EA035363B1 - Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors - Google Patents

Abstract

The invention relates to the field of pharmaceutics, namely, provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds and methods comprising administering said compounds to a mammal in need thereof. The invention concerns compounds of formula Ior a pharmaceutically acceptable salt thereof, wherein Y, Z, X, R, Rand Rare defined herein, pharmaceutical compositions thereof and methods of treating a disease for which an inhibitor of KHK is indicated.

Description

Scope of invention

The invention provides substituted 3-azabicyclo [3.1.0] hexanes as ketohexokinase inhibitors, methods for preparing said compounds, and methods comprising administering said compounds to a mammal in need thereof.

Background of the invention

Diabetes is a serious public health threat due to its increasing prevalence and associated health risks. The disease is characterized by high blood glucose levels due to defects in insulin production, insulin action, or both. There are two main forms of diabetes mellitus, type 1 and type 2. Type 1 diabetes mellitus (T1D) develops when the body's immune system destroys the beta cells of the pancreas, the only cells in the body that produce the hormone insulin, which regulates blood glucose. In order to survive, people with type 1 diabetes must receive insulin, which can be injected or pumped. Type 2 diabetes mellitus (commonly referred to as T2D) usually begins with either insulin resistance or when there is insufficient insulin production to maintain an acceptable glucose level.

Although T2D is most commonly associated with hyperglycemia and insulin resistance, other diseases associated with T2D include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hypertension, and non-fatty hypertension liver disease (NAFLD).

NAFLD is a hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions including steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis of the liver, and finally hepatocellular carcinoma. NAFLD and NASH are considered major fatty liver diseases because they are common in the largest proportion of individuals with elevated liver lipids. The severity of NAFLD / NASH is based on the presence of lipid, inflammatory cell infiltration, hepatocyte proliferation, and degree of fibrosis. Although not all individuals with steatosis progress to NASH, they make up a significant proportion.

Recent human evidence suggests that fructose consumption may contribute to the development of NAFLD / NASH (Vos, M.V., and Lavine, J.E. (2013), Hepatology 57, 2525-2531). Compared to glucose, fructose significantly increases primary lipid synthesis (Stanhope, KL, Schwarz, et al. (2009), J. Clin Invest 119, 1322-1334), a marked characteristic of the NAFLD patient (Lambert, JE, et al. ( 2014), Gastroenterology 146, 726-735). Human studies have shown that short-term intake of fructose causes an increase in liver triglycerides, and that eliminating fructose can reverse the accumulation of hepatic triglycerides (Schwarz, JM, Noworolski, et al. (2015) J. Clin Endocrinol Metab 100, 2434-2442 ). In addition, in adolescents with NAFLD, a 50% reduction in sugar intake within 10 days reduced hepatic triglyceride by 20% (Schwarz, JM, Noworolski, et al. (2015), PP07-3: Isocaloric Fructose Restriction for 10 Days Reduces Hepatic De Novo Lipogenesis and Liver Fat in Obese Latino and African American Children.http: //press.endocrine.org.proxy1.athensams.net/doi/abs/10.1210/endo-meetings.2015.OABA.6.PP07-3).

The high prevalence of T2D, obesity, and NAFLD / NASH, as well as related comorbidities such as cardiovascular disease and stroke, have led to an increased need for both prevention and therapeutic interventions. The currently existing T2D range pharmacotherapy strategies include agents that increase insulin secretion, affect the action of insulin (thiazolidinediones (TZD), biguanides), alter lipid metabolism (TZD, fibrates), affect the behavior of basic nutrition, promote the excretion of glucose in urine ( SGLT2 inhibitors) and nutrient absorption decreasing (lipase inhibitors). The inhibition of KHK fructose metabolism provides a new alternative to current treatment strategies.

