo Te min. | «m) 142-151 QHd) | acid or 1.68 - « m)«1.54 - (3H J NTS 1.99 - 2.10 « m):1.80 (SH x 5 32.86 - 2.93 2H. 3 m" x 3.00 - 3.08 (2H«m) 3.66 «m):3.33 -3.37 (1H 4.31 « d): 4.08 (111 s)«(1H 7.60 « d)« 6.45 (1H. 3 « d)¢ 7.74 (111 3 s):12.50 (1H

- 11 - 436; 11110105 (400.13 MHz pri cab £1 cyclohexylcarbamoy

HPL « t)« DMSO-d6) 0.97 3H 1)-6-propylsulfanyl-

CR | 120-m)l.13-1.18 (1H|pyridin-2-yl}-3- = piperidyl]oxy]acetic 251|139-145.m)a27¢4H| PPS? min. | 1.51 - 1.67 (4He 8 or (4Hem) 0 NS 1.79 - 1.70 ars 2.93-:m)1.98-2.02 (1H 0 5 3.18 -3.30 » m):3.01 2H ml 2H. m).(2H 3.47 - H 3.82 - 103.66 (111) 4.08 - 4.09 » 003.87 (1H “4.14 - 4.18 (1H: 0 7.60 » 00 6.52 (1 Hem) 07.74 011 3 2.50) 420;|{HNMR (400.13MHz | 1-[5-8]

HPL (cyclohexylcarbamoy « ty DMSO-dé6) 0.97 (3H 1)-6-propylsulfanyl- 0 for CR | 127.132.s)1.124H | pyridin-2-yl]-3-meh or = methyl-piperidine-3- : 1 Nig 2.76 | 1:48 -1.55 (IH m)(4H carboxylic acid 5 min. | RST 1.65 - 1.85 (7Hem) (1He 2.03 (1H 2.06 LV 3.25 - 102.94 - 14 2H 73.35 111) 3.65 LV 014.10 011 03.23 01 6.50 (1H: 5.75 (1H d) 7.71 (1H: 17.60) (1H 448 | HNMR (400.13 MHz | 2-[1-[5- 1]

HPL (cyclohexylcarbamoy ¢t)xDMSO-d6) 0.96 (3H 1)-6-propylsulfanyl- 0 0

CIR 1 117.131s)1.05(6H | pyridin-2-yl]-4- free = piperidyl]-2-methyl- and Keg 290 | 1.57 - 1.66 )511: 1 propanoic acid 3 min. | “m) 1.72 - 1.84 (SHm) and 02.95 (211 102.81 2H 4.46 » 13.65 - (1H 7.59 « d)s 6.49 (111 1) 7.74 111 0-73 (1 12.09 (1H”d) ): Yes

- 1. - 460; | 111115 (400.13 MHz | 1-]1-]5-T

HPL | 001450-40 0.96 GH | 1 gomoosutfanl.

CR 1 156 - 1.11 - 1.29 (7H | pyridin-2-yl}-4- .ps 190-201 | Wood (11H re so min. | 2.21 - 2.31 (2H: 3 or ; 2.95 (2H: t)c 2.84 (2Hem) AL " { x 3.65 - 3.67 (Hit) « d) 6.50 (1H: d)«4.47 (2H « d) 7.74 (1H.d).7.60 (1H s) (11.95) 1H «446 | HNMR (400.13 MHz | 1-[1-]-5)

HPL | DMSO-d6) 0.73 - 0.75 ee a

CR | <0.94-1.01 (SHem)«@H | Tafjoo 2 114 - = «m)¢ 1.11 - 1.16 (1Hm) piperidyl]cyclopropan 287 1.43 - 1.34 yram - 27 SR | &1-carboxylic acid salinity 1.57 - 1.66 « 001.52 (2H Hod N 4 «1.72 - 1.79 (4H. 3 » 2.94 (2H. 0: 2.80 (2H.m) 4.42 - 4.46 « 5) 3.66 (1Ht) 7.59 « d)« 6.49 (1H.1 «7.73 (1H.d)- 7.61 (1H s)¢ 12.00 (1H:d) «408 | 1111118 (400.13 MHz | 4-[5-51]

HPL | 001450-46 0.96 (3H re oe”

CR | 124-cm)1.07-119 1H | pyridin-2-wood | 157-166 main | orion p min. | «1.71 - 1.79 (4H.1 or 3.32 - « t) 2.95 (2Hun) SRE 3.61 - 3.67 « m):3.37 2H 7 N «3.78 - 3.81 (1H.m)”(2H oe for 3.97 - 4.02 ( 1Hem) 6.55 « m)4.19 - 4.22 (2H 7.81 « d)« 7.66 (1H. 3 s) 12.92 (1H: d)((1H

Yuva

71 - - intermediate compound 1 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide ye N = p2 cI” ONT Tc to a solution of 2,6-acid dichloronicotinic (0.4 00 g” 77.18 mmol) in 01 (01 mL) DCM a few drops of DMF were added followed by the addition of 0 drops of oxalyl chloride (7.77 mL; YUNA mmol). The reaction mixture was stirred at room temperature for 2 hours until gas bubbles stopped. The solvent was evaporated at reduced pressure to obtain an oil. (Jw 1+) DCM was added and the reaction mixture was cooled in an ice bath and 57.71 (Js 0.9 A) cyclohexylamine mmol) was slowly added keeping the temperature below Yo m. The reaction mixture was stirred at room temperature overnight.

0 The reaction mixture was extracted into the DOM and washed with saturated bicarb (00?mL); Water (Te) ml) and brine. The solvent was evaporated at reduced pressure to yield a brown/red solid. recrystallized in hexane/ethyl acetate and filtered to yield a white solid (AAT) g; R mmol; aA %(

'H NMR (400.13 MHz DMSO-dg) 51.12 - 1.18 )111 p 1.21 - 1.25 (1He zm 9 )2114 an)¢ 1.30 - 1.34 (1He m)e¢ 1.55 - 1.59 (111 m)¢ 1.70 - 1.73 )211 p 1.84 (2H¢ me 3.69 - 3.77 (1H m)« 7.62 - 7.64 (1H« d)« 7.93 (1H¢ d)« 8.46 (1H: d)

MS m/e MH" 273

Yavs

177 - - intermediate compound 7 6-chloro-N-cyclohexyl-2-propylsulfanyl-pyridine-3-carboxamide i or ps Cl N 5 to a solution of (Y.4V0) propane thiol ml » 7.84? mmol) in DMF to a solution of NaHMDS in ml (YT) THF was slowly added; 77.0001 millimoles). The mixture was stirred for 10 minutes 0 at room temperature and then slowly added to a solution of:

2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide (intermediate compound oY 8.55 g; .4 mmol) in DMF (0 5 mL). The reaction mixture was stirred at room temperature for two hours. The reaction was stopped and most of the THF was stopped and the DMF was evaporated. The product was extracted with 100 DCM (ml) and washed with YO water (ml twice) and YO (brine ml). The solution was dried at 0 1/8504 and evaporated at reduced pressure to yield a light pink solid. The solid was ground in hexane and filtered; All colored impurities entered the solution so that

(IVT ala YAS) white solid sale leaves 'H NMR (300.072 MHz: DMSO-dg) 0.98 (3H: t)¢ 1.21 - 1.25 (1H¢ m)« 1.28 3811 0 1.59 - 1.68 (3H¢ m)¢ 1.71 (111 d)¢ 1.73 - 1.74 (1H¢ in m 1.83 211 d)¢ 3.04 211 0 3.61+8.74 (1H<m)« 7.26 (111 d)¢ 7.73 (111) d)« 8.30 (111 pH MS m/e MH” 313

and starting material oF The following examples were prepared in a manner similar to Example No. (1); Using a suitable intermediate: aminoester from MS MH" 446 | .1HNMR (400.13 MHz 2-[(3S)-1-[5-oY .DMSO-d6) 1.05 - 1.35 (7H (cyclohexylcarbamoyl) Co of 1.54-1.88 «d) 1.44 3H am) cyclopentylsulfanyl-b LA 206-225 @H am) (1TH | yoridin 2 y1]-3- 2 2.91-2.98 «d) 2.73 (111 am) | piperidyl] acetic acid 3.60 - 3.65 (1H “m) “(1H an) 3.88 - 3.95 (1H am) “d) 4.29 (1H his 4.20 (1H “d) 7.61 (1H “d) 6.47 (IH 5) “12.14 (1H has “7.78 (1H dji) | JHNMR (400.13 MHz 2-[(35)-1-[5- ov pL | 0150-49 111-116 (IH (cyclohexylcarbamoy) }) | 143- am) 12-137 (4H rs cyclopentylsulfanyl- ey ilaha = 203-22 am) 1.45 (12H | puridin.o. A 2.81 | um) 2.35246 (2H m) GH | yl]pyrrolidin -3- min. | 3 0g (1H rs 2.53-2.6 (1H | yl]acetic acid am) 3.36 - 3.43 (1H «dd) 3.9-4.01 «m) 3.5-3.8 3H 762 «d) 6.09 (1H m) (IH 12.2 le 7.67 (1H his (1H s)). “(1H ¢437 | 1H NMR (400.13 MHz 2-[(3R)-1-[5- of {pL | 0450-46) 1.07 - 1.18 (2H (cyclohexylcarbamoyl) 2 6 o or

CR | Ns 120-135 (4H am) cyclopentylsulfanyl- “oy Ns ~ 20 - am) 145 - (11H pyridin-2- A 73 |.) 2.42 (2H am) 2.17 3H | yl]pyrrolidin-3-min | 307. Rs 2.54 - 2.64 (1H | yl]acetic acid 3.35 - 3.44 am) 3.12 (IH 3.55 - 3.73 GH am) «(1H am) 3.93 - 4.00 (1H am) «d) 7.62 (1H «d) 6.09 (IH 5) 12.15 (1H d) 7.67 (1H yava)

- 1176 - Wi 1115 (400.13 MHz 2-])318(-1-[5- .DMS0-d6) 1.11 - 1.33 (6H (cyclohexylcarbamoyl) 0 O ew 2 pe

CR | ns 143-189 (SH mM) oo opentylsulfanyl- 0 wh = 271+ am) 207-225 GH | pyridin-2-y1]-3- 2 2.80 | 292-3.00 am) 278 (1H | piperidyl]acetic acid mm. 1 359.370 (1H am) (1H cm) 3.89 - 3.97 (1H mn) 425- am) 4.15 -4- (IH «d] 6.46 (1H am) «4.32 (IH «d] 7.72 (1H zv) «7.60 (1H 5) «12.07 (1H g) | THNMR (300.073 MHz | 1-[1-[5- SE 1 0

HPL s)DMSO-d6)0.73(1H(cyclohexylcarbames)Ly

CR | 123-130 9) LOCH rumau ulfanyl-2 = ¢1.06 - 1.54 (3H am) «(3H pyridin-2-yl]-3- 3.03 |.m) 1.46 - 1.76 (17H am) | piperidyl]cyclopropan min. | Tzeh 2.12-2.01 RS Djo | e-1-carboxylic acid 3.85 »( 3.61 (1H «m) «(1H 434-438 an) 4.02 (1H 7.60 »d) «6.46 (1H «m) «(2H d) 7.76 (1H pH) (1H) Intermediate compound ?: 6-chloro-N-cyclohexyl-2-(cyclopentylthio)nicotinamide LO N ~ Or Zo cr” ONT Ts 0 (V.AE) added cyclopentanethiol 7.77 mmol) as one part to 7 +- (Y +) 2,6-dichloro-N-cyclohexylnicotinamide g” 1.77 mmol) 5 sodium carbonate p: 7.1” A) gram; 16 mmol) in You (DMF) 0 ml The resulting suspension was stirred at Java degree

m Y \ — temperature of 0 4 °C for three hours. and then cool the mixture; and evaporated it” and (Je You) DCM was added and the mixture was washed with water (0 ml for three times) and brine (+ © ml); It was dried at (504 p/1) ¢, filtered and evaporated to obtain a pale yellow viscous solid. They were pulverized with hexane:ethyl acetate 1, filtered and dried to obtain: aha 0 A) 6-chloro-N-cyclohexyl-2-(cyclopentylthio)nicotinamide ° 00.7%) on Via a white solid . 3.95 - 3.86 Tess (1He) 3.73 - 3.62 Tess (He me 2.1 - 221 (2He) (1H: 1 8.29 (1H¢ d) 7.73 HPLC tg = 3.16 min.¢m/z (ESI+) (M+H)+ = 01 339 The following examples were prepared in a manner similar to Example (1); using intermediate compound 4; and a suitable aminoester starting material:

- 171 -

MS m/e "HNMR & Compound Example Name

MH" 446 | HNMR (400.13 MHz | 21610-1-]5- 3" (cyclohexylcarbam 0 0

HPLC | DMSO-d6) 1.14 1.40 oy])-6- 1 or

R= 1.55-1.81 «m) «(10H cyclohexylsulfanyl-Lo Ns 2 85 pyridin-2- 0 min. | 2.00 - 2.03 211 «m) «(9H | y]]pyrrolidin-3- «m) 2.14 -2.18 ( 1H am) | YHacetic acid 2.55 "m) "2.38 - 2.47 2H 3.07- "m) "2.63 (1H 3.34 - 3.443 "m) "3.11 (1H 3.53 - 3.75 (4H "m) "(1H 760 "d) "6.09 (1H ) pm «d] «7.66 (1H «d) «(1H s) «12.15 (1H 460 | (JHNMR (400.13 MHz | Z1GR-1-1)>- oA (cyclohexylcarbam 0)

HPLC | DMSO-d6) 1.11 - 149 | Zaun ope oA

R= "1157.19 «m) «(12H cyclohexylsulfanyl- 0 Ns 2.97 pyridin-2-yl]-3- 0 min. 1 1.96 - 2.04 ps «(11H piperidyl]acetic 2.12 -2.27 (2H rs) 2H | 214 am) “2.72 -2.79 (1H x 3.63 x 2.93 - 3.00 (1H 4.16 - “m) ”- 3.71 QH <6.46 (1H x 4.27 H 7.72 “d) 7.59 (1H” d) s) 12.08 (1H «d] «(1H ava :

- 177 - : 4 Intermediate compound 6-chloro-N-cyclohexyl-2-cyclohexylsulfanyl-pyridine-3 -carboxamide ] > N ~ ct” NT 5 This intermediate compound was prepared in a manner similar to that shown for the intermediate?: - 2.01 (211 m) 3.66 - 3.75 (2H ft) 7.25 (1H d) 7.71 (1H d)« 8.29 (1116 d)

HPLC tg = 3.14 min¢ém/z (ESI+) (M+H)+ = 353 and starting material 1 The following examples were prepared in a manner similar to Example (1); Using a suitable intermediate compound: aminoester of 0

MS m/e 'H NMR 8 yw cm Call MH" J Ae) 472 JH NMR (300.072 MHz | 2-[3S)-1-[5-(2- 04 adamantylcarba 1.30") «CDCls ) 1.02 GH | pmovl)-6-p1m 1.52 - «m) « 1.39 (1H propylsulfanyl-[od pyridin-2-yl]-3- 1.66 - 1.81 «m) «1.61 (IH piperidyl]acetic N 1.83 2.10 «m) «(8H acid «d) 2.32 2H am) «(11H 2.97 am) 2.78 - 2.89 (1H 3.09- «n) » 3.06 (1H 420-431 am) 3.26 2H «d) «6.38 (1H m) (3H 7.91 (1H d) 7.20 (1H d)

-\YA - «474 «1H NMR (400.13 MHz 2-[(39)-1-[5-(2- 1.

HPLC | and CDCI3) 1.04 3H car 9 ] XJ = 2.99 o Lewy Ham 1 212- am) 672.1 (16H | propylsulfanyl- SNe 320-324 “m) 2.32 (2H Dentin N 3.60 -3.75 (4H an) ) (2H | ylJoxyacetic acid 4.23- s) 4.17 (2H NH 434-438 am) 4.29 (1H "d) 6.10 (1H "m) "(1H d) 7.91 (1H "d) "7.14 (1H 474) 1H NMR (400.13 MHz | 2-[GR)-1-[5-(2- +11)

HPLCR |.) [DMSO-d6) 0.98 (3H adamantylcarba 1 1 XJ =3.01 yl)-6 0 or Co. (14-149 2H | propylsulfanyl-b LA 1.61-1.68 «m) »1.61 (2H Wa 3 "1.69-1.81 (6H "m) "(2H 1 ylJoxyacetic acid rs "1.81 - 1.85 (2H ns 3.0 "s) ¢1.95-2.03 (4H 3.36-3.44 (1H "t) (2H ns (3H 3.45-3.58″ rbs “m) 3.88-3.93 (1H 4.02 am) 4.2-4.3 (1H “s) “2H” d) ¢7.5 (1H “d) “6.1 (1H s) ) ‎ 2 1.59 - «m) 1.5-158 (2H | propylsulfanyl- N 1.91.97 «m) «1.89 (11H 0 2.04 - 2.09 (2H «m) «2H | ylJacetic acid am) 2.12-2.2 (1H only 2.54- “m) 2.41 - 2.46 (2H 3.04 (2H “m) 2.63 (1H 3.37- “d) 3.1 (1H “t) 3.52-3.6 “m) 3.41 (1H 3.70 - 3.74 (1H “m)” ( 1H “m) 3.93-4.0 (1H bs 7.56 (1H “d) 6.13 (1H 12.2 “d) 7.65 (1H bs 5).” (1H avd

- 179 - 444 1H NMR (300.072 MHz | GR)-1-[5-(2- +1 adamantylcarba ox' 1.61 3H) «CDC13) 1.03 (t | moyl)-6- bs J 224 - (16H) -2.09 (m | propylsulfanyl- NN - pyridin-2- TL 3 . 1 7 = 3 3 1 2H) 2.42 (m yllpyrrolidine-3- I f" 3.48 -3.72 (m 3H) Sa | carboxylic acid 4.21 - 2H ) 3.79 (d 2H) 6.09 (d < 1H) «4.31 (m 7.90 1H) 7.15 (d 1H) 1H) «d 458 1H NMR (300.073 MHz | 2-[GR)-1-{5-(2-4) adamantylcarba b 3H) (1150-06H 0.94 (t 1-6.a moyl) J 18H) 1.45 - 2.23 (m propylsulfanyl- Ch Ns pyridin-2- LL 249-2.63 2H) 2.19 | yjpyrrolidin-3 - I 0 2.96 - 3.10 (m 1H) (m | yl] Jacetic acid 3.28 - 3.44 (m 1H) 3H) 3.60 1H) 3.46 - 3.59 (m 3.91 - dH) «3.70 (m «6.08 (d «1H) 3.98 (m 7.62 (1H) 7.56 (d by 1H) «(d 444 1H NMR (300.073 MHz) 1 (28)-1-[5-(2- 10 adamantylcarba 9 (3H) 014150-06 0.95 (t | moyl)-6- oe p (19H) 1.42 - 2.14 (m propylsulfanyl- N Ns pyridin-2- LL 2.81 (1H) 2.20-237(m | yjpourolidine-2- N 2.99 - (1H) «2.97 (m carboxylic acid) ° 3.37 - 3.59 (1H) 3.14 (m 3.90 - 3.98 (m 2H) «(m 6.17 «1H) «4.49 (d 1H) 7.56 - 7.69 (m 1H) «(d (12.21 - 12.66 (m 2H) 1H)

- .MS MS m/e | HNMR 8 Compound Example No. Name

MH" 456 | TH NMR (300.073 (1S,5R)-3-[5-(2- 11 1)

0.96 MHz, DMSO-d6 | adamantylcarbamoyl)-6- ae m (t, 3H), 1.38 (s, 1H), propylsulfanyl-pyridin-2-yl]- 1.50 (d, 2H), 1.56 - 3-azabicyclo[3.1 .0]hexane-6- : 5 1.86 (m, 10H), 1.91 (s, | carboxylic acid 2H), 2.05 (d, 2H), 2.22 (s, 2H), 3.01 (t, 2H), 3.49 (d , 2H), 3.78 (d, 2H), 3.89 - 3.99 (m, 1H), 6.14 (d, 1H), 7.53 -7.70 (m, 2H), 11.80 - 12.82 (m, 1H) 444 | THNMR (300.072 (3S)-1-[5-(2- 17 1)

MHz, CDCI3) 1.03 (t, |adamantylcarbamoyl)-6- De 2 3H), 1.60 - 2.11 (m, propylsulfanyl-pyridin-2- CL. 16H), 2.21 - 2.41 (m, |yl]pyrrolidine-3-carboxylic 0 pr 2H), 3.15 - 3.29 (m, acid 3H), 3.46 - 3.71 (m, 2H), 3.75 (d, 2H), 4.26 (d, 1H), 6.05 (d, 1H), 7.18 ( d, 1H), 7.89 (d, 1H) 575 |

460; | 1H NMR (400.13 4-[5-(2-)

HPL | 0.97 MHz, DMSO-d6 | adamantylcarbamoy!)-6- A

Ps

CtR | BH, t), 1.52 (2H, 1), propylsulfanyl-pyridin-2-Rb N { = | 1.58 - 1.66 (2H, m), yl]morpholine-2-carboxylic mk 2.76 | 1.72 -1.79 (2H, m), acid min. | 1.81 - 1.84 (6H, m), 1.92 - 1.96 (2H, m), 2.06 - 2.09 (2H, m), 3.00 (2H, d), 3.33 - 3.39 (2H, m), 3.61 - 3.67 (1H, m) ), 3.77 - 3.80 (1H, m), 3.96 - 4.02 2H, m), 4.19 - 4.23 (2H, m), 6.56 (1H, d), 7.67 (1H, d), 7.72 (1H, d), 12.90 (1H, s) :)*( intermediate compound

N-(2-adamantyl)-2,6-dichloro-pyridine-3 -carboxamide

Cl _N cl for 7 © XO : mmol) to acid 001 filled AVY ( oxalyl chloride was added dropwise 0

13 - - an (4.74) 2,6-dichloronicotinic © mmol) and 0.01 (N,N-dimethylformamide ml 0 mmol) in the DOM at 71 m over a period of 10 minutes under nitrogen, and the resulting suspension was stirred at 70 °C for two hours. The resulting mixture was evaporated to dryness, and the remaining azeotroped was distilled using toluene to obtain the crude acid chloride; which was dissolved in DCM (YO) 0 ml) and added in parts to a volatile solution of 000 aa 1.79 (2-adamantanamine hydrochloride mmol) and YT (N-Ethyldiiisopropylamine ml; 051 mmol) in DCM cooled to 0 dap C over a period of Vo min under nitrogen and the resulting suspension was stirred at Yo C for 2 hours. The reaction mixture was evaporated to dryness and stirred with water (0 ml) for 10 minutes, and the precipitate 0 was collected by filtration, washed with water twice (Jo YO X), and dried under vacuum to obtain the compound: can 16.0 (N-) 2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide 79548) as a cream solid that was used without further purification. ), 1.79 (2H, s), 1.82 - 1.96 (8H, (1H, m), 7.39 (1H, d), 8.19 (1H, d), 7.01 - 6.92 ,g m), 2.07 2H, 5 ), 4.27 (1H, m/zYESI+) (M+H)+ = 325; HPLC tr = 2.66 min. Intermediate compound (1): N-(2-adamantyl)-6-chloro-2-propylsulfanyl -pyridine-3 -carboxamide A Labb © IO 11 «Ja ] added. £0) propanethiol mmol) to :

-\YY - sodium mmol) and 11 g ©. 7 N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide and nitrogen (ml) at 70 pM under (50 mmol DMF) in EA cp p4) carbonate £14) EtOAc Stir the resulting suspension at +0 m for ? hours. The reaction mixture was diluted using (Je YO) and washed with water (? times * 00 ml) and then with saturated saline (Je at 14850, filtered and evaporated to obtain the raw product that was organic layer © : For ethyl acetate/hexane 7111 recrystallization from (FAS £.9 g) N-(2-adamantyl)-6-chloro-2-propylsulfanyl-pyridine-3-carboxamide 'H NMR ( 300.072 MHz, CDCI3) - 431 (m, 1H), 6.85 - 6.96 (m, 1H), 7.06 (4, 1H)) 7.90 (d, 1H) m/z (ESI+) (M+H)+ = 365; HPLC tg = 3.23min And with a starting material (V), the following examples were prepared in a manner similar to Example (1), using the intermediate compound: aminoester suitable from

MS Example 1 m/e HNMR § Name 1 Compound MH CUM 506: | 111018 (400.13 MHz, | 2-35(-1-5-2- 24)

HPLC CDCI3) 1.6-2.07 (20H, adamantylcarbamoyl)-6- {R = m), 2.13 - 2.21 (4H, m), cyclopentylsulfanyl-0 ° R 3.60 - 3.75 (4H, m), 4.15 - | pyridin-2-yl]pyrrolidin-3- O° or 3.19 | 425(@H,m),4.18 2H, | ylloxyacetic acid wk-rest min. | , ZO 4.35 -4.37 (1H, m), AN 6.10 (1H, d), 7.15 (1H, d), 7.90 (1H, d) 500 | TH NMR (400.13 MHz, |2-[GR)-1-[5-2- v ;

HPLC CDCI3) 1.6-2.07 (20H, adamantylcarbamoyl)-6-*5 N XJ

R= m), 2.13 - 2.21 (4H, m), cyclopentylsulfanyl-absorption or 3.60 - 3.75 (4H, m), 4.15 - | pyridin-2-ylJpyrrolidin-3->) 1 7 3.21 | 425(H,m),4.18 2H, | yloxyacetic acid AN min. s), 4.35 - 4.37 (1H, m), 6.10 (1H, d), 7.15 (1H, d), 7.90 (1H, d)

L(V) intermediate compound Ah

-\Y¢ - N-(2-adamantyl)-6-chloro-2-cyclopentylsulfanyl-pyridine-3 -carboxamide I J N ~ Or ~~ ONT Ts sun added anhydrous sodium carbonate (70. ca 01.08 mmol) at once to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (No. 0 g; 1. 507 mmol) cyclopentyls 0 compounds (0,04 filling 17.57 mmol) in (Je 0+) DMF under nitrogen, and the resulting suspension was stirred at 10 C for 7 hours . The reaction mixture was concentrated, diluted with (Jo 10+) DOM, washed sequentially with water (two times Vo X ml) and 0 (de VO) saturated brine. The organic layer was dried over MgSO, and filtered. and fumigation to obtain the raw product. This was pulverized with isohexane:EtOAc 4:1 0 to obtain the desired yield (0.1 (JAY (aa) as a white powder. (18H, m), 2.02-2.1 (2H, m), 2.21 - 2.27 1.94 - 1.60 1H NMR (400.13 MHz, CDCl3) (2H, m), 4.12 - 4.19 (1H, m), 4.26 (1H, d), 6.90 (1H, d), 7.05 (1H, d) , 7.89 (1H, d) m/z (ESI+) (M+H)+ = 391; HPLC tg = 3.62 min. The following examples were prepared in a manner similar to Example (1); using intermediate compound (A) A suitable starting material 10 from: aminoester Example MS Compound Name 16 | m/e No. MH'

- 170 - 514: | IHNMR 2-[(3S)-1-[5-(2- 7.0

HPLC | (400.13 MHz, adamantylcarbamoyl)-6-A or {R= | 0031.32.33 | cyclohexylsulfanyl-5 salt 3.36 | (26H, 0(, 3.57- | pyridin-2-yl]pyrrolidin- 0 0 min. 3.78 (4H, m), 3-ylJoxyacetic acid 3.94-4.05 (1H, m), 4.17 (2H, 5), 425- 43 (1H, m), 4.35-4.4 (1H, m), 6.10 (1H, d), 7.28 (1H, d), 7.93 (1H, d) 514; |1H NMR (400.13 | 2-[(3R) -1-[5-(2-vv

HPLC | MHz, DMSO- adamantylcarbamoyl)-6- o tR tR 40 1.2-1.49 (5H, |cyclohexylsulfanyl- m or 3.38 { m), 1.51 - 1.64 pyridin-2-yl]pyrrolidin- os Ls min. | (3H, m), 1.66-1.9 | 3-ylJoxyacetic acid 0 (10H, m), 1.9- 1.96 (2H, m), 2.06-2.2 (6H, m), 3.4-3.5 (1H, m), 3.53-3.62 (3H, m), 3.78-3.88 (1H, m), 3.92-4.0 (1H, m), 4.07 (2H, 5), 4.3-4.35 (1H, s), 6.16 (1H, d), 7.58 (1H, d), 7.64 (1H, d) ), 12.5 (1H, s). (A) Intermediate compound

N-(2-adamantyl)-6-chloro-2-cyclohexylsulfanyl-pyridine-3 -carboxamide

Pe

O.L

H

~ cr” Yi A mmol) at once to 0Y.0A “Ja Y.Y +1) anhydrous sodium carbonate 17.57 mmol) ano ( N-(2-) was added adamantyl)-2,6-dichloro-pyridine-3-carboxamide 0

cyclohexyl 5 compounds 7.0 (1.07 0 mmol ml) in Je 0 (DMF) under nitrogen and the resulting suspension was stirred at 1 M for 7 h. The reaction mixture was concentrated and diluted with DOM (+10 ml) and washed in London with water (2 times Vo x ml) and saturated saline (VO) 0 ml and the organic layer was dried over MgSO, 5, filtered and evaporated to obtain the raw product. This was pulverized with isohexane:EtOAc 4:1 to obtain the desired yield (1.0 g; 7957) as a white powder. (1H, 5), 1.36 - 1.42 (2H, m), 1.42 (H, d), 1.31 h IH NMR (400.13 MHz, DMSO-d) (1H, 5), 1.49 (1H, d) ), 1.53 (1H, 5), 1.58 (1H, 1), 1.70 (4H, d), 1.77 (1H, 5), 1.82 (6H, 1.45 d), 1.95 (2H, 5), 1.97 - 2.00 (2H, m), 2.06 - 2.09 (2H, m), 3.76 (1H, 1), 3.99 (1H, 1), 7.25 (1H) d), 7.69 - 7.71 (1H, m), 8.28 (1H , d) m/z (EST+) (M+H)+ = 405; HPLC tg = 3.77 min. The following examples were prepared in a manner similar to Example (1); using intermediate compound (1) and a suitable starting material from: \o aminoester Example MS Compound 1 Name 8 m/e 'HNMR No. MH'

- 1177 - 444 | 1H NMR (300.072 MHz, | 2-[(3R)-1-[5-(2- vy 3)

CDCI3) 1.38 (t, 3H), 1.61 adamantylcarbamoyl)-6- °o - 1.80 (m, SH), 1.81 - ethylsulfanyl-pyridin-2- a N 3 2.09 (m, 9H), 2.19 - 233 | yllpyrrolidin-3-ylJacetic methyl (m, 1H), 2.54 (d, 2H), acid I XO 2.74 (quintet, 1H), 3.09 - 3.22 (m, 1H), 3.24 (q, 2H), 3.49 ( q, 1H), 3.60 - 3.73 (m, 1H), 3.80 (t, 1H), 4.22 - 4.33 (m, 1H), 4.42 - 4.82 (m, 1H), 6.08 (d, 1H), 7.09 (d, 1H), 7.89 (d, 1H) 430 | 1H NMR (300.072 MHz, | 3R)-1-[5-(2-vi)

CDCI3) 1.38 (t, 3H), 1.63 | adamantylcarbamoyl)-6- lyde - 1.80 (m, 4H), 1.81 - ethylsulfanyl-pyridin-2- 3 N 2.08 (m, 10H), 2.28 - 2.40 yl]pyrrolidine-3-carboxylic shale ( m, 2H), 3.24 (q, 3H), | acidCL. 3.48 - 3.60 (m, 1H), 3.61 I XO -3.72 (m, 1H), 3.80 (d, 2H), 4.22 - 4.30 (m, 1H), 6.09 (d, 1H), 7.07 (d, 1H), 7.89 (d, 1H) 430 | 1H NMR (300.072 MHz, | (3S)-1-[5-(2- 074)

CDCI3) 1.38 (t, 3H), 1.63 adamantylcarbamoyl)-6- BD - 1.80 (m, 4H), 1.81 - ethylsulfanyl-pyridin-2- / N 2.08 (m, 10H), 2.28 - 2.40 yl]pyrrolidine -3-carboxylic ChNS (m, 2H), 3.24 (q, 3H), | acid 3.48 - 3.60 (m, 1H), 3.61 I pur - 3.72 (m, 1H), 3.80 (d, 2H), 4.22 - 4.30 (m, 1H), 6.09 (d, 1H) , 7.07 (d, 1H), 7.89 (d, 1H) 442 | THNMR (300.072 MHz, | (1S,5R)-3-[5-(2-vo)

CDCI3) 1.38 (t, 3H), 1.58 | adamantylcarbamoyl)-6- J 0 - 1.63 (m, 1H), 1.64 - ethylsulfanyl-pyridin-2- 8 0 M 1.81 (m, 4H), 1.81 - 2.09 | yl}-3- Al-laschem re (m, 10H), 2.33 (s, 2H), azabicyclo[3.1.0]hexane-6- TL. 3.21 (q, 2H), 3.58 (d, 2H), | carboxylic acid ° jo 3.88 (d, 2H), 4.22 - 4.28 (m, 1H), 6.06 (d, 1H), 7.01 (d, 1H), 7.87 (d, 1H) (6): the intermediate compound

N-(2-adamantyl)-6-chloro-2 -ethylsulfanyl-pyridine-3-carboxamide H Ah

AYA - - Cl 2 5 1 for FO 0 added. vv) ethanethiol (ml) 5.84 mmol) to: N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide 7 g; 1.19 mmol (V.400) sodium carbonate 5 g; 18.45 mmol) in DMF (VY) ml) at 0"C under nitrogen© and the resulting suspension was stirred at +0C for ? hours. The reaction mixture was diluted with Yoo)EtOAc ml ) and washed it with water 79 times (Je Yeo X) and then with saturated brine (Yo ml) 0, and the organic layer was diluted on 1418507, filtered and evaporated to obtain the crude product that was recrystallized from ethyl acetate/hexane Ive to get: AQ C0 EAR ) N-(2-adamantyl)-6-chloro-2-ethylsulfanyl-pyridine-3-carboxamide %( . (t, 3H), 1.66 - 1.81 (m, 4H) , 1.85 - 1.96 (m, 1.40 E' H NMR (300.072 MHz, CDCI3) 8H), 2.03 - 2.12 (m, 2H), 3.26 (, 2H), 4.22 - 431 (m, 1H), 6.78 - 6.89 (m, 1H), 7.06 (d, 1H), 7.89 (d, 1H) m/z (ESI+) (M+H)+ = 351; HPLC tg = 3.05 min. Examples were prepared following in a manner similar to Example (1); using the intermediate compound (+ 1) and with a suitable prefix 10 of aminoester: Example MS 1 Compound 1 Name & m/e HNMR No. MH D |

- va - 430 | 1111111 2 2-[(3R)-1-[5-(2- vi)

MHz, CDCI3) 1.61 - 1 adamantylcarbamoyl)-6- bl 1.82 (m, SH), 1.81 - methylsulfanyl-pyridin- o 2.11 (m, 10H), 2.17 - | 2-yl]pyrrolidin-3- a wd 231 (m, 1H), 2.53 (d, | ylJacetic acid TL. 2H), 2.58 (s, 3H), I ja 2.65 - 2.79 (m, 1H), 3.10 - 3.22 (m, 1H), 3.40 - 3.55 (m, 1H), 3.59 - 3.72 (m, 1H), 3.74 - 3.87 (m, 1H), 4.20 - 4.32 (m, 1H), 6.06 (d, 1H), 6.97 (d, 1H), 7.85 (d, 1H) 416 | 1H NMR (300.072|(3R)-1-[5-(2-vy)

MHz, CDCI3) 1.62 - | adamantylcarbamoyl)-6- oe’ 1.80 (m, 4H), 1.81 - | methylsulfanyl-pyridin-3 2.10 (m, 10H), 2.26 - | 2-yl]pyrrolidine-3- prophet" 2.40 (m., 2H), 2.58 (s, | carboxylic acid 3H), 3.25 (quintet, 1 pr 1H), 3.49 - 3.61 (m, 1H), 3.61 - 3.74 (m, 1H), 3.81 (d, 2H), 4.20 - 4.30 (m, 1H), 6.08 (d, 1H), 6.96 (d, 1H), 7.86 (d, 1H) ) 428 | 1THNMR (300.072 (1S,5R)-3-[5-(2-VA)

MHz, CDCI3) 1.53 - 1 adamantylcarbamoyl)-6- J ow 2.10 (m, 15H), 2.34 | methylsulfanyl-pyridin- © he (s, 2H), 2.56 (s, 3H), | 2-y1]-3- m TC 3.59 (d, 2H), 3.90 (d, |azabicyclo[3.1.0]hexane- NNN 2H), 4.18 - 4.31 (m, | 6-carboxylic acid © 0 1H) , 6.05 (d, 1H), 6.90 (d, 1H), 7.84 (d, 1H) (01): intermediate compound

and p_N-(2-adamantyl)-6-chloro-2-methylsulfanyl-pyridine-3 -carboxamide Cl! _N 5 1 L FO (cpa +44) sodium thiomethoxide 9.84 mmol) was added to: N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide ) ¥ g; 1.9 mmol) in Ve (Joo) at 71 °C below ©010086. The resulting solvent was stirred at 20 °C for − hours. The reaction mixture was diluted with EtOAc (0 ml) and washed with ela (ela). ¥ times “01 ml) and saturated saline solution (YO) ml). The organic layer was dried on 148507, filtered and evaporated to obtain the crude product that was purified by crystallization of isohexane [EtOAc] to obtain: 1 N-(2-adamantyl)-6-chloro-2-methylsulfanyl-pyridine-3 -carboxamide < ¢ p> 1 52 6) as a white solid. 2.12 (m, 2H), 2.61 (s, 3H), 4.22 - 4.33 (m, 1H), 6.73 - 6.82 (m, 1H), 7.07 (d, 1H), 7.87 (d, 1H) m/z (ESI+) M+H)+ = 337; HPLC tg = 2.97 min. 1 The following examples were prepared in a manner similar to example (1) using the intermediate compound (VY), a starting material, m Ja = ¢, and an appropriate aminoester.

- 161 - ML | 1 the es m/e 'H NMR 8 compound [Name].

MH" 474; 1H NMR (400.13 MHz, | 2-[(3S)-1-[5- va)

HPLC | DMSO-dé6) 0.99 (3H, [((2r,55)-5- .

R= |t),1.35-1.43 (2H, m), | hydroxy-2- . A 208 | 1.59-1.8 (9H, m), adamantyl (carbam) ory min. 1.96-2.14 (5H, m), oil]-6- 5 2.16-2.28 (1H, m), 2.41 | propylsulfanyl- -2.47 (2H, m), 2.53 - pyridin-2- 2.63 (1H, m), 3.06 (2H, |yl]pyrrolidin-3- t), 3.10 (1H, dd), 3.4 - | yl]acetic acid 3.5 (1H, m), 3.56-3.65 (1H, m), 3.71-3.8 (1H, m), 3.9-3.97 (1H, m), 4.42 (1H, s), 6.17 (1H, d ), 7.57 (1H, d), 7.69 (1H, d), 12.2 (1H, 5). 502 | IHNMR (300.073 4-[[[5-[((21,55)-5- | A.