Ketohexokinase (KHK) is the main enzyme in the metabolism of fructose and catalyzes the conversion of fructose to fructose-1-phosphate (F1P). KHK is expressed as two alternative mRNA splicing variants, designated KHKa and KHKc, resulting from alternative splicing of the third exon. The affinity and capacity of KHKc for phosphorylation of fructose is much higher than KHKa, as evidenced by the much lower Km (Ishimoto, Lanaspa et al., PNAS 109, 4320-4325, 2012). While KHKa is widely expressed, KHKc expression is highest in the liver, kidney and intestines, the main sites of fructose metabolism in the body (Diggle CP, et al. (2009) J. Histochem Cytochem 57: 763-774; Ishimoto, Lanaspa, et al. ., PNAS 109, 4320-4325, 2012). In addition, the loss of functional mutations has been observed in humans with no adverse effects, except for the appearance of fructose in the urine after consuming sugar.

A more severe condition involved in fructose metabolism is hereditary fructose intolerance (HFI, OMIM # 229600), which is caused by defects in aldolase B (GENE: ALDOB), which is the enzyme responsible for the cleavage of F1P and is found directly in the forward direction of the KHK stage in pathways (Bouteldja N., et al., J. Inherit. Metab. Dis. 2010 Apr; 33 (2): 105-12; Tolan, DR, Hum Mutat. 1995; 6 (3): 210-8; http: //www.omim.org/entry/229600). This is

- 1,035363 a rare disease that is estimated to affect 1 in 20,000 people and mutations result in an accumulation of F1P, ATP depletion and an increase in uric acid, the combination of which causes hypoglycemia, hyperuricemia and lactic acidosis, among other metabolic disorders. HFI impairs the body's ability to metabolize dietary fructose, resulting in acute symptoms such as vomiting, severe hypoglycemia, diarrhea, and abdominal distress, leading to long-term development of liver and kidney defects, damage and potentially death (Ali M. et al. ., J. Med. Genet. 1998 May: 35 (5): 353-65). Patients usually suffer during the first years of life before diagnosis and the only treatment is to avoid fructose in the diet. This becomes challenging due to the presence of this macro nutrient in most foods. In addition to physical symptoms, many patients feel emotionally and socially isolated as a result of their unusual diets and constantly try to adhere to strict dietary restrictions (HFI-INFO Discussion Board, http://hfiinfo.proboards.com. Accessed 14 December 2015). Even when they occur without symptoms, some patients develop NAFLD and renal disease, highlighting the inadequacy of self-dietary restriction as the only treatment option and the high unmet medical need for the condition.

In hyperglycemic conditions, endogenous fructose production occurs via the polyol pathway, the pathway by which glucose is converted to fructose with sorbitol as an intermediate. The activity of this pathway increases with hyperglycemia. In these studies, the authors showed that KHK null mice were protected against glucose-induced weight gain, insulin resistance, and hepatic steatosis, suggesting that endogenously produced fructose may contribute to insulin resistance and hepatic steatosis in hyperglycemic conditions (Lanaspa, MA, et al., Nature Comm. 4, 2434, 2013). Thus, inhibition of LNA is expected to be effective in many diseases that are affected by changes in one or both of endogenous or absorbed fructose.

There remains a need for easy therapy for cardiometabolic and related diseases, including diabetes (T1D and / or T2D), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA), early onset T2D (EOD), atypical diabetes occurring in young age (YOAD), young adult diabetes (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease ( eg, acute renal impairment, tubular dysfunction, proximal tubular proinflammatory changes), diabetic retinopathy, adipocytic dysfunction, visceral fat, obesity, eating disorder, excessive sugar cravings, dyslipidemia (including hyperlipidemia, hypertriglyceride, high cholesterol) and low cholesterol HDL), hyperinsulinemia, NAFLD (including related diseases such as steatosis, NASH, fibrosis, liver cirrhosis and hepatocellular carcinoma), HFI, coronary arterial disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular elasticity, congestive cardiac myocardium (eg, necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral degeneration , cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose , hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorder, foot ulcers, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

Blueprints

FIG. 1 is an X-ray powder diffractogram of the crystalline free acid of Example 4.