0.96 MHz, DMSO-d6 | hydroxy-2- 9 ) 3H), 1.15 - 1.42 (m, | adamantyl)carbam for O 4H), 1.43 - 2.21 (m, oil]-6- CL 21H), 3.00 ( 2H), 3.10 | propylsulfanyl- I JO -3.20 (m, 2H), 3.19 - pyridin-2- 3.65 (m, 1H), 3.79 - ylJamino]methyl]c 3.89 (m, 1H), 6.16 (d, cyclohexane-1- 1H), 6.96 - 7.09 (m, carboxylic acid 1H), 7.42 - 7.52 (m, 2H), 11.32 - 12.50 (m, 1H) 488 | IHNMR (300.073 4-[[5-[((2r,5s)-5- AN

0.96 MHz, DMSO-d6 | hydroxy-2- (t,3H), 1.13 - 1.49 (m, | adamantyl)carbam 7H), 1.51 - 1.75 (m, oyl]-6- on o 8H), 1.86 - 2.07 (m, propylsulfanyl- > 9H) , 2.09 - 2.22 (m, pyridin-2- 1H), 2.99 ) 2H), 3.64 - | ylJamino]cyclohex ® 2 3.79 (m, 1H), 3.80 - ane-1-carboxylic Ns 8 3.89 (m, 1H), 6.14 (d, acid 1H), 6.85 (d, 1H), 7.42 - ] jan 7.51 (m, 2H)

- 167 - 488 | 1H NMR (300.073 4-[[5-[((2r,5s)-5- AY)

0.95 MHz, DMSO-d6 | hydroxy-2- mmH (t, 3H), 1.32 (d, 2H), adamantyl)carbam 1.47 - 1.80 (m, 13H), oyl]-6- L 1.81 - 2.09 (m, 8H) , propylsulfanyl-NI 233-2.45(m, 1H), | pyridin-2-TL 2.98 (t, 2H), 3.80 - 3.88 | yl]Jamino]cyclohex and "(m, 1H), 3.88 - 4.02 (m, | ane-1-carboxylic © 0 1H), 4.20 - 4.56 (m, acid 1H), 6.21 (d, 1H), 6.88 (d, 1H), 7.41 - 7.52 (m, 2H) 488;1H NMR (400.13 MHz, |2-[(3S)-1-[5- AY)

HPLC | DMSO0-d6) 0.95 (3H, [(2r,5s)-5- 0 tR t), 1.24 - 1.48 (4H, m), | hydroxy-2-° = 2.19 | 1.56 - 1.72 (9H, m), adamantyl]carbam B A min 1.81 - 1.88 (2H, m), oyl]-6- MCl 1.93 - 2.07 (5H, d), propylsulfanyl- I ~ “0 2.13 - 2.27 (2H, m), pyridin-2-yl}-3- 2.72 -2.78 (1H, m), piperidyl]acetic 2.90 - 3.06 (3H, m), acid 3.83 - 3.88 (1H, m), 4.20 (1H, d), 4.29 (1H, d), 4.43 (1H, s), 6.49 (1H, d), 7.61 (1H, 4d), 7.67 (1H, d), 12.16 (1H, s) 474, 1H NMR (400.13 MHz, |1-[5-[[(2r,5s)-5- A)

HPLC | DMSO-d6) 0.96 (3H, hydroxy-2- 0 {R t), 1.29 - 1.36 (2H, m), | adamantyl] carbam “0 2 -2.06 | 1.44 - 1.75 (9H, m), oyl]-6- TL min 1.82 - 1.89 (2H, m), propylsulfanyl- : No 1.93 - 2.07 (6H, m), pyridin-2- 2.52 - 2.59 (1H, m) , yl]piperidine-4- 2.96 - 3.10 (4H, m), carboxylic acid 3.84 - 3.88 (1H, m), 4.23 - 4.30 (2H, m), 4.43 (1H, s), 6.55 (1H, d), 7.61 (1H, d), 7.69 (1H, d), 12.28 (1H, s)

- Vey - 488: 1H NMR (400.13 MHz, | 2-[(3R)-1-[5- AO)

HPLC | DMSO-d6) 0.95 (3H, [[(2r,5s)-5- tR t), 1.22 - 1.49 (4H, m), | hydroxy-2- =221 1 1.55 - 1.74 (6H, m), adamantyl]carbam . min 1.78 - 1.90 (3H, m), oyl]-6- oN, 1.92 - 2.07 (7H, m), propylsulfanyl- © 2 2.17 - 2.20 (2H, m), pyridin-2-yl]-3- NN 2 2.72 - 2.78 (1H, m), piperidyl]acetic Chm, 2.90 - 3.06 (3H, m), acid ° 3.84 - 3.88 (1H, m), 4.17 - 4.24 (1H, m), 4.26 - 4.33 (1H, m) ), 4.43 (1H, s), 6.49 (1H, d), 7.61 (1H, d), 7.67 (1H, d), 12.16 (1H, s) 488; 1H NMR (400.13 MHz, | 2-[1-[5-[[(2r,55)-5- | ym HPLC 1 DMSO0-dé6) 0.95 (3H, hydroxy-2- tR t), 1.09 - 1.20 (2H, m), | adamantyljcarbam =2.13 |1.29-1.36 2H, m), 1.5 | oil}-6-oo min - 1.74 (10H, m), 1.92 - | propylsulfanyl-b 2.06 (6H, m), 2.17 (2H, |pyridin-2-yl]-4- Nn d), 2.88 - 2.99 (4H, m), | piperidylJacetic Com 3.83 - 3.89 (1H, m), acid ° 7 4.32 - 4.39 (2H, m), 4.43 (1H, s), 6.52 (1H, d), 7.61 (1H, d), 7.66 (1H, d) , 12.11 (1H, s) 472; 1H NMR (400.13 MHz, |(1R,5S)-3-[5-AY]

HPLC | DMSO-d6) 0.97 (3H, [[(2r,5s)-5- tR t), 1.29 - 1.40 (3H, m), | hydroxy-2-=2.03 | 1.58 - 1.74 (8H, m), adamantyl]carbam 1 min 1.92 - 2.06 (5H, m), oil]-6- A y 2.18 - 2.21 (2H, m), propylsulfanyl- WAN Ns 3.01 (2H, 1), 3.50 2H, | pyridin-2-yl]-3- Cm, d), 3.79 (2H, d), 3.83 - | azabicyclo[3.1.0]h ° 3.88 (1H, m), 4.43 (1H, | exane-6- s), 6.15 (1H, d), 7.61 carboxylic acid (1H, d), 7.64 (1H, d), 12.28 (1H, s)

Yyaiva

488 | 1H NMR (400.13 MHz, |1-[5-[[(2r,55)-5- AA)

HPLC | DMSO-d6) 0.96 (3H, |hydroxy-2- 05 8 0.1.17 34, 5), 1.31 - | adamantyl] carbam + A = 222 | 1.40 (4H, m), 1.57 - oil]-6- [oe min | 1.74 (8H.m), 1.92 | propylsulfanyl- ro 2.07 (7H, m), 2.95 - pyridin-2-yl]-4- 3.01 2H, m), 3.19 - methyl-piperidine- 3.26 (2H, m), 3.84 - 4-carboxylic acid 3.88 (1H, m), 3.95 - 4.03 (2H, m), 4.43 (1H, 5), 6.54 (1H, d), 7.61 (1H, d), 7.68 (1H, d), 12.44 (1H, 5) 1H NMR (400.13 MHz, |1-[5-[[(2r,5s)-5- AQ 460; | DMSO-d6) 0.96 (3H, hydroxy-2- C1701 |©), 1.30 - 1.38 (2H, m), | adamantyljcarbam S 1.59 - 1.74 (8H, m), oyl]-6- . = 2.02 | 1.93 -2.07 (5H, m), propylsulfanyl- DS min | 2.11 -2.28 (2H, m), pyridin-2-Ig. ’ 3.00 - 3.04 (2H, m), yl]pyrrolidine-3- TL. 3.17 - 3.25 (1H, m), carboxylic acid S m) - 3.42 - 3.56 (2H, m), 3.60 - 3.70 (2H, m), 3.84 - 3.89 (1H, m), 4.43 (1H, s) ), 6.17 (1H, d), 7.61 (1H, d), 7.64 (1H, d), 12.53 (1H, s) 474; | TH NMR (400.13 MHz, | 2-[(3R)-1-[5- q.

HPLC | 014580-00 0.96 (3H, | [[(2r,55)-5- 9 tR | t), 1.31 - 1.38 (2H, m), | hydroxy-2-=o=2.11 | 1.59 - 1.73 (9H, m), adamantyl]carbam P A min | 1.92 - 2.08 (5H, d), oyl]-6- all 2.14-2.18 (1H, m), | propylsulfanyl- SMS 2.41 -2.47 (2H, m), pyridin-2- ° 2.53 - 2.59 (1H, m), yl]pyrrolidin-3- 3.00 - 3.05 (2H, m), yl]acetic acid 3.08 - 3.12 (1H , m), 3.38 - 3.43 (1H, m), 3.52 - 3.60 (1H, m), 3.68 - 3.76 (1H, m), 3.87 - 3.88 (1H, m), 4.37 (1H, s), 6.13 (1H , d), 7.53 (1H, d), 7.64 aH, d), 12.18 (1H, s) ava

— \ $ MG 500:1 TH NMR (400.13 MHz, | 3-[1-[5-[[(2,55)-5- | 1)

HPLC | DMSO0-d6) 0.97 (3H, |hydroxy-2-tR |t), 1.17 - 1.22 (2H, m), | adamantyl]carbam =2.30 1.31 - 1.57 (6H, m), oil]-6- . min | 1.59 - 1.75 (8H, m), propylsulfanyl- ° 1.79 - 1.87 (1H, m), pyridin-2-yl]-3- 1.93 - 2.08 (5H, m), piperidyl]propanoi bn 2.29 (2H, ©), 2.63 - 2.69 | c acid Mah (1H, m), 2.91 - 3.07 I ~ Do (3H, m), 3.85 - 3.89 (1H, m), 4.17 - 4.23 (1H, m), 4.27 - 4.33 (1H, m) , 4.37 (1H, 5), 6.51 (1H, d), 7.60 (2H, d), 12.00 (1H, s) 516; | 1H NMR (400.13 MHz, |2-[1-[5-[(2,55)-5-|qv

HPLC | DMSO-dé6) 0.96 (3H, hydroxy-2-tR = 1t1),1.09-1.10 3H, s), adamantyl)carbam 2.44 | 1.15 (3H, 5), 1.31 - 1.41 | oil}-6- 1 min. | (4H, m), 1.55 - 1.66 propylsulfanyl- (6H.m), 1.71 (4H, m), | pyridin-2-y1]-3- 2 J 1.95 - 2.04 (5H, m), piperidyl]-2- 2.66 (111, 1), 2.80 (1H, |methyl-propanoic TL t),2.87- 2.91 (1H, m), | acid I bitter 3.09 - 3.16 (1H, m), 0 3.40 (2H, q), 3.86 (1H, 5), 4.35 (1H, d), 4.45 (1H, d), 6.46 (1H, d) , 7.60 (1H, d), 7.68 (1H, d), 12.25 (1H, 5) (11): the intermediate 2,6-dichloro-N-((2r,5s)-5-hydroxyadamantan-2- yl)nicotinamide

Cl_NCl and “OH 115.30 mM an 7 ( 2,6-dichloronicotinoyl chloride”) was added dropwise to a solution of 119.6 0 G 01 (4-aminoadamantan-1-ol) of lite to a solution of (Jo 001 (DCM mol) in

mmol) 5 Y£.AY) N-Ethyldiiisopropylamine filling 07.©7 mmol) in THF at JY over a period of 0 min under 01008©0. The resulting suspension was stirred at room temperature for VA 1 hour. The resulting mixture was diluted with EtOAc (0 ml) and washed sequentially with water and saturated saline (501 ml). The organic layer was dried at 14850, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica with stepwise eluting from zero to EtOAc 7000 in 0014. The pure fractions were evaporated to dryness to obtain: 51 (aa 858 ) 2,6-dichloro-N -(5-hydroxyadamantan-2-yl)nicotinamide 0 as a white solid. (2H, m), 1.60 - 1.67 (4H, d), 1 69 - 1.38 - 1.31 h 1H NMR (400.13 MHz, DMSO-d6) (2H, m), 1.87 - 1.94 (2H, m) ), 1.99 - 2.00 (1H, m), 2.04 - 2.09 (2H, m), 3.91 -3.96 1.76 (1H, m), 4.47 (1H, 5), 7.64 (1H, d), 7.95 (1H, d), 8.49 (1H, d) m/z (ESI-) (M-H)- = 339; HPLC tg = 1.59 min. Intermediate compound (17) 6-chilero-N-((2r,5s)-5-hydroxy-2-adamantyl)-2-propylsulfanyl-pyridine-3 -carboxamide 0 J OH IAN H 2 Cl N §

- 169 -

The crosslinker 1-0:0 011 717 (ml; 0 VETO mmol) was added once to: 2,6-dichloro-N-(5-hydroxy-2-adamantyl)pyridine-3-carboxamide (° g 10.159 mmol) can 17 ( sodium carbonate 47.976 mmol) in DMF (©mL). The resulting suspension was stirred at 0 m for ? hours. The mixture was cooled and evaporated, Yo. (DCM © ml) was added and the mixture was washed ela (?50 X ml times) then with saline (0 ml). It was dried over B0]01, filtered, and evaporated to a viscous pale yellow solid. This was crushed with 4:1 hexane:ethyl acetate, filtered and dried to obtain the desired yield as a white solid (0

4 0 g; ), 1.97-2.03 (2H, s), 3.0 (2H, 1), 3.83-3.9 (1H, m), 4.34 (1H, 5), 7.2 (1H, d), 7.65 (1H, d), 8.18 ( 1H, d) m/z (ESI+) (M+H)+=381; HPLC t = 2.34 min. and a starting material (OF). The following examples were prepared in a manner similar to Example (1); Using the intermediate compound: a suitable aminoester from F

- 1 5/-

MS Example m/e "HNMR 8 Name 1 Compound MH" No. 500; | 1H NMR (400.13 MHz, | 2-]35(-1-]6- qv

HPL | DMSO-dé6) 1.33-1.4 2H, cyclopentylsulfanyl-5-

CtR | m), 1.45-1.78 (13H, m), [((2r,5s)-5-hydroxy-2- = 1.9-2.2 (8H, m), 2.36-2.48 adamantyl)carbamoyl] 2.25 | (2H, m), 2.53 -2.58 (1H, | pyridin-2- min. | m),3.08 (1H, dd), 3.37- | ylJpyrrolidin-3- A 3.41 (1H, m), 3.5-3.62 ylJacetic acid Ley LAA (1H, m), 3.63 - 3.75 (1H, 2 m), 3.84-3.9 (1H, m), 3.95 -4.04 (1H, m), 4.37 (1H, s), 6.12 (1H, d), 7.52 (1H, m), 7.64 (1H, d), 12.2 (1H, s). 514; | 1HNMR (400.13 MHz, 2-[(3S)-1-[6- q¢

HPL | DMSO-d6) 1.22-1.74 cyclopentylsulfanyl-5-

CtR | (17H, d), 1.82 -2.26 (11 [[(2r,5s)-5-hydroxy-2- =23 | H,m),2.72-2.79 (1H, adamantyl]carbamoyl] : 4min | m), 2.92 - 3.01 (1H, m), pyridin-2-yl}-3- o 3.84 - 3.89 (1H, m), 3.93 - | piperidyljacetic acid ° 4.01 (1H, m), 4.15 - 4.22 B (1H, m), 4.26 - 4.32 (1H, rpm, m), 4.37 (1H, s), 6.48 (1H, Wm. d ), 7.60 (1H, d), 7.61 (1H, © d), 12.08 (1H, s) 500; | 1H NMR (400.13 MHz, | 2-[(3R)-1-[6- 40)

HPL | DMSO-d6)1.31-1.37 cyclopentylsulfanyl-5-

CtR | (2H, ,p 1.49-1.73 [((2r,5s)-5-hydroxy-2- j= = (13H, m), 1.94 - 2.18 adamantyl)carbamoyl] ; zH 2.22 | (8H, m), 2.42 (2H, d), pyridin-2- Cl nA min. |2.53 - 2.60 (1H, m), 3.08 |yl]pyrrolidin-3- my -3.12 (1H, m), 3.36 - yl]acetic acid g - 3.44 (1H, m), 3.53 - 3.60 (1H, m), 3.68 - 3.75 (1H, m), 3.84 - 3.89 (1H, m), 3.96 - 4.04 (1H, m), 4.37 (1H, s), 6.12 (1H, d), 7.52 (1H, d), 7.64 (1H, d), 12.14 (1H, s)

- ea - 486; | 1111111 (400.13 MHz, | (3R)-1-[6-41]

HPL | DMSO-d6)1.31-1.38 cyclopentylsulfanyl-5-

CtR 1 (2H, m), 1.50-1.73 [((2r,5s)-5-hydroxy-2- = (12H, m), 1.92 - 2.38 adamantyl)carbamoyl] 2.14 | (9H, m), 3.19 - 3.24 (1H, | pyridin-2- 0 min. | m), 3.46 - 3.53 2H, m), | yl]pyrrolidine-3- 5 & 3.61 - 3.68 (2H, m), 3.84 | carboxylic acid N NSS -3.89 (1H, m), 3.97 - TS. 4.05 (1H, m), 4.37 (1H, © s), 6.17 (1H, d), 7.54 (1H, d), 7.64 (1H, d), 12.46 (1H, s) 486; | 1THNMR (400.13 MHz, |(25)-1-[6-ay]

HPL | DMSO-d6) 1.32-1.73 cyclopentylsulfanyl-5-o

CtR | (14H, m), 1.92 - 2.07 [((2r,5s)-5-hydroxy-2- th & = (9H, m), 2.17 - 2.34 (2H, | adamantyl)carbamoyl] NN 2.06 |m) , 341-357 (2H, m), | pyridin-2-TL. min. | 3.84 - 3.89 (1H, m), 3.95 | yl]pyrrolidine-2- 4 ND -4.02 (1H, m), 4.36 (1H, | carboxylic acid s), 4.50 - 4.55 (1H, m), 6.18 (1H, d), 7.58 - 7.63 (2H, m) , 12.40 (1H, s) 498: | 1H NMR (400.13 MHz, |(1R,5S)-3-[6-aA

HPL | DMSO-d6) 1.32 1.39 cyclopentylsulfanyl-5- .

CtR | (3H, m), 1.49-1.72 [((2r,5s)-5-hydroxy-2- O = (12H, m), 1.93 - 2.04 adamantyl)carbamoyl] HOA Ns 2.15 | (5H, m), 2.09 - 2.21 (4H, |pyridin-2-yl]-3- Chm, min. |m), 3.48 - 3.53 (2H, m), | azabicyclo[3.1.0]hexa ° 3.78 - 3.88 (3H, m), 3.95 | ne-6-carboxylic acid - 4.02 (1H, m), 4.36 (1H, s), 6.14 (1H, d), 7.56 (1H, d), 7.61 (1H, d), 12.19 (1H, s) 500; | IHNMR (400.13 MHz, | 1-[6- 44

HPL | DMSO-d6) 1.30 - 1,37 cyclopentylsulfanyl-5-o

CtR | (2H, m), 1.47 - 3 [((2r,5s)-5-hydroxy-2- 0 b = (14H, m), 1.84 - 1.88 adamantyl)carbamoyl] NS 2.21 | (2H, m), 1.94 - 2.14 (7H, |pyridin-2-Cy, min. |m),2.52-2.62 (1H, m), | yl]piperidine-4- ° 3.03 - 3.10 (2H, m), 3.84 | carboxylic acid -3.89 (1H, m), 3.93 - 4.00 (1H, m), 4.22 - 4.29 (2H, m), 4.36 (1H, s), 6.53 (1H, d), 7.59 - 7.64 (2H, m) , 12.19 (1H, s)

_ \ Ov — (17) The intermediate 6-chloro-2-cyclopentylsulfanyl-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3- : carboxamide and “OH . ( VY) This intermediate was prepared in a manner similar to that of the intermediate 0 1H NMR (400.13 MHz, DMSO-d6) 6 1.31 - 1.37 (2H, m), 1.47 - 1.74 (12H, m), 1.94 - 2.00 ( 3H, m), 2.04 - 2.09 (2H, m), 2.12 - 2.20 (2H, m), 3.90 - 3.97 (2H, m), 4.39 (1H, s), 7.25 (1H, d), 7.71 (1H, d), 8.22 (1H, d) m/z (ESI+) (M+H)+ = 407; HPLC tg = 2.52 min. The following examples were prepared in a manner similar to Example (1); Using the intermediate compound (£ 1) and a suitable starting material: 0 aminoester from

MS: (example m/e HNMR 8 NY)

MH' | 5 Boat No. 514 | 1H NMR (300.072 MHz, |2-[3R)-1-[6- re

CDCI3) 1.21 - 1.85 (m, |cyclohexylsulfanyl- 2 16H), 1.85- 1.99 (m, |5-[((2r,55)-5- I 0 4H), 2.05 - 2.36 (m, 6H), |hydroxy -2- Ga 2.48 - 2.58 (mn, 2H), 2.74 |adamantyl) TL. (quintet, 1H), 3.17 (t, carbamoyl]pyridin- I Jo 1H), 3.48 (q, 1H), 3.57 - | 2-yl]pyrrolidin-3- 3.70 (m, 1 0 3.74 - 3.87 | yl]acetic acid (m, 1H), 3.92 - 4.05 (m, 1H), 4.18 - 427 (m, 1H), 6.08 (d, 1H), 7.22 (d, 1H), 7.92 (d, 1H) 500 |1H NMR (300.073 MHz, |(2S)-1-[6-1

DMSO0-d6) 1.13 -6 cyclohexylsulfanyl- 0 (m, 17H), 1.80 - 2.11 (m, | 5-[((2r,55)-5- nb tah 10H), 2.16 - 2.39 (m, hydroxy- 2- (1H), 2.94 - 3.66 (m, 1H), |adamantyl)carbamoy TL 3.74 -3.89 0 2H), 4.39 | 1pyridin-2- 1 0 (s, 1H), 4.47 (d, 1H), yl]pyrrolidine-2- 0 6.15 (d, 1H), 7.53 - 7.64 | carboxylic acid (m, 2H) 500 | 1H NMR (300.073 MHz, |(3R)-1-[6-I.

DMSO0-d6) 1.16 - 1.50 cyclohexylsulfanyl- (m, 7H), 1.49 - 1.84 (m, |5-[((2r,5s)-5- 9H), 1.85 - 2.10 (m, 7H), |hydroxy-2 - 2.10 - 2.29 (m, 2H), 3.03 | adamantyl)carbamoy o=¢° -3.55 (m, 3H), 3.56 - }pyridin-2- 3 OQ 3.69 (m, 2H), 3.71 - 3.91 | yl]pyrrolidine-3- Alb -S (m, 2H), 4.30 - 4.48 (m, | carboxylic acid TL. 1H), 6.15 (d} 1H), 7.55 6 eo (d, 1H), 7.60 (d , 1H) 528; | IHNMR (400.13 MHz, | 2-[(3S)-1-[6-yor

HPLC | DMSO-d6) 1.25 1.46 cyclohexylsulfanyl-0

R (9H, m), 1.55 - 1.76 5-[[(2r,55)-5- 0 —2 47 | (10H, m), 1 P -2.07 hydroxy-2- Ng min (9H, m), 2.13 - 2.27 (2H, | adamantyl]carbamoy lab" re m), 2.73 - 2.79 (1H, m) ), | l]pyridin-2-yl]-3- my, 2.93 -3.01 (1H, m), 3.68 | piperidyl]acetic acid © -3.77 (1H, m), 3.84 - 3.89 (1H, m), 417 -428 (2H, m), 4.37 (1H, s), 6.48 (1H, d), 7.58 - 7.63 (2H, m), 12.09 (1H, s)

I

— \ 0 Y — (16:) Intermediate 6-chloro-2-cyclohexylsulfanyl-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3- carboxamide

Cl Al 5 L 1 © jal "OH (VY) This intermediate was prepared in a manner similar to that of the intermediate 0 1H NMR (400.13 MHz, DMSO-d6) 6 1.32 - 1.48 (7H, m), 1.56 - 1.74 (9H, m), 1.92 - 2.09 (7H, m), 3.74 - 3.79 (1H, m), 3.88 - 3.93 (1H, m), 4.39 (1H, s), 7.25 (1H, d), 7.70 (1H, d), 8.23 (1H, d) m/z (ESI+) (M+H)+ = 421; HPLC tg = 2.64 min. The following examples were prepared in a manner similar to example (1); using the intermediate compound ( 10) and prefix 0: aminoester suitable from yaivia

- 1 c, for example, add [a]ss | »» Esen

MH cm. No. 516; 1H NMR (400.13|2-[(3S)-1-[5-ys)

HPLC tR 1 MHz, DMSO0-d6). [[(2r,5s)-5-hydroxy-9 = 2 46min | 0.89 (6H, d), 1.22 - | 2- ° 1.56 (6H, m), 1.59 - adamantyl]carbamoyl 2 J 1.74 (8H, m), 1.79 - | ]-6-(3- has 2.06 (7H, m), 2.12 - | methylbutylsulfanyl) Lm, 2.26 (2H, m), 2.73 - | pyridin-2-yl}-3- © 2.79 (1H, m), 2.92 - | piperidyljacetic acid 3.00 (2H, m), 3.03 - 3.11 (1H, m), 3.83 - 3.88 (1H, m), 4.21 - 429 (2H, m), 443 (1H, s), 6.49 (1H, d), 7.61 (1H, d), 7.67 (1H, d), 12,16 (1H, s) 488; IH NMR (400.13 | QR)-1-[5-[((2r,58)-5-|yo

HPLC tR | MHz, DMSO-d6) | hydroxy-2-m =2.25 0.91 (6H, d), 1.31 - | adamantyl)carbamoyl 3 J min. 1.38 (2H, m), 1.49 - | ]-6-(3- NON _s 1.56 (2H, m), 1.62 - | methylbutylsulfanyl) Com 1.73 (7H, m), 1.92 - | pyridin-2- 5 ° 2.08 (5H, m), 2.16 - | ylpyrrolidine-3- 2.25 (2H, m), 3.04 - | carboxylic acid 3.10 (2H, m), 3.17 - 3.24 (1H, m), 3.45 - 3.53 (2H, m), 3.65 - 3.69 (2H, m), 3.87 - 3.88 (IH, m), 4.37 (1H, s) ), 6.17 (1H, for 7.55 (1H, d), 7.64 (1H, d), 12.45 (1H, s) 500; IH NMR (400.13 | (1R,5S)-3-[5- 1

HPLC tR | MHz, DMSO0-d6) | [((2r,5s)-5-hydroxy- © 2226 | 091 (6H, d), 130 - | 2- A J min. 1.40 (3H, m), 1.48 - | adamantyl)carbamoyl HNN 2 1.54 (2H, m) ), 1.62 - | 1-6-3- Um. 1.73 (7H, m), 1.92 - | methylbutylsulfanyl) 8 2.07 (5H, m), 2.18 - | pyridin-2-yl]-3- 2.22 (2H, m), 3.04 - | azabicyclo[3.1.0]hex 3.08 (2H, m), 3.47 - | ane-6-carboxylic acid 3.54 (2H, m), 3.79 - 3.87 (3H, m), 437 (1H, s), 6.15 (1H, d), 7.57 - 7.62 (2H, m), 12.20 (1H, s) )

_ \ m ¢ —_ (10) Intermediate 6-chloro-N-((2r,5s)-5-hydroxy-2-adamantyl)-2-(3 -methylbutylsulfanyl)pyridine-3- carboxamide

Cl_N J ye! OH (VY ) This intermediate was prepared in a manner similar to that of the intermediate. 1H NMR (400.13 MHz, DMSO-d6) 0.86 - 0.98 (6H, m), 1.30 - 1.38 (2H, m), 1.48 - 1.53 ( 2H, m), 1.62 - 1.74 (7H, m), 1.94 - 2.00 (3H, m), 2.07 - 2.10 (2H, m), 3.07 - 3.11 (2H, m), 3.89 - 3.94 (1H, m), 4.39 (1H, s), 7.26 (1H, d), 7.72 (1H, d), 8.23 (1H, d) m/z (ESI+) (M+H)+ = 409; HPLC tg = 2.61 min. prefix (V1) and the following examples were prepared in a manner similar to example (1); using intermediate compound 0: :aminoester suitable from

MS m/e 1 Example No

— \ 00 — 536; 1H NMR (400.13|2-[(3S)-1-[6-yoy)

HPLC tR | MHz, DMSO-d6) | benzylsulfanyl-5-1 = 2.30min | 1.21 - 1.46 (4H, [[(2r,5s)-5-hydroxy- 8 0 m), 1.57 - 3 2- b (8H, m), 1.78 - adamantyl]carbamoy TL 2.05 (7H, m) , 2.11 | l]pyridin-2-yl]-3- °pa -2.24 (2H, m), piperidyl]acetic acid 2.72-2.80 (1H, m), 2.92 - 3.00 (1H, m), 3.82 - 3.87 (1H, m) ), 4.17 - 4.35 (4H, m), 6.51 (1H, d), 7.19 - 7.23 (1H, m), 7.26 - 7.28 (2H, m), 7.35 - 7.37 (2H, m), 7.65 - 7.70 (2H , m) (17) 2-benzylsulfanyl-6-chloro-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3-carboxamide

Cl a l 5 l 1 © ja! Oh

AVY) This intermediate was prepared in a manner similar to that of the intermediate. 'H NMR (400.13 MHz, DMSO-ds) 61.28 - 1.35 (2H, m), 1.58 - 1.73 (6H, m), 1.89 - 2.06 (5H, m), 3.86 - 3.90 (1H, m), 4.33 (2H, 5), 4.44 (1H, 5), 7.21 - 7.25 (1H, m), 7.28 - 7.32 (3H, m), 7.40 - 7.44 (2H, m), 7.78 (1H, d), 8.30 (1H, d)

— 1 m "1 — m/z (ESI+) (M+H)+ = 429; HPLC tg = 2.44 min. and substance (VV) using intermediate compound ¢ (V) The following example was prepared by Similar to the example: aminoester with a suitable prefix of °

MS me Example No. 550: 1H NMR (400.13 2-[(35)-1-[5- Veal

HPLC | 1.21 MHz, DMSO-d6 | [[(2r,55)-5- o tR - 1.51 (4H, m), 1.59 - 1 hydroxy-2- =2.41mi | 1.74 (TH, m), 1.79 - adamantyl] carbamo NON 8 n 2.06 (8H, m), 2.10- | ylJ-6- Lm, 2.22 (2H, m), 2.74 - phenethylsulfanyl- © 2.80 (1H, m), 2.87 - pyridin-2-yl}]-3- 3.02 3H, m), 3.22 - piperidyl]acetic 3.40 2H , m), 3.83 - acid 3.88 (1H, m), 4.24 - 4.30 (1H, m), 4.43 (1H, s), 6.52 (1H, d), 7.18 - 7.31 (5H, m), 7.62 - 7.68 ( 2H, d), 12.17 (1H, s) (19) Intermediate 6-chloro-N-((2r,5s)-5-hydroxy-2-adamantyl)-2-phenethylsulfanyl-pyridine-3- carboxamide

— \ m VY —

Cl_N 5 mCl and “OH 'H NMR (400.13 MHz, DMSO-dg) 81.29 - 1.37 (2H, m), 1.60 - 1.66 (4H, m), 1.68 - 1.75 (2H, m) , 1.91 - 2.08 (5H, m), 2.89 - 2.93 (2H, m), 3.27 - 3.33 (2H, m), 3.87 - 3.92 (1H, m), 4.46 (1H, 5), 7.20 - 7.26 (1H, m), 7.30 - 7.34 (SH, m), 7.77 (1H, d), 8.30 (1H, d) m/z (ESI+) (M+H)+ = 443; HPLC tg = 2.59 min ° and substance (VA) The following example was prepared in a manner similar to that of Example (1); Use the intermediate compound:aminoester with an appropriate prefix of

MS Example m/e "HNMR 8 compound [Name

MH" No. 472; | IHNMR (400.13 2-[(3S)-1-[5-[[(2r,58)- | y.4q

HPL | MHz, DMSO-d6) 5-hydroxy-2-°

CtR [1.00 (3H,1), 1.23 - adamantyl]carbamoyl 0 -2.2 1 1.34 (1H, m), 1.38 - | ]-6-propoxy-pyridin- 1 A min | 1.51 3H, m), 1.63 - | 2-yl]-3- oC 1.93 (13H, m), 1.99 - | piperidyl]acetic acid No 2.08 (3H, m), 2.13 - 2.28 ° (2H, m), 2.79 - 2.86 (1H, m), 2.98 - 3.06 (1H, m), 3.97 - 4.02 (1H, m), 4.09 - 4.16 (1H, m), 4.22 - 428 (1H, m), 4.32 - 4.40 (2H, m), 4.42 (1H, s), 6.44 (1H, d), 7.96 (1H, d), 8.03 (1H , d), 12.09 (1H, s)

— \ o A —_ 500; | 1H NMR (400.13 2-[1-[5-[((2r,55)-5- VY.

HPL | MHz, DMSO-d6) hydroxy-2-0

CtR | 0.99 (3H,1), 1.10 adamantyl)carbamoyl 0 = (3H, s), 1.15 (3H, 5), | ]-6-propoxy-pyridin- A 2.44 | 1.39 (2H,t), 1.47 2-yl]-3-piperidyl]-2-MAN ; 0 min. | (2H, d), 1.66 (5H, methyl-propanoic CL m), 1.73 (6H, m), acid 0 0. 1.78 - 1.86 (2H, m), 2.02 - 2.07 3H, m), 2.69 (1H, 1 ), 2.84 (1H, t), 3.90 - 3.95 (1H, m), 4.25 - 4.28 (1H, m), 4.34 - 4.40 (2H, m), 4.42 (1H, s), 4.46 - 4.50 (1H, m ), 6.41 (1H, d), 7.96 (1H, d), 8.03 (1H, d), 12.19 (1H, 5) (VA) intermediate 6-chloro-N-((2r,5s)-5 -hydroxy-2-adamantyl)-2-propoxy-pyridine-3-carboxamide

Cl _N 0 to 1 0 “OH mmol) to 1 “Ja 1( THF molar in 1 bis-sodium hexamethyldisilylamide added 0 mmol) 1 mg; YE) 2, 6-dichloro-N-(5-hydroxyadamantan-2-yl)nicotinamide ml) and washed with (+1) EtOAc for two hours. The reaction mixture was diluted with 051 and heated to 1 ml). The organic layer (Yo) and saturated brine (Yo) were sequentially dried using water, filtered and evaporated to obtain the crude product. MgSO was purified on an organic layer

_ \ 0 9 — 70,000 with stepwise elutriation from zero to silica flashing on crude chromatography B until dryness to obtain pure fractions and pure fractions were evaporated .DCM in EtOAc (797 mg) As a substance (YE) 6-chloro-N-(5-hydroxyadamantan-2-yl)-2-propoxynicotinamide . White solid © 'H NMR (400.13 MHz, DMSO-ds) 80.99 (3H, t), 1.41 - 1.45 (2H, m), 1.64 - 1.67 (4H, m), 1.72 - 1.84 (5H, m), 2.01 - 2.08 (3H, m), 3.96 - 4.01 (1H, m), 4.34 (2H, t), 4.49 (1H, s), 7.22 (1H, d), 8.10 (1H, d), 8.16 (1H, d) m/z (ESI+) (M+H)+ = 365; HPLC tg = 2.39 min (111) Ex. ys (1R,58S,61)-3-(6-(Cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl)pyridin-2 - yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 0 —N

N

H | Rama X N N 5

Ont

Th 0 0 mmol) to a stirred solution of 0.44 cana V+ ¥) lithium hydroxide monohydrate was added from: 10 (1R,58,6r)-methyl 3-(6-(cyclopentylthio)-5- (3-(pyridin-3-yl)pyrrolidine-1-carbonyl)

- 11.0 pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate mL). The resulting solution (Y (ele) ml/©) methanol (mmol) in + AY cane £14) was stirred in organic solvent ABS 1 hour. YE was removed at ambient temperature for a standard time. The resulting citric suspension was extracted in vacuo, and the resulting solution was acidified using organic acid (ml). The organic layers were washed (V) times ¥) with EtOAc m, then dried on (Je 701) sat brine and saturated brine (Je Yo 7 pH (HCl number) with a solution: and filtration and evaporation of the product (MSOy) (1R,58,6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1 -carbonyl)pyridin-2- yl) - 3-azabicyclo[3.1.0Thexane-6-carboxylic acid (195mg, 50%).1 111 NMR (400.13 MHz, DMSO-d6) 1.25 (1H, 5), 1.40 (1H, s), 1.50 - 1.72 (6H, m), 1.90 - 2.10 (1H, m), 2.10 - 2.20 (3H, m), 2.29 - 2.35 (1H, m), 3.30 - 3.55 (5H, m), 3.64 (1H, 5), 3.72 - 3.95 ( 3H, m), 4.01 - 4.07 (1H, m), 6.16 (1H, d), 7.30 — 7.80 (2H, m), 7.71 (1H, s), 8.40 — 8.60 (2H, m), 12.18 (1H, s) m/z (ESI+) (M+H)+ = 479 Vo : (1R,58,6r)-methyl 3-(6-(cyclopentylthio)-5-(3-(pyridin-3) was prepared -yl)pyrrolidine-1 -carbonyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate after. Lad as described starting material used as starting material mmol ) to a solution of 1.01 (Ja ,..4 ) oxalyl chloride add dropwise and then drop 0

2-(cyclopentylthio)-6-((1R,5S,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0}hexan-3-yl) nicotinic acid (380 mg, 1.05 mmol) in DCM (© ml)/DMF (1 drop) at 0 °C under nitrogen and the resulting solution was allowed to warm at ambient temperature for 2 hours. The reaction mixture was evaporated to dryness and redissolved in A (DCM ml). The solution was cooled to 0°C and then treated with a solution of 0100 cana 1711 (3-pyrrolidin-3-ylpyridine mmol) 7.019 “Jw +. £Y'A) triethylamine 5 mmol) in DCM (© ml). The resulting reaction was allowed to warm to ambient temperature and stir at said temperature for 2 hours. The reaction mixture was diluted with DCM (+ mL) and dialyzed sequentially with 1 mL Te (JeTo)elas and saturated saline (Vr mL). The organic layer was dried organic layer on MgSO, filtering and evaporating it to obtain the raw product. The crude product was purified b

: blink on 511168 for chromatography (IR,58,6r)-methyl 3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1-carbonyl) pyriflin-2-yl )-3-azabicyclo[3.1.0]hexane-6-carboxylate (400 mg, 77 %)

yellow oil. m/z (ESI+) (M+H)+ = 493; HPLC tR = 1.84 min. 1H NMR (400.13 MHz, CDCI3) § 1.58 - 1.70 (4H, m), 1.71 - 1.80 (3H, m), 2.11 - 2.20 (3H, m), 2.25 (2H, s), 2.36 (1H, s), 3.40 - 3.60 (4H, m), 3.69 (4H, s), 3.74 - 3.87 (4H, m), 1:05 - 4.12 (2H, m), 5.99 ( 1H, d), 7.20 — 7.30 (2H, m), 7.57 (1H, s), 8.40 — 8.60 (1H, m)

2-(cyclopentylthio)-6-((1R,5S,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0]hexan-3-yl) nicotinic acid was prepared.

used as a starting material, as described below.

A solution of: (1R,58,6r)-methyl 3-(5-(tert-butoxycarbonyl)-6-(cyclopentylthio)pyridin-2-yl)-3- azabicyclo[3.1.0]hexane was stirred. -6-carboxylate (intermediate compound ATA 71 mg; 7.71 mmol) in hydrogen chloride (£ mol at 0 ) (dioxane ml; 011 mmol) at ambient temperature for 0 hours. Ah) 0 was the solvent in vacuum to obtain: 2-(cyclopentylthio)-6-((1R,58,6r)-6-(methoxycarbonyl)-3-azabicyclo[3.1.0]Thexan-3- yl) nicotinic acid (760 mg, 91%) as yellow solid m/z (ESI+) (M+H)+ = 363: HPLC tR = 2.48 min. 1H NMR (300.072 MHz, CDCI3) 6 1.50 - 1.80 (7H, m), 2.10 — 2.25 (2H, m), 2.29 (2H, s), 3.61 -3.71 (5H, m), 3.80 - 4.00 (2H, m) ), 4.02 - 4.11 (1H, m), 6.00 (1H, d), 8.03 (1H, d)

117 - - intermediate compound (19) tert-butyl 2,6-dichloropyridine-3-carboxylate 0 a 6 — Cl N Cl Suspension of acid (YAY can V0) 2,6 was heated -dichloronicotinic mmol) in toluene (Ja 171) 0 up to 0 C under 0 p 0 »Nh. And to this suspension was added: 7017.50 (Je 1/4.9) N,N-dimethylformamide di-tert- butyl acetal mmol) by dropwise and the resulting solution was stirred at 0 C for ½ h. The reaction mixture was evaporated to dryness, re-dissolved in 6/20 (+ Yo ml) and washed successively with NaHCO; 0 ml) and saturated brine (00 (Ja) and the organic layer was dried on MgSO4 yo. Filtered and evaporated to obtain the crude product Calg. Purification of the crude product by flash chromatography on silica With stepwise eluting from 01 to EtOAc 771 in .isohexane and pure fractions were evaporated to dryness to obtain: (YYY) tert-butyl 2,6-dichloronicotinate g (ZAA) as pale jal oil .pale yellow oil 1TH NMR (300.073 MHz, DMSO0-d6) 6 1.54 (9H, s), 7.67 (1H, d), 8.23 (1H, d)

(V+) The intermediate is 10 methyl (1R,58)-3-[6-chloro-5-[(2-methylpropan-2-yl)oxycarbonyl]pyridin-2-yl]-3- azabicyclo[3.1. 0]hexane-6-carboxylate

10165 - - 0 mer H 2 N N Cl “ One A 1 PY suspension of (1R,5S,6r)-methyl 3-azabicyclo[3.1.0]hexane- 6-carboxylate (44.¥ 70016 cana mmol) 5 0010# can ©) tert-butyl 2,6-dichloronicotinate mmol) 1.216 (Ja Y. vv) triethylamine mmol) in (Je On ) DMA at 0 ambient temperature overnight. The reaction mixture was evaporated to dryness, redissolved in EtOAc (+10 ml) and washed sequentially with whe 1 citric acid (94 ml), water (0 ml) and saturated brine (00 ml). The organic layer was dried at 14850 C, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica with stepwise sequencing from 01 to EtOAc 7708 in -isohexane, and pure fractions 0 were evaporated to obtain: (IR,58 ,6r)-methyl 3-(5-(tert-butoxycarbonyl)-6-chloropyridin-2-yl)-3-azabicyclo[3.1.0] hexane-6-carboxylate (2.18g, 31%).