FIG. 2 is an X-ray powder diffractogram of the crystalline sodium salt of Example 5.

FIG. 3 presents the structures of examples from table. 4.

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Detailed description of the invention

The present invention relates to compounds of formula (I)

R ¹

(I) or a pharmaceutically acceptable salt thereof, in which

Y is N or C-CN;

Z is N or CH;

X is N or CR ³ ;

with the proviso that at least one of Y, Z or X is N;

R ¹ is C _3-7 cycloalkyl or a 4-7 membered heterocyclic moiety, wherein the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents, independently selected from —C _1-3 alkyl and —OH, wherein —C _1-3 alkyl is substituted with 0 to 3 halogen atoms, and with the proviso that no more than one —OH substituent exists; or N (C _1-3 alkyl) 2, II ^^ alkyl) or NI 1 (C _3-4 cycloalkyl), each C _1-3 alkyl being substituted with 0 to 1 OH;

R ² represents - (L) m-CON (R ^N ) 2, - (LJm-SORS, -L- (CH2) nSO2R ^S , -L- (CH2) „CO2H, -L (CH2) nC (O) R ^C , -L- (CH2) _n CONHSO ₂ R ^S , -L- (CH2) nSO2 NHCOR ^S , -L- (CH2) _n SO ₂ NHCONH ₂ or -L- (CH ₂ ) _n tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

RN is H or —C _1-3 alkyl;

RS is H or —C _1-3 alkyl;

L is CH ₂ , CHF or CF ₂ ;

R ^C is —C _1-4 alkyloxy, —C _1-4 alkyloxycarbonyloxy — C _1-4 alkyloxy, or —C _1-4 alkylcarbonyloxy — C _1-4 alkyloxy;

R ³ is H, halogen, —CN, —C _1-3 alkyl, —OC _1-3 alkyl, —C _1-3 alkyl substituted with 1 to 3 halogen atoms, or —C _3-4 cycloalkyl; and

R ⁴ is cyclopropyl, cyclobutyl, or —C _1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

Another embodiment relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, in which X, Y and Z are any one of the following:

Another embodiment relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, in which

Y is N or C-CN;

Z is N or CH;

X is CR ³ ;

with the proviso that at least one of Y or Z is N;

R ¹ is C _3-7 cycloalkyl or a 4-7 membered heterocyclic moiety, wherein the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents, independently selected from —C _1-3 alkyl and —OH, wherein —C _1-3 alkyl is substituted with 0 to 3 F atoms (where halogen is F), and with the proviso that no more than one —OH substituent exists; or N (C _1-3 alkyl) ₂ , NH (C _1-3 alkyl) or NN (C _3-4 cycloalkyl), each C _1-3 alkyl being substituted with 0 to 1 OH;

R ² represents - (L) „, - CON (R ⁿ ) 2, - (LVSORS, -L- (CH2) nSO2R ^S , -L-CCH ^ COjH, -L (CH2), C (O) R ^c , -L- (CH2) nCONHSO2R ^S , -L - (CH2) nSO2NHCOR ^S , -L- (CH2) nSO2NHCONH2 or -L- (CH2) n

- 3 035363 tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

RN is H or —C _1-3 alkyl;

R ^S is H or —C _1-3 alkyl;

L is CH2, CHF or CF2;

R ^C is —C _1-4 alkyloxy, —C _1-4 alkyloxycarbonyloxy-C _1-4 alkyloxy, or —C _1-4 alkylcarbonyloxy-C'1 _-4 alkyloxy;

R ³ is H, halogen, —CN, —C _1-3 alkyl, —OC _1-3 alkyl. —C _1-3 alkyl substituted with 1 to 3 halogen atoms, or —C _3-4 cycloalkyl; and

R ⁴ is —C _1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

Another embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which

Y is C-CN;

Z is N;

X is CR ³ ;

R ¹ is C _3-7 cycloalkyl or a 4-7 membered heterocyclic moiety, wherein the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents, independently selected from —C _1-3 alkyl and —OH, with the proviso that there is no more than one —OH substituent;

R ² is - (L) m-CON (R ^N ) 2, - (L) m-SO2R ^S , -L- (CH2) nSO2R ^S , -L- (CH2) nCO2H, -L (CH2) nC ( O) RC, -L- (CH2) nCONHSO2R ^S , -L- (CH2) nSO2NHCOR ^S, or -L- (CH2) n-temrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R ⁿ is H or —C _1-3 alkyl;

R ^S is H or —C _1-3 alkyl;

L is CH ₂ , CHF or CF2;

RC is —C _1-4 alkyloxy, —C _1-4 alkyloxycarbonyloxy-C _1-4 alkyloxy, or —C _1-4 alkylcarbonyloxy-Cj _-4 alkyloxy;

R ³ is H, halogen, —CN, —C _1-3 alkyl, —OC _1-3 alkyl, —C _1-3 alkyl substituted with 1 to 3 halogen atoms, or —C _3-4 cycloalkyl; and

R ⁴ is —C _1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

Another embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which

Y is N;

Z is N;

X is CR ³ ;

R ¹ is C _3-7 cycloalkyl or a 4-7 membered heterocyclic moiety, wherein the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents, independently selected from —C _1-3 alkyl and —OH, with the proviso that there is no more than one —OH substituent;

R ² represents - (L) m-CON (R ^N ) 2, - (L) m-SO2R ^S , -L- (CH2) nSO2R ^S , -L- (CH2) nCO2H,

-L- (CH2) nC (O) RC, -L- (CH2) nCONHSO2R ^S , -L- (CH2) nSO2NHCOR ^S, or -L- (CH2) n-temrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R ⁿ is H or —C _1-3 alkyl;

R ^S is H or —C _1-3 alkyl;

L is CH ₂ , CHF or CF2;

RC represents -C _1-4 alkyloxy, C _1-4 alkiloksikarboniloksi-C _1-4 alkyloxy or -C1 _-4 alkylcarbonyloxy-C1 _-4 alkyloxy;

R ³ is H, halogen, —CN, —C _1-3 alkyl, —OC _1-3 alkyl, —C _1-3 alkyl substituted with 1 to 3 halogen atoms, or —C _3-4 cycloalkyl; and

R ⁴ is —C _1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

Another embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which

Y is N or C-CN;

Z is N or CH;

X is CR ³ ;

- 4 035363 with the proviso that at least one of Y or Z is N;

R ¹ is C _3-7 cycloalkyl or a 4-7 membered heterocyclic moiety, wherein the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents, independently selected from —C _1-3 alkyl and —OH, with the proviso that there is no more than one —OH substituent;

R ² is - (L) m-CON (RN) 2, - (L) m-SO2RS, -L- (CH2) nSO2R ^S , -L- (CH2) _n CO ₂ H, -L (CH ₂ ) _n C (O) R ^C , -L- (CH2) nCONHSO2R ^S , -L- (CH2) _n SO ₂ NHCOR ^S, or -L- (CH ₂ ) _n- tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R ⁿ represents H or -CH ₃ ;

R ^S represents H or -CH ₃ ;

L is CH ₂ , CHF or CF ₂ ;

R ^C is —C _1-4 alkyloxy, —C _1-4 alkyloxycarbonyloxy — C _1-4 alkyloxy or —C _1-4 alkylcarbonyloxy-Q _-4 alkyloxy;

R ³ is H, —Cl, —CH ₃ , —CH2 CH3, —O — CH3, cyclopropyl or CN; and

R ⁴ is —CF ₃ , —CHF2, or —CF2CH3.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein RN is H or —CH3.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which RS is H or —CH3.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ² is —CH ² CO ² H (n is 0 and L is CH 2). Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ² is -CH2CO2H, -CH2CO2CH3, or -CH2CO2CH2CH3 (n is 0, R ^C is is OCH3 or OCH ₂ CH ₃ when present and L is CH ₂ ). Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ² is -CH2CH2CO2H, -CH2CH2CO2CH3, or -CH2CH2CO2CH2CH3 (n is 1, R ^C is is OCH3 or OCH2CH3 when present and L is CH2).