IH NMR (400.13 MHz, CDCI3) 1.47 (1H, 1), 1.50 (9H, 5), 2.19 - 2.21 (2H, m), 3.50 - 3.53 (2H, m), 3.62 (3H, 5), 3.77 (2H, d), 6.12 (1H, d), 7.86 (1H, d) m/z (ESI+) (M+H)+ = 353; HPLC tR 2.75 min. Vo intermediate compound (71) Ah

Vio - = methyl (1R,5S)-3-[6-cyclopentylsulfanyl-5-[(2-methylpropan-2-yl)oxycarbonyl]pyridin- 2-yl]-3-azabicyclo[3.1.0 ]hexane-6-carboxylate 0 [saa : H | 7 7s kmR Oxi z Ba 7 00 010177 (cyclopentanethiol ml VAY mmol) was added to a volatile solution of 0a (aa 00 potassium tert-butoxide .moa, wab i butoxid 631 + g; oY mmol) in DMA (£ ml). The resulting suspension was stirred at ambient temperature for 10 minutes under nitrogen, then treated with a solution of: (IR,58,6r)-methyl 3-(5-(tert-butoxycarbonyl)-6-chloropyridin-2-yl )-3-azabicyclo[3.1.0] hexane-6-carboxylate ca Y..4 ) ,9 mmol) in (Je °) DMA . The resulting reaction mixture was stirred at 0° ambient temperature for 2 hours and then treated with a solution (111301 V0 mL). The Je tall mixture was diluted with (JaVo) EtOAc and washed sequentially with (JYo (NH,Cl) water (JeYO) and saturated brine (0 ml). The organic layer was dried layer on 1850, filtered and evaporated to obtain the crude product.The crude product was purified by flash chromatography on silica with gradual sequencing from 01 to EtOAc 770 in -isohexane and vo parts were evaporated. Pure fractions to dryness to obtain: (IR,5S,6r)-methyl 3 -(5-(tert-butoxycarbonyl)-6-(cyclopentylthio)pyridin-2-yl)-3- azabicyclo[3.1] 0]hexane-6-carboxylate (0.974 g (ZVE). As a colorless oil.

1H NMR (300.072 MHz, CDCI3) 1.55 - 1.82 (16H, m), 2.10 — 2.22 (2H, m), 2.27 (2H, 1), 3.60 (2H, d), 3.70 (3H, s), 3.87 (2H, d), 4.00 - 4.08 (1H, m), 5.95 (1H, d), 7.90 (1H, d) m/z (ESI+) (M+H)+ = 419; HPLC tR = 3.43 min. and material (YY), and the following examples were prepared in a manner similar to example (111); Using the intermediate compound 0:aminoester with an appropriate prefix of

MS Example m/e "HNMR 8 Compound Name

MH" No. 493 | 1H NMR (400.13 (1S,5R)-3-[6-VAY

MHz, DMSO-d6) cyclohexylsulfan 0 iN 120-132 (4H, m), | yl-5-(3-pyridin-3- \ ro-0 1.38 - 1.45 (4H, m), | ylpyrrolidine-1- .LI A 1.60 (1H, d), 1.72 carbonyl)pyridin- T (2H, 5) , 1.95 - 2.05 | 2-y1]-3- (3H, m), 2.18 (2H, s), | azabicyclo[3.1.0] 2.29-235(1H, m), | hexane-6- 3.25-3.49 (4H, m), | carboxylic acid 3.71 (4H, d), 6.16 (1H, d), 7.34 (2H, d), 7.65 - 7.80 (1H, m), 8.45 - 8.50 (2H, m), 11.80 (1H, brs) (YY) intermediate compound i

- Vv - methyl (IR,5S)-3-[6-cyclohexylsulfanyl-5-[(2-methylpropan-2-yl)oxycarbonyl]pyridin- 2-yl}-3-azabicyclo[3.1.0]hexane-6- carboxylate 0 ort

H | — 4 1 of +5

Oi 7 A 0 using a method similar to that of ( Yo) from the intermediate (YY ) the intermediate (?1) used for the preparation of the intermediate 1H NMR (400.13 MHz, 0003) was prepared. 6 1.24 - 1.46 (5H, m), 1.49 (9H, s), 1.52 (1H, t), 1.55 - 1.65 (1H, m), 1.73 - 1.76 (2H, m), 2.00 - 2.10 (2H, m) , 2.20 - 2.22 (2H, m), 3.52 (2H, d), 3.63 (3H, s), 3.70 — 3.85 (3H, m), 5.87 (1H, d), 7.83 (1H, d) m/z ( ESI+) (M+H)+ = 433; HPLC tR = 3.60 min. 01 and substance (V£) The following examples were prepared in a manner similar to Example (111); using the intermediate compound: aminoester with an appropriate prefix of

MS Example 1 m/e HNMR § Compound [Name].

MH Rukm

- VTA - 469 | 1H NMR (500.13 MHz, 2-[(3S)-1-[6- 1

DMSO0-d6) 0.99 (3H, 1), propylsulfanyl-5- . 1.28 - 1.38 (1H, m), 1.51 - | (3-pyridin-3-mi Se ave 1.54 (1H, m), 1.66 - 1.74 | ylpyrrolidine-1- CyO (BH, m), 1.86 - 1.90 (1H, |carbonyl)pyridin- 3 m), 1.94 - 1.98 (1H, m), 2-yl}-3- 2.01-2.05 (1H, m), 2.17 - | piperidyl] acetic 2.28 (2H, m), 2.34 - 2.38 | acid (1H, m), 2.80 - 2.86 (1H, m), 3.00 — 3.07 (1H, m), 3.09 - 3.13 (2H, m), 3.38 - 3.45 (1H, m), 3.47 - 3.54 (2H, m) ), 3.57 - 3.64 (1H, m), 3.82 - 3.86 (1H, m), 4.07 - 4.13 (1H, m), 4.20 - 4.24 (1H, m), 6.48 (1H, d), 7.31-17.35 (2H , m), 7.69 (1H, d), 8.44 - 8.46 (1H, m), 8.53 (1H, d), 11.50 (1H, s) 469 | 1HNMR (400.13 MHz, 2-[(3S)-1-[6- VY ¢

CDCI3) 0.99 (3H, t), 1.27 | propylsulfanyl-5- . (1H, m), 1.50 - 1.62 (1H, | (3-pyridin-2- O° Sow LT m), 1.63 - 1.78 (3H, m), ylpyrrolidine-1-b oJ 1.85 - 1.99 (1H, m), 2.00 - |carbonyl)pyridin-3 2.10 (1H, m),2.20-2.45 | 2-yl]-3- (4H, m), 2.68 — 2.80 (1H, | piperidyl]jacetic m), 2.90 - 3.00 (1H, m), acid 3.01-3.09 (2H, m), 3.57 - 3.94 (5H) , m), 4.10 - 4.30 (2H, m), 6.29 - 6.33 (1H, m), 7.19 - 7.35 (3H, m), 7.60 - 7.70 (1H, m), 8.58 (1H, d) 406 | THNMR (400.13 MHz, |2-[(3S)-1-[5-m6 ‎DMSO0-d6) 0.94 (3H, t), (piperidine-1- 1.20 - 1.30 (1H, m), 1.44 - | carbonyl)-6- 1.49 (6H, m), 1.58 - 1.70 | propylsulfanyl- (5H, m), 1.81 - 1.89 (2H, |pyridin-2-yl]-3- °m), 2.13 - 2.26 (2H, m), | piperidyl]acetic 0.0 Or 2.71-2.76 (2H, m), 2.88 - | acid NS LA @ 2.95 (1H, m), 2.98 - 3.09 N (2H, m), 4.15 (1H, d), 4.27 (1H, d), 6.40 (1H, d), 7.25 (1H, d), 12.05 (1H, s) yiva

- 118 - 470 | 1THNMR (400.13 MHz, 2-[(3S)-1-[6-yy

DMSO0-d6) 0.94 3H, s), | propylsulfanyl-5- 1.20 - 1.30 (1H, m), 1.35 - | (3-pyrazin-2- 1.50 (1H, m), 1.61 - 1.65 | ylpyrrolidine-1- (3H, m), 1.75 - 1.90 (2H, | carbonyl)pyridin- 0 m), 2.12 - 2.34 (4H, m ), 2-yl]-3- op oro 2.65 - 2.75 (1H, m), 2.89 - | piperidyl]acetic 1S N 4 2.95 (1H, m), 2.95 - 3.01 | acid (2H, m), 3.45 - 3.65 (5H, m), 4.10 - 4.20 (1H, m), 4.23 - 4.33 (1H, m), 6.50 (1H, s), 7.36 (1H, d), 8.52 - 8.69 3H, m), 12.03 (1H, 5) 442 | 111 1111 + (300.072 MHz, | 2-[(3S)-1-[5-(4,4-1

CDCI3) 1.00 (3H, t), 1.31 | difluoropiperidine- - 1.39 (1H, m), 1.53 - 1.77 | 1-carbonyl)-6- (4H, m), 1.92 - 2.09 (6H, |propylsulfanyl-m), 2.32 (2H, d), 2.75 - pyridin-2-yl]-3- o 2.82 (1H, m) , 2.90 - 3.05 | piperidyl]acetic o 0 m (1H, m), 3.05 - 3.15 (2H, | acid NS Ws STF m), 3.67 (4H, br s), 4.17 - N 4.30 (2H, m), 6.33 (1H , d), 7.24 (1H, d) 474 | ITHNMR (300.072 MHz, | 2-[(3S)-1-[6- YY A

CDCI3) 1.00 3H, t), 1.23 | propylsulfanyl-5- . - 1.38 (1H, m), 1.50 - 1.81 | ] 3- mh AAD (7H, m), 1.93 (1H, d), (trifluoromethyl)pi of 2.00 - 2.15 (4H, m), 2.31 | peridine-1- § (2H, d), 2.39 (1H, brs), carbonyl |pyridin- 2.73 - 3.01 (4H, m), 3.02 - | 2-yl]-3- 3.16 (2H, m), 4.10 - 4.30 | piperidyl]acetic (2H, m), 6.33 (1H, 4d), acid 7.22 (1H, d) 474 | THNMR (300.072 MHz, | 2-[(3S)-1-[6- 14

CDCI3) 1.00 (3H, t), 1.28 | propylsulfanyl-5- - 1.38 (1H, m), 1.50 - 1.80 | [4- (6H, m), 1.83 - 1.95 (3H, | (trifluoromethyl)pi m), 2.00 - 2.15 (3H, m), peridine-1- o 2.22 - 2.32 (3H, m), 2.70 | carbonyl]pyridin- Onp© NN —282(1H,m),2.83- | 2-yI]-3- from Bm 3.02 (311, m), 3.04 - 3.15 | piperidyl]acetic (2H, m), 4.22 (2H, m), acid 6.33 (1H, d), 7.25 (1H, d

Yive

_ \ Y . — 449 | 1TH NMR (400.13 MHz, 2-[(3S)-1-[5-(4- 7)

DMSO0-d6) 0.94 (3H,t), carbamoylpiperidium. 1.18 - 1.22 (1H, m), 1.40 | ne-1-carbonyl)-6- 0.0 No - 1.53 3H, m), 1.63 - propylsulfanyl-mL" 1.80 (5H, m), 1.81 - 1.89 |pyridin-2-yl]-3- 5 " ( 2H, m), 2.14 - 2.26 (2H, | piperidyljacetic m), 2.30 - 2.36 (2H, m), acid 2.67 - 2.73 (1H, m), 2.88 - 2.97 (1H, m), 2.99 - 3.09 (2H, m), 4.16 (1H, d), 428 (1H, d), 6.51 (1H, d), 6.81 (1H, s), 7.25 (1H, d), 7.29 (1H, s), 12.17 (1H, 5 ) 460 | 1HNMR (400.13 MHz, 2-[(3S)-1-[5- 171)

DMSO0-d6) 0.43 0.53 (cyclohexyl- (4H, m), 0.94 (3H, t), 1.10 | cyclopropyl- - 1.20 (1H, m), 1.22 - carbamoyl)-6- 1.31 (3H, m), 1.40 — 1.50 | propylsulfanyl- (1H, m), 1.56 - 1.70 (5H, | pyridin-2-yl]-3- oo 0 @ m), 1.73 - 1.91 (7H, m), 1 piperidyljacetic ©0S 2.14 - 2.26 (2H, m ), 2.53 - | acid vv oR 2.62 (1H, m), 2.69 - 2.74 3 (1H, m), 2.89 - 2.96 (1H, m), 2.97 - 3.10 (2H, m), 3.80 -- 3.90 (1H, m), 4.15 ( 1H, d), 4.26 (1H, d), 6.47 (1H, d), 7.30 (1H, d), 12.09 (1H, s) 474 | 1THNMR (400.13 MHz, 2-[(3S)-1-[5-YY)

DMSO0-d6) 0.20 (2H, s), | (cyclohexyl- 0.40 (2H, 5), 0.94 GH, 1), | (cyclopropylmethy 0 and 1.08 )311 s), 1.20— 1.35 | I)carbamoyl)-6- COL (2H, m), 1.20 - 1.59 (13H, |propylsulfanyl- in m), 1.80- 1.93 (2H, m), pyridin-2-yl]-3- N 2.14 - 2.25 (2H, m), 2.65 | piperidyl]acetic —2.75 (1H, m), 2.88 - acid 2.98 (1H, m), 3.00 — 3.20 (3H, m), 4.14 (1H, d), 4.27 (1H, d), 6.50 (1H, 4d) , 7.23 (1H, d), 11.90 (1H, d)

448 | 111 11117 (400.13 MHz, 2-[(3S)-1-[5- a DMSO-d6) 0.94 (3H, t), (cyclohexyl-ethyl- 1.08 - 1.31 (5H, m), 1.34 - | carbamoyl)-6- 1.45 (3H, m), 1.42 - 1.70 | propylsulfanyl- (13H, m), 1.82 - 1.92 (2H, |pyridin-2-yl]-3-m), 2.13 2.28 (2H, m), | piperidyljacetic n m ( 2.80 (1H, 0, 2.95 (1H, t), | acid oC 3.01-3.10 (2H, m), 4.14 Yo (1H, d), 4.27 (1H, d), 6.50 5 (1H) , d), 7.22 (1H, d), 12.10 (1H, s) 462 | 1THNMR (400.13 MHz, 2-[(3S)-1-[5- 17)

DMSO0-d6) 0.93 (3H, t), (cyclohexyl- 1.10 - 1.85 (20H, m), 1.81 | propan-2-yl- -1.90 (3H, m), 2.14 - 2.26 | carbamoyl)-6- (2H , m), 2.64 - 2.70 (1H, |propylsulfanyl-m), 2.83 - 2.95 (IH, m), | pyridin-2-yl]-3- p m ( 3.06 (3H, s), 3.58 (1H, 5), | piperidyl]acetic NS CO 4.13 (1H, d), 4.27 (1H, d), | acid YN 6.48 (1H, d), 7.16 (1H, d), 5 12.20 (1H, s) 436 |11111116 (300.072 MHz, | 2-[(3S)-1-[5-[(4- \Yo)

CDCI13) 1.02 (3H, t), 1.31 | hydroxycyclohexy m - 1.51 (5H, m), 1.52 - 1.63 | -6-[1 adsorbent 1(6 oo lump) (1H, m), 1.67 - 1.79 (3H, | propylsulfanyl- NS 0 m), 1.90-2.17 (7H, m), | pyridin-2-yl] -3- N 2.31 (2H, d),2.79 - 2.86 |piperidyl]acetic (1H, m), 2.93 - 3.07 (1H, | acid m), 3.08 - 3.20 (2H, m), 3.62 - 3.70 (1H, m), 3.85 —4.03 (1H, m), 4.18 - 4.32 (2H, m), 6.35 (1H, d), 6.53 (1H, d), 7.78 (1H, d) 536; |111 1111 (300.073 MHz, |2-[(3S)-1-[6-YY"

HPL | DMSO0-d6) 0.96 (3H, t), propylsulfanyl-5- .

CR | 1.25 (2H, m), 1.64 (7TH, | [3-[2-lolum mh =| m), 1.83 - 1.90 (4H, m), (trifluoromethyl)p > nN > 2.86 | 2.18 (2H, m), 2.60 - 3.07 | henyl]pyrrolidine- 5 min. | (4H, m), 3.72 (1H, s), 1- 4.00 - 4.13 (1H, m), 6.49 | carbonyl]pyridin- (1H, s), 7.43 (3H, 5), 7.65 | 2-yl]-3- - 7.88 (3H, m), 12.09 (1H, | piperidyl]acetic 59) acid

- 1/7 - 550; | 111 NMR (700.03 MHz, 2-[(3S)-1-[5-bY

HPL 1 DMSO-d6) 0.97 3H, 1), [((2r,5s)-5- 0 )

C tR | 1.20 - 1.32 (2H, m), 1.35 - | methylsulfonyl-2- 0.0 re =| 1.49 3H, m), 1.58 - 1.70 | adamantyl) carbam NS, L: 2.34 | 3H, m), 1.79 - 1.90 2H, | oil]-6-min. | m), 1.90 - 2.00 (4H, m), propylsulfanyl- 2.00 - 2.10 (5H, m), 2.10 - | pyridin-2-yl]-3- 2.25 (3H, m), 2.75 (1H, 0. | piperidyl]acetic 2.83 (3H, s), 2.90 - 3.00 acid (2H, m), 3.00 - 3.05 (1H, m) ), 3.90 (1H, s), 4.20 (1H, d), 4.25 (1H, d), 6.50 (1H, d), 7.60 (1H, d), 7.75 (1H, d)

YY intermediate compound tert-butyl 2-chloro-6-[(3S)-3-(methoxycarbonylmethyl)-1 -piperidyl]pyridine-3- carboxylate 0 M’ 7

N N Cl from the intermediate compound (14) was prepared using a method similar to that of (YY). 1H, m), 1.48 — 1.60 (10H, m), 1.69 - 4 (1H, m), 1.87 - 1.90 (1H, m), 2.01 - 2.05 (1H, m), 2.21 - 2.33 (2H, m), 2.80 - 2.85 (1H, m), 3.00: -3.05 (1H, m), 3.68 (3H, s), 4.18 (2H, d), 6.45 - 6.47 (1H, m), 7.90 - 7.92 (1H, m) m/z (ESI+) (M+H)+ = 369; HPLC tR = 2.99 min. (Y¢) intermediate compound

- 177 - tert-butyl 6-[(35)-3 -(methoxycarbonylmethyl)-1 -piperidyl}-2-propylsulfanyl -pyridine-3- carboxylate 0 iS Mmm! N N ( for those 3 Bilas of intermediate 9 ) using the ( Ve ) method the intermediate compound was prepared . ( H used to prepare the intermediate ) leaching 'H NMR (400.13 MHz, CDCl; ) 51.04 (3H , t), 1.30 - 1.37 (1H, m), 1.53 - 1.63 (10H, m), 1.62 - 1.79 (3H, m), 1.89 - 1.93 (1H, m), 2.03 - 2.10 (1H, m), 2.23 - 2.34 (2H, m), 2.74 - 2.87 (1H, m), 2.99 - 3.10 (3H, m), 3.69 (3H, 5), 4.28 (2H, 1), 6.28 (1H, d), 7.92 (1H , d) m/z (ESI+) (M+H)+ = 409; HPLC tR = 3.49 min. and substance (Y0) and the following examples were prepared in a manner similar to example (111); using intermediate compound 0: aminoester suitable prefix from

MS Example m/e "HNMR 3 compound [Name

MH" No

- 176 —- 495 1H NMR (400.13 MHz, 2-[(3S)-1-[6- \YY

DMSO0-d6) 1.20 — 1.30 cyclopentylsulfan oo (1H, m), 1.45 - 1.80 (8H, | yl-5-(3-pyridin-3-m m), 1.81 - 1.89 (2H, m), ylpyrrolidine-1- 2 2.02 - 2.40 (6H, m), 2.71 carbonyl)pyridin- (1H, 1), 2.92 (1H, 1), 3.25 - | 2-y1]-3- 3.65 (4H, m), 3.70 (1H, s), | piperidyl]acetic 4.05 (1H, 1), 4.14 (1H, d), | 40 4.27 (1H, d), 6.49 (1H, d), 7.30 — 7.40 2H, m), 7.73 (1H, s), 8.45 (1H, d), 8.52 (1H, s), 12.05 (1H, s) 490 1H NMR (400.13 MHz, 2-[(3S)-1-[6- VYA | owe to DMSO0-d6) 1.01 - 1.10 cyclopentylsulfan NS (Le (7H, m), 1.17 - 1.70 (13H, | y1-5-[3-(2- A m), 1.83 - 1.92 (3H, m), hydroxypropan-2- 2.07 - 2.26 (4H, m), 2.65 — |yl)piperidine-1- 2.75 (2H, m) ), 2.85 - 2.96 carbonyl]pyridin- (2H, m), 3.97 - 4.04 (1H, 2-yl}-3-m), 4.12 - 4.18 (2H, m), piperidyl]acetic 4.25 (1H, d), 6.49 (1H, d), | acid 7.22 (1H, d), 12.06 (1H, s) (Yo) Intermediate compound tert-butyl 2-cyclopentylsulfanyl-6-[(3S)-3 -(methoxycarbonylmethyl)-1 -piperidyl] pyridine-3-carboxylate 0 ago Joh

N N 5 using a method similar to that (Y 9) of the intermediate ( Yo ) was prepared. The intermediate ( AR ) used for the preparation of the intermediate of Example (1); using the intermediate (776) and a starting material Ailes and the following examples were prepared using an appropriate aminoester method

- 18 -

MS Example m/e "HNMR & compound"—the name

MH" No. 482 | ITH NMR (400.13 | 2-[(3R)-1-[5- YY4 | for 9 mah

MHz, DMSO-d6) | (cyclohexylcarbamoyl)- Y or 1.10 - 1.16 (1H, m), | 6-phenethylsulfanyl- O US 1.20 - 1.35 (5H, m), | pyridin-2-yl]-3- 1.38 —1.52 (1H, m), | piperidyl]acetic acid 1.57 - 1.92 (7H, m), 2.09 - 2.22 (2H, m), 2.72 — 2.81 (1H, m), 291 (2H, t), 2.93 - 3.05 (1H, m), 3.18 - 3.35 (3H, m), 3.64 - 3.67 (1H, m), 4.25 (2H, 1), 6.50 (1H, d), 7.18 - 7.31 (5H, m), 7.64 (1H, d), 7.74 (1H, d) ), 12.07 (1H, 5) 482 1 TH NMR (400.13 | 2-[(3S)-1-[5- Wolo o 9 0

MHz, CDCI3) 1.18 - | (cyclohexylcarbamoyl)- or 1.32 (6H, m), 1.35 - | 6-phenethylsulfanyl-b Vs 1.46 (2H, m), 1.53 - | pyridin-2-yl]-3- 1.65 (2H, m), 1.65 - | piperidyl]acetic acid 1.75 (3H, m), 1.91 - 2.02 (2H, m), 2.24 (2H, d), 2.73 - 0 (1H, m), 2.90 - 3.10 (3H, m), 3.35 - 3.49 (2H , m), 3.93 - 4.02 (1H, m), 4.25 - 4.33 (2H, m), 6.38 (1H, d), 6.49 (1H, 4d), 7.19 - 7.32 (5H, m), 7.81 (1H, d ) (Y1) intermediate compound 6-chloro-N-cyclohexyl-2-phenethylsulfanyl-pyridine-3-carboxamide

Av - - ) 0 0 Cl N 0 To a solution of ethanethiol phenyl —Y (115 μl; 17 mmol) in (Je ¥) DMF NaHMDs (”. ml; 7.7 mmol.) The reaction mixture was stirred at ambient temperature for 2 minutes and then added to a solution of: 2,6-dichloro-N-cyclohexyl-pyridine-3-carboxamide 0 (intermediate compound 100681 o) mg YY mmol) in DMF (Y) ml). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated under reduced pressure and the resulting residue was divided between EtOAc (Ja Y +) citric acid (1) and separated The layers were separated and the organic layer was washed with NaHCO; saturated 0 01 (mL), water 01 (mL), brine 01 (mL) and then dried over (MgSO) This solid was pulverized using 111/20/56 (by (41) to obtain a white solid Vet) mg (FAS “H NMR (400.13 MHz, DMSO-dg) 1.11 - 1.35 (5H, m), 1.57 - 1.60 (1H, m), 1.70 - 1 73 (2H) m), 1.78 -1.85 (2H, m), 2.85 — 2.95 (2H, m), 3.25 - 3.29 (2H, m), 3.65 - 3.72 (1H, m), 7.20 - 7.27 (1H, m), 7.28 - 7.34 (SH, m), 7.79 (1H, d), 8.38 (1H, d)

- 1/9 - m/z (ESI+) M+H)+ = 375; HPLC tR = 3.04 min. and a starting material (YV) using the intermediate compound (1). The following example was prepared in a manner similar to the example: a suitable aminoester from

MS Example m/e "HNMR 8 Compound: Name No. MH" 483 | ITHNMR (400.13 | 2-[(3S)-1-[5-11

MHz, DMSO-d6) (cyclohexylcarbamoyl)- 1.23 (6H, d), 1.35 - | 6-(2-pyridin-3- 5 1.50 (1H, m), 1.57 - | ylethylsulfanyl)pyridin- oH 1.87 (8H, m), 2.08 — | 2-y1]-3-piperidyl]acetic 2.22 (2H, m),2.76 | acid (1H, t), 2.90 - 3.00 (2H, m), 3.20 - 3.40 (3H, m), 3.63 - 3.66 (1H, m), 4.26 (2H, t), 6.51 (1H, d), 7.30 - 7.34 (1H, m), 7.65 - 7.69 2H, m), 7.82 (1H, d), 8.41 - 8.43 (1H, m), 8.45 (1H, d), 12.20 (1H, s) (YV) intermediate compound ‎ 6-ctioro-N-cyclohexyl-2-(2-pyridin-3-ylethylsulfanyl)pyridine-3-carboxamide

-YYA-

LO

N

7 =

Cl N 5 2 << No (16). In a manner analogous to the intermediate compound (YY) the intermediate compound 'H NMR (300.072 MHz, CDCl) 1.16 H - 1.34 (3H, m), was made. 1.35 - 1.50 (2H, m), 1.61-1.78 (4H, m), 1.95 — 2.07 (1H, m), 2.97 - 3.05 (2H, m), 3.38 — 3.45 (2H, m), 3.92 - 4.04 (1H , m), 6.16 (1H, d), 7.06 (1H, d), 7.21 - 7.25 (1H, m), 7.62 - 7.66 (1H, m), 7.76 (1H, d), 8.45 - 8.48 (1H, m) ), 8.55 (1H, d) m/z (ESI+) (M+H)+ = 376; HPLC tR = 1.49 min.) and a starting material (YA) using intermediate compound (V) and the following example was prepared by Similar to the example: aminoester suitable from 0

MS Example m/e | 15 compound name

MH" No

- 179 - 484 | 111 next. 3) 2-[(3S)-1-[5- YY |. 0 to MHz, DMSO0-d6) 1.05 | (cyclohexylcarbamoyl)- or - 1.35 (5H, m), 1.35 - 6-(2-pyrazin-2- YN 1.50 (1H, m), 1.57 - ylethylsulfanyl)pyridin- 2 1.83 (7H, m), 2.09 - 2 yl]-3-piperidyl]acetic IJ 2.24 (2H, m), 2.64 - acid 2.78 (2H, m), 2.90 - 3.00 (1H, m), 3.13 (2H, t), 3.30 - 3.48 (3H, m) , 3.62 (1H, s), 4.28 (2H, d), 6.51 (1H, d), 7.67 (1H, d), 7.81 (1H, d), 8.49 (1H, s), 8.56 (2H, s), 12.21 (1H, s) (YA) intermediate 6-chloro-N-cyclohexyl-2-(2-pyrazin-2-ylethylsulfanyl)pyridine-3 -carboxamide 1 > N

O.L

~

Cl N 5 LA (76) In a similar manner to the intermediate (YA) the intermediate complex was made 0 'H NMR (400.13 MHz, DMSO-d¢) 51.05 - 1.35 (5H, m), 1.53 - 1.63 (1H, m), 1.68 - 1.75 (2H, m), 1.75 — 1.83 (2H, m), 3.16 (2H, t), 3.46 (2H, 0. 3.63 - 3.68 (1H, m), 7.31 (1H, d), 7.79 (1H, d), 8.37 (1H, d), 8.51 (1H, d), 8.59 - 8.61 (2H, m) m/z (ESI+) (M+H)+ = 377; HPLC tR = 2.20 min. 1l using the intermediate compound (9) and a starting material (1) and the following example was prepared in a manner similar to example Y

_ \ A and :aminoester suitable from

MSmle | Example Dr. Rkm 346: | IHNMR(400.13|-[3S)-1-[5-"-

HPLC MHz, DMSO-d6) (cyclohexylcarbamo °0

R = | 1.01-142 (7H, m), | yDpyridin-2-yl]-3- mmh or 1.31 1.47-2.0 (8H, m), 2. | piperidyl] acetic acid Ly nN min 14 - 2.20 (2H, m), 2.94 (1H, 5), 3.12 (1H, s), 3.72- 3.74 (1H, m), 4.24 (2H, d), 7.12 (1H) , 8.14 (1H,d), 8.22 (1H,S), 8.49 (1H, 5) (15) Intermediate compound 6-chloro-N-cyclohexylnicotinamide 0 or 1 2

ClN©. 0 1-hydroxybenzotriazole 5 mg (© mmol) (YYA) 6-chloronicotinic acid To a solution of : triethylamine (Je Yo) dichloromethane (mmol) volatile was added at 5.47 cane 010) © g; 47.* mmol). and after (EDACHCI (001 mmol) £ followed by the addition of 11 µL (Ja 1.0) 07; mmol) and the stirring was continued for 710) cyclohexylamine minutes; Another hour has been added

NaHCO; ml) and extracted it with a solution (© +) dichloromethane and the reaction mixture was diluted using

Yava

- YAN - ml (and dried after 0) ml (and brine 0) Molar (5 ml) and p 1 HCl (0 ml) saturated: the solvent in vacuum to obtain and filter Aly MgSO, It contains : 719 mg (as a cream solid. 40+) 6-chloro-N-cyclohexylnicotinamide 'H' NMR (400.13 MHz, (W-0150) 81.12 - 1.18 (1H, m), 1.24 - 1.35 (4H, m), 1.61 (1H, d), 2.73 - 1.75 (2H, m), 1.81 - 1.82 (1H, m), 1.84 (1H, d), 3.74 - 3.78 (1H, m), 7.63 - 7.65 (1H, m), 8.22 - 8.25 (1H, m), 8.49 (1H, d), 8.81 - 8.82 (1H, m)

MS m/e (M-H) + 237 and a starting material (01) using the intermediate compound (1) and the following example was prepared in a manner similar to the example: an appropriate aminoester:

MS Example m/e 'HNMR 8 Compound A: The name

MH RCM 398; 1H NMR (400.13 2-[(3S)-1-[5-(2- VY)

HPLC | MHz, DMSO-d6) adamantylcarbamoy tR = 1.25 - 1.44 (2H, m), | Dpyridin-2-yl]-3- 1.77 1.50 (2H, d), 1.68 | piperidyljacetic acid min | (3H, d), 1.82 (8H, oo 9 lb d), 1.93 (2H, d), or 2.14 (3H, d), 2.23 - oN 2.29 (1H, m), 2.85 (2H, d) , 4.01 (1H, t), 4.27 (2H, d), 6.82 (1H, d), 7.71 (1H, d), 7.94 - 7.97 (1H, m), 8.58 (1H, d), 12.18 (1H, s) (1 (30) Intermediate compound

-YAY-

N-adamantan-2-yl-6-chloronicotinamide 0 , IAN NH

SZ

Cl N was prepared using a method similar to that used for the preparation of compound (Ye). Intermediate 'H NMR (400.13 MHz, DMSO-d) 81.52 (2H, d), 1.72 (2H, 1.78 - 1.85 (6H, m),1.98© (2H, 5), 2.11 (2H, d), 4.04 (1H, 1), 7.61 - 7.63 (1H, m), 8.21 - 8.29 (2H, m), 8.79 - 8.80 (1H, m)

MS m/e (M+H)+ 291 precursors (YY); Using the intermediate compound (1), the following example was prepared in a manner similar to the example: aminoester suitable from 0

-VAY-

MS Example m/e 'HNMR & compound' the name

MH" No. 484; 1H NMR (400.13 2-[(3S)-1-[5- f HPLC | MHz, DMSO-d6) (cyclohexylcarbam {R= |091-1.04 (3H, m) , |oyl)-6-[2-(4- 2.91 1.21-1.28 (4H, m), fluorophenyl)ethox min 1.55-1.64 (7H, m), y]pyridin-2-yl]-3- 1.82 (1H , d), 2.14 - | piperidyl]acetic 2.19 (1H, m), 2.22 - | acid oo Fae 2.28 (1H, m), 2.90 NS (> (2H, d), 3.10 (2H, 1), 3.64 (1H) , 1), 4.16 (1H, d), 4.25 (1H, d), 4.66 - 4.70 (2H, m), m 6.44 (1H, d), 7.13 - 7.18 (2H, m), 7.29 - 7.37 (3H, m), 7.99 (1H, d), 12.19 (1H, 5) (31) Intermediate compound 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy] nicotinamide

L.L

Zz cl N 0

F

1 mM; 1 7777 (intermediate 2,6-dichloro-N-cyclohexylnicotinamide stirred 0 4-fluorophenethyl alcohol mL). To this solution was added 4 (1,4-dioxane mol) in molar) in 1 (bis-sodium hexamethyldisilylamide mmol) followed by the addition of 010 mg; VO mmol). The tube was sealed and subjected to microwave heating at 10 011 ml (THF).

- YAS - 10) for two hours. The solvent was evaporated and the remainder was diluted with water (Biotage Initiator 0 Ww) M Nou ml). The combined extract was washed with Yo * solution (twice dichloromethane ml) and extracted with

Si0; filtration and evaporation. The crude product was purified on MgSO, ml) and dried on (Yr) brine: from zero to 740 to obtain acetate/isohexane g) with eluting using cane VOY (4 pounds) 6-chloro -N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide 0 + (as white solid. 'H NMR (400.13 MHz, DMSO-d) 50.99 - 1.33 (SH, m), 1.54 - 1.74 (SH, m), 3.10 (2H, (2H, m), 7.21 (1H, d), 7.35 - 7.39 (2H, 7.18 - 7.12 L (1H, m), 4.63 2H, 3.72 - 3.65 ,0 m), 7.70 (1H, d), 8.11 (1H, d) MS m/e (M+H)" 377. \ The following example was prepared by the Alles method for Example (1); using intermediate compound (FY) and an appropriate starting material: aminoester

-Yao-

MS Example m/e "HNMR 3 Compound: Name

MH" No. 432: 1H NMR (400.13 MHz, | 2-[(3S)-1-[5- YW lo 9 0

HPLC | DMSO0-d6) 0.95 (6H, d), | (cyclohexylcarbamo or tR = 1.17 - 1.44 (7H, m), 1.55 | y1)-6-(3- 1 1" ? 3.04m | - 1.68 (6H, m), 1.74 - methylbutoxy)pyrid 2 in 1.87 (5H, m), 2.12 - 2.26 |in-2-yl]-3- (2H, m), 2.77 - 2.83 (1H, | piperidyl]acetic acid m), 2.96 - 3.02 (1H, m), 3.77 ( 1H, t), 4.14 (1H, d), 4.25 (1H, d), 4.39 - 4.43 (2H, m), 6.43 (1H, d), 7.67 (1H, d), 8.00 (1H, d), 12.19 (1H, bs). Intermediate (TY) Intermediate 0 11111112 (400.13 MHz, DMSO-dg) 50.94 (6H, d), 1.17 - 1.24 (1H, m), 1.28 (2H, d), 1.36 (2H, t), 1.55 - 1.59 (1H, m), 1.63 - 1.71 (2H, m), 1.66 - 1.71 (2H, m), 1.75 - 1.83 (ZH, m), 1.85 (1H, 5), 3.77 (1H, t), 4.38 (2H, t), 7.20 (1H, d), 7.94 (1H, d), 8.09 (1H, d)

MS m/e (M+H) 325 and a starting material (YY) using intermediate compound 1 1) The following example was prepared in a manner similar to Example 0

Yava

- YA - :aminoester Suitable for

MS Example m/e 'HNMR 8 Compound The name

MH" No. 480; | IHNMR (400.13 2-[(3S)-1-[5- ay;

HPL | MHz, DMSO-d6) (cyclohexylcarbamoyl)- o 0

CtR |129(7H,4d),1.54- |6-3- og © or = 1.67 (4H, m), 1.80 - phenylpropoxy)pyridin- and a grain of 3.07 | 1.88 (4H, m), 2.04 - 2-yl]-3-piperidyl]acetic min | 2.26 (4H, m),2.78 | acid (3H, d), 2.96 (1H, d), 3.75 -3.82 (1H, m), 4.11 (1H, d), 422 (1H, d), 4.34 - 4.40 (2H, m), 6.43 (1H, d), 7.18 - 7.24 (3H, m), 7.29 - 7.32 (2H, m), 7.70 (1H, d), 8.00 (1H, d), 12.17 (1H, s) (YY) intermediate compound 6- chloro-N-cyclohexyl-2-(3-phenylpropoxy)nicotinamide i or = cl N 0 using a method identical to that used in preparing the compound (YY) and then preparing the intermediate compound (7) with the NMR intermediate (400.13 'MHz, DMSO-d) 81.23 (5H, d), 1.56 (1H, d), 1.69 (2H, d), 1.86 (2H, adv)

- VAY - d), 2.04 - 2.11 (2H, m), 2.77 (2H, t), 3.77 - 3.80 (1H, m), 4.33 (2H, t), 7.18 - 7.21 (2H, m), 7.22 - 7.24 (2H, m), 7.28 - 7.32 (2H, m), 8.02 (1H, d), 8.07 (1H, d)

MS m/e (M+H) 373. and a starting material (v ¢ ) using intermediate compound 1 1) The following example was prepared in a manner similar to the metal: aminoester suitable for © example 5 m m/e HNMR & compound: name

MH" No. 467;HP | 111 NMR (400.13 2-[(3S)-1-[5- the LCtR | MHz, DMSO-d6) 0.94 | (cyclohexylcarbam =1.67 | (2H, d) , 1.05-1.35(4H, | oil)-6-(2-pyridin- 0 0 min | m), 1.39-1.70 (7H, m), |3- mmh or 1.84 (2H, d), 2.14 - ylethoxy)pyridin- NTN Te 2.20 (1H, m), 2.22 - 2-yl]-3- 2.28 (1H, m), 2.83 piperidyljacetic 6 1 (1H, d), 3.00 (1H, d), | acid 3.14 ( 2H, 0. 3.64 (1H, t), 4.15 (1H, d), 4.25 (1H, d), 4.69 - 4.73 (2H, m), 6.44 (1H, d), 7.30 (1H, d), 7.35 - 7.38 (1H, m), 7.75 - 7.77 (1H, m), 7.98 (1H, d), 8.45 - 8.47 (1H, m), 8.54 (1H, d), 12.19 (1H, s) (78) Composite mediator

- 1m - 6-chloro-N-cyclohexyl-2-(2-pyridin-3 -ylethoxy)nicotinamide ] =

Cl N 0 -

UN

Then prepare the intermediate compound (¢ 0) using a method similar to that used for the preparation of compound (7)) Intermediate 'H NMR (400.13 MHz, DMSO-de) 51.01 - 1.05 (1H, m), 1.08 (1H, s ), 1.10 - 1.11 (1H, m), 1.14 - 1.18 (1H, m), 1.25 (1H, d), 1.53 - 1.57 (1H, m), 1.62 - 1.66 (2H, m), 1.69 - 1.74 (2H , m), 3.13 (2H, 1), 3.66 - 3.70 (1H, m), 4.65 (2H, 1), 7.21 (1H, d), 7.33 - 7.36 (1H, m), 7.73 - 7.78 (2H, m) ), 8.08 (1H, d), 8.45 - 8.46 (1H, m), 8.54 (1H, d)

MS m/e (M+H)" 360 and a starting material (V0) The following example was prepared in a manner similar to Example (1); using an intermediate compound 0:aminoester suitable for

MS m/e 1 Example No

- VAS - 376; 1H NMR (400.13 2-[(3S)-1-[5- Ya lo 0 0

HPLC | MHz, DMSO-d6) (cyclohexylcarbamo or tR = 1.31 (7H, d), 1.62 yl)-6-methoxy- YN ? 2.45 (4H, d), 1.84 (4H, d), pyridin-2-yl ]-3- min 2.19 (2H, d), 2.79 - piperidyl] acetic acid 2.84 (1H, m), 3.01 (1H, d), 3.75 - 3.78 (1H, m), 3.93 (3H, s), 4.13 ( 1H, d), 4.30 (1H, d), 6.43 (1H, d), 7.61 (1H, d), 7.99 (1H, d), 12.19 (1H, s) (Yo) intermediate 6-chloro- N-cyclohexyl-2-methoxynicotinamide 1 or

Zo

Ci N 0 \ for those used in the preparation of compound A Blea using the (v ° ) method The intermediate compound was prepared ° (TY ) intermediate 'H NMR (499.8 MHz, DMSO-d) 81.19 (1H, d), 1.27 - 1.37 (4H, m), 1.57 - 1.59 (1H, m), 1.71 (2H, t), 1.83 (2H, d), 3.77 (1H, d), 3.97 GH, d), 7.19 - 7.21 (1H, m), 7.97 (1H, d), 8.05 - 8.07 (1H, m)

MS m/e (M+H)" 9 Ve The following example was prepared in a manner similar to example (1); using intermediate compound (7?) and a suitable aminoester starting material:

MS Example m/e "HNMR 8 Compound Name

MH" No. Ah

- 1. = 404; 1H NMR (400.13 | 2-[(3S)-1-[5- Yee lo 0

HPLC | MHz, DMSO-d6) | (cyclohexylcarbamoyl)-oe tR= 1.02 (3H, t), 1.19 - | 6-propoxy-pyridin-2- yon 5 2.79 1.44 (7H, m), 1.56 | yl]-3-piperidyl]acetic min (1H, d), 1.66 (3H, | acid d), 1.81 (6H, d), 2.13-2.26 (2H, m), 2.77 - 2.83 (1H, m), 2.99 (1H, t), 3.77 (1H, t), 4.13 (1H, d), 4.23 - 4.35 (3H, m), 6.43 (1H, d), 7.70 (1H, d), 8.00 (1H, d), 12.17 (1H, s) intermediate (7?) 6-chloro-N-cyclohexyl-2-propoxynicotinamide $e oc lL

Cl ' N b CH, using a method similar to that used to prepare the compound (v 1 ) and then prepare the intermediate (¥ 1 ) intermediate 1H NMR (400.13 MHz, DMS0-d6) 6 1.00 3H , t), 1.17 - 1.39 (5H, m), 1.54 - 1.57 (1H, m), 1.67 - 1.70 (2H, m), 1.75 - 1.81 (2H, m), 1.84 (2H, 5), 3.76 - 3.79 (1H, m), 4.30 (2H, 1), 7.20 (1H, d), 7.97 (1H, d), 8.09 (1H, d)

MS w/e (M+H)" 7 and a starting material (VV) The following example was prepared in a manner similar to Example (1); using the intermediate compound

- 181 -: Aminoester is suitable for

MS Example m/e 'HNMR § compound . name

MH" No. 429: 1H NMR (400.13 2-[(3S)-1-[5- vey |. 0 0

HPLC | MHz DMSO-d) (cyclohexylcarbamoyl)- or tR= i he 8 0 21 d), 6-(1-piperidyl)pyridin- stink no 1.82 131 (1H, 5), 1.34 2-yl]-3-piperidyljacetic min (1H, s), 1.42 (1H, d), | acid 1.54 (2H, d), 1.63 - 1.64 (5H, m), 1.71 (2H, d), 1.81 (2H, d), 1.86 (2H, s), 1.90 (1H, 5), 2.12 - 2.17 (1H , m), 2.20 - 2.26 (1H, m), 2.72 - 2.97 (2H, m), 3.01 - 3.03 (4H, m), 3.71 (1H, 1), 4.15 (1H, d), 4.22 (1H, d) ), 6.44 (1H, d), 7.83 (1H, d), 8.69 (1H, d), 12.16 (1H, 5) (TY) Intermediate compound 6-chloro-N-cyclohexyl-2-piperidin-1 - ylnicotinamide

I I$ ~~ NH

I

Cl N a mmol) 1 mg; YY 9 2,6-dichloro-N-cyclohexylnicotinamide sealed 0.9 mm; YE ©) potassium carbonate 9 mm 0101 mol) piperidine (5 M for 1 hour. 151 ml) in a microwave tube heated (initiator) at £ (butyronitrile mol) at

Yavi

- yay - dichloromethane (ml) and extracted it using Y0) and the reaction mixture was diluted using ads water. filtered and evaporated MgSO04 ml). The combined extracts were dried on Yo * (twice ethyl acetate/isohexane g) with eluting using 11(2) Purification of the crude product on: and obtaining Ly 0 from zero to as a white powder. (% YY mg; 001( 6-chloro-2 (piperidine)-N-cyclohexylnicotinamide © 1H NMR (400.13 MHz, DMSO-d6) 81.21 (5H, d), 1.56 - 1.60 (7H, m), 1.69 - 1.73 (2H, m), 1.83 (2H, d), 3.29 - 3.30 (4H, m), 3.65 - 3.68 (1H, m), 6.80 (1H, d), 7.55 (1H, , 8.31 L (1H, d)

MS m/e (M+H)+ 322 and subject (YA). The following example was prepared in a manner similar to that of Example (1); Using the intermediate compound 0:aminoester as an appropriate prefix for

MS m/e 1 Example #498: 11110016 (400.13 MHz, | 2-[(3S)-1-[6-[2- ro

HPLC | DMSO-d6) L12 (IH, d), | (4- p__ 1.25 (5H, s), 1.39 (1H, d), wave tR = 1.45 (1H.d), 1.58 - 1.87 chlorophenyl)eth or 3.16 (8H, m), 2.12 - 2.17 (1H, | Ylamino]-5- EN min m), 2.20 - 2.26 (1H, m), (cyclohexylcarba 2.74 (1H, d), 2.79 - 2.86 | moyl)pyridin-2- (2H, m), 2.86 (1H,m), y]-3: 3.54 2H, @),3.64 (1H, 9), | 7000 or 0 420 2H. d), 5.95 rings d), | Piperidyljacetic 7.25 (2H, d), 7.34 (2H, d), | acid 7.59 (1H, d), 7.76 (1H, t), 12.15 (1H,bs). (TA) intermediate compound

- 1,7 - 6-chloro-2-{[2-(4-chlorophenyl)ethyl]amino} -N-cyclohexylnicotinamide

LO

AZ

0 N NH

Cl using a method similar to that used for the preparation of the compound (v A ) The intermediate compound (YY) intermediate 'H NMR (400.13 MHz, 1450-00 51.09 - 1.29 (SH, m), 1.58 - 1.78) was prepared. (5H, m), 2.85 (2H, 1), 3.57 (2H, , lv 3.68 (1H, d), 6.62 (1H, d), 7.28 (2H, d), 7.35 (2H, d), 7.94 (1H, d), 8.25 (1H, d), 8.62 (1H, t)

MS m/e(M+H) 393. prefix sala (V4 ) and the following example was prepared in a manner similar to example ( )( » using the intermediate compound: aminoester suitable for > 00

MS m/e "HNMR 8 Compound Example No. Name

MH’

- Vat - 509; 1H NMR (400.13 2-[(3S)-1-[5- y gv 9 0

HPLC | MHz, DMSO-d6) (cyclohexylcarbamo N° or (R= |1.09-130(7H,m), |yl)-6-3-(4-r Wo 276 1.45 (1H, d), 1.38- fluorophenyl ) min |1-80 (10H, m), 2.11 - pyrrolidin-1- 2.34 3H, m), 2.64 - | yllpyridin-2-y1]-3- 2.73 (1H, m), 2.89 piperidyljacetic acid : (1H, d), 3.52 (2H, d), 3.56 (1H, d), 3.61 (1H, d), 3.69 (1H) , t), 4.18 (2H, d), 6.05 (1H, d),7.12-7.17 (2H, m), 7.33 (3H, m), 7.79 (1H, d) (74) Intermediate 6-chloro -N-cyclohexyl-2-[3-(4-fluorophenyl)pyrrolidin-1 -yl]nicotinamide 0 0 4 cl N N

F

Then, the intermediate compound (9 0) was prepared using a method similar to that used for the preparation of compound 8 (TV) intermediate 'H NMR (400.13 MHz, DMSO-d) 81.19 (5H, d), 1.66 (5H, d), 1 96 -2.02 (1H, m), 2.26 - 2.28 (1H, m), 3.39 (1H, d), 3.44 (1H, d), 3.51 - 3.55 (2H, m), 3.63 - 3.66 (1H, m) , 3.71 -3.75 (1H, m), 6.65 (1H, d), 7.14 - 7.19 (2H, m), 7.32 - 7.36 (2H, m), 7.46 (1H, d), 8.31 (1H, d) 01

MS m/e (M+H)" 402. The following example was prepared in a manner similar to example ( \ ) ' using intermediate compound (2) and a suitable starting material: aminoester J

- 1 and 0 -

MS Example m/e "HNMR 8 Compound - Name

MH" No. 477, 1H NMR (400.13 2-[(3S)-1-[5- Yet | for 9 mah

HPLC | MHz, DMSO-d6) (cyclohexylcarba or tR= 1.01 -1.11 3H, m), | moyl)-6-(3,4- 1 “1 2.85 1.20 - 1.30 (3H, m), dihydro-1H- min 1.32-1.67 (4H, m), isoquinolin-2- 1.68-1.93 (4H, m), yDpyridin-2-yl]- 2.12-2.25 (2H, m), 3-piperidyl]acetic 271-277 (1H, m), |acid 2.94-3.0 (3H, m), 3.49 (2H, t), 3.68 ( 1H, t), 4.10 (1H, d), 4.25 (1H, d), 4.30 (2H, s), 6.36 (1H, d), 7.15 (5H, d), 7.71 (1H, d), 8.36 (1H , d), 12.11(1H, bs) (£1) Intermediate compound 6-chloro-N-cyclohexyl-2-(3,4-dihydroi soquinolin-2(1H)-yDnicotinamide iL 7 2

Ci N N intermediate (+¢) was prepared using a method identical to that used for the preparation of compound 0 (YY) intermediate 'H NMR (400.13 MHz, DMSO-d) 61.05 - 1.40 (SH, m), 1.53 - 1.61 (1H, m), 1.71 (1H, d), 1.68 - 1.73 (1H, m), 1.85 (2H, d),2.90 (2H, m) 3.63 (2H, 1), 3.68 - 3.76 (1H, m) ), 4.47

- 1,5 - 4.57 (2H, m), 6.82 (1H, 1), 7.15 - 7.19 (4H, m), 7.56 (1H, d), 8.35 (1H, d)

MS m/e (M+H)+ 370 The following example is prepared in a manner similar to Example 0 ; Using the intermediate compound (8) and a suitable starting material: aminoester

MS m/e 1 Example #505: 1H NMR (400.13 MHz, | 2-])35(-1-]5- 0

HPLC | DMSO-d6) 1.03-1.28 (cyclohexylcarbamoyl)- Veo | Talmmah 0 _ | (7TH, m), -1 29-1.51 (2H, | 6-(4-phenylpiperazin-1- b NN m), 1.51-1.68 (3H, m), | yDpyridin-2-yl]-3- MO 3.28 | 1.68-1.84 (4H, m), 2.23 - | piperidyljacetic acid min | 2.37 3H, m), 2.76 - 2.82 (1H, m), 2.94 - 3.01 (1H, m), 3.24 (1H, s), 3.25 (6H, m), 3.72 - 3.75 (1H, m), 4.14 (1H, d), 4.23 (1H, d), 6.45 (1H, d), 6.81 (1H, t), 6.99 (2H, d) , 7.22 - 7.26 (2H, m), 7.80 (1H, d), 8.43 (IH, d) (£1) Intermediate compound 6-chloro-N-cyclohexyl-2-(4-phenylpiperazin-1 -yDnicotinamide 0 I$ foe: = cl N N ey using a method identical to that used to prepare compound ( 1 ) and then prepare intermediate compound 0 (YY) intermediate 'H NMR (400.13 MHz, DMSO-d) 81.15 - 1.33 ( SH, m), 1.51-1.61 (1H, m), 1.68-1.77

Yyiva

- 17 - (2H, m), 1.80-1.91 (2H, m), 3.22 (1H, s), 3.24 (3H, 0, 3.49 (4H, 0. 3.71 (1H, 1), 6.80 (1H, t) , 6.88 (1H, d), 6.96 - 6.99 (2H, m), 7.22 - 7.26 (2H, m), 7.61 (1H, d), 8.32 (1H, d)

MS m/e (M+H)" 399. and a starting material (VV); using the intermediate compound (1) and the following example was prepared in a manner similar to the example: an aminoester suitable for © example 552; 1H NMR 2-[(3S)-1-[5- yn a

HPLC R | (400.13 MHz, | (cyclohexylcarbamoyl)- N° Ie aa = 2.53min 1 DMSO-d6) 6-[4-(4- NTN iQ . 1.05- 1.43 (8H, | fluorobenzoyl)piperazin-m), 1.55-1.90 1 -yl]pyridin-2-yl]-3- (8H, m), 2.11 - | piperidyl acetic acid ; 2.25 (2H, m), 2.45 - 2.47 (1H, m), 2.71 - 2.77 (1H, m), 2.94 (1H, d), 3.15 (4H, s), 3.69 - 3.74 (4H, m), 4.11 (1H, d), 4.24 (1H, d), 6.41 (1H, d), 7.29 (2H, t), 7.51-7.55 (2H, m), 7.72 (1H, d), 8.25 (1H, d)

Yyiva

- 18 (47) Intermediate 6-chloro-N-cyclohexyl-2- [4-(4-fluorobenzoyl)piperazin-1 -yl]nicotinamide iO)

CC

A cd” N NY ho

F aS yall and then prepare the intermediate compound ( f ) using a method identical to that used for the preparation of (YY) intermediate oo 'H NMR (400.13 MHz, DMSO-d) 81.02-1.35 (6H, m), 1.58 (1H , d), 1.71 (2H, d), 1.83 (2H, d), 3.39 (5H, s), 3.64 - 3.69 (3H, m), 6.90 (1H, d), 7.27 - 7.32 (2H, m), 7.51 - 7.54 (2H, m), 7.61 (1H, d), 8.36 (1H, d)

MS m/e (M+H)" 445. Using intermediate compound 9 ¢ (and starting material 1 1 ) the following example was prepared in a manner similar to example 0: an aminoester suitable for example ME se "HNMR 8 Name 1 Compound RCM 472: 1H NMR (400.13 MHz, | 2-[(3S)-1-[6-(4- 1 ° 0))

HPLC tR DMSO-d6) 1.02-1.48 acetylpiperazin-1-yl)- O° or 21 99min | (7H m), 1.51-1.98 (8H, 5-B Lv in Sun 77min m), 2.03 3H, s), 2.18 (cyclohexylcarbamoyl) sprayed_A (2H, d), 2.70 - 2.76 (1H , pyridin-2-yl]-3- T m), 2.94 (1H, t), 3.06 piperidyl]acetic acid (2H, 1), 3.12 (2H, 1), 3.54 (4H, d), 3.70 - 3.72 ( 1H, m), 4.12 (1H, d), 4.25 (1H, d), 6.41 (1H, d), 7.73 (1H, d), 8.29 (1H, d), 11.98 (1H, vbs).

- 1,8 (£7) the intermediate compound 2-(4-acetylpiperazin-1-yl)-6-chloro-N-cyclohexylnicotinamide

LJ

0 1 = cl N NY Mann CH, then prepare the intermediate 9 ¢ ( using a similar method as that used to prepare the intermediate (TY) 0 'H NMR (400.13 MHz, DMSO-d¢) 51.21 ( 5H, d), 1.59 (1H, d), 1.72 (2H, d), 1.84 (2H, d), 2.01 (3H, s), 3.36 - 3.39 (4H, m), 3.52 (4H, ,le 3.66 - 3.70 (1H, m), 6.88 (1H, d), 7.60 (1H, d), 8.36 (1H, d)

MS m/e (M+H)" 365. Using an intermediate compound (¢¢) and a starting material ' (1) The following example was prepared in a manner similar to Example 0:2101006516: suitable for

MS m/e 1 Example MH" HNMR 8 Compound Name #522: 1H NMR )40013 | 2-[3S)-1-[5-9

HPLC tR | MHz, DMSO-d6) | (cyclohexylcarbamoyl)-6-VEA mh ol d 34min | 1.07-1.50 (11H, m), | ) 4- wo 1.57 - 1.86 (8H, m), | ethylsulfonylpiperazin-1-m 2.13 - 2.25 (2H, m), | yD)pyridin-2-yl]-3- 2.67 - 2.74 (1H, m), | piperidyl]acetic acid 294 (1H, d), 3.12 (2H, q), 3.28 (4H, d), 329 (4Hd), 4.10 (1H, d), 4.29 (1H, d), 639 (1H, d) , 7.69 (1H, d), 8.14 (1H, d), 12.19 (1H, s)

f. The intermediate compound (££) 6-chloro-N-cyclohexyl-2-[4-(ethylsulfonyl)piperazin-1-yl] nicotinamide l 0 oC = Cl N N Tl 20 behind 0 The intermediate (¢¢) was prepared using a method identical to that used for the preparation of the oo intermediate (YVv). 1H NMR (400.13 MHz, DMSO-d) 8 1.11 - 1.35 (8H, m), 1.54 - 1.62 (1H, m), 1.71 (2H, (4H, 1), 3.39 - 3.42 (4H, m), 3.63 - 3.70 (1H, m), 6.90 3.25 ,l d), 1.83 (2H, s), 3.11 (2H, (1H, d), 7.60 (1H, d), 8.36 (1H, d) MS m/e (M+H)" 415 0 The following example was prepared by idles for Example 1) using an intermediate compound (£0) and a suitable starting material for :aminoester Example: MS m/e 1H NMR (400.13 2-[(3S)-1-[6-[4 - y 44 ;570 HPLC tR | MHz, DMSO-d6) 0.74 | (benzenesulfonyl)p = 2.66min | - 1.42 (7TH, m), 1.5-iperazin-1-yl}-5- 0 . Po mH (7H, m), 1.79- (cyclohexylcarbam 1.71 1 N W b (2H, m), 2.13 - oyl)pyridin-2-yl]- 1.90 (2H, m), 2.68 - 3-piperidyl]acetic 0 2.24 (1H, m), 2.99 acid 2.74 (4H, s), 3.13 (4H, t), (1H, m), 3.59 - 3.52 (1H, d), 4.28 4.06 (1H, d), 6.43 (1H, s), (3H, m), 7.73 - 7.68 (2H, m), 7.78 - 7.76 (1H, s), 8.16 (1H, 7.80 d), 12.22 (1H, s)

_ Y 0 \ — (£0) Intermediate compound 6-chloro-N-cyclohexyl-2- [4-(phenylsulfonyl)piperazin-1-yl] nicotinamide we oc

Z cl” ON N

TL 0 1 "- 0 for those used in the preparation of the Atlee compound using the (to) method, and then the preparation of the intermediate compound. (v) the intermediate (no) o

MS m/e (M-+H)" 464. Using the intermediate compound (5) and a starting material (1), the following example was prepared in a manner similar to the example: aminoester suitable for 1080/61 Example No. 564 ;HP | 1H NMR (400.13 2-[(3S)-1-[5- youl, 9 for 100.MHz, DMSO-d6) |(cyclohexylcarbamoyl)-° mohr = 2.83m | 1.08-1.49 (7H, m), | 6-(4- Von i .in 1.53 - 1.87 (8H, m), | phenylmethoxycarbonylp Y 2.16 - 2.22 (2H, m), | piperazin-1-yl)pyridin-2 - 2.72 - 2.78 (1H, m), |yl]-3-piperidyl]acetic 2.90-3.00 (1H, m), | acid 3.11 (4H, 1), 3.55 (4H, s), 3.71(1H, s) , 4.08 (1H, d), 4.24 (1H, d), 5.12 (2H, s), 6.41 (1H, d), 7.33 - 7.39 (5H, m), 7.75 (1H, d), 8.25 (1H, d) ), 12.12 (1H, bs) (£1) intermediate compound 11 A

— Y 0 Y — benzyl 4-[6-chloro-3 -(cyclohexylcarbamoyl)pyridin-2-yl] piperazine-1-carboxylate i

Or: oN NY mana 4 Then prepare intermediate compound 1) using a method identical to that used for preparing intermediate compound (YY) 1H NMR (400.13 MHz, DMSO-d¢) 5 1.05-1.35 (SH, m), 1.58 (1H, d), 1.7 1 (2H, d), 1.83 (2H, d), 3.4-3.48(4H, m), 3.50 (4H, 5), 3.69 (1H, d), 5.11 ( 2H, s), 6.88 (1H, d), 7.32 - 7.39 (5H, m), 7.60 (1H, d), 8.35 (1H, d)

MS m/e (M+H)" 7 and starting material (£V);" Using the intermediate compound (1), the following example was prepared in a manner similar to the example: aminoester J suitable 0 i.

— a. Example MS compound: name & m/e 'HNMR No. MH' of 9,| 1H NMR (400.13 2-[(35)-1-[5- yoy 403 HPLC: | MHz, DMSO-d6) 0.90 | (cyclohexylcarbamoyl)- or tR = (3H, t), 1.27-1.30 (7H, | 6-propylamino-pyridin- NTONNTONn m), 1.61-1.74 (10H, 2-yl]-3-piperidyl]acetic 2.71 min m), 2.10 - 2.24 (2H, acid m), 2.90-2.80 (2H, m), (2H, 1), 3.67 (1H, 3.27 bs), 4.19-4.24 (2H, m), 5.92 (1H, d), 7.58 (1H, d), 7.75 (1H, 4d), (1H, bs) , 12.12 8.76 (1H, bs) intermediate (£7) 6-chloro-N-cyclohexyl-2-(propylamino)nicotinamide. or 1 CH 2 ao ONT SNH NTE 0 The intermediate (£V) was prepared using a similar method as that used for the preparation of the intermediate (TV) 'H NMR (400.13 MHz, DMSO-d¢) 50.91 (3H, 0.1.21-35 (SH, m), 1.57 (3H, d), 1.75 (4H, d), 3.27 - 3.31 (2H, m), 3.70 (1H, m), 6.59 (1H, d), 7.95 (1H, d), 8.26 (1H, d), 8.68 (1H, 1) MS (M+H)= 1 11 01 296

— no to . The following example was prepared in a manner similar to example (”)1 using the intermediate compound (£A) and a suitable starting material for :aminoester Example compound name 6p | MSmle MH X No. 1H NMR (400.13 | 2-[(3S)-1-[5- yoy ;465 HPLC | MHz, DMSO-d6) (cyclohexylcarbamoyl)-6- 0 ° ( 7H, (phenethylamino)pyridin- Oy © or 1.48 - 1.08 0 a b m), 1.58 - 1.88 2-yl]-3-piperidyljacetic (8H, m), 2.11 - acid ge 28 ( 1H, m), 2.21 2.17 (1H, m), 2.26- (4H, d), 3.55 2.77 (2H, s), 3.65 (1H, (2H, d), 4.24 , ) 5 (1H, d), 7.17 - 5.95 (5H, m), 7.59 7.31 (1H, 5), 7.76 (1H, d), 8.81 (1H, s), (1H , s) 12.16 intermediate compound (£4) 6-choro-N-cyclohexyl-2-[(2-phenylethyl)amino] nicotinamide oC 1 Z Cl N NH | then prepare intermediate compound ) ¢A (using the Ales method for that used to prepare the intermediate compound (YY).

—_ Y m — 'H NMR (400.13 MHz, DMSO-dg) 81.24 - 1.30 (5H, m), 1.75 (5H, d), 2.85 (2H, 1), 3.55 - 3.60 (2H, m) , 3.60-3.71 (1H,m), 6.62 (1H, d), 7.21 - 7.32 (5H, m), 7.94 (1H, d), 8.25 (1H, d), 8.65 (1H, s)

MS (M+H)= 358 prefix sala (£9 ) The following example is prepared in a manner similar to example (1); Using the intermediate compound: aminoester suitable for

MS m/e 1 Example CUM 479; | 11111118 (400.13 | 2-[(3S)-1-[5- Yor | o 9 for HPLC | MHz, DMSO-d6) | (cyclohexylcarbamoyl)- or tR 2 1.19 (7H, d), 1.61 6-(methyl-phenethyl- 1 " 2.12 | (8H, d), 1.81 - 1.89 | amino)pyridin-2-yl]-3- min | ( 2H, m), 2.12 - piperidyl]acetic acid 2.26 (1H, m), 2.70 -2.75 (1H, m), 2.82 (4H, d), 2.93 (1H, t), 3.47 - 3.56 (2H, m), 3.62 - 3.66 (1H, m), 4.20 (2H, d), 6.26 (1H, d), 7.19 3H, ,(7.27 2H, d), 7.54 (1H, d), 8.00 (1H, d) ), 12.15 (1H, bs).(£9) Intermediate 6-chloro-N-cyclohexyl-2-[methyl(2-phenylethyl)amino] nicotinamide ge 2 7 cl N N

CH, 11 J

- 7.91 - The intermediate compound (£4) was prepared using a method identical to that used for the preparation of the compound. (YY) Intermediate 'H NMR (400.13 MHz, DMSO-d) 1.10-1.33 H (5H, m ), 1.50-1.80 (5H, m), 2.83 (2H, 1), 2.94 (3H, 5), 3.57 (1H, d), 3.59 (1H, d), 3.64 - 3.67 (1H, m), 6.69 ( 1H, d), 7.19 - 7.22 (1Hpm), 7.25 - 7.32 (4H, m), 7.46 (1H, d), 8.32 (1H, d)

MS (M+H)=372 The following example was prepared in a manner similar to example (0) using intermediate compound (0) and a starting material: aminoester suitable for

MS m/e : Ex. 417: 1H NMR (400.13 2-[(3S)-1-[5- ye

HPLC tR | MHz, DMSO-d6) 0.82 (cyclohexylcarbamoyl)- o =1.64 (3H, t), 1.08 - 1.71 6-(methyl-propyl-rg Pas min (13H, m), 1.81 (4H, d), | amino )pyridin-2-yl]-3-b LA 2.10-2.22 (2H, m), piperidyl]acetic acid 2.64 -2.71 (1H, m), 2.76 (3H, 5), 2.86 (1H, d), 3.14 - 3.25 (2H, m), 3.63 - 3.68 (1H, m), 4.11 (1H, d), 4.20 (1H, d), 6.18 (1H, d), 7.49 (1H, d), 8.22 (1H, d), 12.16 (1H, 5) (0+) Intermediate 0 6-chloro-N-cyclohexyl-2-[methyl(propyl)amino] nicotinamide or 1 2 oN

CH, HC

_Y. 7 — Intermediate compound (0) was prepared using a method identical to that used for the preparation of compound (YV) Intermediate 'H NMR (400.13 MHz, DMSO-d) 50.41 (3H, t), 1.10 - 1.34 (SH , m), 1.48-1.60 (3H, m), 1.69 - 1.73 (2H, m), 1.81 (2H, d), 2.89 (3H, s), 3.30-3.40 (2H, m), 3.63 - 3.67 (1H , m), 6.64 (1H, d), 7.42 (1H, d), 8.32 (1H, d)

MS (M+H)=310 The following example is prepared in a manner similar to example (1); Using the intermediate compound (0) and a suitable starting material: aminoester

MS m/e Example No. 415; 1H NMR (400.13 2-[(3S)-1-[5-yoo

HPLC | MHz, DMSO-d6) (cyclohexylcarbam oo 1 0 {R= 1.47-1.91 (19H, m), |oil)-6-pyrrolidin-1- or 185 214-221 (2H, m), | yl-pyridin-2-yl]-3- 0D min 2.64 (1H, d), 2.86 piperidyl]acetic (1H, s), 3.48 (4H, s), | acid 3.68 (1H, m), 4.09 (1H, d), 4.19 (1H, d), 6.00 (1H, d), 7.29 (1H, d), 7.81 (1H, d), 12.16 (1H, bs) ( 21) Intermediate compound 0 6-chloro-N-cyclohexyl-2-pyrrolidin-1-ylnicotinamide

L.L

= any

_ Y 0 A — intermediate compound ( ) 0) was prepared using a similar method as that used for preparation of intermediate compound (YY) 'H NMR (400.13 MHz, DMSO-d) §1.00-1.35 (6H, m) 1.50 - 1.71 (4H, m), 1 .80 - 1.87 (6H, m), 3.33 - 3.37 (2H, m), 3.64 - 3.67 (1H, m), 6.60 (1H, d), 7.41 (1H, d) ), 8.28 (1H, d)

MS (M+H) = 308°. The following example was prepared in a manner similar to Example (1); Using the intermediate compound (0) and a suitable starting material: aminoester

MS Example m/e "HNMR 8 Compound - Name

MH" No. 431; 111 aaa ) 53 2-](35(-1-]5- you |, 0 0

HPLC 1 MHz, DMSO-d6) (cyclohexylcarbamoyl)-° or tR= |1.10-1.48 (7H, m), | 6-morpholin-4-yl-yo i! 2.24 |1.58-1.73 (4H, m), | pyridin-2-yl]-3- min 1.75-1.92 (4H, m), piperidyljacetic acid 2.12 - 2.26 (2H, m), 2.73 - 2.79 (1H, m), 2.97 (1H, d), 3.09 (4H, 1), 3.68 - 3.73 (5H, m), 4.12 (1H, d), 4.24 (1H, d), 6.41 (1H, d), 7.75 (1H, d), 8.33 (1H, d), 12.10 (1H , s) (27) Intermediate compound 6-chloro-N-cyclohexyl-2-morpholin-4-ylnicotinamide

Ll = ct” T NY What Yyavia

- 7.8 Using a method similar to that used for the preparation of compound ( oy ) intermediate compound (YY) intermediate 'H NMR (400.13 MHz, DMSO-d¢) 1.02-1.33 H (5H, m) was prepared ), 1.52-1.65 (1H, d), 1.70-1.80 (2H, m), 1.81-1.90 (2H, m), 3.30-3.40 (4H, m), 3.68-3.72 (5H, m), 6.88 (1H , d), 7.59 (1Hgd), 8.30 (1H, d)

MS (M+H)= 324. l using intermediate compound 90 ° (and starting material 1) and then preparing the following example in a manner similar to the example: an aminoester suitable for

MS m/e : Example #417: IH NMR (400.13 | 2-[(3S)-1-[5- yov 0 111.03 MHz, DMSO-d6) | (cyclohexyl-methyl- ~° a =2.66min | 0.83 - 0.93 (3H, t), | carbamoyl)-6- " a 1.04 - 1.27 (4H, | propylamino-pyridin- 5 m), 1.35-1.74 (9H, | 2-yl]-3- m), 1.74 - 1.91 | piperidyl]acetic acid (4H, m), 2.11 - 2.24 (2H, m), 2.62 - 2.70 (1H, m), 2.79 (3H, s), 2.88 (1H, m), 3.24-3.39 (RH, m), 3.82 - 3.88 (1H, m), 4.14 (1H, d), 4.21 (1H, d), 591 (1H, 4d), 6.51 (1H, t), 7.17 (1H, d), 12.10 (1H, bs).

- 11 — (57) Intermediate 6-chloro-N-cyclohexyl-N-methyl-2-(propylamino)nicotinamide 0 ps oe

ClNS

CH, using a method similar to that used for the preparation of compound (oY) intermediate compound (YV) intermediate 0 m/z (EI+) -310: HPLC tg = 2.93 min. The following example was prepared in a manner similar to example (1); Using the intermediate compound (£°) and a suitable aminoester starting material:

MS m/e Example RM 431: 1H NMR (500.13 | 2-[(3S)-1-[5- oA

HPLC tR | MHz, DMSO-d6) | (cyclohexyl-methyl-meh 8 0 =2.47min | 0.86 (3H, 0.11 - | carbamoyl)-6- rock 1.33 (4H, m), 1.47 | (methyl-propyl- ( “ 3 - 1.71 (10H, m), amino)pyridin-2-yl]- 1.78 (2H, d), 1.84 | 3-piperidyl]acetic - 1.88 (1H, m), acid 1.92 - 1.97 (1H, m), 2.14 - 2.24 (2H, m), 2.75 (2H, d), 2.77 3H, s), 2.87 (3H, 5), 2.95 (2H, m), 4.02 (1H, d),4.11-4.15 (1H, m), 6.04 (1H, d), 7.09 (1H, d), 11.85 (1H, vbs).

(54) Intermediate Compound 6-chloro-N-cyclohexyl-N-methyl-2- [methyl(propyl)amino]nicotinamide

L.L

Ny

CiN§

CH,

GS yall using a method similar to that used for the preparation of ( o ¢ ) intermediate compound (YY) intermediate oo m/z (EI+) (M+H)+ = 324; HPLC t = 2.90 min. ; Using the intermediate compound (00) and a starting material (1), the following example was prepared in a manner similar to the example: aminoester J suitable MS Example m/e "HNMR 8" Compound Name

MH" No. 360; | 1H NMR (400.13 2-[(3S)-1-[5- y od 9 for HPLC | MHz, DMSO-d6) (cyclohexylcarbamoyl)- nd oe tR = 11.20) 7H,d), 1.71 6-methyl-pyridin-2-yl]- No 1.18 | (811, d),2.10-2.16 | 3-piperidyllacetic acid min | (1H, m), 2.22 - 2.27 (1H) , m), 2.39 (3H, 5), 2.65 - 2.71 (1H, m), 2.87 (1H, d), 3.66 - 3.69 (1H, m), 4.18 - 4.23 (2H, m), 6.59 (1H, d ), 7.47 (1H, d), 7.87 (1H, s), 12.16 (1H, s) os

101 - - Intermediate compound (00) 6-chloro-N-cyclohexyl-2-methylnicotinamide or 7 A cI” NT CH, a solution of 0 (2-methyl-6) acid was stirred -chloronicotinic mg; 015 mmol) 0.57 (aaa 0 ( 1-hydroxybenzotriazole s 0 mmol) in (J Yo) dichloromethane then triethylamine (07 μl 4.07 mmol) and 0/20 (0) were added. (Yo)cana mmol) and stirred for ∼ minutes, then 0176 mM (cyclohexylamine) (cyclohexylamine) was added and the reaction mixture was stirred for another 17 hours at room temperature. The reaction mixture was diluted with YO) dichloromethane ml), washed with NaHCO; saturated, 1 0 M HCI water, brine, dried on 148507, filtered, and evaporated the solvent evaporated to obtain: 06) 6-chloro-2-methyl- N-cyclohexylnicotinamide advent VY 7 (as brown powder Js for resulting gray. (5H, d), 1.58 (1H, s), 1.70 - 1.74 (2H, m), 1.82 51.23 and 01150-0 ' H NMR (400.13 MHz, 1.85(2H, m), 2.47 3H, s), 3.72 (1H, 1), 7.39 (1H, d), 7.73 (1H, d), 8.37 (1H, d) - MS m/e M+H)+253

- 1017 - using the intermediate compound (07) and a starting material (1) Jad; the following example was prepared in a similar way: an aminoester suitable for

MS m/e 'HNMR & compound name number example

MH" 412; 1H NMR (400.13 2-[(3S)-1-[5-(1- TH)

HPLC | MHz, DMSO-d6) adamantylcarba 0 ¢ > {R= |1.18-128 (1H, m), |moyl)-6- °° or 1.50 | 1.35 - 1.45 (111, m), | methyl-pyridin- B N min 1.64 (TH, s), 1.80 - 2-yl]-3- 1.86 (2H, m), 2.02 piperidyl]acetic (9H, 5), 2.10-2.16 acid (1H, m) ), 2.21 - 2.27 (1H, m), 2.37 (3H, s), 2.64 -2.69 (1H, m), 2.83 - 2.89 (1H, m), 4.16 -4.22 (2H, m), 6.57 (1H, d ), 7.41 (1H, d), 7.45 (1H, s), 12.16 (1H, s) (21) intermediate compound

N-adamantan- 1-yl-6-chloro-2-methylnicotinamide 0 | ) or 7 2 cl” SN” and e Using a method identical to that used for the preparation of the compound ( eo ) the intermediate compound (TY) intermediate 'H NMR (400.13 MHz, DMSO-dg) 51.65 ( 6H, s), 2.04 (9H, s), 2.47 (3H, d), 7.36 (1H, z

MS m/e (M+H)+ 305 01 The following example has been prepared in a manner similar to Example (1); Using intermediate compound (97) and starting material

- 1 - : aminoester J Suitable MS Example m/e "HNMR 3 Compound: Name:

MH" No. 412: | IHNMR (400.13 2-[(3S)-1-[5-(2- 1)

HPLC | MHz, DMSO-d6) 1.23 adamantylcarbamoyl)- 0 (R= |(1H1),140(1Ht), | 6-methyl-pyridin-2- °° oc 1.52 1.50 (2H, d), 1.63 - yl]-3 -piperidyl]acetic by nN min 1.67 (1H, m), 1.70 (2H, | acid s), 1.82 (8H, d), 1.92 (24, 5), 2.06 (2H, d), 2.11-2.28 ( 2H, m), 2.40 (3H, 5), 2.66 - 2.71 (1H, m), 2.88 (1H, d), 3.98 (1H, 1), 4.21 (2H, d), 6.60 (1H, 0 7.48 (1H) , d), 7.88 (1H, d), 12.18 (1H,bs) (0) intermediate compound

N-adamantan-2-yl-6-chloro-2-methylnicotinamide 0 )

C.L.

A ci” ONT TCHj. using a method similar to that used to prepare the compound ov ) and then prepare the intermediate (00) Intermediate 'H NMR (400.13 MHz, DMSO-d¢) 61.52 (2H, d), 1.71 (2H, 5) , 1.78 - 1.82 (5H, m), 1.85 (1H, s), 1.94 (2H, s), 2.03 (2H, d), 2.47 (3H, 5), 4.04 (1H, d), 7.38 - 7.40 (1H , m), 7.73 (1H, d), 8.39 (1H, d) 01

MS m/e (M+H)+305 L using intermediate compound 79 1 (and starting material 1) and the following example was prepared in a manner similar to the example

Yyiva

— Y \ o —: aminoester J suitable for example compound) noun 18 A No. 454; 1H NMR (400.13 | 2-[(3S)-1-[5-(2-yy)

HPLC tR | MHz, DMSO-dé6) adamantylcarbamoyl)-6- -2 08min | 0.87 (3H, 1), 1.24 | butyl-pyridin-2-y1]-3- Mb A AP - 1.33 (3H, m), piperidyl]acetic acid 1.37 - 1.52 3H, m), 1.57 - 1.66 (3H, m), 1.71 (2H, s), 1.79 (6H, d), 1.85 (2H, s), 1.93 (2H, 5), 2.05 -2.27 (4H, m), 2.68 - 2.76 (3H, m), 2.90 (1H, d ), 3.99 (1H, d), 4.21 (2H, d), 6.58 (1H, d), 7.44 (1H, d), 7.86 (1H, d), 12.09 (1H, bs) 438; 1H NMR (500.13 1 3-[5-(2- yy

HPLC tR | MHz, DMSO-d6) adamantylcarbamoyl)-6- —1.84min | 0-90 3H, 1), 5 butyl-pyridin-2-yl]-3- (2H, q), 1.40 (1H, |azabicyclo[3.1.0Jhexane- t), 1.56 (2H, d), 6-carboxylic acid o 1.64 - 1.70 (2H, g AP m), 1.76 (2H, s), NON 1.81 - 1.88 (6H, A m), 1.98 (2H, s), o 2.06 (2H, d), 2.19 ( 2H, 5), 2.81 (2H, t), 3.50 (2H, d), 3.82 (2H, d), 4.03 (1H, s), 6.30 (1H, d), 7.37 (1H, d), 7.49 (1H , d)

Yavi

Intermediate (OA) ethyl)-3-aminohept-2-enoate N 0 can ALY A) ethyl 3-oxoheptanoate 48.17 mmol) 5 ammonium acetate °) was stirred to 6 g + 0 mmol) in (Ja Ae ) ethanol at room temperature for 7 hours. Then the solvent was evaporated and the residue was stirred in 0 (dichloromethane ml) Te Baal min. The formed solid was filtered, and the filtrate was washed with (00) water (Je), then a saturated saline solution (1) (5 ml), dried at 14850, filtered, and evaporated to obtain: (V.A) 3-aminohept-2-enoate H 4%% ( as .pale yellow oil 1H NMR (300.072 MHz, CDCl3) § 0.90 (3H, t), 1.19 - 1 29 (3H, m), 1.31 - 1.38 (2H, (1H, 5) 4.52, has m), 1.47 - 1.57 (2H, m), 2.06 - 2.13 (2H, m), 4.09 (2H, MS m/e (M+H) +172. Intermediate compound (59) 5-ethyl 1-methyl-4-(1-aminopentylidene)pent-2-enedioate 0 He 7 B 0 N 0 \o

11 - - V.A) ethyl -3-aminohept-2-enoate (Ham 49.176 mmol) was stirred in A+ (toluene ml) Codi (Jw £.AT0) methyl propiolate 4.77 *) added The reaction mixture was stirred under Np at 100 C for AT 1 hour. The solvent was evaporated to obtain orange oil. The chromatography (D510) with sequential filtering using 6-701 ethyl acetate/isohexane / 0 yielded: 5-ethyl 1-methyl -4-)1_aminopentylidenc) pent-2-enedioate (9.0 g) ZA as yellow oil. (SH, m), 1.60 - 1.68 (2H, 1.50 - 1.35 LU, (3H, 0.96 AH) 1H NMR (300.072 MHz, CDCL) m), 2.05 (1H, 5), 2.54 (2H, 1), 3.74 (3H, 5), 4.13 (1H, q), 4.26 (2H, q), 6.21 (1H, d), 7.64 (1H, m) 7.70- MS m/e (M+H)+256.1 (3+) intermediate compound ethyl 2-butyl-6-oxo-1,6-dihydropyridine-3-carboxylate 0 x] Akh Soo

H

CH, V.A can Y) S-ethyl 1-methyl-4-(1-aminopentylidene) pent-2-enedioate (mVomol) 001(sodium tertButoxides mg; 1 mmol) stirred in (Yo) NMP mL). The solution was heated at 088 C for ; hours to obtain a very dark solution. when the reaction mixture is cooled; yaiva

YA - - was diluted with ice / water (00 (de) and the resulting precipitate was filtered, washed with water (01 ml) and dried to obtain: (011 *) ethyl 2-butyl-6-0x0-1,6- dihydropyridine-3-carboxylate g //a7) as gray powder.(3H,t), 1.28 (3H, 1), 1.31 - 1.38 (2H, m), 0 0.90' H NMR (400.13 MHz, DMSO) -ds) (1H, d), 7.82 (1H, d), 11.97 (1H, 5), 6.21 l (2H, m), 2.90 (2H, m), 4.22 (2H, 1.58 - MS m/e (M+H)+224. Intermediate (11) ethyl 2-butyl-6-chloronicotinate 0 0 | = ao on CH, 0 stirred 0.17 cana £00 ) ethyl 2-butyl-6-oxo-1,6-dihydropyridine-3-carboxylate mmol) in 0 (phosphorous oxychloride filling Veo mmol) and heated to NY.C for 2 hours to obtain Brown clear solution “Wait it up. The reaction mixture was evaporated and the residue was raised in EtOAc (YO) mL); They were washed with water (Je YO) then saturated brine (da YO) and then dried on 148507, filtered and evaporated. The chromatography of the residue on (:58:0) with Vo elutriation with 70-01 ethyl acetate/isohexane yielded ethyl 2-butyl-6- Y40 (chloronicotinate mg) ZA) as a clear oil

'H NMR (400.13 MHz, DMSO-dg) 50.91 (3H, 0, 1.30 - 1.39 (SH, m), 1.58 - 1.65 (2H, m), 3.02 (2H, 1), 4.34 (2H, q), 7.48 (1H, d), 8.16 - 8.19 (1H, m)

MS m/e (M+H)+ 242 (37) Intermediate compound 2-butyl-6-chloronicotinic acid 0 OH | 72 NN Cl N CH, ethyl 2-butyl-6-chloronicotinate (¥40 mg 0.17 mmol) was stirred in (V+) methanol mL) and sodium hydroxide was added ¥ molar )¥ «Ja; millimoles). The mixture was stirred at room temperature for 11 hours. The solvent was evaporated and the residue was eluted in Ye (ela [zt mL) 0 and acidified with ¥ M HCI. The lactic solution was extracted with dichloromethane (two times Yo X =) and the combined extracts were dried over MgSOq4, filtered, evaporated, and pulverized with isohexane to yield Yo +) 2-butyl-6-chloronicotinic (aes mg (AAT as a white solid. 'H NMR (400.13 MHz, DMSO-dg) 80.90 (3H, t), 1.29 - 1.38 (2H, m), 1.58 - 1.66 (2H, m), $:06 (2H, 1), 7.45 (1H, d), 8.17 (1H, d), 13.41 (1H, s)

MS m/e (M+H)+ 214.

yy. - — intermediate compound (7 1) N-adamantan-2-yl-2-butyl-6-chloronicotinamide JO): NH | 2 Cl Si CH, A solution of 0101 “Js +.1 +0) oxalyl chloride mmol) in (J Y) dichloromethane 0 was added dropwise to a volatile solution of (71) 2-butyl-acid 6-chloronicotinic mg; 1 mM (Js in Yo) dichloromethane ml) during a period of two minutes under nitrogen and the resulting solution was stirred at room temperature for ; hours. The reaction mixture was evaporated to dryness and dissolved in DCM (©mL). This solution was added dropwise to a volatile solution of adamantane -7 hydrochloride amine (VAA (mg 1 mmol) and N-ethyldiisopropylamine (de AY) 0 4.01 mmol) in (01) dichloromethane mL) over a two-minute period under «©0. The resulting solution was stirred at room temperature for VT 1 hour. The reaction mixture was diluted with (Jo¥+) DCM and washed sequentially with 1-1 M HCI, then saturated NaHCO; The organic layer was dried over MgSO, filtered and evaporated to obtain: 0 ) N-adamantan-2-yl-2-butyl-6-chloronicotinamide 00 mg AY 0 .