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ² is - (L) m-CON (R ^N ) 2, - (L) _m -SO ₂ R ^S , -L- (CH2) nSO2R ^S , -L- (CH2) _n CO ₂ H, -L- (CH2) nC (O) R ^C , -L- (CH2) nCONHSO2R ^S , - L- (CH2) nSO2NHCOR ^S or -L- (CH2) n-temrazol-5-yl.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ³ is H, —Cl, —CH ₃ , —CH ₂ CH ₃ , —O -CH ₃ , cyclopropyl or CN.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ⁴ is —CF3, —CHF2, or —CF2CH3.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ¹ is cyclobutyl (C ₄ cycloalkyl) which has from 0 to 3 substituents independently selected from —CH3 and —OH, provided that not more than one —OH substituent exists.

Another embodiment relates to any other embodiment as discussed herein with respect to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which R ¹ is a 4-7 membered heterocyclic moiety selected from azetidin-1-yl, pyrrolidine -1-yl, and piperidin-1-yl (where R ¹ is a 4-7 membered heterocyclic moiety) which has 0 to 3 substituents independently selected from —CH ₃ and —OH, provided that there is no more than one -OH substituent.

A preferred embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which X, R ² , m, n, RN, R ^S , L, R ^C , R ³ , and R ⁴ have any of the embodiments described in herein, wherein R ¹ is azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, which have 0 to 2 —CH3 substituents, and which have 0 to 1 —OH substituent, and wherein Y is C-CN and Z is N, or Y and Z are each N.

Another preferred embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which X, R ² , m, n, RN, R ^S , L, R ^C , R ³ , and R ⁴ have any variant

- 5,035363 embodiments described herein, in which R ¹ is azetidin-1-yl which has 1 to 2 —CH ₃ substituents and which has 0 to 1 —OH substituents, and wherein Y is C -CN and Z is N, or Y and Z are each N.

Another embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, in which Y is C-CN and Z is N, or Y and Z are each N.

Another embodiment of the invention relates to compounds of formula (Ia)

silt and the H atoms at the bridging carbon are in the same plane, and at the same time X, Y, Z, R ² , m, n, R ⁿ , R ^s , L, R ^c , R ³ and R ⁴ have any variant implementation described in this document.

Another embodiment of the invention relates to compounds of formula (Ib)

or their pharmaceutically acceptable salts, in which R ^{2 is a} substituent on azabicyclo [3.1.0] hex-6yl and the H atoms at the bridging carbon are in the same plane, and X, Y, Z, R ² , m, n , R ⁿ , R ^s , L, R ^c , R ³ and R4 have any of the embodiments described herein.

The term alkyl, as used herein, means a straight or branched chain monovalent hydrocarbon group of the formula —C _n H ( _{2n + 1} ). Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, and hexyl.

The term cycloalkyl as used herein means a cyclic, monovalent hydrocarbon group of the formula —C _n H ( _{2n —} i) that contains at least three carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term alkyloxy, as used herein, means an alkyl substituent attached through an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.

The term alkyloxycarbonyloxy as used herein means an alkoxy group attached through a carbonyl group (—CO—). Non-limiting examples include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.

The term alkylcarbonyloxy as used herein means an alkyl group attached through a carbonyloxy group (—C (= O) —O—). Illustrative examples include methylcarbonyloxy, ethylcarbonyloxy, and t-butylcarbonyloxy.