1H NMR (400.13 MHz, DMSO-d¢) 0.87 (3H, 0.1.24 1.34 (2H, m), 1.50 (2H, d), 1.57 - 1.64 (2H, m), 1.71 (2H, 5) ), 1.82 (6H, d), 1.92 (2H, 5), 2.03 (2H, d), 2.77 (2H, 1), 4.05 (1H, 1), 7.38 (1H, d), 7.70 (1H, d) , 8.43 (1H, d) MS m/e (M+H)+ = 347

; Using the intermediate compound (14) and a starting material (1), the following example was prepared in a manner similar to the example: aminoester J suitable MS example m/e "HNMR & compound name

MH" No. 402: 1H NMR (400.13 2-[(3S)-1-[6-butyl-5- VE | 0 0 0

HPLC | MHz, DMSO-d6) (cyclohexylcarbamoyl) Or tR = 0.87 (3H, t), 1.02- pyridin-2-yl]-3- ow 1.65 1.48 (10H, m), 1.55 - piperidyl]acetic acid min 1.88 (9H, m), 2.11 - 2.27 (2H, m), , 2.75 (3H, 1), 2.88 (1H, d), 3.67 (1H, 5), 4.20 (2H, 1), 6.57 (1H, d), 7.42 ( 1H, d), 7.84 (1H, d), 12.07 (1H, s) (1£) intermediate 2-butyl-6-chloro-N-cyclohexylnicotinamide ° i

A

N.S

Cl N and Nan The intermediate compound (14) was prepared using a method similar to that used for the preparation of the compound

AY) Median 1H NMR (400.13 MHz, DMSO-d¢) 0.87 (3H, t), 1.09 - 1.36 (7H, m), 1.56 - 1.63 (3H, m), 1.70 - 1.74 (2H , m), 1.83 (2H, s), 2.78 (2H, t), 3.69 - 3.76 (1H, m), 7.38 (1H, d), 01 7.70 (1H, d), 8.39 (1H, d)

MS m/e (M+H)" 295

The following example was prepared in a manner similar to example (1); Using the intermediate compound (10) and a suitable starting material: aminoester

MS Example m/e "HNMR § Compound: Name

MH" No. 386 1H NMR (400.13 2-[(3S)-1-[5- view | 4 9 0

HPLC | MHz, DMSO-d6) (cyclohexylcarbamoyl oe tR 0.78 - 0.97 (6H, m), | )-6-cyclopropyl-Yo = 22m | 1.07-1.45 (7H, d), pyridin-2-yl]-3- in 1.55-1.90 (7H, d), piperidyl]acetic acid 2.10-2.23 (2H, m), 2.65-2.70 (1H, m), 2.84 - 2.91 (1H, m), 3.68 -3.71 (1H, m), 4.09 (1H, d), 4.17 (1H, d), 6.50 (1H, d), 7.41 (1H, d), 7.88 (1H, d), 12.09 (1H, s) (10) intermediate compound 6-chdoro-N-cyclohexylnicotinamide

Ne b | 2

Cl N (internationally patented 6-chloro-2-cyclopropylnicotinoyl chloride) a solution of was added dropwise to a volatile solution of (J ¥.0) 0014 mmol) in 1 g; (..711). (0.1 fill; +.7 +1) N-ethyldiisopropylamine 5 mmol) 0.56 "Jw +. VV) cyclohexylamine and m.nitrogen was stirred during a two-minute period under 71 ml (at ©) THF (mmol) in Teor ve

DCM The resulting solution was kept at room temperature for two hours. The reaction mixture was diluted with

Then (Je V+) is saturated NaHCO; ml) then V+) ? Molar HCI and sequentially washed with (J 01) from an Organic layer separation cartridge and the organic layer 0 (Jee) saturated brine ml) was collected and evaporated to obtain the crude product (VO) phase separation cartridge Which then collected and filtered the solid to get the infected substance Eto and that was crushed using: and dried under vacuum to get 0 as a white solid. (779) 6-chloro-N-cyclohexyl-2-cyclopropylnicotinamide m/z (EI+) (M+H)+ = 279; HPLC tg = 2.43 min. The following example was prepared in a manner similar to Example (1); using intermediate compound (11) and a suitable starting material: aminoester for example ME a 'H NMR § Name 1 Compound No. 138 TH NMR (400.13 | 2-[(3S)-1-[5-2- '1

HPLC{R| MHz, DMSO-d6) | adamantylcarbamoyl)-oo 1 ym = 2.74min } 0.78 - 0.81 (2H, 6-cyclopropyl- CO m), 0.84-1.00 pyridin-2-yl]-3- (2H, m), 1.20- piperidyl]acetic acid 1.44 (2H, m), 1.51 (2H, d), 1.61 - 1.64 (1H, m), 1.71 (2H, 5), 1.83 (8H, d), 1.94 (2H, 5), 2.05 - 2.22 (4H) , m), 2.42 - 2.46 (1H, m), 2.65 - 2.71 (1H, m), 2.88(1H, t), 4.01 (1H, 1), 4.10 (1H, d), 4.18 (1H, d), 6.52 (1H, d), 7.43 (1H, d), 7.86 (1H, d),12.01 (1H, vbs). ys

Yava

- 74+ - (11) intermediate compound

N-adamantan-2-yl-6-chloro-2-cyclopropylnicotinamide oO 2

Cl N The intermediate compound (11) was prepared using a method identical to that used for the preparation of the compound. (1 °) Intermediate oo m/z (EI+) (M+H)+ = 331; HPLC tr = 2.92 min. The following example was prepared in a manner similar to example (0) ¢ using intermediate compound (17) and a suitable aminoester starting material:

MS m/e Example RM 454 1H NMR (400.13 2-[(3S)-1-[6- YY

HPLC tR | MHz, DMSO-d6) cyclopropyl-5-oo for Ao = 1.75min | 0.78 - 0.81 (2H, m), | [[(2r,55)-5-hydroxy-2- 0.91 (1H, q), 0.97 adamantyl]carbamoyl] (1H, t), 1.25 (2H, s), | pyridin-2-yl]-3- 1.33 (2H, d), 1.41 piperidyljacetic acid (1H, s), 1.63 (4H, d), 1.73 (2H, d), 1.79 (2H, d), 1.94 (1H, 5), 1.98 (2H, d), 2.06 (2H, s), 2.10 - 2.15 (1H, m), 2.17 - 2.22 (1H, m), 2.41 - 2.46 (1H, m), 2.68 (1H, d) , 2.88 (1H, d), 3.92 (1H, t), 4.09 (1H, d), 4.18 (1H, d), 4.37 (1H, s), 6.51 (1H, d), 7.42 (1H, d), 7.83 (1H, d), 11.99 (1H, bs)

Y Y oo — intermediate compound (1V) Trans-4-chloro-2-cyclopropyl-N-((2r,5s)-5-hydroxyadamantan-2-yl)nicotinamide 0 z © Cl N intermediate was prepared using a method identical to that used for the preparation of intermediate 0 ( “> ) . m/z (E+) (M+H)+ = 347; HPLC tg = 1.86 min. Ex 118 2 -[(3R)-1-[5-(Cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2-y1}-3- piperidyl] acetic acid LO 0 0 T Oo CL © 0 a 6-Chloro-N-cyclohexyl-2-propylsulfanyl-pyridine-3-carboxamide (intermediate compound can VET 7 5.176 mmol) mixed; methyl-(R)-3-piperidine acetate hydrochloride s )+ .4+ (aan 5.776 mmol) 5 KoCO3 (¥ 4 g 1.548 mmol) butyronitrile in a microwave tube and stirred at 171 °C for 2 hours. The mixture changed from a slightly soluble white mixture of 1 to an orange solution. Most of the butyronitrile was evaporated under reduced pressure. 01 elo (01 elo ml) was added and the product extracted in EtOAc (twice (Jo 660 X) and washed with 7 pH

0 mL (and dried over MgSO; filtered and evaporated under reduced pressure to obtain Cu) orange. Celite was preloaded and purified by flash column chromatography “Si0;) and eluting luent gradient: from ja/ to (EtOAc hexane 78 0) to obtain: methyl 2-[ (3R)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl] acetate as a slightly yellow oil that has been crystallized to yield a white solid (1.10). g; (Lov) and then the crude mixture was dissolved in (Je Yo) THF under AN) dry glass vessel and 0 1 N solution of (Jw 7.97 (LIHMDS 7.97 mmol) at After stirring for 2 hours at room temperature, Mel (149 μl 7.11 mmol) was added and the resulting clear yellow solution was stirred at room temperature overnight. The reaction was stopped and divided between 1 (EtOAC 5 ml) and 1111.01 saturated aqueous (de 01) and the aqueous layer was extracted using EtOAc (2 times Yo X ml) and 1 layers were dried 118:50 organic matter, filtered and evaporated to obtain a clear yellow gum. Purification by flash column chromatography (:510; with stepwise eluting: 'hexane (EtOAc) 7230 to 7850 (EtOAc) yielded On : methyl 2-[(3R)-1-[5-(cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetate trap

71 - - as colorless gum (YE cane tov) (%). The gum was dissolved in methanol and an aqueous solution of NaOH (71.¥) was added to fill; 9.77 mmol). The reaction mixture was stirred at room temperature for ; hours. TLC has shown no further starting material 08©21. The MeOH was evaporated under reduced pressure and the remaining solution was acidified to a pH of 0 4.1. The product was extracted in DCM (two times Yo X ml), washed with 01 saline (01 ml), dried at 14,850 °C, and evaporated the solvent under reduced pressure to obtain: 2-[(3R)-1-[5-( cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3-piperidyl] acetic acid as colorless gum and pulverized in ether to yield a white solid (voy) 01 mg; (Zax (3H, t), 1.00 - 1.09 (2H, m), 1.25 - 1.40 (2H, 50.94 (and 01180-2 'H NMR (400.13 MHz, m), 1.47 - 1.55 (4H) , m), 1.56 - 1.81 (8H, m), 1.84 - 1.91 (2H, m), 2.20 - 2.26 (2H, m), (4H, m), 2.95 (1H, m), 2.97 - 3.11 ( 2H, m), 4.15 (1H, d), 4.27 (1H, 4d), 6.50 2.90 - 2.70 (1H, d), 7.23 (1H, d), 12.22 (1H, br s) MS m/ e 4 Vo and the following example was prepared in a manner similar to the example (VIA) using intermediate compound (1) and a starting material suitable for: aminoester

-YYA-

MS Example m/e 'HNMR 8 compound [Name

MH" No. 434 | 1H NMR (400.13 MHz, | 2-[(3S)-1-[5- 174

DMSO0-d6) 0.94 (3H, 0. | (cyclohexyl-methyl- 9 1.05 - 1.11 (2H, m), | carbamoyl)-6- op Pa 1.20 - 1.30 (2H, m), | propylsulfanyl- 1 1 1.41 - 1.51 (4H, m), |pyridin-2-yl]-3- 5 1.56 - 1.69 (8H, m), | piperidyl]acetic acid 1.80 - 1.90 (2H, m), 2.14 - 2.26 (2H, m), 2.65 - 2.85 (4H, m), 2.85 -2.95 (1H, m), 2.99 - 3.09 (2H, m), 4.15 (1H, d), 4.28 (1H, and 6.50 (1H, d), 7.23 (1H, d), 12.15 (1H, br s) (VV) Example [(3S)-1-{5-[((2r,5s)-5-Methoxyadamantan-2-yl)(methyl)carbamoyl ] -6-(propylthio)pyridin-2-yl} piperidin-3-yl]acetic acid 0

N_N5©

N

0 : rice 0” \ sla mmol) in 1-9 vol 1) sodium hydroxide solution added dropwise: of stirred solution to stirred solution (Ja ..40 ) methyl [(35)-1-{5-[((2r,55)-5-methoxyadamantan-2-yl)(methyl)carbamoyl]-6- (propylthio)pyridin-2-yl} piperidin-3-yl ] acetate

-Yva - (intermediate compound 19; 97 mg; VA ++ mmol) in (Je ©) MeOH at VA m over a minute period. The resulting solution was stirred at 80 °C for 0 £ hours. The reaction mixture was adjusted to pH 0.£ using M HCI and the reaction mixture was diluted with (de 5 1(EtOAc) and washed sequentially with To water (ml) then saturated brine (Yo) ml) . The organic layer 0 was dried over MgSO, filtered and evaporated to obtain the crude product. The crude product was purified by preparative HPLC (silica column “Phenomenex Gemini 018 1108 (axia) © micros of YY mm diameter; 100 mm hero); Using decreasingly polar mixtures of water (containing MeCN) 7 0.5 NH as sequential filter materials. The fractions containing the required compound were concentrated under reduced pressure to remove the mass of (CH3CN), and the colorless solution was adjusted to pH 4.5 using 1 M HCI, and the white solid was separated by filtration and washed with water (twice (do). © X and dried under vacuum to obtain: [(3S)-1-{5-[((2r,55)-5-methoxyadamantan-2-yl)(methyl)carbamoyl]-6-(propylthio) pyridin -2-yl}piperidin-3-yl]acetic acid as a white solid. (3H, m), 1.58 - 1.77 (9H, m), 1.80 - 2.00 (4H, m), 2.14 - 2.26 (3H, m), 2.39 - 2.45 (2H, m), 2.70 - 2.75 (1H, m) , 2.91 - 3.13 (9H, m), 4.01 - 4.04 (1H, m), 4.11 - 4.19 (1H, m), 4.25 - 4.28 (1H, m), 6.51 (1H, d), 7.27 (1H, d) , 12.09 (1H, s) m/z (ESI+) (M+H)+ = 516; HPLC tr = 2.67 min

Yayavia

- The intermediate (TA) 6-chloro-N-((2r,5s)-5 -methoxyadamantan-2-yl)-N-methyl-2-(propylthio)nicotinamide and 6-chloro- N-((2r,5s)-5 -hydroxyadamantan-2-yl)-N-methyl-2-(propylthio) nicotinamide J ENGNG TL IO 0 ' drip was added : z

6-chloro-N-((2r,5s)-5-hydroxyadamantan-2-yl)-2-(propylthio)nicotinamide (intermediate TA OY + g; 1 mmol) to sodium hydride (dispersed 710 in oil) (0.47 0.011 aa mmol) in (Je ©) DMF and cooled to 0 °C over a period of 2 minutes under nitrogen) and the resulting suspension was warmed and stirred at 71 m for an hour. The temperature was lowered to 0°C and 010 “de +” was added. +19) mM methyl iodide (Use on one time) and the suspension was warmed and stirred at 71 C VA Baal for another hour. The reaction mixture was quenched with saturated Sle ammonium chloride (©mL) and then diluted Using (Je 50( EtOAc) and washing sequentially with water (0 ml) then saturated saline (01 ml). The organic layer was diluted on Vo 118504, filtered and evaporated to obtain the crude product. The organic layer was purified Raw output by flash chromatography on silica with step-by-step filtering from zero to EtOAc 7000

in 0014. The pure fractions were evaporated to dryness to obtain: 6-chloro-N-((2r,5s)-5-methoxyadamantan-2-yl)-N-methyl-2-( propylthio)nicotinamide

Clear glass: (719 cpa 0.0 VY) 6-chloro-N-((2r,5s)-5-hydroxyadamantan-2-yl)-N-methyl-2-(propylthio)nicotinamide. White solid. (ZVY g; +7) 6-chloro-N-((2r,5s)-5-methoxyadamantan-2-yl)-N-methyl-2-(propylthio)nicotinamide. 1H NMR (400.13 MHz, DMSO-d¢) 8 0.97 (1H, t), 1.49 - 1.55 (2H, m), 1.61 - 1.77 (8H, m), 1.92 - 1.99 (2H, m), 2.15 - 2.20 ( 1H, m), 2.39 - 2.46 (2H, m), 2.99 (3H, s), 3.11 - 3.16 (5H, m), 3.95 - 4.15 (1H, m), 7.29 (1H, d), 7.64 (1H, d) m/z (ESI+) (M+H)+ = 409; HPLC tg = 2.88 min 6-chloro-N-((2r,5s)-5-hydroxyadamantan-2-yl)-N-methyl-2-(propylthio)nicotinamide. 1H NMR (400.13 MHz, DMSO-d) 6 0.97 (1H, 0.1.46 - 1.52 (2H, m), 1.59 - 1.77 (8H, m), 1.90 - 1.98 (2H, m), 2.10 - 2.14 (1H, m), 2.29 - 2.37 (2H, m), 3.00 (3H, s), 3.14 (2H, 1), 3.95 - 4.12 (1H, m), 4.41 (1H, 5), 7.29 (1H, d), 7.64 (1H, d) m/z (ESI+) (M+H)+ = 395; HPLC tg = 2.42 min (19) intermediate

Methyl [(3S)-1-{5-[((2r,55)-5-methoxyadamantan-2-yl)(methyl)carbamoyl]-6- (propylthio)pyridin-2-yl} piperidin-3-yl] acetate 0 0”

A

QL

©jain

Yava

Added: 6-chloro-N-((2r,5s)-5-methoxyadamantan-2-yl)-N-methyl-2-(propylthio)nicotinamide. VA can +. VE ) + mmol) .(S)-methyl 2-(piperidin-3-yl)acetate and heating +.+0Y) HCL 717 µmol) NV can vo AA) potassium carbonate s ++ mmol) in 0 butyronitrile (?mL) sia p m over a period of 1 hour under 0100860. The yield was stirred at NY m for VIA 1 h. The reaction mixture was stirred with (Ja © +) BOA and washed sequentially with Yo water (ml) and then with brine (Je 01 (brine). The organic layer was dried at 14880, filtered and evaporated to obtain the crude product. To : methyl [(35)-1-{5-[((2r,5s)-5 -methoxyadamantan-2-yl)(methyl)carbamoyl]-6- (propylthio)pyridin-2-yl} piperidin -3-yljacetate (Vv) mg; A 00 as yellow gum. m/z (ESI+) (M+H)+ = 530; HPLC tg = 3.13 min Ex. (YVY) [(3S) )-1-{5-[((2r,55)-5 -Hydroxyadamantan-2-yl)(methyl)carbamoyl]-6-(propylthio) pyridlin-2-yl} piperidin-3-yl]acetic acid 0 2 N _N ¢ ruble rice “OH.”

0 - 0 (AY) ele mmol) in 0.159 aa t) sodium hydroxide A stirred solution was added dropwise to a volatile solution (Je methyl [(35)-1-{ 5-[(5-hydroxyadamantan-2-yl)(methyl)carbamoyl] -6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetate M over a period of 1 min. 1 YA was stirred at (Ja ° ) MeOH mmol) in YY mg; 1171 ) 5 using £.0 pH h. The reaction mixture was adjusted to 10 m for VA duration. The resulting solution was sequentially in ml) and sequentially washed (EtOAc? molar and the reaction mixture was diluted with HCI organic and the organic layer (Je 0 ) and saturated brine (Je 01) ela were dried using DCM, filtered and evaporated to obtain the crude product. The rest was dissolved in MgSO, On the layer to remove the nylon millipore filter and filter the light suspension through a nylon membrane filter (Lm 01) 0: Evaporation resulted in obtaining the solid material [(39-1-15-]) (2.,59(-5 -hydroxyadamantan-2-yl)(methyl)carbamoyl] -6-(propylthio) pyridin-2-yl} piperidin-3-yljacetic acid as a white solid. (% aA mg; ‎ YY ) 1H NMR (400.13 MHz, DMSO-de) 0.95 (3H, t), 1.24 - 1.29 (2H, m), 1.41 - 1.52 (3H, m), 1.57 - 1.72 (8H, m), 1.82 - 2.00 (4H, m), 2.10 - 2.26 (3H, m), 2.30 - 2.35 (2H, m), 2.69 - 2.75 (1H, m), 2.90 - 3.11 (6H, m), 3.99 - 4.03 (1H , m), 4.11 - 4.88 (1H, m), 4.24 - 4.30 (1H, m), 4.38 (1H, 5), 6.51 (1H, d), 7.26 (1H, d), 12.09 (1H, s) m /z (ESI+) (M+H)+ = 502; HPLC tg = 2.29 min

Yava

(V+) intermediate compound

Methyl [(3S)-1-{5-[((2t,5s)-5-hydroxyadamantan-2-yl)(methyl)carbamoyl]-6- (propylthio)pyridin-2-y1} piperidin-3-yl] acetate 0 4 P N _N RLC FO “OH © Added: 6-chloro-N-((2r,5s)-5-hydroxyadamantan-2-yl)-N-methyl-2- (propylthio)nicotinamide .can +.YAQ) no mmol) to (S)-methyl 2-(piperidin-3-yl)acetate Rho potassium CAN +.V0£) carbonate 07. ¥ mmol) in (Ja©) butyronitrile was heated to Vr.C during an hour period under nitrogen and the resulting suspension was stirred at 1”0 C for 118 hours. The reaction mixture was diluted with 1 (BOA©mL) and washed sequentially with Yr water (mL) and brine (01mL). The organic layer was dried on 14850, filtered and evaporated to obtain the crude product 0. The crude product was purified by flash chromatography on silica with a gradual sequential filtering from zero to EtOAc 0 in DCM. Evaporation of the pure Ja fractions by dehydration to obtain: methyl [(3S)-1-{5-[((2r,5s)-5-hydroxyadamantan-2-yl)(methyl)carbamoyl] -6- (propylthio) pyridin-2-yl}piperidin-3-yl]acetate as a white solid oe yiva

~Yro - 1H NMR (400.13 MHz, DMSO-d¢) 0.95 (3H, t), 1.27 - 1.32 (1H, m), 1.41 - 1.52 (3H, m), 1.58 - 1.70 (9H, m) , 1.79 - 2.00 (4H, m), 2.11 (1H, s), 2.25 - 2.36 (4H, m), 2.71 - 2.77 (1H, m), 2.90 - 3.10 (6H, m), 3.62 (3H, 5) , 3.99 - 4.03 (1H, m), 4.11 - 4.17 (1H, m), 4.22 - 4.28 (1H, m), 4.38 (1H, s), 6.52 (1H, d), 7.27 (1H, d) m/ z (ESI+) (M+H)+ = 516; HPLC tg = 2.68 min ° (YVY) Example {(3S)-1-[5-(Adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl} acetic acid

L.A

Os oe 1 ~

N N : 0 A solution of 0.76 can + was added dropwise. 0 0Y) lithium hydroxide mmol) in 1 (mL) water to a volatile solution of: methyl {(35)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin- 2-yl]piperidin-3- yl} acetate (intermediate compound 1.47 mmol cama Yo VY) in (Jw Y) THF 5 (J ¥) MeOH at 1 18 C in 55% 1 min . The resulting solution was stirred at 80 °C for 10 hours. EtOAc (54 ml) was normalized and washed sequentially with Ye (ela ml) and saturated saline (Je 1).

-yy-

The organic layer was dried over MgSO, filtered and evaporated to obtain: {(3S)-1-[5-(adamantan-1 -ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3 -yl} acetic acid

YA ) mg A 1 as a white solid. 'H NMR (400.13 MHz, DMSO-d¢) 80.95 (3H, t), 1.21 - 1.49 (2H, m), 1.55 - 1.70 (9H, m), 1.78 - 1.89 (2H, m), 1.99 - 2.06 (9H, m), 2.11 - 2.25 (2H, m), 2.70 - 2.76 (1H, m), (3H, m), 4.19 (1H, d), 4.27 (1H, d), 6.45 ( 1H, d), 7.31 (1H, 5), 7.53 (1H, d) 3.03 - 2.87 m/z (ESI+) (M+H)+ = 472; HPLC tg = 3.12 min Intermediate compound (V1) N-adamantan-1-yl-2,6-dichloronicotinamide 0 0 cr CONT Ney added 2,6-dichloronicotinoyl chloride ) 4.71 g ; 01 mmol) in DCM (J ¥ +) drip into a volatile suspension of 01 can 7.07 (l-aminoadamantane mmol) YE “dw 4019( N-ethyldiisopropylamine mmol) in 01 (DCM ml) at zero ve degrees during a period of yo min under “010086. The resulting suspension was stirred at room temperature for VA 1 hour. The reaction mixture was diluted with EtOAc (+ +0 mL) and washed sequentially with Veo (J) water and (00) brine (Jw), and the organic layer was dried on 148507, filtered, and evaporated.

- No, to obtain the crude product 0, and the crude product was purified by flash chromatography on silica with a gradual sequential filtering from zero to m Et.0 in -DCM, and 1 was evaporated for the pure parts. Ja fractions dryness to obtain: 0.0V) N-adamantan-1-yl-2,6-dichloronicotinamide 1 g A as a white solid. 'H NMR (400.13 MHz, DMSO-d¢) 51.63 - 1.67 (6H, m), 2.01 - 2.08 (9H, m), 7.61 (1H, 0 d), 7.90 (1H, d), 8.12 ( 1H, 5) m/z (ESI+) (M+H)+ = 366; HPLC tg = 2.66 min Intermediate compound (YY) N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide 0 or b N § ) 0 .1 was dripped add 0 Ja +. (£49) 1-propanethiol 50.9 mmol) to : (0.17 N-adamantan-1-yl-2,6-dichloronicotinamide g © mmol) and | potassium (0 Y) carbonate g YO mL (Use in 1 °) butyronitrile ml) at 71 C during a period of two minutes under onitrogen and the resulting suspension was heated at 1501 C for two hours . vo and the reaction mixture was diluted with 6/20 T+ (mL) and washed sequentially with water (Je 01) and saline

saturated saline 01 (ml). The organic layer was dried at 0.1/850 and filtered

- YYA - : and evaporated to obtain a solid (ZV + + g; Y.Y)) N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide white p' H NMR ( 400.13 MHz, DMSO-d) 60.97 (3H, 0.1.61 - 1.66 (8H, m), 2.01 - 2.07 (9H, m), 8.04 (2H, 1), 7.24 (1H, d), 7.67 (1H, d) ), 7.94 (1H, 5) m/z (ESI+) (M+H)+ = 365; HPLC tg = 3.30 min (YF) intermediate compound methyl {(3S)-1-[5-(adamantan-1) -ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3- yl}acetate 0 =

N N § \ mM 1 g; +.¥10) N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide -(S)-methyl 2-(piperidin-3) added -yl)acetate mol) to 1 mmol) 1 g; 1 £10) potassium carbonate y (Use 1 mm spa 0.19 4) HCI m heated for 2 hours. 10051 at (Ja (; butyronitrile in ml) and solution (1 ml) and washed sequentially with © p.) EtOAc and 84% of the reaction mixture was diluted with Vo ml). The organic layer was dried at 14850 C, filtered and evaporated to obtain (01) saline.

- ye - with silica elongation and flash on raw output chromatography. The crude product was purified to pure fractions and the pure hexane fractions were evaporated in EtOAc 75 0 step by step from zero to . Dehydration to obtain methyl {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl} acetate . g « ¢£ % (as white solid 0 71 5) (' H NMR (400.13 MHz, DMSO-d) 50.96 (3H, t), 1.22 - 1.33 (1H, m), 1.37 - 1.48 (1H, m) , 1.55 - 1.69 (9H, m), 1.76 - 1.91 (2H, m), 1.99 - 2.06 (9H, m), 2.23 - 2.35 (2H, m), 2.72 - 2.78 (1H, m), 2.87 - 3.02 ( 3H, m), 3.61 (3H, s), 4.18 (1H, d), 4.26 (1H, d), 6.46 (1Hyd), 7.31 (1H, s), 7.54 (1H, d) m/z (ESI+) (M+H)+ = 486; HPLC tg = 3.54 min ( 1 YY) Ex. 385)-1-[6-(Propylthio)-5-(tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin- 2-yl]piperidin-3-yl} acetic acid , =

N N S

> vo

74.0 ml) 000 (ele mmol) in 01794 g; +. 00) Lithium hydroxide solution was added dropwise: To a volatile solution of methyl {(35)-1-[6-(propylthio)-5 -(tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin-2- yl] piperidin-3-yl} acetate M over a minute VA ml) at Y) THF 5 ml) ¥) MeOH mmol) in 147 mg; YAA) 1 h. 10 m for one VA. The resulting solution was stirred at ? Molar and the reaction mixture HCI was diluted using ¢.© pH and the reaction mixture was adjusted to a number of

Ye. ) and saturated brine (Je 1 ml) and sequentially washed with SA water (EtOAc using 1/850, filtered and evaporated to obtain an organic layer ml). The organic layer was dried: 0 {(35)-1-[6-(propylthio)-5 -(tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin-2-yl]piperidin-3- yl}acetic acid (7000 mg; VY) 'H NMR (400.13 MHz, DMSO-d) 50.95 (3H, 0.1.25 - 1.88 (11H, m), 2.13 - 2.25 (2H, m), 2: 72 - 2.77 (1H, m), 2.85 - 3.02 (3H, m), 3.33 - 3.40 (2H, m), 3.84 - 3.90 (3H, m), 4.21 (1H, d), 4.30 (1H, d), 6.49 (1H, d), 7.64 (1H, d), 7.91 (1H, d), 12.18 (1H, 5) m/z (ESI+) (M+H)+ = 422; HPLC tg = 2.05 min

Intermediate compound (VE) 2,6-dichloro-N-(tetrahydro-2 H-pyran-4-yl)nicotinamide rice 1 or 27 N Cl 0 A solution of £.YY was added ) 2,6-dichloronicotinoyl chloride g; 01 mmol) 0 in DCM (Y+) ml) dropwise into a stirred suspension of 4-aminotetrahydropyran G (Y+¥) 01 mmol) N-5 ethyldiisopropylamine (£.14 g Y¢ mmol) in (Je 1) DCM at zero degrees Celsius. During a period of 1 minute under nitrogen, the resulting suspension was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (0 ml) and washed sequentially with water (5 ml) and saturated saline (04 ml). The organic layer was dried at 14850, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica with stepwise eluting from zero to EtOAc 7001 in DCM and the pure fractions were evaporated to dryness to obtain: 6-dichloro-N-( tetrahydro-2 H-pyran-4-yl)nicotinamide ,2 as a white solid. 'H NMR (400.13 MHz, DMSO-dg) 81.43 - 1.53 (2H, m), 1.78 - 1.83 (2H, m), 3.37 - 3.43 (2H, m), 3.83 - 3.88 (2H, m), 3.91 - 4.00 (1H, m), 7.66 (1H, d), 7.98 (1H, d), 8.65 (1H, d) m/z (ESI+) (M+H)+ = 273; HPLC tg = 1.28 min Yyivi

Intermediate (Vo) 6-chloro-2-(propylthio)-N-(tetrahydro-2 H-pyran-4-ylnicotinamide Sol Or 2 Cl N N 1( sodium) was added molar hexamethyldisilazide in (THF) (2 ml; 9 mmol) to a © solution of 1-propanethiol (84 g; 4 mmol) in DMF under .nitrogen and this solution was added to a solution of Y.4Y) 2,6-dichloro-N-(tetrahydro-2H-pyran-4-ylnicotinamide g; 4 mmol) in (Jo V £) DMF under Np and stirred for VA h. The reaction mixture was diluted with 106 (Ja 001) and washed sequentially with water (do 5 1) and brine (1 © ml). The organic layer was dried over MgSO, filtered and evaporated to obtain the yield. The crude product was purified by flash chromatography on silica with stepwise sequencing from zero to EtOAc 750 in DCM, and the pure fractions were evaporated to dryness to obtain: cam 7.01 (2, 6-dichloro-N-(tetrahydro-2 H-pyran-4-ylnicotinamide 797) as white solid.' H NMR (400.13 MHz, DMSO-dg) 50.97 (3H, 1), 1.45 - 1.55 (2H, m ), 1.59 - 1.68 (2H, m), 1675 - 1.79 (2H, m), 3.04 (2H, 1), 3.34 - 3.43 (2H, m), 3.84 - 3.96 (3H, m), 7.29 (1H , d), 7.78 (1H, d), 8.49 (1H, d) m/z (ESI+) (M+H)+ = 315; HPLC tg = 2.17 min intermediate compound (V1)

-yes-

Methyl {(3S)-1-[6-(propylthio)-5-(tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin-2-yl] piperidin-3-yl} acetate for Ma 0 ~

N N { : 6-chloro-2-(propylthio)-N-(tetrahydro-2 H-pyran-4-yl)nicotinamide ~~ © ) 8 g 10' mmol) was added to S.(. )-methyl 2-(piperidin-3-yl)acetate and CAA aa VAS ) HCI mmol) 5 can +.1+V) potassium carbonate 7.97 mmol) was heated in Y) butyronitrile ml) at 160m over a period; hours. The reaction mixture was diluted with 1 (Jo 5) DCM and washed sequentially with 01 water (mL) and 71 (mL) brine. The organic layer was dried over MgSO, 01, filtered, and evaporated to obtain the yield. The crude product was purified by flash chromatography on silica with a gradual sequential filtering from zero to MeOH: 7001: in a stick *"at. The pure parts were evaporated to dryness to obtain (19:1) EtOAc methyl {(3S)-1-[6-(propylthio)-5-(tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin-2-yl] piperidin-3-yl} acetate 0.71 3 1 g; 71) as a white solid.

- Yee - 'H NMR (400.13 MHz, DMSO-d) 60.95 (3H, t), 1.23 - 1.34 (1H, m), 1.37 - 1.93 (10H, m), 2.24 - 2.35 (2H, m), 2.73 - 2.79 (1H, m), 2.86 - 3.00 (3H, m), 3.33 - 3.41 (2H, m), 3.61 (3H, s), 3.83 - 3.93 (3H, m), 4.19 (1H, d), 4.29 ( 1H, d), 6.50 (1H, nl 7.64 (1H, m), 7.92 (1H, m) m/z (ESI+) (M+H)+ = 436; HPLC tg = 2.46 min ° { "7: ) Example [(3S)-1-{5-[Methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl} piperidin-3-ylJacetic acid , 3 0 0 _

N N N

(1.7 mmol) in water 7.0 can 071 (sodium hydroxide) and then dropwise add 0 mL solution) to a volatile solution of: methyl [(35)-1-{5-[methyl(tetrahydro-2 H) -pyran-4-yl)carbamoyl]-6-(propylthio)pyridin- 2-yl}piperidin-3-yl]acetate YAY) mg; 175 mL (Use in MeOH (© mL) at VA m over a period of one minute. The resulting solution was stirred at VA C for 1 hr. The reaction mixture was adjusted to pH 0.£ using M HCI, diluted with 20086 (+0 (Ja) and washed sequentially with 01 mL water and 01 mL saturated brine. The organic layer was dried at 14/850 and filtered by Yyivi

— Y ¢ g — ml) and filter 1 0) DCM Dissolving the residue in [WW] 0 and evaporating it to get the crude product. filter: obtaining the product of [(3S)-1-{5-[methyl(tetrahydro-2 H-pyran-4-yl)carbamoyl] -6-(propylthio)pyridin-2-yl} piperidin-3 -yl]acetic acid . as a white solid (10% (ads YA ) 'H NMR (400.13 MHz, DMSO-d¢) 0.93 (3H, 0.1.23 - 1.29 (1H, m), 1.40 - 1.92 (10H, m), 2.14 - 2.26 (2H, m), 2.67 - 3.55 (9H, m), 3.89 (2H, d), 4.15 (1H, d), 4.28 (1H, d), 4.36 - 4.66 (1H, m), 6.51 (1H, d), 7.26 (1H, d), 12.16 (1H, s) m/z (ESI+) (M+H)+ - 434: HPLC tg =2.13 min \.(VV) intermediate 6-chloro-N -methyl-2-(propylthio)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide 0 > N lL

Cl N 5 added : 011 011 ( 6-chloro-2-(propylthio)-N-(tetrahydro-2 H-pyran-4-ylnicotinamide 0) (dispersed 7760 in oil) 1.0 g sodium hydride drip to (Je (; DMF mmol) in

1 mmol) in DMF (¥ ml) and cooled to 0°C over a period of 2 minutes under “©0” and stirred for YO min. 011 “da 0.0 195 (methyl iodide mmol) was added once and the suspension was heated and stirred at 171°C for 177 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (©mL) and then diluted with EtOAc (+0 0mL) and washed sequentially with 01mL water and 01mL brine. The crude product was purified by flash chromatography on silica with stepwise eluting from zero to EtOAc 7000 in DCM. The pure fractions were evaporated to dryness to obtain: (YY) 6-chloro-N -methyl-2-(propylthio)-N-(tetrahydro-2 H-pyran-4-yDnicotinamide £.+4g) as a colorless clear. (1H, t), 1.50 - 1.18 lv (3H) + 3H, 0.95 E (Rotamers) and 01150-4 'H NMR (400.13 MHz, (4H + 4H, m), 1.75 - 1.85 (2H + 2H, m), 2.67 (3H, s), 2.89 (3H, s), 3.07 - 3.18 (3H 1.68 3H, m), 3.27 - 3.37 (1H, m), 3.42 (1H + 1H, d), 3.81 (1H + 1H, d), 3.93 - 3.97 (1H + + 1H, m), 4.53 - 4.63 (1H, m), 7.28 - 7.31 (1H + 1H, m), 7.64 - 7.68 (1H + 1H, m) m/z (ESH) ( M+H)+ = 329; HPLC tg = 2.28 min S516 intermediate (YA) Methyl [(35)-1-{5-[methyl(tetrahydro-2 H-pyran-4-yl)carbamoyl) ]-6-(propylthio)pyridin- 2-yl}piperidin-3-yl]acetate i NTs | ©

Added : 0.4 g; 0.4 A) 6-chloro-N-methyl-2-(propylthio)-N-(tetrahydro-2 H-pyran-4-yl)nicotinamide g; +.YOY) HCI (S)-methyl 2-(piperidin-3-yDacetate mmol) was heated to (011 ¥) butyronitrile (8.45 mmol) in ». Y) potassium carbonate 5 mmol) 1 (Jo 1+) DCM over a period; hours. The reaction mixture was diluted with 1 M ov at (do © ml). The organic layer (brine 71) was dried and brine (do 01) was washed sequentially with water, product 0 was purified, filtered and evaporated to obtain the crude product MgSO, on organic layer 700 with a gradual sequencing of zero to silica flash on crude chromatography B: and the pure fractions were evaporated to dryness to obtain DCM in EtOAc methyl [(35)-1-{5-[methyl(tetrahydro-2 H-pyran-4) -yl)carbamoyl] -6-(propylthio)pyridin- 2-yl}piperidin-3-yl]acetate as a white solid. (Lov ca 0 0 ) 'H NMR (400.13 MHz, DMSO-dg) 60.94 (2H , t), 1.25 - 1.31 (1H, m), 1.44 - 1.93 (10H, m), 2.25 - 2.36 (2H, m), 2.68 - 2.84 (4H, m), 2.88 - 3.11 (3H, m), 3.13 - 3.49 (2H, m), 3.83 3.94 (2H, M), 4.14 (1H, d), 4.24 - 4.27 (1H, m), 6.52 (1H, d), 7.26 (1H, d) m/z (ESI+) ) (M+H)+ = 450; HPLC tr = 2.52 min (Yvo) Example 2-[(3S)-1-[6-Cyclohexylsulfanyl-5-[[(2r,55)-5-(difluoromethoxy) )-2-adamantyl] carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetic acid

-YE¢ - M has 0 F 8 y | 0 N N S to a solution of : methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(21,55)-5-(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin-2- yl]pyrrolidin-3-yljacetate Molar Y sodium hydroxide (Je ¥'+) methanol mmol) was added in 0.04 cana Tee) 0 001" (Ja 0.11 mmol) and stirred The mixture was at ambient temperature for 171 h.The reaction mixture was acidified with 1 M citric acid (Je Tv) and evaporated to about half its volume, then (Ja 0+) ethyl acetate was added and the mixture was sequentially washed with water (twice). Yo x ml) and saturated brine (YO) ml). The organic layer was dried over MgSO, filtered and evaporated. As a white powder (YY / “mg 0) to obtain the yield Asked 01 1H NMR (400.13 MHz, DMSO-d) 1.22-1.47E (7H, m), 1.55-1.64 (1H, m), 1.66-1.79 (3H, m), 1.81 — 2.25 (14H, m), 2.36 - 2.46 (2H, m), 2.55 - 2.64 (1H, m), 3.08 (1H, dd), 3.36 - 3.40 (1H, m), 3.5-3.6 (1H, m), 3.7 - 3.85 ( 2H, m), 3.9-3.96 (1H, m), 6.12 (1H, d), 6.86 (1H, t), 7.6 (1H, d), 7.62 (1H, d), 12.15 (1H, s) m/ z (ESI+) (M+H)+ = 564; HPLC tg = 3.12 min. Vo

Yyiva

Intermediate compound (V4) 6-chloro-2-cyclohexylsulfanyl-N-((2r,5s)-5 -hydroxy-2-adamantyl)pyridine-3- carboxamide Mor : IAN Cr : and Cl N 5 M anhydrous sodium carbonate (£ ca 0140 771.77 mmol) was added once to 2,6-dichloro-N-((2r,5s)-5-hydroxy- 2-adamantyl)pyridine-3-carboxamide 9 g ANA mmol) AVA can 07 ) cyclohexyl mercaptan mmol) in DMF (04 ml) under 08. The resulting suspension was stirred at 20 m sad hours. The reaction mixture was concentrated, diluted with (Jo 10+) DCM, and washed sequentially with water (Vo x lip (0 ml) and saturated saline (VO) ml). The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product which was pulverized using isohexane:FtOAc 04 to obtain the required product (0.¥ (aa 190) as a white powder. 1H NMR (400.13 MHz, DMSO-d) 6 1.32 - 1.5 (7H, m), 1.59 - 1.8 (10H, m), 1.94-2.05 (5H, m), 2.06-2.15 (2H, m), 3.7-3.85 (1H, m), 3.91-3.97 (1H, m), 4.39 (1H, 5), 7.25 (1H, d), 2.69 (1H, d), 8.23 (1H, d) m/z ( ESI+) (M+H)+ = 421; HPLC tr = 2.7min.

Yo. — — intermediate (A+) methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[((2r,5s)-5 -hydroxy-2-adamantyl)carbamoyl] pyridin- 2-yl]pyrrolidin-3-yl]acetate bitter NN A 0 added once anhydrous potassium carbonate (+.4A0) g; VAY mmol) to (S)-methyl 2-(pyrrolidin-3-yl)acetate hydrochloride (No. 7 0.78 aa mmol) and : 6-chloro-2-cyclohexylsulfanyl-N- ((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3- carboxamide 1 ) g; 7.748 mM (Use in 0 (l ©) butyronitrile and the resulting suspension was stirred at 111 C for 0 7 days. The reaction mixture was cooled, diluted with (Jo 5 0) (BIOAC) and washed sequentially with water (ml Bitter Tox) and 0 ml saturated brine. The organic phase was dried over MgSO; filtered and evaporated into orange oil. The crude product was purified by flash chromatography on silica using EtOAc and the pure fractions were evaporated to dryness to obtain: methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[( (2r,55)-5 -hydroxy-2-adamantyl)carbamoyl] pyridin-2-yljpyrrolidin-3-yl]acetate VEL) mg; £09 (as a pale yellow foam.

— Y m \ —_ 1H NMR (400.13 MHz, DMSO-d¢) § 1.22 - 1.45 (7H, m), 1.57-1.8 (10H, m), 1 .92-2.09 (7H, m), 2.14 -2.23 (1H, m), 2.53-2.65 (1H, m), 3.1 (1H, dd), 3.36-3.44 (1H, m), 3.5-3.6 (1H, m), 3.63 (3H, s), 3.66 -3.84 (2H, m), 3.84 - 3.9 (1H, m), 4.37 (1H, s), 6.12 (1H, d), 7.54(1H, d), 7.63 (1H, d) m/z (ESI+) (M+H)+ = 528; HPLC tg = 2.84 min. (A) The intermediate methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(2r,55)-5 -(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin-2-yl] pyrrolidin-3-yl]acetate 1 rd 2 9 rb 7 avs | A' ~

N N 5 1

Y.VY (T ml 2-(fluorosulphonyl)difluoroacetic acid) A solution of: was added dropwise to a solution of (anhydrous Ja) (? acetonitrile) in (Use m methyl 2-[ (3S)-1-[6-cyclohexylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl] pyridin-2-yl]pyrrolidin-3-yljacetate mmol) in + YA cama 0 V) copper (I) iodides mmol) 0.786 mg; Aqueous Y acetonitrile

Y 0 Y —_ the resulting solution at 0°C for 00 min. The reaction mixture was concentrated, diluted with 06:2 (+0 mL) and washed sequentially with water (two times Jo YO X) and saturated brine YO) ml). The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product as orange oil. The crude product was purified by flash chromatography on silica with a stepwise eluting of 0 to EtOAc Joo in .isohexane and the pure fractions were evaporated to dryness to obtain the desired yield (0 TE mg; Av %) as pale yellow foam (.pale yellow foam). 8H, m), 1.43-1.52 (1H, m), 1.53-1.67 1.34 - 1.1 NMR (400.13 MHz, DMSO-dg) 111 GH, m), 1.72 - 1.83 (4H, m), 1.84 — 2.1 (11H, m), 2.4 - 2.58 (1H, m), 2.99 (1H, dd), (1H, m), 3.39 - 3.47 (1H, m), 3.5 (3H, 5), 3.54 - 3.7 (2H, m), 3.79 - 3.85 (1H, 3.231-3.33 m), 6.12 (1H, d), 6.75 (1H, 1), 7.48 (1H, d), 7.51 (1H, d).m /z (ESI+) (M+H)+ = 578; HPLC tg = 3.6 min. (VV) Example 2-[(3S)-1-[6-Cyclohexylsulfanyl-5-[[(2r,5s) )-5-(difluoromethoxy)-2-adamantyl] ‎carbamoyl]pyridin-2-yl]-3-piperidyl]acetic acid ‎9 0 o_O XN | H F

ZZ

N N 5 Failed

_ Y o Y — : to a solution of methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(2r,55)-5 -(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin- 2-yl]-3-piperidyl]acetate

Y sodium hydroxide (J ¥+) methanol mmol) was added in 0.10 v 0 )

Yo mmol) and the mixture was stirred at ambient temperature for a period of 01110. Filling 5. Wea 0 hour approximately, then dana and evaporated until half (do To) 1 citric molar and the mixture was acidified The reaction was with acid and brine (Ja Yo X (liye) and the mixture was washed sequentially with water (Ja © 1 (ethyl acetate) added to 14880, filtered and evaporated the organic layer. The organic layer YO was dried ) saturated 0 as white foam. 0 Ao » to obtain the desired yield (6 mg 1H NMR (400.13 MHz,) W-1450 6 1.26-1.5 (10H, m), 1.55-1.78 (4H, m), 1.8-2.08 (12H, m), 2.10-2.3 (4H, m), 2.75 (1H, dd), 2.97 (1H, dd), 3.68-3.78 (1H, m), 3.92 - 3.97 (1H, m), 4.18-4.3 (2H, m), 6.49 (1H, d), 6.87 (1H, 1), 7.60 (1H, d), 7.68 (1H, d), 12.07 (1H) s) m/z ( ESI+) (M+H)+ = 578; HPLC tg = 3.28 min. (AY) Intermediate compound methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[((2r,5s)-5) -hydroxy-2-adamantyl)carbamoyl]pyridin-2-yl]-3-piperidyl]acetate

Yivia

— Y o ¢ — 1 Jon 0 0 B N

EL

each ON’ 5 mmol) to YT can 01145 (anhydrous potassium carbonate was added once in g “© mmol) and: +. £74) (S)-methyl 2-(piperidin-3-yl)acetate hydrochloride 6-chloro-2-cyclohexylsulfanyl-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3 -carboxamide m for 111 ml). The resulting suspension was stirred at (10 mmol butyronitrile) in 7.74 ea) 0 days. ¥ (do 30 X (twice elas ml) and washed with BLOC (0*) and the reaction mixture was cooled and diluted with On (0.50 p08) the organic layer was filtered (ml) and the organic layer (V) was dried and brine and evaporated to orange oil. Ethyl acetate was evaporated with silica flash on chromatography and the crude product was purified B0: Until dry to obtain pure fractions methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl ] pyridin-2-yl]-3-piperidyljacetate as pale yellow foam. (AVE compiled 410) 1H NMR (400.13 MHz, DMSO-dg) 6 1.15-1.43 (9H, m), 1.48-1.69 (10H, m), 1.70 — 2.0 (9H, m), 2.14-2.31 (2H, m), 2.71 (1H, dd), 2.85 - 2.95 (1H, m), 3.54 (3H, s), 3.6-3.7 (1H, m), 3.77-3.83 (1H, m), 4.07-4.21 (2H, m), 4.3 (1H, s), 6.43 (1H, d), 7.53 (2H, d), 7.55 (1H, d) m/ z (ESI+) (M+H)+ = 542; HPLC tg = 3.00 min.

Yyiva

Yoo — ~ intermediate compound (AY) methyl 2-[(3S)-1- [6-cyclohexylsulfanyl-5 -[[(2r,55)-5-(difluoromethoxy)-2-adamantyl] carbamoyl[pyridin-2-yl]-3-piperidyl]acetate (pe te) 0 ar >< mi ( H F N N S © A solution of +.Y1Y) 2-(fluorosulphonyl)difluoroacetic acid was added ml 3.21 mmol) in aqueous VY acetonitrile (? (Je) to a solution of: methyl 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[((2r,55) )-5-hydroxy-2-adamantyl)carbamoyl] pyridin-2-yl]-3-piperidyl]acetate 0175 cana do) mM copper (I) iodides (Use (11.8 mg; 1. 75 mmol) in 0 266001021 No (Je YV) Ale and warmed to 100 C. during an hour under nitrogen and the resulting solution was stirred at £0 C for 1 min. The reaction mixture was concentrated and diluted with EtOAc (+0 ml) and washed sequentially with Yo x lise water (ml) and saturated saline (0 ¥ ml). The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product as orange oil. 1 The crude product was purified by flash chromatography on silica with eluting from 0 to EtOAc Lov in .isohexane and then evaporating the pure fractions to dryness.

- You - as pale yellow foam (LAY (ome 104) desired product .pale yellow foam 1H NMR (400.13 MHz, DMSO-d) 6 1.26 - 1.52 (10H, m), 1.58 — 2.08 ( 15H, m), 2.09 - 2.12 (3H, m), 2.24 - 2.39 (2H, m), 2.78 (1H, dd), 2.94 - 3.01 (1H, m), 3.62 (3H, s), 3.68 - 3.77% (1H, m), 3.92 - 3.97 (1H, m), 4.15-4.3 (2H, m), 6.49 (1H, d), 6.87 (1H, t), 7.61 (1H, d), 7.69 (1H, d) ) m/z (ESI+) (M+H)+ = 592; HPLC tg = 3.72 min. ( 1 YY) Example 2-[(3S)-1-[6-Cyclopentylsulfanyl-5-[[(2r) ,5s)-5-(difluoromethoxy)-2-adamantyl] ‎carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetic acid

Seas g Ns 0 : to a solution of methyl 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin -2-yl[pyrrolidin-3-yl]acetate 1 sodium hydroxide (Je Y'+) methanol mmol) was added in 0.4 cana Ver) 0 10 mmol) and the mixture was stirred at . surroundings for 1.40 mL (1.71) molar hours. Yava

— Y ov — ml) and evaporated to about half its volume, then Tr) 1 molar citric The reaction mixture was acidified with acid and brine (Je Yo x) and the mixture was washed sequentially with water (twice) (Je©) ethyl acetate was added to 14880, filtered and evaporated organic layer (ml).The organic layer YO (saturated) was dried as a white powder (LAY « mg © Te) to obtain the required yield 1H AMR (400.13 MHz, DMSO-dg) 1.42 (2H, d), 1.49 - 1.75 (7H, m), 1.84 -5 (14H, m), 2.42 (2H, d), 2.55 - 2.62 (1H, m) ), 3.08 (1H, dd), 3.37 - 3.41 (1H, m), 3.5-3.6 (1H, m), 3.69 - 3.74 (1H, m), 3.92 — 4.05 (2H, m), 6.12 (1H, d ), 6.86 (1H, 1), 7.58 (1H, d), 7.64 (1H, d), 12.15 (1H, s) m/z (ESI+) (M+H)+ = 550; HPLC tg = 3.01 min.

(Ae) intermediate compound 0 6-chloro-2-cyclopentylsulfanyl-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3- carboxamide

pe "OH a or H p27 Cl N S anhydrous potassium carbonate (4 + .1 c 771.717 mmol) is added once to Vo : Yyiva

— Y m A —

AVE aa 9 2,6-dichloro-N-((2r,5s)-5-hydroxy-2-adamantyl)pyridine-3-carboxamide mL) induce o. ) DMF mmol) in AYA ml . . 7 ) cyclopentyl mercaptan (mmol) The resulting suspension was stirred at 30 m for 7 hours. 439 .nitrogen

Yo X ml) and sequentially washed with (two times You) DCM, and the reaction mixture was concentrated and diluted using (0118 p. 50) organic layer ml) and the organic layer was dried (1 0 ml) and saturated brine 0 isohexane:EtOAc 1:4 was filtered and evaporated to obtain the raw product which was pulverized as a white powder. (1A (aa 7.7) to obtain the desired yield 1H NMR (400.13 MHz, DMSO-d) 6 1.38 (2H) , d), 1.47 - 1.6 (2H, m), 1.64-1.85 (10H, m), 1.94-2.08 (3H, m), 2.1-2.15 (2H, m), 2.16 - 2.28 (2H, m), 3.90 - 3.97 (2H, m), 4.45 (1H)s), 7.3 (1H, d), 7.70 - 7.75 (1H, m), 8.28 (1H, d) m/z (ESI+) (M+H)+ = = 407; [pyridin-2-ylJpyrrolidin-3-yl]acetate 1 pe OH \ 0 N N

H

®

N N S

O1

Yyava

— Y m 9 — mmol) to V.YY C 0 1) anhydrous potassium carbonate was added once: mmol) and YET pl 2441 ( (S )-methyl 2-(pyrrolidin-3-yl)acetate hydrochloride 6-chloro-2-cyclopentylsulfanyl-N-((2r,5s)-5 -hydroxy-2-adamantyl)pyridine-3- carboxamide for 111 minutes Ml). The resulting suspension was stirred at 1©) butyronitrile g; 7.47 mmol) in 1 0 ? days.

Yoox lis) and sequentially washed with water (Je 5 1 (EtOAc) and the reaction mixture was concentrated and diluted using (MgS04) on an organic layer, and the organic layer was dried (JaVO) ml) and saturated brine, filtered and evaporated To obtain orange oil. EtOAc was evaporated using silica flash chromatography and the crude product was purified with 0:pure parts to dryness to obtain methyl 2-[(3S)-1-[6). -cyclopentylsulfanyl-5-[((2r,5s)-5 -hydroxy-2-adamantyl)carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetate (79 g) as pale yellow foam. (1) 1H NMR ( 400.13 MHz, DMSO-d) 6 1.3-1.4 (2H, m), 1.48-1.78 (13H, m), 1.9-2.22 (8H, m), 2.55-2.7 (1H, m), 3.1 (1H, dd) , 3.35-3.45 (1H, m), 3.52-3.6 (1H, m), 3.63 (3H, s), 3.68 - 3.73 (1H, m), 3.85-3.92 (1H, m), 3.98 - 4.05 (1H, m), 4.37 (1H, s), 6.12 (1H, d), 7.52 (1H, d), 7.64 (1H, d) m/z (ESI+) (M+H)+ = 514; HPLC tg = 2.68 min .

Y 1 . — _ intermediate (AT) methyl 2-[(3S)-1-[6-cyclopentylsulfanyl-5 -[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl] carbamoyl] pyridin-2-yl]pyrrolidin-3-yl]acetate Ke bitter x m JH F | 0 N N 5 © A solution of 2-(fluorosulphonyl)difluoroacetic acid (+.YAY) was added dropwise 1 ml? mmol) in aqueous VY acetonitrile (? ml) to a solution of: methyl 2- [(3S)-1-[6-cyclopentylsulfanyl-5-[((2r,55)-5 -hydroxy-2-adamantyl)carbamoyl] pyridin-2-yl]pyrrolidin-3-yljacetate qe.) mg 0.85 mmol) 08 ) copper (I) iodides (mg; TY + .mmol) in anhydrous 0 acetonitrile (Je YY) and heated to 'to m through 1 hour under .nitrogen and the resulting solution was stirred at £0 C for 1 min.The Jeo lil mixture was concentrated, diluted with EtOAc (+0 ml) and washed sequentially with (Yo x lin) elas (Je and saturated brine (Je YO).The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product as orange oil. The crude product was purified by flash chromatography on silica. With 0 to EtOAc Toe eluting in .isohexane the pure fractions were evaporated to dryness to yield the desired yield (5 mg IVY) as a pale yellow foam.

1H NMR (400.13 MHz, DMSO-d) 6 1.27-1.36 (2H, m), 1.37-1.65 (7H, m), 1.73 - 1.82 (5H, m), 1.83-1.92 (5H, m), 1.96-2.1 (6H, m), 2.4-2.57 (1H, m), 3.0 (1H, dd), 3.25 - 3.35 (1H, m), 3.4-3.5 (1H, m), 3.51 (3H, s), 3.55-3.65 (1H, m), 3.8-3.93 (2H, m), 6.12 (1H, d), 6.57 (1H, t), 7.49 (1H, d), 7.54 (1H, d) m/z (ESI+) (M +H)+ = 564; HPLC tg = 3.46 min. ° (YYA) Example 2-[(3S)-1-[6-Cyclopentylsulfanyl-5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin-2-yl ]-3-piperidyl]acetic acid 0 ....0 0 0 Ser B 3 B | H F U N N 5 : to a solution of 0 methyl 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl] carbamoyl [pyridin-2-yl]-3-piperidyl]acetate 1 M sodium hydroxide (Ja Yo) methanol mmol) was added at 110 cana Vit (10 h. 10 mmol) and the mixture was stirred at ambient temperature for 1.011 mL; 1.07) and evaporate it to about half its volume then 1 molar (Ja Ya) citric and then acidify the reaction mixture with \o (Je Yo X) acid (twice olay mixture (ml) and the mixture was washed sequentially (©) ethyl acetate by adding MgSO, on an organic layer (ml). The organic layer (YO) was dried and saturated brine

A Lay as a foam (we mix and fumigate it to get the required product) 1 mg

1H NMR (400.13 MHz, DMSO-dg) 6 1.23-1.35 (1H, m), 1.38-1 .75 (10H, m), 1.8-1.93 (6H, m), 1.95-2.06 (4H, m), 2.08 -2.27 (7H, m), 2.75 (1H, dd), 2.98 (1H, dd), 3.9-4.03 (2H, m), 4.15-4.23 (1H, m), 4.25-4.34 (1H, m), 6.49 (1H, d), 6.87 (1H, t), 7.61 (1H, d), 7.68 (1H, d), 12.1 (1H, s). m/z (ESI+) (M+H)+ = 564; HPLC tg = 3.13 min. ° (AV) intermediate compound methyl 2-[(3S)- 1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5 -hydroxy-2-adamanty!)carbamoyl] pyridin-2-yl] -3-piperidyl]acetate 0 Se 0 0 > mB 0 R N N S mmol) to V.TV 0 mL (0.109) anhydrous potassium carbonate added once ye : mmol) and 1.476 cpa ».471( (S)-methyl 2-(piperidin-3-ylacetate hydrochloride 6-chloro-2-cyclopentylsulfanyl-N-((2r,5s)-5 -hydroxy- 2-adamantyl)pyridine-3- carboxamide M for 111 ml.The resulting suspension was stirred at 0 (butyronitrile c. 7.47 mmol) in 1)

Yo x ml) and washed with water (twice 0 +) EtOAc and the reaction mixture was cooled and diluted with 0? 1 days

MgSO; on the organic layer and the organic layer was dried. (Jo V+) and saturated brine (Je) were filtered and evaporated to obtain orange oil. EtOAc was flash-evaporated on 8 using chromatography and the crude product was purified by

Pure fractions: until dryness to obtain pure fractions methyl 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[(2r,5s)- (5-hydroxy-2-adamantyl)carbamoyl] pyridin- 2-yl]-3-piperidyl]acetate

011 5 (g; 4m) as white foam. (17H, m), 1.79 - 2.2 (9H, m), 2.25-2.35 1.28-1.75 6 and 01150-0 1H NMR (400.13 MHz, (2H) , m), 2.77 (1H, dd), 2.92-3.02 (1H, m), 3.61 (3H, s), 3.84 - 3.87 (1H, m), 3.92-4.0 (1H, m), 4.12 - 4.18 (1H, m), 4.24 - 4.30 (1H, m), 4.37 (1H, s), 6.49 (1H, d), 7.59 (1H, d), 7.61 (1H, d) m/z ( ESI+) M+H)+ = 528; HPLC tg = 2.86 min. 1. Intermediate (AN) methyl 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s )-5-(difluoromethoxy)-2-adamantyl] carbamoyl]pyridin-2-yl]-3-piperidyl]acetate Per O° > N H F N N 5 was drip added A solution of “Jw +.£YY) 2-(fluorosulphonyl)difluoroacetic acid 50117 0 mmol) in anhydrous acetonitrile (? ml) to a solution of: methyl 2-[(3S)-1- [6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]

Ys — - pyridin-2-yl]-3-piperidyl]acetate 0.08 cana 110(mmol) 1.47 cama +. V4) copper (I) iodides mmol) in anhydrous acetonitrile (Je YY) and heating it to m m over an hour period under “010086. The resulting solution was stirred at £0 C for Te min.

Yo * ml) and sequentially washed with water (2 times © 1) BIOAC reaction mixture was concentrated and diluted with 0 1850, on an organic layer and the organic layer was dried 0 (Je YO) ml) and saturated brine b b) Crude product was purified and the pure fractions were evaporated to dryness to obtain -isohexane in EtOAc 7586 to 0

0 Desired output (ITY cane Vou) as a pale yellow foam. NMR (400.13 MHz, DMSO-dg) 6 1.24 - 1.34 (1H, m), 1.40-1.74 (10H, m), 1.81-1.94 111 (6H, m), 1.95 - 2.21 (9H, m), 2.23 - 2.37 (2H, m), 2.78 (1H, dd), 2.94 - 3.01 (1H, m), 3.62 (3H, 5), 3.90 - 4.00 (2H, m), 4.16 - 4.19 (1H, m) ), 4.27 - 4.32 (1H, m), 6.49 (1H, d), 6.89

(1H, 1), 7.61 - 7.63 (1H, d), 7.67 (1H, d) m/z (ESI+) (M+H)+ = 578; HPLC tg = 3.55 min.

Vo (179) Example 2-[(3S)-1-[5-[[(2r,55)-5-(Difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsul fanyl-pyridin-2- yl}-3-piperidyl]acetic acid

- Yio - 1 reply 9

O70 = N p | H F 27

N N § : to a solution of methyl 2-[(3S)-1-[5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyl|carbamoyl]-6- propylsulfanyl-pyridin-2- [yl]-3-piperidyl]acetate M ¥ sodium hydroxide (Ja 71 (methanol mmol) was added at 0.54 mg; 850 (h. 10 mmol) and the mixture was stirred At ambient temperature for a period of 109.40 filling VV) and evaporated until about half of its volume, then (Je Vo) 1 molar citric acidified the mixture with alg acid (ml) and saline solution Yo x and washed the mixture sequentially With water (twice (Je 0+) ethyl acetate added to 14850, filtered and evaporated organic layer ml). The organic layer (YO) saturated white foam (1 mg%; Vou) was dried to obtain the desired yield 0 1H NMR (400.13 MHz, DMSO-d) 0.96 (3H, 0. 1.22 - 1.33 (1H, m), 1.40-1.52 (3H, m), 1.58 - 1.7 (3H, m), 1.8-1.94 (6H, m), 1.95-2.07 (4H, l 2.11 - 2.3 (5H, m), 2.80 (1H, dd), 2.9-3.1 3H, m), 3.9-3.98 (1H, m), 4.17-4.25 (1H, m), 4.27 - 4.32 (1H, m), 6.49 (1H, d), 6.87 (1H, t), 7.61 (1H, d), 7.68 (1H, d), 12.09 (1H, s) m/z (ESI+) (M+H)+ = 538; HPLC tg = 2.96 min.\o (A) intermediate methyl 2-[(3S)-1-[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsul fanyl- pyridin-2-yl]-3-piperidyl]acetate

1 John

H

N N N

mmol) at once to V.AA can 0.1 AA) anhydrous potassium carbonate added mmol) 7.17 can ».*0( (S)-methyl 2-(piperidin-) 3-yl)acetate hydrochloride (aa ) 6-chloro-N-(5-hydroxy-2-adamantyl)-2-propylsulfanyl-pyridine-3-carboxamide ml (Y©) butyronitrile mmol) at 7.17 0 m for ? days. The reaction mixture was cooled and diluted with 111 and the resulting suspension was stirred at 148507, brine and 01 X brine were dried (2 times elas), washed (Jw © +) EtOAc on 148507, filtered and evaporated. to orange oil. -[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl- pyridin-2-yl]-3-piperidyljacetate as pale yellow foam. (LAE aa VY) 1H NMR (400.13 MHz, DMSO-dg) 0.96 (3H, 1), 1.25 - 1.36 (3H, m), 1.40 - 1.46 (1H, m), 157 - 1.77 (9H, m), 1.79 -2.1 (7H , m), 2.24 - 2.38 (2H, m), 2.7 (1H, dd), 2.93 - 3.06 (3H, m), 3.62 (3H, 5), 3.82-3.9 (1H, m), 4.13-4.21 (1H , m), 4.24 - 4.3 (1H, m), 4.37 (1H, s), 6.50 (1H, d), 7.60 (1H, d), 7.62 (1H, d) m/z (ESI+) M+H) + = 502; HPLC tg = 2.64 min.

(3+) intermediate compound methyl 2-[(3S)-1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyljcarbamoyl]-6- propylsulfanyl-pyridin-2-yl] -3-piperidyl]acetate

0 1 —F >< 0.__0 H F | b Zo Ng : 0. A solution of (+.£0Y) 2-(fluorosulphonyl)difluoroacetic acid mL £¥4 mmol in aqueous Y acetonitrile (¥ mL) was added to the solution From : methyl 2-[(3S)-1-[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl-pyridin-2-yl]-3- piperidyl]acetate (7.19 (1.1 mmol) can vo Af) copper (I) iodides +88 mmol) in acetonitrile anhydrous 0 (Y v ml) and heated to mm mm over a period of one hour Under 010:0880. The resulting solution was stirred at 0°C for 70 minutes. The reaction mixture was concentrated, diluted with EtOAc (© ml) and washed sequentially with YO XY water (ml) and saturated saline (YO (ml)). The organic layer was dried on MgSO, filtered and evaporated to obtain the crude product as orange oil. ve and the crude product was purified by flash chromatography at 501168” with stepwise elutriation 01 to EtOAc 780 at 0A”©1900. The pure fractions were evaporated to dryness to obtain the desired yield (pa AY 77°) as a pale yellow foam.

- 0 - 111 NMR (400.13 MHz, DMSO-d) 6 0.96 (3H, t), 1.24 - 1.34 (1H, m), 1.38-1.5 (3H, m), 1.58 - 1.71 (3H, m), -1.76 2.08 (10H, m), 2.09-2.2 (3H, m), 2.24 - 2.35 (2H, m), 2.81 (1H, dd), 2.91 - 3.08 (3H, m), 3.62 (3H, s), 3.92- 3.98 (1H, m), 4.15-4.22 (1H, m), 4.24 - 4.32 (1H, m), 6.50 (1H, d), 6.87 (1H, 0, 7.61 (1H, d), 7.69 (1H, ) c m/z (ESI+) (M+H)+ = 552; HPLC tg = 3.39 min.° (VA ) Example 2-[(35)-1-[5-[[(2r,5s) )-5-(Difluoromethoxy)-2-adamantyl carbamoyl] -6-propylsulfanyl- pyridin-2-yl]pyrrolidin-3-yljacetic acid 1 pe "0 0 0 | _ H F

N N § : to a solution of 0 methyl 2-[(3S)-1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6- propylsulfanyl-pyridin-2 -yl]pyrrolidin-3-yl]acetate

Y sodium hydroxide (J ¥'+) methanol mmol) was added in 0.41 cana 0 (01 01 ambient for a period shall mmol) and the mixture was stirred at 014.04 °C. 1 molar and evaporated to about half its volume, then (Je Vo) 1 molar citric h. The mixture was acidified with vo acid and a solution (Jw Yo Xx) (twice elas) and the mixture was sequentially washed ( Jw 0 ( ethyl acetate) was added

Yivia

and filtered, MgSO, onto an organic layer (ml). The organic layer (Yo) saturated saline was dried and evaporated to obtain the desired yield (170 mg; 791) as a pale yellow powder. 1H NMR (400.13 MHz, DMSO-dg) 8 6 (3H, t), 1.40 - 1.47 (2H, m), 1.59 1.75 (3H, m), 1.85-2.24 (12H, 5), 2.41 - 2.47 (2H, m), 2.55-2.65 (1H, m), 3.03 (2H, 1), 3.1 ( 1H, dd),e3.37 - 3.41 (1H, m), 3.52-3.6 (1H, m), 3.7-3.78 (1H, m), 3.92-3.98 (1H, m), 6.13 (1H, d), 6.87 (1H, t), 7.60 (1H, d), 7.64 (1H, d), 12.15 (1H, s) m/z (ESI+) (M+H)+ = 524; HPLC tg = 2.86 min. (31) The intermediate compound methyl 2-[(38)-1-[5-[((2r,5s)- 3-hydroxy-2-adamantyl)carbamoyl] -6-propylsulfanyl- pyridlin-2-yl]pyrrolidin -3-yl]acetate 0 Jo "OH 0 IAN

N N

mmol) at once to VAM can 001 AA) anhydrous potassium carbonate added : mmol) 0.17 g 77 ) (S)-methyl 2-(pyrrolidin-3- yl)acetate hydrochloride 6-chloro-N-((2r,5 5)-5-hydroxy-2-adamantyl)-2-propylsulfanyl-pyridine-3 -carboxamide M for 111 ml). The resulting suspension was stirred at 10) butyronitrile g; 7.17 mmol) in 1 ( vo ? days.

Yavs

d The reaction mixture was cooled and diluted with Ou ( EtOAc mL); It was washed with water (twice Ye Xx ml) and brine (1 Ja) and the organic phase was dried on MgSO, filtered and evaporated to orange oil. The crude product was purified by flash chromatography on silica Using (EtOAc) the pure fractions were evaporated to dryness to obtain: methyl 2-[(3S)-1-[5-[(2r,55)-5 -hydroxy-2- adamantyl)carbamoyl] -6-propylsulfanyl- pyridin-2-yl]Jpyrrolidin-3-yl]acetate (1VY (an 9.44) as -pale yellow solid 1H NMR (400.13 MHz, DMSO-d) § 0.96 (3H, t), 1.33 - 1.36 (2H, m), 1.59 - 1.75 (9H, m), 1:92-2.08 (SH, m), 2.11-2.23 (1H, m) ), 2.53-2.7 (1H, m), 3.03 (2H, t), 3.08 - 3.13 (1H, m), 3.39 - 3.41 (1H, m), 3.52-3.61 (1H, m), 3.63 (3H , 5), 3.69 - 3.74 (1H, m), 3.85 - (1H, m), 4.37 (1H, 5), 6.13 (1H, d), 7.53 (1H, d), 7.64 (1H, d) 3.92 m/z (ESI+) (M+H)+ = 488; HPLC tg = 2.52 min. Intermediate (37) methyl 2-[(3S)-1-[5- [[(2r,5s) )-5-(difluoromethoxy)-2-adamantyl]carbamoyl] -6- propylsulfanyl-pyridin-2-yl]pyrrolidin-3-yl]acetate i J 9 N N §

A 77/1 - - A solution of 411 (2-(fluorosulphonyl)difluoroacetic acid .+ ml ¥.9A mmol) in anhydrous acetonitrile (¥ ml) was added to a solution of: methyl 2-[(3S)-1-[5-[((2r,5s)-5-hydroxy-2 -adamantyl)carbamoyl]-6-propylsulfanyl- pyridin-2-yl]pyrrolidin-3-yl [acetate av. ) 0 g; 48 mmol) 1 ) copper (I) iodide mg; x mmol) in anhydrous acetonitrile (do YY) and heated to 45 °C during an hour under nitrogen, and the resulting solution was stirred at ato for Ye min. The reaction mixture was concentrated, diluted with BIOAC (© ml) and washed sequentially with water (¥ (J Yo x) and saturated brine (Yo ml). The organic layer was dried at 0.04850. filtered and evaporated to obtain the crude product as orange oil.The crude product was purified by flash chromatography on silica with gradual sequencing 01 to EtOAc 780 in -isohexane, and the pure parts were evaporated to dryness to obtain the required product ) + VE cana Va 0 as -pale yellow foam NMR (400.13 MHz, DMSO-d) § 0.96 (3H, 1), 1.39-1.48 (2H, m), 1.59 - 1.78 (3H, 111 m), 184 - 1.95 (4H, m), 1.96-2.06 (SH, s), 2.07-2.22 (SH, 1), 2.53 - 2.7 (1H, m), 3.03 (2H, 1) , 3.1 (1H, dd), 3.33 - 3.46 (1H, m), 3.52-3.6 (1H, m), 3.63 (3H, s), 3.70 - 3.77 (1H, m), 3.91 - 3.97 (1H, m), 6.13 (1H, d), 6.88 (1H, t), 7.60 (1H, d), 7.64 (1H, d) m/z (ESI+) (M+H)+ = 538; HPLC tg = 3.29 min

(VAY) Jie 2-[(3S)-1-[5-[[(21,55)-5 -(Difluoromethoxy)-2-adamantyl] carbamoyl]-6-propoxy-pyridin- 2-yl]-3- piperidyl acetic acid

Q 0 h sr b 0 0 H F 7 N N 0 ee to a solution of HY methyl 2-[(3S)-1-[5-[[(2r,55)-5-(difluoromethoxy) -2-adamantyl[carbamoyl]-6-propoxy- pyridin-2-yl]-3-piperidyl]acetate (0 ) aggregate 1.77 mmol) in MeOH (©mL) was added sodium hydroxide ¥ 1 molar (Y oa mmol) and the resulting mixture was stirred at ambient temperature for YE 1 hour.

The mixture was evaporated to about a quarter of its volume, then water (0 ml) was added and the mixture was acidified using 1 M citric acid (¥ d=), which led to the formation of a white precipitate. The mixture was stirred for a period of time. Ye min, filtered, washed with water, and dried in vacuum at 0 ºC to obtain:

2-[(38)-1-[5-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl] -6-propoxy-pyridin-2-yl}-3- piperidyl]acetic acid

4 mg; (111) 1

-YVY - 1H NMR (400.13 MHz, DMSO-d¢) 5 1.00 (3H, t), 1.2-1.35 (1H, m), 1.37-1.49 (1H, m), 1.5-1.6 (2H, m), 1.61 - 1.96 (11H, m), 1.97-2.08 (2H, m), 2.1-2.3 (SH, m), 2.82 (1H, dd), 2.95-3.06 (1H, m), 4.03-4.09 (1H, m) , 4.1 - 4.2 (1H, m), 4.25 - 4.28 (1H, m), 4.31 - 4.41 (2H, m), 6.45 (1H, d), 6.9 (1H, 0, 7.97 (1H, d), 8.02 ( 1H, d), 12.2 (1H, s).m/z (ESI+) (M+H)+ = 522; HPLC tr = 2.97 min.° (37) -[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl] -6-propoxy-pyridin-2- yl]-3-piperidyl]acetate. 0 on 0 0 XN ps

N N { (ether (¥ molar solution in trimethylsilyldiazomethane LA of a 1 : mmol) to a volatile solution of 0 mL +.YY4) 2-[(3S)-1-[5-[ ((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl]-6-propoxy-pyridin-2-yl]-3- piperidyljacetic acid ml) at 77 °C over a period ©) toluene : methanol 1 :¥ mmol) in 0.44 cana 00 v) min. The resulting solution was stirred at ambient temperature for 1 hour. 10 h 1

-YV¢ - The mixture was stirred at TMSdiazomethane 001 µl also added dropwise and dripped at ambient temperature for an hour using silica flash chromatography and the mixture was evaporated and the crude product was purified by : The pure fractions were evaporated to dryness to obtain EtOAc methyl 2-[(35)-1-[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propoxy-pyridin -2- yl]-3-piperidyl]acetate .e Lay as a colorless oil and then crystallizes upon precipitation to a solid 1H NMR (400.13 MHz, DMSO-dg) 6 1.00 (3H, t), 1.18 - 1.45 (4H, m ), 57 - 1.9 (13H, m), 1.93 — 2.05 (3H, m), 2.2 - 2.32 (2H, m), 2.79 (1H, dd), 2.9 - 3.0 (1H, m), 3.6 (3H, s ), 3.92-3.98 (1H, m), 4.04-4.1 (1H, m), 4.17 - 4.23 (1H, m), 4.26 - 4.35 (1H, m), 4.4 (1H, s), 6.4 (1H, d ), 7.92 (1H, d), 8.0 (1H, b m/z (ESI+) (M+H)+ = 486; HPLC tg = 2.63 min. (34) Intermediate methyl 2-[( 3S)-1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl]carbamoyl]-6-propoxy-pyridlm-2-yl]-3-piperidyl]acetate

O° NON Free 1S H F U N N §

Yyivi

Y 7 o — — A solution of 0114 “Jw +.) YA) 2-(fluorosulphonyl)difluoroacetic acid mmol) in anhydrous acetonitrile (Je 1) was added dropwise to a solution of : methyl 2-[(3S)-1-[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propoxy-pyridin-2- yl]-3-piperidyl]acetate 0 ° g (0.41 mmol) copper (I) iodides (4 mg ...0 mmol) in anhydrous acetonitrile (0) (Jw) and heated until over a period of 1 hour under nitrogen and the resulting solution was stirred at 0°C for Te min.The reaction mixture was concentrated, diluted with 1086 YO (1086 YO ml) and washed sequentially with (01 XY) water and 100 saturated brine (ml). The organic layer was dried over MgSO;0, filtered and evaporated to obtain the crude product as orange oil. The crude product was purified by flash chromatography on 511168; 01 was eluted to EtOAc Lov in .isohexane and the 1 pure fractions were evaporated to dryness to obtain the desired yield (+ VV mg; 54%( as .pale yellow foam (3H, t), 1.24-1.38 (1H, m), 1.5-1.64 (4H, m), 1.7-1.06 NMR (400.13 MHz, CDCl;) 111 61H, m), 1.82 —2.18 (11H, m), 2.2-2.32 (5H, m), 2.81 (1H, dd), 3.00 - 3.07 (1H, m), 1.8 - (3H, 5 ), 4.10 - 4.15 (1H, m), 4.24.3 (2H, m), 4.36 - 4.42 (2H, m), 6.28 (1H, d), 6.37 3.69 (1H, 1), 8.10 (1H, d), 8.26 (1H, d) m/z (ESI+) (M+H)+ = 536; HPLC tg = 3.46 min. Yyiva

of the corresponding acid compounds. (1Y0) The following examples were prepared in a manner similar to the example method Example MS me 'HNMR § Name 1 Compound No. 536: IH NMR (400.13 MHz, | 3R )-1-[6-YA

HPLC DMSO-d6) 1.36-1.44 (2H, |cyclopentylsulfanyl

R= m), 145-173 (6H, m), | -5-[[(2r,55)-5- ‘ 0 Je 1.88-1.91 (4H, m), 1.92- | (difluoromethoxy)- or a 2.92 2.06 (4H, m), 2.07 - 2.3 | 2- Min. (7H, m), 3.13-3.27 (1H, | adamantyl carbamo ° A m), 3.43 - 3.58 (2H, m), | yl]pyridin-2- 3.60 - 3.72 (2H, m), 3.89- | yl]pyrrolidine-3- 3.95 (1H, m), 3.96 - 4.04 | carboxylic acid (1H, m), 6.17 (1H, d), 6.9 (1H, 1), 7.64 (1H, d), 7.69 (1H, d), 12.5 (1H, s). 548; IH NMR (400.13 MHz, | (IR,5S)-3-[6-VA]

HPLC DMSO-d6) 1.32-1.44 (2H, |cyclopentylsulfanyl

R = m), 145-174 (TH, m), | -5-[[(2r,55)-5- - 0 Ks 1.83 - 1.90 (4H, m), 1.92- | (difluoromethoxy)- or ¢ 2.92 201 (4H, m), 2.05221 | 2- MN min. (7H, m), 3.45-3.55 (2H, | adamantyljcarbamo NHL A m), 3.72 - 3.85 (2H, m), | yl]pyridin-2-yl]-3- ° 3.88-4.02 (2H, m), 6.14 | azabicyclo[3.1.0]he (1H, d), 6.89 (1H, t), 7.60 | xane-6-carboxylic (1H, d), 7.69 (1H, d), 12.3 | acid (1H, s). 524; IH NMR (400.13 MHz, | 2-[(3R)-1-[5- A

HPLC | DMSO-d6) 0.96 (3H, 1), | [[(2r,55)-5- {R = 1.37 - 1.45 (2H, m), 1.57- | (difluoromethoxy)- ¢ 0 mer 1.77 (3H, m), 1.83 - 1.90 | 2- oP oC J 2.84 (4H, m), 1.93-2.04 (4H, |adamantyljcarbamo Loy Ws min. m), 2.08222 (4H, m), | yl}-6- 3 2.39 - 2.49 (2H, m), 2.53 - | propylsulfanyl- 2.62 (1H, m), 3.01 (2H, t), | pyridin-2- 3.05-3.14 (1H, m), 3.3- | yl]pyrrolidin-3- 343 (IH, m), 3.5-3.62 | yl]acetic acid (1H, m), 3.65-3.78 (1H, m), 3.9-3.98 (1H, m), 6.13 (1H, d), 6.9 (1H, t), 7.65 (1H, d), 7.67 (1H, 0 12.20 (1H, 5)). 510; 1H NMR (400.13 MHz, | 1-[5-[[(2r,55)-5- A ] 0

HPLC DMSO0-d6) 0.9 (3H, t), | (difluoromethoxy)- A m R= 1.3-1.4 (2H, m), 1.5 - 1.62 | 2- oa or m (2H, m), 1.77-1.89 (4H, | adamantyl]carbamo J 2.77 m), 1.92.0 (4H, m), -2.03 | yI]-6-min. 2.24 (5H, m), 2.96 (2H, t}, | propylsulfanyl- 3.1-3.22 (1H, m), 3.37- | pyridin-2- 3.48 (ZH, m), 3.52-3.65 | yl]pyrrolidine-3- (2H, m), 3.83-3.9 (1H, m), | carboxylic acid 6.13 (1H, d), 6.84 (1H, 1), 7.6 (1H, d), 7.64 (1H, d), 12.5 (1H, 3).

-YVV-

(YA) Example (S)-2-(1-(5-(Cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2-yl)piperidin-3-yl) acetic acid

0 CI 7 N N | 0 to a volatile solution of: (S)-methyl 2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetate v.OF ana YE ) mmol) in 10 mL methanol) at room temperature to a solution of ¥ (1.7 N) sodium hydroxide was added; 90.? mmol) and the resulting solution 0 was stirred at 10 °C for VA h. The reaction mixture was evaporated to dryness, dissolved in Yo (EtOAc mL) and washed sequentially with HCI? molar ml) and saturated saline (01 ml). The organic layer was dried over MgSO, filtered and evaporated to obtain: (S)-2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2-yl) piperidin-3-yl) acetieacid (ada YY°) 751 as a white solid.

1H NMR (400.13 MHz, DMSO-d¢) 6 0.95 (3H, t), 1.13 - 1.18 (1H, m), 1.22 - 1.30 (6H, m), 1.55 - 1.65 (4H, m), 1.70 - 1.84 ( SH, m), 1.93 - 2.00 (1H, m), 2.13 - 2.24 (2H, m), 2.80 (1H, 1), 2.93 - 3.02 (3H, m), 3.62 - 3.68 (1H, m), 4.03 ( 1H, d), 4.11 (1H, d), 7.63 (1H, d), 7.95 (1H, d), 12.17 (1H, 5) m/z (ES+) (M+H)+ = 438; HPLC tg = 2.83 min. 5 (30) Intermediate 2,6-dichloro-N-cyclohexyl-5-fluoronicotinamide B F | I = cl N cl : mmol) to EY.AT ml ?.16) oxalyl chloride was added in parts by dichloromethane (mmol) in 04.79 can ¥) 2,6-dichloro- 5-fluoronicotinic uncle 0 m. The resulting suspension was stirred at 70°C for an hour. 01 at (Je £0) (Ja V+) DCM and the reaction mixture was evaporated to dryness and dissolved in “Jw Y.£0) cyclohexylamine and this solution was added to parts volatile solution of M. The resulting solution was stirred at Yo ml (at +) dichloromethane mmol) in YY.¢"m for 0 hours. 01 vo) 1 N HCI and washed sequentially with (Jo 5 1) DCM and the reaction mixture was diluted with

-Nor- (Je), water 01 (ml), 01100 saturated (Je 01) and saturated brine (01 ml). The organic layer was dried over MgSO, filtered and evaporated to obtain on the raw output.(5H, 1), 1.57 (1H, m), 1.70 (2H, m), 1.84 (2H, 1.28 (f-0 0 1/18 1H NMR (400.13 MHz, m), 3.72 (1H, m), 8.21 - 8.23 (1H, d), 8.54 - 8.58 (1H, d) m/z (ESI+) M+Acetonitrile = 332; HPLC tg = 2.33 min.° intermediate compound) 3 %( 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide B F 1( = cl N | A solution of “Ja AY 4) amide (trimethylsilyl) was added (4 8.7 mmol) in THF (1 0 M) to a volatile solution of “Jw”.177 (1-propanethiol 1.87 mmol) in DMF (Ja 4) at 0 C over a period of 7 minutes under air.The resulting suspension was stirred at 10°C for 10 minutes.Y) 2,6-dichloro-N-cyclohexyl-5-fluoronicotinamide (g; T.AY mmol) was added in DMF

Ya. — - (Jo 01) at room temperature. The reaction mixture was evaporated to dryness and dissolved in EtOAc (VO) mL) and washed sequentially with water (+ Y mL) and saturated brine (10 mL). The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product. 0 The crude product was purified by flash chromatography on silica with a zero step elucidation to EtOAc ye in -isohexane and the pure fractions were evaporated to dryness to obtain: ca 0 ( 6 - chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide 40 7) as white solid 00/256810 (M+H)+ = 331; HPLC tg = 2.98 min. (AY) intermediate compound (S)-methyl 2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetate 0

FZ

N N

YAY) (S)-methyl 2-(piperidin-3-yl)acetate hydrochloride mg added; 0176 milli

YAY = - mol) to compound 6-chloro-N-cyclohexyl-5-fluoro-2-(propylthio)nicotinamide ) + « © mg; 0.51 mmol) 5 potassium carbonate (41 μl” 1.81 mmol) in butyronitrile (01 ml) at room temperature Bla under air. The resulting suspension was stirred at 1710°C for 80 hours. The reaction mixture was evaporated to dryness, dissolved in EtOAc (+©mL), and washed sequentially with water (0?mL) and saturated saline (01mL). The organic layer was dried on MgSO, filtered and evaporated to obtain the crude product. The crude product was purified by flash chromatography on silica with a zero eluting to EtOAc Tov in isohexane and the pure fractions were evaporated to dryness 01 to obtain: (S)-methyl 2 -(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2- yl)piperidin-3-yl)acetate (ana AR ) 9) as a white solid. 1H NMR (500.13 MHz, DMSO-dg) 8 0.96 (3H, 1), 1.10 - 1.17 (1H, m), 1.24 - 1.32 (5H, m), 1654 - 1.64 (4H, m), 1.70 - 1.73 ( 3H, m), 1.80 - 1.84 (3H, m), 1.97 - 2.02 (1H, m), (2H, m), 2.82 (1H, 1), 2.96 (2H, 1), 3.02 (1H, 1) ), 3.61 (3H, 5), 3.60 - 3.66 (1H, 2.31 - 2.26 m), 4.02 (1H, d), 4.08 (1H, d), 7.63 (1H, d), 7.91 (1H, d) m/z (ESI+) (M+H)+ = 452; HPLC tg = 3.29 min. Yiva

-YAY-

( \ AY) Example (R)-2-(1-(5-(Cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin-2-yl)piperidin-3 -yl) acetic acid

Rice F 0 0 Xx N , 7 I, 2 N \ 0 0 was prepared in a manner similar to that previously reported from: 6-chloro-N-cyclohexyl-5-fluoro-2-( propylthio)nicotinamide using : (8)-methyl 2-(piperidin-3-yl)acetate hydrochloride followed by ester hydrolysis as previously described to obtain the desired compound (+14 mg) as a white solid. (3H, t), 1.08 - 1.22 (2H, m), 1.26 - 1.30 (5H, 0.95 h 1H NMR (400.13 MHz, DMSO-d¢) m), 1:55 - 1.65 (4H, m), 1.70 - 1.84 (5H, m), 1.93 - 1.98 (1H, m), 2.16 - 2.21 (2H, m), (1H, 1), 2.93 - 3.00 (3H, m), 3.60 - 3.70 (1H, m), 4.02 (1H, d), 4.11 (1H, d), 7.63 2.80 (1H, d), 7.95 (1H, d), 12.17 (1H, 5) m/z (ESI+ ) (M+H)+ = 438; HPLC tg = 2.81 min. Yyiva

- YAY - A number of starting materials for: 0 were prepared as part of the previous work program and used according to the following procedures: ‎(R)-ethyl 2-(pyrrolidin-3-yloxy)acetate hydrochloride

HCI

68 0

A ~( 0 : oo 105.47 (; g tert-Butyl (3R)-3-(ethoxycarbonylmethoxy)pyrrolidine-1-carboxylate was dissolved and stirred at ambient temperature for (Je 0+) 1, 4-dioxane mmol) in 1101 4N in times “25 ml” and dry it under a vacuum for 1 , 4-dioxane 9 hours and evaporate it jointly using 1 quenching - () as orange oil is 2 - ( pyrrolidin-3-yloxy)acetate hydrochloride to obtain (7% 10 g; v.Y) precipitation hardness 01 1H NMR (400.13 MHz, DMSO-ds) 6 1.21 (3H, t), 1.89 - 1.98 ( 1H, m), 2.05 - 2.10 (1H, m), 3.14 - 3.4 (4H, m), 4.14 (2H, q), 4.18 (2H, s), 4.29 - 4.33 (1H, m), 9.29 (1H, broad s), 9.65 (1H, broad s). tert-butyl (3R)-3-(ethoxycarbonylmethoxy)pyrrolidine-1-carboxylate QS yall, used as a starting material, was prepared as described below: 1

YAS - - A solution of (trimethylsilyl) in THF (5017 fill 508715 mmol) was added dropwise to a volatile solution of *.41 can 01( (R)-tert-butyl 3-hydroxypyrrolidine-1- carboxylate mmol) in 0 (DMF ml) over a period of 10 minutes under 0100860. The resulting solution was stirred at ambient temperature for 10 minutes. bromo and (A.9Y) ethyl acetate g were added; (oT) 0 by drip in 10 minutes ll) of temperature; (maintaining the temperature below 70 °C using a cold water bath) and the reaction mixture was stirred at that temperature for yh. The reaction mixture was evaporated, Yo + EtOAc (ml) added, and washed sequentially with water (£ times * 50 ml) and 1 saturated saline (9 ml). The organic layer was dried over MgSO, filtered and evaporated to yield the crude product (VE) as orange oil. 0 The crude product was purified by flash chromatography at 511:08 with step-down filtering 01 to EtOAc 750 in -isohexane and the purified fractions were evaporated to dryness to obtain the product (6 aa 777 ) as a pale yellow oil 1H NMR (400.13 MHz, DMSO-d¢) 6 1.21 (3H, t), 1.41 (9H, 9), 1.83-2.01 (2H, m), -3.2 ( 4H, m), 4.12 (2H, s), 4.1-4.2 (5H, m) 3.32 (S)-¢thyl 2-(pyrrolidin-3-yloxy)acetate hydrochloride HCI )0 0 and 0 0 — 75"A1

_Y A oO - : prepared in a manner similar to that reported from 117.7 mm aa). (No (S)-tert-butyl 3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate as oil solidified at precipitation. 0 001 mol) to obtain the desired yield (1 g 1H NMR (400.13 MHz, DMSO-d) 6 1.21 (3H, t), 1.86 - 1.97 (1H, m), 2.04 - 2.12 (1H, m), 3.1 - 3.3 (4H, m), 4.12 2H, , and ZO 4.17 (2H, s), 4.27 - 4.33 (1H, m), 9.3 (1H, broad s), 9.55 (1H, broad s) (S)-tert-butyl ~~ 3-(2-ethoxy-2-oxoethoxy (pyrrolidine-1-carboxylate aS all) used as a starting material was prepared as described below: It was prepared in a manner similar to that previously mentioned from mmol) to obtain 5.40 can (01) (S)- tert-butyl 3-hydroxypyrrolidine-1-carboxylate 0 .pale yellow oil g; , 1.41 (9H, s), 1.83-2.01 (2H, m), 3.2- 3.32 (4H, m), 4.12 (2H, s), 4.1-4.2 (5H, m) (R)-methyl 2-(pyrrolidin -3-yl)acetate hydrochloride

HCI

N oO —0

Vo Ah

YAT - - (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid )© was stirred g; 10111 mmol) in 1101; titrated in dioxane (©mL) at ambient temperature for yo h. The mixture was evaporated and co-evaporated with dioxane (1 x 71 ml) and dried under 0 vacuum and dissolved in methanol (+ 5 ml) at 10 C and saturated solution using 1101 gas. It was then Allow the reaction mixture to warm to ambient temperature and evaporate. The remainder was co-evaporated with methanol (2 X 1 mL) toluene s (? times Te X mL) and co-dried 1H NMR (400.13 MHz, DMSO-d¢) 6 1.52 - 1.57 (1H, m), 2.063- 2.13 (1H, m), 2.47 - m), 2.7-2.8 (1H, m), 3.03 - 3.12 (1H, m), 3.14 - 3.25 (1H, m), 3.27 - 3.48 3H , ,311) :2.59 m), 3.61 (3H, 5), 9.42 (2H, 5) (S)-methyl 2-(pyrrolidin-3-yl)acetate hydrochloride HCI N ge 0 was prepared in a manner similar to that previously mentioned from: CE 70181 can ©) (S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylacetic ~~ mmol) to obtain the desired yield (; g;) 7000 as yellow oil.

- YAY - 111 NMR (400.13 MHz, DMSO-dg) 6 1.52 - 1.57 (1H, m), 2.063 - 2.13 (1H, m), 2.47 - 2.59 (3H, m), 2.7-2.8 (1H, m), 3.03 - 3.12 (1H, m), 3.14 - 3.25 (1H, m), 3.27 - 3.48 (3H, m), 3.61 (3H, s), 9.42 (2H, s).

Ethyl 2-methyl-2-(3-piperidyl)propanoate hydrochloride 0 0

N

H—CI . ethanol (mmol) in 5.7 can V.A+) ethyl 2-methyl-2-pyridin-3-yl-propanoate was stirred mg; 0.09 mmol) under an atmosphere of YAY alumina on rhodium ml) and 75 V + + h. 11 m for YO and at pressure; bar and at a temperature of 100 ml of HCI, a catalyst was added to remove the catalyst, celite, and the reaction mixture was filtered through hydrochloride, and the solvent was evaporated under low pressure to form the dioxane salt ; NV 0 as brown scalded oil ethyl 2-methyl-2-(3-piperidyl)propanoate hydrochloride to yield (7 0.a g; 1) oil 111 NMR (300.073 MHz, DMSO-d) 81.07 - 1.08 (6H, m), 1.20 (3H, t), 1.52 - 1.70 (2H, m), 1.80 (1H, m), 1.96 - 2.04 (1H, m), 2.60 - 2.80 (2H, m), 3.05 - 3.19 (2H, m), 4.08 (2H) q), 8.75 - 9.35 (2H, m) used as a starting material as ethyl 2-methyl-2-pyridin-3-yl-propanoate was prepared and the compound was prepared The description follows:

} YAN — - to a solution of 0.701 (ethyl 3-pyridyl acetate g; 01 mmol) in THF (Yo) mL) solution of .8 was added; Molar of potassium bis(trimethylsilyl)amide in “Ja A+) toluene 60 mmol). The mixture was stirred at ambient temperature for +V min. Before adding Mel (99.¥ TE cde mmol) on one time. The reaction mixture was then stirred at room temperature for 10 oo hours. The reaction mixture was evaporated to dryness and dissolved in DCM (Yo ml) and washed sequentially with 111101 YO (ml) and s (5 ml) and saturated brine (Yo ml). The organic layer was dried. on MgSO, filtered and evaporated to obtain the crude product.The crude product was purified by flash chromatography on silica with a zero step-down eluting to +70 EtOAc 0 in .isohexane and the pure fractions were evaporated pure fractions until dry to obtain:

0 A) 2-methyl-2-pyridin-3-yl-propanoate vol. 9.7 mmol; £V %(as orange oil. 7.39 - 7.35 µL (2H, 4.08 µg) 1H NMR (400.13 MHz, DMSO-dg) 81.14 (3H, 1), 1.55 (6H, (1H, m) ), 7.70 - 7.75 (1H, m), 8.46 - 8.48 (1H, m), 8.56 (1H, d) m/z (ESI+) (M+H)+ = 194; HPLC tg = 0.71 min.

00d ethyl 1-(3-piperidyl)cyclopropane-1-carboxylate hydrochloride ~~ 0 0 N H—Cl was prepared in a manner similar to that mentioned by reacting ethyl 2-pyridin-3-ylacetate with:

«ethyl 1-pyridin-3-ylcyclopropane-1-carboxylate to obtain 1,2-dibromoethane thereafter to obtain the desired compound as brown oil (quantitative reaction 'H NMR (400.13 MHz, DMSO-dg) 81.03 - 1.22 (5H, m), 1.23 - 1.28 (2H, m), 1.45 - 1.83 (SHem), 2.67 - 2.93 (2H, m), 3.02 - 3.36 (2H, m), 4.01 - 4.08 (2H, m), 8.75 - 9.35 (2H, m) ethyl 1-(3-piperidyl)cyclobutane-1-carboxylate hydrochloride 0 B 0 N H—CI was prepared in a manner similar to that previously mentioned by the reaction of ethyl 2-pyridin-3-ylacetate to obtain 1,3-dibromopropane to give ethyl 1-pyridin-3-ylcyclobutane-1-carboxylate which was then hydrogenated to obtain the desired compound as brown oil deli ) Quantitative. 5H, m), 2.58 - 2.78 (2H, m), 3.19 (2H, d), 4.13 (2H, q), 8.90 - 9.42 (2H, d)

Vo ethyl 2-methyl-2-(4-piperidyl)propanoate YH

Ya. - | - 0 x" N stirred V.VY can 0.9 0( ethyl 2-methyl-2-pyridin-4-yl-propanoate mmol) in rhodium log (Je Yoo ) ethanol on YO (alumina mg 0.0/9 mmol) under an atmosphere of hydrogen at a pressure of 4 bar and a temperature of YO 2 for 11 hours.0 and the reaction mixture was filtered through celite to remove the catalyst and the solvent was evaporated under reduced pressure to obtain ethyl 2-methyl-2-(4-piperidyl)propanoate as quantitative Gey black oil (6H, s), 1.17 (3H). , 0. 1.25 - 1.33 (2H, m), 1.04 6 W-0150 1H NMR (300.073 MHz, (1H, d), 1.52 - 1.64 (2H, m), 1.80 (1H, s), 2.55 - 2.61 (2H, m), 3.09 (2H, d), 4.05 1.48 (2H) q) ethyl 2-methyl-2-pyridin-4-yl-propanoate used as 4534 starting material was prepared As described below: To a solution of 1.017 (Je 0105 ) ethyl 4-pyridy! acetate mM) in (Ja Ye.) DMF LIHMDS V0.1 (0) was added; 10.00 mmol). The reaction mixture was stirred at room temperature for 1 hour before 11118405 was also added (10.10 ml; 1 5 mmol). The reaction mixture was stirred for another hour at room temperature before yavia was added

911 - - methyl iodide (also VY) ml; 115.4 mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness, dissolved in (Je 10+) DCM, and washed sequentially with saturated NH,Cl (Yo ml) and 0 (c ml) and saturated brine (Yo ml). The organic layer was dried over MgSO, filtered and evaporated to obtain the crude product. The crude product was loaded onto celite and purified by flash chromatography on silica with zero stepwise eluting to EtOAc 78 0 at 0A*©1900. The pure fractions were evaporated to dryness to obtain 9.90 can 001 11 (ethyl 2-methyl-2-pyridin-4-yl-propanoate mmol 45 7) as yellow oil. m/z (ESI) (M+H)+ = 194; HPLC tg = 2.44 min ethyl 1-(4-piperidyl)cyclobutane-1-carboxylate 0 » N was prepared in a manner similar to that mentioned previously by reacting ethyl 4-pyridil acetate with ethyl 1-pyridin to obtain quantitative reaction (2H, t) , 1.10 - 1.23 (5H, m), 1.50 - 1.54 (2H, 1.06 h 1H NMR (300.073 MHz, DMSO-d) m), 1.63 - 1.75 (3H, m), 1.83 (1H, s) , 1.95 - 2.01 (2H, m), 2.22 - 2.28 (2H, m), 2.42 (1H,

- Yay - d), 2.99 (1H, d), 4.07 2H, q) ethyl 1-(4-piperidyl)cyclopropane-1-carboxylate y x

N

With ethyl 4-pyridil acetate, it was prepared in a manner similar to that previously mentioned, by the reaction of which ethyl 1-pyridin-4-yleyclopropane-1 -carboxylate 1,2 dibromoethane ethyl 0 was then hydrogenated to obtain the required compound. As black oil (by quantum reaction). 111 NMR (300.073 MHz, DMSO-dg) 0.73 - 0.78 (2H, m), 0.92 - 0.98 (2H, m), 1.14 (3H, 1), 1.23 - 1.32 ( 2H, m), 1.42 - 1.50 (2H, m), 2.38 (2H, 1), 2.89 - 2.93 (4H, m), 4.01 (2H, 9) ethyl 2-(3-piperidyloxy)propanoate | 0 0 0 L: \ Obtaining ethyl 2-pyridin-3-yloxypropanoate was prepared in a manner similar to that mentioned previously from (quantitative reaction) black gum on the required compound as black gum 1H NMR ( 300.073 MHz, (W-1150 6 1.17 - 1.22 (SH, m), 1.25 - 1.27 (2H, m), 1.38 (2H) d), 1.64 - 1.68 (2H, m), 1.76 - 1.86 (2H, m), 2.76 - 3.05 (2H, m), 3.36 - 3.42 (1H,

Yyivi

- yar - m), 4.03 - 4.18 (3H, m) ethyl 2-methyl-2-(3-piperidyloxy)propanoate 0

N 0 0”: Prepared in a manner similar to that previously mentioned to obtain the desired compound as black gum ethyl 2-methyl-2-pyridin-3-yloxy-propanoate, quantitative reaction). 1H NMR (300.073 MHz) , DMSO-d6) 6 1.20 (3H, 0.1.23 - 1.28 (2H, m), 1.30 (6H, 5), 1.54 - 1.59 (1H, m), 1.82 - 1.91 (1H, m), 2.20 - 2.29 ( 2H, m), 2.69 (1H, d), 2.95 - 2.97 (2H, m), 3.17 - 3.28 (1H, m), 4.10 (2H, q) ethyl 2-(3-piperidyloxy)acetate 0 0

N oJ 7: Then prepare it in a manner similar to that previously mentioned to obtain the required compound as brown gum ethyl 2-(2-chloropyridin-3-yl)oxyacetate (quantitative reaction) \o 1H NMR (300.073 MHz) , DMSO-d6) 6 1.20 (3H, t), 1.54 - 1.65 (2H, m), 1.76 - 1.84 (2H, m), 2.89 - 2.95 (4H, m), 3.13 - 3.19 (1H, m), 3.68 - 3.76 (1H, m), 4.12 (2H, q), 4.20

(2H, s) for the final products. And ester is done, and as part of the previous work program, the number of intermediate compounds has been distinguished in typical examples, giving the following:

MS m/e "HNMR & Name: Ester

MH’ 564; 1H NMR (300.13 MHz, | methyl 2-[(3S)-1-

HPLC | CDCI3) 0.97 (3H, t), [5-[((2r,55)-5- | 0 tR = 1.15- 1.35 (2H, m), methylsulfonyl-2- O° db 272 1.55 - 1.75 ( 5H, m), adamantyl)carbam and Kim p. min. | 1.82 - 1.87 (1H, m), oyl]-6- N 1.94 - 2.26 (14H, m), propylsulfanyl- 2.70 - 2.80 (4H, m), pyridin-2-yl]-3- 2.92 -3.01 (1H, m), piperidyl]acetate 3.07 - 3.18 2H, m), 3.63 (3H, s), 4.11 -4.25 (3H, m), 6.32 (1H, d), 7.05 (1H, d), 7.84 (1H, d) 442; 1H NMR (300.072 methyl (IR,5S)-3- | >No

HPLC | MHz, CDCI3) 1.59 (t, [5-(2- oP H tg = 1H), 1.64 - 1.81 (m, adamantylcarbamo XO 3.09 4H), 1.82 - 2.07 (m, y1)-6 H to the power S $min 10H), 2.24 - 2.29 (m, methylsulfanyl- Qs 2H), 2.56 (s, 3H), 3.58 | pyridin-2-yl}-3- I 0 (d, 2H), 3.70 (s, 3H), azabicyclo[3.1.0]h 3.87 (d, 2H), 4.20 - 4.30 | exane-6- (m, 1H), 6.05 (d, 1H), carboxylate 6.82 - 6.93 (m, 1H), 7.84 (d, 1H) 514; | 1H NMR (300.072 methyl (3R)-1-[6-1

HPLC | MHz, CDCI3) 1.29 - cyclohexylsulfanyl | o tr = 2.38 (m, 26H), 3.23 -5-[((21,55)-5- bs 0 2.65 (quintet, 1H), 3.47 - hydroxy-2- no min. 3.58 (m, 1H) ), 3.59 - adamantyl)carbam Aw 3.70 (m, 1H), 3.72 - oyl]pyridin-2- Ts 3.81 (m, SH), 3.94 - yl]pyrrolidine-3- 0 Xn 4.05 (m, 1H), 4.19 - carboxylate 4.27 (m, 1H), 6.11 (d, 1H), 7.14 - 7.20 (m, 1H), 7.92 (d, 1H)

-Ydo-458:1H NMR (300.072 methyl (3S)-1-oy"

HPLC | MHz, CDCI3) 1.03 (t, [(2r,55)-5-(2- 2 tR = 3H), 1.61 - 2.09 (m, adamantylcarbamo f 3.33 16H), 2.31 (q, 2H), 3.15 | yl)-6- NA NS min. -3.28 (m, 3H), 3.45 - propylsulfanyl- Cs 3.87 (m, 7H), 4.22 - pyridin-2- 4.32 (m, 1H), 6.10 (d, yl]pyrrolidine-3- 0 2 1H), 7.04 - 7.13 (m, carboxylate 1H), 7.90 (d, 1H) 429; 1H NMR (300.072 methyl 3-[5-0 0

HPLC | MHz, CDCI3)0.70 (t, | (cyclohexylcarbam 26 t= 1311, 1.20- 1.52 (m, oil)-6- 8 JL 0 3.06 7H), 1.58 - 1.69 (m, propylsulfanyl- 0 9 1 min 1H), 1.70 - 1.82 (m, pyridin-2- N 2H), 1.95 - 2.09 (m, yljoxybenzoate 2H), 2.71 (t, 2H), 3.93 (s, 3H), 3.96 - 4.08 (m, 1H), 6.31 (d, 1H), 6.68 (d, 1H), 7.33 (d, 1H), 7.48 (t, 1H), 7.81 (s, 1H), 7.91 (d, 1H), 7.95 (d, 1H) 458; 1H NMR (300.072) methyl 2-[(3R)-1-1/

HPLC | MHz, CDCI3) 1.38 (t, [5-(2- pu tr = 3H), 1.61 - 1.81 (m, adamantylcarbamo | 0° * 328 | SH), 1.81-2.08(m, |yl)-6 m b min.10H), 2.24 (q, 1H), 2.49 | ethylsulfanyl- NS (d, 2H), 2.65 - 2.79 (m, |pyridin-2- Cs 1H), 3.10 - 3.21 (m, yl]pyrrolidin-3- I 0 1H), 3.23 (q, 2H), 3.48 | yl]acetate (g, 1H), 3.59 - 3.69 (m, 1H), 3.71 (s, 3H), 3.79 (t, 1H), 4.21 - 4.31 (m, 1H), 6.08 (d, 1H), 6.99 - 7.05 (m, 1H), 7.88 (d, 1H) 493 1H NMR (400.13 MHz, |methyl (1R,5S)-3- 9 N

CDCI3) 1.63 (4H, m), | [6-cyclopentyl < rh(" 1.69 -1.80 BH, m), | sulfanyl-5-(3- 1 or \ / 211-220 BH.m), | pyridin-3-yl 0 NTS 2.25 (2H , s), 2.36 (1H, | pyrrolidine-1- N° 4 2 s), 3.52 - 3.60 (4H, m), | carbonyl)pyridin- 3.69 (4H, s), 3.74 - 3.87 | 2 -yl]-3-azabicyclo (4H, m), 4.05 - 4.12 [3.1.0]hexane-6- (2H, m), 5.99 (1H, d), carboxylate 7.21 -17.29 2H, m), 7.57 (1H , s), 8.41 — 8.47 (1H, m)

Yyiva

504 1H NMR (300.072 methyl 2-[(3S)-1- || 0

MHz, 01013( 1.10 - [6- 0° XN ON 1.40 (10H, m), 1.52 - cyclopentylsulfany or Th 1.80 (12H, m), 1.86 - 1-5-[3-(2- eh no 5 1.95 (2H, m), 2.08 - hydroxypropan-2- A 2.16 (3H, m), 2.26 - yl)piperidine-1- 2.29 (2H, m), 2.60 (1H, |carbonyl]pyridin- 5), 2.72 -2.79 (2H, m), |2-yl]-3- 2.92 - 3.01 (1H, m), piperidyl]acetate 3.69 (3H, s), 4.03 - 4.16 (2H, m), 4.24 (1H, d), 6.31 (1H, d), 7.19 (1H, 0) 420 1H NMR (300.072 methyl 2-[(3S)-1-||0

MHz, CDCI3) 1.01 3H, | [5-(piperidine-1- | pp ©), 1.22 - 1.35 (1H, m), | carbonyl)-6- » © 1.62 -1.78 (11H, m), | propylsulfanyl- 0 11 9 1.87 - 1.93 (1H, m), pyridin-2-yl}-3- N 2.03 - 2.13 (1H, m), piperidyl]acetate 2.22 - 2.35 (2H, m), 2.71 -2.80 (1H , m), 2.92 - 3.02 (1H, m), 3.05 - 3.17 (2H, m), 3.43 - 3.65 (3H, m), 3.69 (3H, 5), 4.13 —-4.25 (2H, m), 6.32 ( 1H, d), 7.21 (1H, d) 456; 1H NMR (400.13 MHz, |methyl (1S,5R)-3-1b i

HPLC | DMSO-d6) 1.26 (3H, 1), | [5-(2- NE N tR = 1.49 - 1.54 3H, m), adamantylcarbamo WON Ns 3.31 1.71 (2H, s), 1.77 - 1.81 | yl)-6-TL min. | (5H, m), 1.84 (1H, s), | ethylsulfanyl-1 ~2 1.91 2H, s), 2.05 - 2.08 | pyridin-2-yl]-3- (2H, m), 2.23 - 2.24 azabicyclo[3.1.0]h (2H, m), 3.03 (2H, q), exane-6- 3.51 (2H, d), 3.62 (2H, | carboxylate s), 3.81 (2H, d), 3.92 - 3.97 (1H, m), 4.01 - 4.09 (1H, m), 6.15 (1H, d), 7.62 - 7.67 (2H, m)

434: | 11110018 (400.13 MHz, | methyl 2-])38(-1- || ° 0

HPLC | DMSO-d6) 0.95 (311, 0, |). [5- Wal Mb, Lbt 110-118 | alive | (cyclohexylcarbam or 3.14 | 1.20-1.30 (5H, m), oyl)-6-b Ns min. 1.42 (1H, d), 1.60 (3H, |propylsulfanyl-N m), 1.64 - 1.69 (2H, m), | pyridin-2-yl]-3- 1.73 (1H, m), 1.79 (3H, | piperidyljacetate©), 1.85 - 1.90 (1H, m), 2.29 (2H, m), 2.73 - 2.79 (1H, m), 2.86 - 3.00 (3H, m), 3.63 (4H, d), 4.18 (1H, d), 4.27 (1H, d), 6.48 (1H, d), 7.62 (1H, d), 7.79 (1H, d) 444 : |IH NMR (400.13 MHz, |methyl (3S)-1-[5- .

HPLC | DMSO-d6) 1.27 3H, 1), | (2- or Jey tg = 1.52 (2H, d), 1.72 (2H, |adamantylcarbamo | 1 325 |s),1.78-1.86 (6H, m), |yl)-6- | NWT min. 1.92 (2H, s), 2.08 2H, | ethylsulfanyl- vw 5 0, 2.15 -2.21 (1H, m), | pyridin-2- s 2.24 - 2.30 (1H, m), yl]pyrrolidine-3- 3.06 (2H, q), 3.27 -3.36 | carboxylate (2H, m), 3.48 - 3.58 (2H, m), 3.67 (3H, s), 3.70 - 3.75 (1H, m), 3.94 - 3.99 (1H, m), 6.19 (1H, d), 7.58 ( 1H, d), 7.67 (1H, d) 452; | IHNMR (500.13 MHz, |methyl 2-[GR)-1- || o 10

HPLC | 101150-060 (0.96 3H, t), | [5- M Fan. tr = 1.06 - 1.11 (1H, m), (cyclohexylcarbam T ref 329 11.24 - 1.32 (5H, m), oyl)-3-fluoro-6- | = min. 1.54 - 1.64 (4H, m), propylsulfanyl- N 1.70 - 1.73 (3H, m), pyridin-2-yl]-3- 1.80 - 1.84 (3H, m), piperidyl]acetate 1.97 - 2.02 (1H, m) , 2.26 -2.31 (2H, m), 2.82 (1H, ©), 2.96 (2H, 1), 3.02 (1H, 1), 3.61 (3H, 5), 3.60 - 3.66 (1H, m), 4.02 (1H , d), 4.08 (1H, d), 7.63 (1H, d), 7.91 (1H, d) chi

500: 111 NMR (300.073 ethyl 1-[1-[5- ™ 6 for HPLC | MHz, DMSO-d6) 0.81 - | (cyclohexylcarbam | pyr? tR = 0.88 (2H, m), 1.00 - 1.08 | oyl)-6- N salt 3.71 (2H, m), 1.15 BH,¢), cyclopentylsulfany 5 min. 1.25 (3H, m), 1.35 - 1.41 | l-pyridin-2-yl]-3- (1H,m), 1.44 - 1.50 piperidyl]cyclopro (5H,m), 1.48 - 1.74 pane-1- (10H,m), 1.75 - 1.82 carboxylate (2H,m) ), 2.03 - 2.11 (2H, m), 2.71 - 2.89 (2H, m), 3.60 - 3.65 (1H, m), 3.87 -3.93 (1H, m), 3.98 - 4.07 (2H, ,rw 4.32 - 4.45 (2H, m), 6.47 (1H, d), 7.57 - 7.60 (1H, d), 7.72 (1H, d) 448;1H NMR (400.13 MHz, |methyl 4-[[[5-o

HPLC | CDCI3) 0.87 - 0.98 (5H, |(cyclohexylcarbam for tR = m), 1.12 - 1.25 (3H, m), |oyl)-6- or 3.09 1.29 - 1.41 (4H, m), propylsulfanyl- NT SNE Nsmin. 1.49 - 1.55 (2H,m), pyridin-2-7 1.61 - 1.70 (4H,m), yl]amino]methyl]c ; N 1.83 (2H, d), 1.92 - 1.97 | yclohexane-1- (4H, m), 2.14 2.22 carboxylate (1H, m), 3.06 (2H, t), Po 3.15 (2H, t), 3.59 (3H, s), 3.82 -3.83 (1H, m), 4.90 (1H, s), 6.01 (1H, d), 6.43 (1H, d), 7.62 (1H, d) 476, | 1H NMR (400.13 MHz, | ethyl 2-[1-[5- > 8]

HPLC | 010013( 0.96 (3H, 1), (cyclohexylcarbam | 0-20 mM, tR= 11.12 311,9, 1.15 (3H, | oil)-6- 348 |s),1.17-1.22 (4H, m) ), | propylsulfanyl- Foy " min. 1.23 (1H, d), 1.30 - 1.38 | pyridin-2-yl]-3- N (2H, m), 1.45 - 1.55 piperidyl]-2- (2H, m), 1.58 - 1.75 methyl-propanoate (9H, m), 1.92 - 1.96 (2H, m), 2.59 - 2.65 (1H, m), 2.70 - 2.74 (1H, m), 2.96 - 3.03 (1H, m), 3.12 - 3.19 (1H, m), 3.88 - 3.95 (1H, m), 4.09 (2H, q), 4.33 (2H, d), 6.25 (1H, d), 6.38 (1H, d), 7.70 (1H, d)

Yyiva

- yaa - 498 HNMR (400.13 MHz, | methyl 2-[(3S)-1- | 0 0

DMSO-dg) 1.09 - 1.15 | [5- with re (1H, m), 1.21 - 1.31 (cyclohexylcarbam | l (5H, m), 1.40— 1.48 | oyl)-6-(2-pyrazin- NS Ns (1H, m) , 1.57 - 1.65 2- (2H, m), 1.69 - 1.75 ylethylsulfanyl)pyr AN (4H, m), 1.81 - 1.91 idin-2-y1]-3- Ne (1H, m), 2.19 --2 piperidyl] acetate (2H, m), 2.73 -2.79 (1H, m), 2.90 — 3.00 (1H, m), 3.12 (2H, f(3.35(2H, 1),3.39-3.46 (1H, m), 3.56 (3H, s), 3.58 - 3.63 (1H, m), 4.22 (1H, d), 4.32 (1H, d), 6.52 (1H, d), 7.67 (1H, d), 7.82 (1H, 4d), 8.49 (1H, d), 8.52 - 8.55 (2H, m) 496 H NMR (400.13 MHz, |methyl 2-[(35)-1-|0 O)

CDCl) 1.21-1.33 (3H, |[5-in or m), 1.41 — 1.50 (3H, m), | (cyclohexylcarbam | JH 1.53 - 1.63 (2H, m), oyl)-6- NS NTS 1.68 - 1.73 (3H, m), phenethylsulfanyl- 1.88 - 1.92 (1H, m), pyridin-2-yl}-3- 1.96 - 2.00 (2H, m), piperidyl]acetate 2.03 - 2.09 (1H, m), 2.22 (2H, d), 2.75 - 2.81 (1H, m), 2.98 - 3.04 (3H, m), 3.36 - 3.47 (2H , m), 3.65 (3H, s), 3.90 -- 4.03 (1H, m), 4.23 - 4.30 (2H, m), 6.33 — 6.43 2H, m), 7.19 - 7.32 (5H, m), 7.78 (1H , d)

Claims (1)

C Claims 1 1 - Compound with formula (1): RY - 9 a “Or x | N° a Le 1 1 (l) where: ; be about a single bond [bondr p1] p80” or -0-, or -8-; or NRI15)—where © is RP of concurrent or adsorbent hydrogens or RY forms splice 1 plus the nitrogen atom to which they are bonded to a ring Saturated with a number of atoms from; to 7; : about ple RU is 1 Cigalkyl, “in absolute Cygalkynyl, Cs.scycloalkyl, Cs.scycloalkylCy.salkyl, A Ci.icycloalkylCy alkenyl, Cs.jcycloalkylCysalkynyl, phenyl, phenylC,.;alkyl, 1 heteroaryl, heteroarylC_salkyl, heterocyclyl, or heterocyclylCj.zalkyl Ye : each of them has an optionally substituted by a group; or two groups; or three to be chosen from 11 (hydroxy, halo, oxo, cyano, trifluoromethyl, cisalkoxy, carboxy moiety) VY C1.3alkylS(O)p- VY (where « is a zero, a 1, a 7, or “) and: 1 € R'CONR?)-, C(0)-, R¥OC (0)- and (R*)(R*INSO,- Vo has an optional substitution with the number of substitution groups 1 or 7; Craalkyl is R (where 11 and tcyano 3 < halo s chydroxyl ?is independently selected from 11 A choice 1 and “C independently from hydrogen and 1 Walden,© has an optional substitution of a number — ray chalo 5 hydroxyl substituent groups 1 or ?; or? Independently selected from VA nitrogen together plus an RY atom form the carboxy U cyano s and two “shells?” and V9 in the form of alg]) 7 has the number of members of ; to the saturated ring to which they are attached to a saturated ring Ye in heterocyclyl and an additional heterocyclyl group Choice of optional substituting groups for 71 : the first 0 wanted it:”)16 of YY 9) or 1 (where “a is a yellow or RY, RUCO- RUSOK YY is in !82 optional substitution with the number of substitution groups 1; or ? Cus R¥CHOC(0)-5 ; ? ¢ or trifluoromethyl and cyano s <hydroxy <halo chosen independently from Sy YO thydrogen is R' when © is a bond it can be YT Yv R? is chosen from Ce.12polycycloalkyl(CHp)m- 9 «Cs.cycloalkyl(CHa)m- (where YA polycycloalkyl s cycloalkyl rings optionally include one or two atoms per ring and are YA can be selected independently from coxygen 5 “nitrogen and sulfur ¢sulfur” and “” is a zero, 1 0, or ¥ and optionally replaces the rings by the number of substitution groups −1, −, or © is 1 independently selected from (RE 13 are selected from Cj.cycloalkyl 5 hydrogen ©Abu Lakbar and ¢C3.cycloalkylmethyl YY form 18 and 23 Lae plus a nitrogen atom to which they bond to a monosaturated system ;? saturated mono or bicyclic ring or bridge system optionally containing one or two additional Yo atoms heterocyclic selected from oxygen s enitrogen and sulfur 1 optionally fusing with a saturated ring; or “partially-saturated” or unsaturated YTV single-loop where in the resulting loop system there is an optional substitution with the number of substitution groups 0; FA, 1, or ¥ is chosen independently of RT 4 R* is selected as a “Cyalkoxy “cyano” Cjaalkyl Yivs Ls strifluoromethyl ( 0 1) RE and 87 are independently selected from: hydroxyl, halo, oxo, carboxy, cyano, trifluoromethyl, rR', R°0-, R'CO-, R'C(0 (0-, 3 R®)R'")N-, 228(0)- Al -(7710R°CONR®)-, £8 where a is zero to 1 and: 0 (LATARMQAF 71 p. 208010877 : 0180 -(2200)0 phenyl s heteroaryl groupss 1 [where phenyl and heteroaryl groups are optionally combined with “heteroaryl 5” phenyl £V or a saturated or partially-saturated Liss loop having EA of © atoms or 1 optionally containing a discontinuous 1; or ?” or £9 chosen independently from the oxygens enitrogen and sulfur and in the resulting ring system 0 is optional substituent with the number of substituent groups 1;, 7, or ¥, independently selected from: Cialkyl, hydroxyl, cyano, trifluoromethyl, triffluoromoxy, halo, C;_4alkoxy, 51 Ci4alkoxyC alkyl, C .4alkoxyCi.salkyl, amino, N-C 1-salkylamino, di- oY N,N-(C;.salkyl)amino, N-C)_salkylcarbamoyl, di-N,N-(Ci.4alkyl) ) carbamoyl, ov C14alkylS(0)r-, Ci4alkylS(0),C alkyl ot 00 where: is a zero, a 1, and ?)]; 1 is in “18 substituents with Crsalkyl having an optional substitution with the number of substitution groups 1 or ?; or OV? Independently selected from ¢cyano _s hydroxyl, halo, C;4alkoxy, carboxy OA Independently selected before, 7 and 77 from hydrogen and in Cpaalkyl optional 4 substituted with hydroxyl, halo, C4alkoxy, carboxy or ¢(cyano ple Pos Te for zero, 1, or ?; 1 is either Ble for M Laie -0(0112)-, -S(CH) ¢ or - NR)(CH) is RZ Yava srs - for hydrogen, cialkyl or Crs alkanoyl where q is zero or 1; and TY is Y is: 1) 4 “C3-7cycloalkdiyl ring or cphenylene ring or cadamantdiyl group or 5 saturated heterocyclic ring with number of © atoms to V (connected by 17 atoms Krebson ring containing Atoms other than heteroatoms dilate Y 1 and A 11 are selected from oxygen “nitrogen and sulfur from Ttmln or -[(B05(]) (where TA independently selects RyRy from L” divorced hydroxyl 5 hydrogen, Cjsalkyl, or RyRy KE 4 together with the carbon atom to which they are attached to the C3-Teycloalkdiyl ring Ve and “” is 1 or SY “© or © or ; or 0) and when it is » greater than 1 then 1 can optionally suppress the group by - (=O or -8-© or group NRY)- where VY 9p is ¢Crsalkyl sl hydrogen (Y 1" Together, X-Y- represents a group with the formula: 1 liter Yo (ZWCR)(RM)]- where: A and it is tcarboxy with a ZUCRDR™ group)]: pyridine is bonded to an A group with a yy bond of 7 having a number of atoms of ; to spirsd is a monomeric heterocyclic ring system; or binary 8 plus an atom other than pyridine to which a nitrogen ring is attached comprising a vq™sulfur ring atom and coxygen s 100860 conjugate to the ring selected from 0 1m is 2 being -0-; or -8-; or -9 to 1108 where each is hydrogen, Cy. Da'as AY al-Isam al-Lamiyyah or al-Talad; AT _be; is zero or 1 over condition when s is zero and + is 4 zeros; : From RY are independently selected AC Cilaskyl, Cpsalkenyl, C,.alkynyl, hydroxy, halo, oxo, cyano, trifluoromethyl, A C1.salkoxy, Ci.3alkylS(O)o- AY DoT for zero, 1, , ?, or Ble n (where AA is 4 moles of OC(0)- and -(0) Ola (At), (1l001108!L) (where eR! is 0 for Craalkyl optional substituting with <hydroxyl i.e. halo or Cyano 1) RYT and  are independently chosen RY of Cpsalkyl s hydrogen optionally substituted with a hydroxyl, halo, C;.alkoxy, carboxy 7 or (cyano or JE alg and aR" plus AY a nitrogen atom that attached to a ring having a number of atoms from − to 7 − 4 be leu from zero or 1 or − 9 RP and RY of Craalkyl s hydrogen are independently selected or can be formed SRB RM 41 plus the carbon atom to which they bond to the ¢Cs.cycloalkyl ring AY is ples about zero, 1, or 4, or a pharmaceutically acceptable salt thereof or an ester thereof to decompose in the living organism.4 Provided that the compound is not: {(35)-1-[5-(adamantan- 1 -ylcarbamoyl)pyridin-2-yl]piperidin-3-yl } opaque acid; Yoo or 011 {(35)-1-[5-(cyclohexylcarbamoyl)-6-(piperazin-1-yl)pyridin-2-yl]piperidin-3-01" yl}acetic acid; 01 — Y “0 —- 04 or a pharmaceutically acceptable salt thereof ester sf thereof is hydrolyzable in the organism. 101 1 7 - Compound according to claim No. (1); where: “© is ©0; or 8 or a single bond and mine is: Crealkyl, strictly speaking Cs.cycloalkyl, Cs.cycloalkylCsalkyl, ¥ C3.scycloalkylC, jalkenyl or CsscycloalkylCs jalkynyl t [(each having an optionally substituted with one, two, or three groups chosen from © C3alkyl, hydroxy, halo, oxo, cyano, trifluoromethyl, C 13alkoxy, Ci.3alkylS (O)p- 1 : (¥ or Y is zero ' or 3 or n (where 7 is A -(7060 807871160 -) 200011 and 877205 (180) (where RY is 4 anna wal ham© 4 Optionally substituting with the number of substitution groups 1-, 7-, or ¥ Vo is chosen independently from shy tcyanos halo hydroxyl KEs and *# independently selected from 1-hydrogen and an alkyl is optionally substituted with 1 groups ; or 7a or 7 is chosen independently VY from <hydroxyl and tweezers sR J 0 cyano carboxy s «Cisalkoxy s 10 T in addition to the nitrogen atom to which they are attached to a saturated ring with the number of atoms of ; to JY b" 1 * - the Ty compound of claim (1); where © is -8- and the Y expression is Crgalkyl or Cy5cycloalkyl or . CsqcycloalkylC.salkyl 1 + - compound according to any of the (FU) claims where m is a zero. - Yr. - : to ;) where 182 are selected from 1) Compound according to any of the claims from - © 1 Copppolycycloalkyl (CHz)m- (where m is a zero " or 1 or ? and optionally replace the rings by the number of substitution groups 01 or ; is chosen independently out of 5 and independently select kg of <hydroxyl and ml (trifluoromethyl 5©) 1 1 - Wy compound of any of the claims 1(1 through 0) where BR is hydrogen Y 1 7 - compound according to any of the claims from 1( to of where 82 and 83 together form Y plus the nitrogen atom to which they are attached to a saturated monocyclic system optionally containing an atom Additional heterocyclic is selected from oxygens “nitrogen ¢ and sulfur” sulfur and has an optional substitution with the number of substitution groups 1; or 7 © is chosen independently from 7 where 187 are selected from <hydroxy, clamp and trifluoromethyl ,-0- is X where oY is to 1 (compound according to any of the claimants of - +1 or atollene or emissivity <hydrogen or -8- or put where A is is a saturated or heterocyclic “cycloalkdiyl” ring that is not an F ring (with a carbon atom attached to the ring) having a V number of atoms from * to heterocyclic .sulphur or oxygen or nitrogen selected from Y or 1 heteroatoms © vy — — 1 1 - the By compound of any of the claims from (1) to oY where -72-7- together represent a group " of the formula: (R10), LJ v [C(RB)(RM)];- ; 0 where: © ring A is bonded to a pyridine group [CORR] is bonded to a tcarboxy group and 1 lm is a “mono-membered, bi- or spiro 1” heterocyclic system It has the number of atoms of ; to 1 and includes a nitrogen atom attached to a pyridine ring and optionally A additionally another heterocycle selected from enitrogen, coxygen and sulfur 4 excise ?; ¢ trifluoromethyl and halo s chydroxy 5 from the polymers” RY are independently selected 0 ;1 is n being a zero; or 11 R“5R” or can form Crsalkyl shydrogen and “8 of RY are independently selected 1” together plus the carbon atom to which they are attached to the urethane ring 0:767610; and 0 " ." or 1 is a zero or a noct VE 1 01 - Compound according to Claim No. (1), where it is: 2-[(3R)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-y1]-3- y piperidyl]acetic acid ¥ 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin -2-yl]piperidine-3 carboxylic ¢ acid °1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperidine-4-carboxylic 1 m acid v -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] -4-piperidyl]acetic A 5[-1[-2 acid 1 -(cyclohexylcarbamoyl)-6- propylsulfanyl-pyridin-2-yl] -3-piperidyl]acetic Ye 5[-1[-2 acid M -[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidine-3 - carboxylic A 1 acid 1 2-[(3S)-1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] -3- V¢ piperidyl}acetic acid Ve - (cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperazin- 1-yl]acetic 1 5[-4[-2 acid VY (3R,5S)-4-[[5-(cyclohexylcarbamoyl) -6-propylsulfanyl-pyridin-2-yl Jamino] 8 adamantane-1-carboxylic acid 4 (3R,5S)-4-[[5 ~(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJamino] ve adamantane-1-carboxylic acid 91 [5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yi] -methyl-amino] YY ]-4 cyclohexane-1-carboxylic acid vv 2 -[(3S5)-1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] pyrrolidin-3- vi yl]acetic acid yo -[5-(cyclohexylcarbamoyl)-6-propylsulfanyl -pyridin-2-yljoxybenzoic acid v1 3 3-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] sulfanylbenzoic acid YY 4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin- 2-yl] sulfanylbenzoic acid YA 4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxybenzoic acid v4 Yava .M 2-]4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxyphenyl] acetic ¥. acid 9 3-[4-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] oxyphenyl] vy propanoic acid vy 2-[4-[5 -(cyclohexylcarbamoy!)-6-propylsulfanyl-pyridin-2 -yl] sulfanylphenoxy] vi acetic acid vo 2- [4-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJoxyphenoxy] acetic v1 acid vY 2-[4-[5-(cyclohexylcarbamoyl)-6-propylsul fanyl-pyridin-2-ylJoxyphenyl] YA propanoic acid va 2-[4-[5-(cyclohexylcarbamoy!)-6-propylsulfanyl-pyridin-2-yljsulfanylphenyl] Ee acetic acid 3 2-[3-[5-(cyclohexylcarbamoyl) -6-propylsulfanyl-pyridin-2-yl] oxyphenyl]acetic acid a 2-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJsulfanylbenzoic acid tt 4-[5 -(cyclohexylcarbamoyl)-6 -propylsulfanyl-pyridin-2-yl] oxycyclohexane-1- to carboxylic acid 3 1- [5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]piperidine-2-carboxylic 32 acid EA 25-1 -[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidine-2- £4 carboxylic acid or 2-[1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4- 2 piperidyl]propanoic acid oY ~- Fy. - 4-[[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] amino]methyl] ov cyclohexane-1-carboxylic acid 24 3-[[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin- 2-yi] amino]propanoic acid °° 1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] azepane-4-carboxylic acid 81 of 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl- pyridin-2-yl] -4-methyl-piperidine-4- oA carboxylic acid 24 (1 S,5R)-3-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-y1]-3- 1 azabicyclo [3.1.0]hexane-6-carboxylic acid 1 4-]]5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-ylJamino]cyclohexane- 1- 11 carboxylic acid w 1-[5-(cyclohexylcarbamoyl)-6 -propylsulfanyl-pyridin-2-yl}-4-propan-2-yl- 14 piperidine-4-carboxylic acid 1 1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3 -methyl- piperidine-4- 1 carboxylic acid 1 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3 -piperidyl]-2- TA methyl-propanoic acid 14 2-[(3R) -1-[5 -(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3- Ve yl]acetic acid except 3-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin -2-yl}-3- for piperidyljpropanoic acid for 2-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]azetidin-3- ve ylJoxyacetic acid ve - FY - 1-[1-[5 (cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] -3- va piperidyl]cyclobutane-1 -carboxylic acid vv 1-[1-[5 _(cyclohexylcarbamoy!l) -6-propylsulfanyl-pyridin-2-yl] -3- VA piperidyl]cyclopropane-1 -carboxylic acid va 2-[1-[5 (eyelohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yllpyrrolidin-3 - As ylJoxyacetic acid AY 2-[[1-[5 _(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] -3- AY piperidyl]oxy]propanoic acid AY 2-[[1-[5 -(cyclohexylcarbamoyl)-6- propylsulfanyl-pyridin-2 -yl]-3-piperidyl]oxy]-2- At methyl-propanoic acid Ao 2-[[1-[5-(cyclohexylcarbamoyl)-6 -propylsulfanyl-pyridin-2-yl]-3- A piperidyl]oxyJacetic acid AY 1-[5 _(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl] -3-methyl-piperidine-3- AA carboxylic acid AQ 2-[1-[5 -(cyclohexylcarbamoyl)- 6-propylsulfanyl-pyridin-2-yl] -4-piperidyl]-2- i methyl-propanoic acid 5 1-[1-[5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4- ay piperidyljcyclobutane-1 -carboxylic acid ay 1-[1- [5-(cyclohexylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-4- it piperidyljcyclopropane-1 -carboxylic acid io 4-[5 _(cyclohexylcarbamoyl)-6 -propylsulfanyl-pyridin-2-yl]morpholine-2- 41 carboxylic acid av 2-[(3R)-1-[5 -(cyclohexylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2-yl]pyrrolidin- A - TAY - 3-yl]acetic acid 4 2-[3R)-1 -[5-(cyclohexylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2-yl]-3- 00 piperidyl]acetic acid 011 2-[(35) -1 -[5-(cyclohexylcarbamoy!)-6-cyclopentylsulfanyl-pyridin-2-yl]-3- 01 piperidyl]acetic acid Vo¥ 2-[(3S)-1-[5 -(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl -pyridin-2-yl]pyrrolidin- Ved 3-yl]acetic acid 0.0 2-[(3R)-1 -[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]pyrrolidin- 011 3- yl]acetic acid 01 2-[(3R)-1 -[5-(cyclohexylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2-yl]-3- 0 piperidyl]acetic acid 01 1-]1 -[5-(cyclohexylcarbamoyl) )-6-cyclopentylsulfanyl-pyridin-2-yl]-3- 00 piperidyl]cyclopropane-1 -carboxylic acid 111 2-[(3S)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2 -yl]-3- NY piperidyljacetic acid WY 2-[(38)-1-[5 -(2-adamantylcarbamoy!)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3 - 114 ylJoxyacetic acid 100 2-[ (3R)-1-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3- LAR yl]Joxyacetic acid VY 2-[(3S)-1-[5 -(2- adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3 - 11 yl]acetic acid 10 (3R)-1 -[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidine- 3- 00 carboxylic acid 171 Yivi 2-[(3R)-1 -[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]pyrrolidin-3- 1 yljacetic acid 1" (2S)-1-[5 -(2-adamantylcarbamoy1) )-6-propylsulfanyl-pyridin-2-yl] pyrrolidine-2- 1 carboxylic acid 1 (1 S,5R)-3-[5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3 - 11 azabicyclo[3.1.0]hexane-6-carboxylic acid 11 (3S)-1-{5 -(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2 -yl]pyrrolidine-3- VYA carboxylic acid AR 4- [5-(2-adamantylcarbamoyl)-6-propylsulfanyl-pyridin-2-yljmorpholine-2- 00 carboxylic acid "1 2-[(3S)-1-[5 -(2-adamantylcarbamoyl)-6-cyclopentylsulfanyl-pyridin- 2- VY yl]pyrrolidin-3-ylJoxyacetic acid 1" 2-[(3R)-1-[5 -(2-adamantylcarbamoyl)-6-cyclopentylsulfanyl-pyridin-2- 14 yl}pyrrolidin-3-ylJoxyacetic acid 'Yo 2-[(3S)-1-[5 -(2-adamantylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2- 1 yl]pyrrolidin-3-ylJoxyacetic acid l 2-[(3R)-1-[5] -(2-adamantylcarbamoyl)-6-cyclohexylsulfanyl-pyridin-2- yl]pyrrolidin-3-ylJoxyacetic acid "1 2-[(3R)-1 -[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl -pyridin-2-yl]pyrrolidin-3- Vee yljacetic acid 01 (3R)-1 -[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl]pyrrolidine-3- VEY carboxylic acid VEY (35) )-1 -[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-yl]pyrrolidine-3 - Vet - Yt - carboxylic acid | Veo (18,5R)-3-[5-(2-adamantylcarbamoyl)-6-ethylsulfanyl-pyridin-2-y1]-3- 1 azabicyclo[3.1.0]hexane-6-carboxylic acid VEY 2-[(3R) )-1-[5-(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin-2-yl]pyrrolidin-3 . MEA yl]Jacetic acid 1 (3R)-1- [5-(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin-2-yl]pyrrolidine-3 - Vou carboxylic acid 10) (1S,5R)-3-[5 -(2-adamantylcarbamoyl)-6-methylsulfanyl-pyridin-2-yl] -3- 01 azabicyclo[3.1.0]hexane-6-carboxylic acid Voy 2-[(38)-1-[5-[((21) ,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl- Vot pyridin-2-yl]pyrrolidin-3-ylJacetic acid oo 4-[[[5-[((2r,5s)-5 - hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl-pyridin-2- 11 ylJamino]methyl]cyclohexane-1-carboxylic acid 00 4-[[5-[((2r,5s)-5-hydroxy-2-adamantyl) )carbamoyl] -6-propylsulfanyl-pyridin-2- V oA ylJaminoJcyclohexane-1-carboxylic acid Ved 4-[[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propylsulfanyl- pyridin-2-yi. ylJamino]cyclohexane-1-carboxylic acid 11 2-[(3S)-1-[5-[(2r,5 s)-5-hydroxy-2-adamantylJcarbamoyl]-6-propylsulfanyl-pyridin- VY 2-yl]- 3-piperidyl]acetic acid y 1-[5-[[(2r,5 s)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl-pyridin-2- Vit yl]piperidine-4-carboxylic acid Vio 2-[(3R)-1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl- Vit pyridin-2-yl]-3-piperidyl]acetic acid Vy Yyaivi - Yio - 2-[1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]Jcarbamoy!]-6-propylsulfanyl-pyridin-2- 114 yl]-4-piperidyl]acetic acid V4 (1R,5S)-3-[5-[[(2r,5s)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsulfanyl- We pyridin-2-yl]-3-azabicyclo[3.1.0 ]hexane-6-carboxylic acid AA 1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl] -6-propylsulfanyl-pyridin-2-yl]- WY 4-methyl-piperidine- 4-carboxylic acid 7 1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl] -6-propylsulfanyl-pyridin-2- Wi yl]pyrrolidine-3-carboxylic acid ve 2-[ (3R)-1-[5-[[(21,55)-5-hydroxy-2-adamantyl]carbamoyl]-6-propylsul fany1- 71 pyridin-2-yl]pyrrolidin-3-yljacetic acid No 3-[1-[5-[[(21,5s)-5-hydroxy-2-adamantyl]carbamoyl] -6-propylsulfanyl-pyridin-2- YA yl]-3-piperidyl]propanoic acid 71 2-[1 -[5-[((2r,5s)-5-hydroxy-2-adamantyl)carbamoyl] -6-propylsulfanyl-pyridin-2- YA. yl]-3-piperidyl]-2-methyl-propanoic acid YM 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2- YAY adamantyl)carbamoyl] pyridin-2-yl]pyrrolidin-3-ylJacetic acid VAY 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,55)-5-hydroxy-2- YAS adamantyl]carbamoyl]pyridin- 2-yl]-3-piperidyl]acetic acid 2-[(3R)-1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2- YAT adamantyl)carbamoyl] pyridin-2-yl]pyrrolidin-3-yl]acetic acid YAY (3R)-1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2-ha adamantyl)carbamoyl] pyridin-2-yl]pyrrolidine-3-carboxylic acid VAS (25)-1-[6-cyclopentylsulfanyl-5-[((2r,5s)-5-hydroxy-2- "0) 19 - adamantyl)carbamoyl]pyridin-2-yl]pyrrolidine-2-carboxylic acid 051 (IR,5S)-3-[6-cyclopentylsulfanyl-5-[((2r,55)-5-hydroxy-2- VAY adamantyl )carbamoyl[pyridin-2-yl]-3-azabicyclo[3,1. 0]hexane-6-carboxylic acid "1 1 -[6-cyclopentylsulfanyl-5-[((21,5 §)-5 _hydroxy-2-adamantyl)carbamoyl]pyridin-2- Vat yl]piperidine-4-carboxylic acid 140 2-[(3R)-1 -[6-cyclohexylsulfanyl-5 -[((2r,5s)-5-hydroxy-2- 141 adamantyl)carbamoyl]pyridin-2-yl]pyrrolidin-3-ylJacetic acid Vay (25)-1- [6-cyclohexylsulfanyl-5- [((2r,5s)-5-hydroxy-2- VA adamantyl)carbamoyl]pyridin-2-yl]pyrrolidine-2-carboxylic acid 144 (3R)-1 -[6-cyclohexylsulfanyl-5-[((2r,55)-5-hydroxy-2- Yoo adamantyl)carbamoyl]pyridin-2-yl]pyrrolidine-3-carboxylic acid 11 2-](35)-1- [ 6-cyclohexylsulfanyl-5- [[(2r,5s)-5-hydroxy-2- VX adamantyl] carbamoyl]pyridin-2-y1]-3-piperidyl]acetic acid 0 2-](35)-1 -]5 -]])2,5:(-5 -3)-6-[alamat [wal-sums-0-2-budh nit] Vet methylbutylsulfanyl)pyridin-2-yl]-3-piperidyl]acetic acid Yeo (3R)- 1 [5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-(3- ARR methylbutylsulfanyl)pyridin-2-yl]pyrrolidine-3-carboxylic acid No (1R, 58)-3-[5-[((21,55)-5-hydroxy-2-adamantyl)carbamoy!]-6-(3- 08 methylbutylsulfanyl)pyridin-2-y1]-3-azabicyclo[3.1.0 ]hexane-6-carboxylic acid Yd 2-[(39)-1-[6-benzylsulfanyl-3-[[(21,55)-5-hydroxy-2-adamantylJcarbamoyl]pyridin- 970 2-yl]-3- piperidyl]acetic acid 711 2-[(3S)-1-[5-[[(2r, 55)-5-hydroxy-2-adamantyl] carbamoyl] -6-phenethylsulfanyl- YY pyridin-2-yl]-3- piperidyl]acetic acid YAY Yava - YY - 2-[(3S)-1-[5-[[(2r,55)-5-hydroxy-2-adamantyl]carbamoyl}-6-propoxy-pyridin-2-yl]- Tie 3-piperidyl]acetic acid 71 2-1 -[5-[((2r,55)-5-hydroxy-2-adamantyl)carbamoyl]-6-propoxy-pyridin-2-yl]-3 - AAR piperidyl]-2-methy!-propanoic acid YVY (1R,58S,6r)-3-(6-(cyclopentylthio)-5-(3-(pyridin-3-yl)pyrrolidine-1- VIA carbonyl)pyridin-2-yl)-3-azabicyclo[3.1 0Jhexane-6-carboxylic acid 71 (18,5R)-3-[6-cyclohexylsulfanyl-5-(3-pyridin-3-ylpyrrolidine-1 -carbonyl)pyridin- YY. 2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 77 2-[(3S)-1-[6-propylsulfanyl-5-(3-pyridin-3-ylpyrrolidine-1 -carbonyl)pyridin-2-yl}- 79 3-piperidyl]acetic acid vy 2-[(3S) -1-[6-propylsulfanyl-5-(3-pyridin-2-ylpyrrolidine-1 -carbonyl)pyridin-2-yl}- Yi 3-piperidyl]acetic acid Yyo 2-[(3S)-1-[5- (piperidine-1-carbonyl)-6-propylsulfanyl-pyridin-2-yl]-3- YY piperidyl]acetic acid YyYv 2-[(3S)-1-[6-propylsulfanyl-5-(3-pyrazin-2- ylpyrrolidine-1 -carbonyl)pyridin-2-yl]- YYA 3-piperidyl]acetic acid Yva 2-[(3S)-1-[5-(4 4-difluoropiperidine-1-carbonyl)-6-propylsulfanyl-pyridin- 2-y1}-3- Y'* piperidyl]acetic acid 77 2-[(3S)-1-[6-propylsulfanyl-5-[3~(trifluoromethyl)piperidine-1-carbonyl]pyridin-2- YY yl] -3-piperidyl]acetic acid 177 2-[(3S)-1-[6-propylsulfanyl-5-[4-(trifluoromethyl)piperidine-1-carbonyl]pyridin-2- AR:yl]-3-piperidyl]acetic acid YYo 2-[(3S)-1-[5-(4-carbamoylpiperidine-1-carbonyl)-6-propylsulfanyl-pyridin-2-yl]-3- 7 Yivia - TVA - piperidyl]acetic acid | YYv 2-[(3S)-1-[5 _(cyclohexyl-cyclopropyl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl] 3 ¥ YA piperidyl]acetic acid 13 2-[(3S)-1-[5 _(cyclohexyl-(cyclopropylmethyl)carbamoyl)-6-propylsulfanyl-pyridin-vi. 2-yl]-3-piperidyl]acetic acid Ye 2-[(3S)-1-[5 ~(cyclohexyl-ethyl-carbamoyl)-6-propylsulfanyl-pyridin-2 -yl]-3- YY piperidyl]acetic acid B 2-])33(-1 [5-(cyclohexyl-propan-2-yl-carbamoyl)-6-propylsulfanyl-pyridin-2-yl]-3- vit piperidyl]acetic acid Y2- [(3S)-1-[5-[(4-hydroxycyclohexyl)carbamoyl] -6-propylsulfanyl-pyridin-2-yl]-3- 7 piperidyl]acetic acid A 2-[(3S)-1- [6-propylsulfanyl-5-[3-[2-(trifluoromethyl)phenyl]pyrrolidine-1- YEA carbonyl ]pyridin-2-yl]-3-piperidyl]acetic acid ved 2-[(35)-1 -[5 -[((2r,55)-5-methylsulfonyl-2-adamantyl)carbamoyl]-6-propylsulfanyl- Yo.pyridin-2-yl]-3-piperidyl]acetic acid Yo) 2-[(3S)-1- (6-cyclopentylsulfanyl-5 -(3-pyridin-3-ylpyrrolidine-1-carbonyl)pyridin- YoY 2-yl]-3-piperidyl]acetic acid YoY 2-[(3R)-1-[5-(cyclohexylcarbamoyl) -6-phenethylsul fanyl-pyridin-2-y1]-3- vot piperidyl]acetic acid2-[(3S)-1- [5-(cyclohexylcarbamoyl)-6-phenethylsulfanyl- Yoo pyridin-2-yl]-3-piperidyl ]acetic acid Yor 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(2-pyridin-3 -ylethylsulfanyl)pyridin-2-yl] 3. Tov piperidyl]acetic acid YoA 2-[(3S) )-1 _[5-(cyclohexylcarbamoyl)-6-(2-pyrazin-2-ylethylsulfanyl)pyridin-2-yl] 3.1 - v4 - piperidyl]acetic acid vi 2-[(3S)-1-[5-(cyclohexylcarbamoyl)pyridin-2-yl]-3-piperidyl]acetic acid Yu 2-[(3S)-1-[5-( 2-adamantylcarbamoyl)pyridin-2-yl]-3-piperidyl]acetic acid vy 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-[2-(4-fluorophenyl)ethoxy]pyridin-2- yl]-3- viv piperidyl]acetic acid vit 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(3-methylbutoxy)pyridin-2-yl]-3- vio piperidyl]acetic acid 711 2 -[(3S)-1-[5-(cyclohexylcarbamoy!)-6-(3-phenylpropoxy)pyridin-2-yl}-3- viv piperidyl]acetic acid TIA 2-[(3S)-1-[5- (cyclohexylcarbamoyl)-6-(2-pyridin-3-ylethoxy)pyridin-2-yl]-3-vid piperidyl]acetic acid YV. 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-methoxy-pyridin-2-yl]-3-piperidyl]acetic 791 acid 77 2-[(3S)-1-[5-(cyclohexylcarbamoyl) -6-propoxy-pyridin-2-yl]-3-piperidyl]acetic acid 77 Ni ‎2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(1-piperidyl)pyridin-2- yl]-3-piperidyl]acetic 17 acid 171 2-[(3S)-1-[6-[2-(4-chlorophenyl)ethylamino]-5-(cyclohexylcarbamoyl)pyridin-2- 17" 711[-3- 010©1071[06116 410 YVA 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-[3-(4-fluorophenyl)pyrrolidin-1-yl]pyridin- 171 2-yl]-3-piperidyl ]acetic acid YA. 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(3,4-dihydro-1H-isoquinolin-2-yl)pyridin-2- YAN yl]-3-piperidyl] acetic acid VAY - FY. - 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(3,4-dihydro-1H-isoquinolin-2-yD)pyridin-2- YAY yl]-3-piperidyl]acetic acid YAS 2 -[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(4-phenylpiperazin-1-yl)pyridin-2-yl]-3- YAS piperidyl]acetic acid YAR 2-[(3S)-1- [5-(cyclohexylcarbamoyl)-6-[4-(4-fluorobenzoyl)piperazin-1-yl]pyridin- ' AY 2-yl]-3-piperidyl]acetic acid YAA 2-[(38)-1-[6 -(4-acetylpiperazin-1-yl)-5-(cyclohexylcarbamoyl)pyridin-2-y1]-3- YA4 piperidylJacetic acid Yq. 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-(4-ethylsulfonylpiperazin-1-yl)pyridin-2-yl]- 751 3-piperidyl]acetic acid Yay 2-[(35)-1 -[6-[4-(benzenesulfonyl)piperazin-1-yl]-5-(cyclohexylcarbamoyl)pyridin- vay 2-yl]-3-piperidyl]acetic acid 9" 2-[(3S)-1-[5- (cyclohexylcarbamoyl)-6-(4-phenylmethoxycarbonylpiperazin-1- Ydo yD)pyridin-2-yl]-3-piperidyljacetic acid val 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylamino-pyridin- 2-yl]-3- vay piperidyljacetic acid YA 2-[(35)-1-[5-(cyclohexylcarbamoyl)-6-(phenethylamino)pyridin-2-y1]-3- vad piperidyl]acetic acid Yeo 2-[ (3S)-1-[5-(cyclohexylcarbamoyl)-6-(methyl-phenethyl-amino)pyridin-2-yl]-3- ve piperidyl]acetic acid 711 2-[(3S)-1-[5-( cyclohexylcarbamoyl)-6-(methyl-propyl-amino)pyridin-2-yl]-3- vey piperidyl]acetic acid Vet 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-pyrrolidin-1-yl -pyridin-2-yl]-3- Veo piperidyl]acetic acid vel 2-[(35)-1 -[5-(cyclohexylcarbamoyl)-6-morpholin-4-yl-pyridin-2-yl]-3- Vey piperidyl]acetic acid YA 2-[(3S)-1 -[5-(cyclohexyl-methyl-carbamoyl)-6-propylamino-pyridin-2-yl]-3- ved piperidyljacetic acid "1 2-](35)- 1 -[5-(cyclohexyl-methyl-carbamoyl)-6-(methyl-propyl-amino)pyridin-2- 5 yl]-3-piperidyljacetic acid YY 2-[(3S)-1 -[5-(cyclohexylcarbamoyl) -6-methyl-pyridin-2-y1]-3 -piperidyl]acetic acid my 2-[(3S)-1-[5-(1 -adamantylcarbamoyl)-6-methyl-pyridin-2-yl]-3 - piperidyl]jacetic vio acid 1 2-[(35)-1 -[5-(2-adamantylcarbamoy!)-6-methyl-pyridin-2-yl]-3 -piperidyl]acetic viv acid IA 2-[(3S) -1-[5-(2-adamantylcarbamoyl)-6-butyl-pyridin-2-yl]-3-piperidylJacetic acid 4 3-[5-(2-adamantylcarbamoyl)-6-butyl-pyridin-2-yl]- 3-azabicyclo[3.1.0]hexane-6-YY. carboxylic acid rm 2-[(3S)-1- [6-butyl-5-(cyclohexylcarbamoyl)pyridin-2-yl]-3 -piperidyl]acetic acid vYY 2-[(3S)-1-[5 -(cyclohexylcarbamoyl) )-6-cyclopropyl-pyridin-2-yl] -3-piperidyl]acetic yyy acid 79" 2-[(3S)-1 -[5-(2-adamantylcarbamoyl)-6-cyclopropyl-pyridin-2-yl] -3 - YYo piperidyl]acetic acid AR 2-[(38)-1-[6-cyclopropyl-5-[[(21,55)-5-hydroxy-2-adamantyl]carbamoy|]pyridin-2- 1 yl ]-3-piperidyl]acetic acid 7 2-[(3R)-1-[5 -(cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2 -yl]-3- "1-ha piperidyl]acetic acidvv. 2-[(38)-1-[5-(cyclohexyl-methyl-carbamoyl)-6-propylsulfanyl-pyridin-2-y1]-3- mw piperidyl]acetic acid 1" [(38)-1-{5- [((2r,5s)-5-methoxyadamantan-2-yl)(methyl)carbamoyl]-6- 7" (propylthio)pyridin-2-yl} piperidin-3-yljacetic acid YT [(35)-1-{ 5-[((2r,55)-5-hydroxyadamantan-2-yl)(methyl)carbamoyl]-6- AL (propylthio)pyridin-2-yl} piperidin-3-yljacetic acid rv {(35)-1- [5-(adamantan-1-ylcarbamoy!)-6-(propylthio)pyridin-2-yl]piperidin-3- YvYy yl}acetic acid YYA {(35)-1-[6-(propylthio)-5-( tetrahydro-2 H-pyran-4-ylcarbamoyl)pyridin-2- 71 yl]piperidin-3-yl} acetic acid ve. [(35)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-ve)yl} piperidin-3-yl]acetic acid vey 2- [(38)-1-[6-cyclohexylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- vey adamantyl]carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetic acid vit 2-[(3S)-1-[6-cyclohexylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- vio adamantyl]carbamoy!]pyridin-2-yl]-3-piperidyl Jacetic acid ven 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- vey adamantyl]carbamoyl]pyridin-2-yl]pyrrolidin-3-yl]acetic acid YEA 2-[(3S)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- vid adamantylJcarbamoyl]pyridin-2-yl]-3-piperidyl]acetic acid Yo. 2-[(35)-1-[5- [[(2r,5s)-5-(difluoromethoxy)-2-adamantyl}carbamoy1]-6- Yo)propylsulfanyl-pyridin-2-yl]-3-piperidyl] acetic acid voy - except 2-[(38)-1-[5-[[(2r,55)-5-(difluoromethoxy)-2-adamantyljcarbamoyl]-6- voy ‎propylsulfanyl-pyridin-2-yl]pyrrolidin-3 -yl]acetic acid voi 2-[(3S)-1-[5-[[(2r,5s)-5-(difluoromethoxy)-2-adamantyl carbamoyl ]-6-propoxy- yoo pyridin-2 -yl]-3-piperidyl]acetic acid vel (3R)-1-[6-cyclopentylsulfanyl-5-[[(2r,5s)-5-(difluoromethoxy)-2- Yov adamantyl]carbamoyl]pyridin -2-yl]pyrrolidine-3-carboxylic acid YoA ‎(IR,58)-3-[6-cyclopentylsulfanyl-5-[[(2r,55)-5-(difluoromethoxy)-2-ved adamantyl] carbamoyl]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid vi. 2-[(3R)-1-[5-[[(2r,55)-5-( difluoromethoxy)-2-adamantyl]carbamoyl]-6- vi propylsulfanyl-pyridin-2-yl]pyrrolidin-3-yl]acetic acid vay 1-[5-[[(2r,55)-5-( difluoromethoxy)-2-adamantyl]carbamoyl]-6-propylsulfanyl- vay pyridin-2-yl]pyrrolidine-3-carboxylic acid vie (S)-2-(1-(5-(cyclohexylcarbamoyl)-3- fluoro-6-(propylthio)pyridin-2-yl)piperidin-3- vie ylacetic acid or (R)-2-(1-(5-(cyclohexylcarbamoyl)-3-fluoro-6-(propylthio)pyridin- via 2-yDpiperidin-3-yl)acetic acid viv TIA or a pharmaceutically acceptable salt thereof. 11 1 - Pharmaceutical composition; Where it comprises a compound according to claim No. (1) in combination with ¥ a diluent diluent or a pharmaceutically acceptable carrier. prophylactic ~~ Y or therapeutic for a warm-blooded organism Jia «warm-blooded animal - YY - YF human. 1 1 - Compounded according to Claim No. (padi] ¢ (1 cadua os VE) - Compounded according to Claim No. Cun (ITF) The drug is a treatment for Metabolic Syndrome Y “ metabolic syndrome, type II diabetes, obesity, or atherosclerosis .111 - Use of a compound according to Claim (1); in the manufacture of a drug used to produce an effect of Y Inhibitory effect of enzyme 11811501 in warm-blooded AS Jie animal ¥ human. ¥Yo - - 11 1 - A process for preparing a compound according to claim No. (1); where [in which 7 is -X-Y-COOH" and other various groups; unless otherwise specified; as is defined in Formula (1) in claim No. [(1) to include any of the operations from a) to e): ; a) Reaction of a compound of formula (2) with a compound of formula (3): Ry, 9 Le o 0 m" 2 1c (3) 2 1 b Reaction of a compound of formula (4) with a compound of formula (5) ( : (R%), 0 R2 X m XX H | 7 _ ON 0 R? 2 a (5) (4) where Ble X is about a leaving group; or 1 =( Reaction of a compound of formula (6) with a compound of formula (7): RY, | 9 , 2c ro © R? 3 72 Na R 27 H 01 0 (6) 1 where Ble TX is about a leaving group; or VY 2) Reaction of a compound of formula (8) with a compound of formula (9): Yyiva 177 - - 0 mg (RD, 2 VY oo b 3 = N xX" R 2 0 0 4 where UX is a leaving group; or \o » (a complex reaction of the form ) 10) with a compound of formula (11): (R%), 0 2 i" + m of x" N Q H (1D) (10) 1" where Ble TUX from a group leaving the leaving group; VA, and then if necessary or required: 1 (1) a compound of formula (1) is converted into another compound of formula (1) ' (Y) ve removal of any tprotecting groups (Y) 7 4,03 'resolving enantiomers YY (4) formation of a pharmaceutically acceptable salt or ester thereof that is hydrolyzable in the organism.