The term alkyloxycarbonyloxy-alkyloxy, as used herein, means an alkyloxycarbonyloxy group attached through an alkyloxy group.

The term halogen, as used herein, refers to F, Cl, Br, I.

The term heterocyclic moiety, as used herein, refers to a cycloalkyl group containing from 4 to 7 carbon atoms in which one or more ring methylene groups (-CH2-) are substituted with a group selected from -O-, -S-, or -N-, and the requirements of the valency -N- are satisfied by H or are the point of attachment.

General abbreviations used in this document:

ADP is adenosine diphosphate;

ATP is adenosine triphosphate;

CDCl ₃ is deuterochloroform;

CO ₂ Et is ethyl carboxylate;

DCM is dichloromethane;

DIPEA is Ν, Ν-diisopropylethylamine;

DMF is dimethylformamide;

DMSO is dimethyl sulfoxide;

EtOAc is ethyl acetate;

h represents hour (s);

- 6 035363

HEPES is 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid;

KCl is potassium chloride;

min represents minute (s);

MgCl ₂ is magnesium chloride;

NaHCO ₃ is sodium bicarbonate;

Na ₂ SO ₄ is sodium sulfate;

NADH is nicotinamide adenine dinucleotide (reduced form);

NAD 'is nicotinamide adenine dinucleotide (oxidized form);

PEP is phosphoenolpyruvate;

K.T. or k.t. is room temperature;

TCEP is tri (2-carboxyethyl) phosphine;

TPO is trifluoroacetic acid;

THF is tetrahydrofuran.

Another embodiment relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, each compound independently selected from one or more of the examples provided herein.

One way of carrying out the invention is to administer a compound of formula (I) in the form of prodrugs. Thus, certain derivatives of the compound of formula (I), which may have little or no intrinsic pharmacological activity, may, when administered to or onto the body, be converted to a compound of formula (I) which has the desired activity, for example by hydrolytic cleavage, into in particular, hydrolytic degradation caused by an esterase or peptidase enzyme. Such derivatives are called prodrugs. Additional information regarding the use of prodrugs can be found in Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). Reference can also be made to Nature Reviews / Drug Discovery, 2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

Prodrugs in accordance with the invention can, for example, be prepared by replacing the corresponding functionalities present in the compounds of formula (I) with certain moieties known to the person skilled in the art from the prior art, as pro-moieties as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Thus, the prodrug according to the invention is (a) an ester or amide derivative of a carboxylic acid in a compound of formula (I); (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group in a compound of formula (I); (c) an amide, imine, carbamate or amine derivative of an amino group in a compound of the form of formula (I); (d) thiosteric, thiocarbonate, thiocarbamate or sulfide derivatives of the thiol group in the compound of formula (I); or (e) an oxime or imine derivative of a carbonyl group in a compound of formula (I).

Some specific examples of prodrugs according to the invention include, where R ² is —L- (CH ₂ ) _n C (O) R ^C. The following are more general guidelines for the prodrugs of this invention:

(i) wherein the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example a compound in which the carboxylic acid functionality hydrogen of the compound of formula (I) is substituted by Cl _-8 alkyl (for example ethyl) or ^ ^ alkyl ^^ O ^ OT ^ (e.g. tBuC (= O) OCH2-);

(ii) wherein the compound of formula (I) contains an alcohol functionality (—OH), an ester thereof, for example, a compound in which the hydrogen of the alcohol functionality of the compound of formula (I) is substituted with —CO (Cl _-8 alkyl) (for example, methylcarbonyl) , or alcohol forms an ester with an amino acid;

(iii) wherein the compound of formula (I) contains an alcohol functionality (—OH), an ether thereof, for example, a compound in which the hydrogen of the alcohol functionality of the compound of formula (I) is substituted with ^^ alkyl ^^ O ^ OT ^ or -CH ₂ OP (= O) (OH) ₂ ;

(iv) where the compound of formula (I) contains an alcohol functionality (-OH), its phosphate, for example, a compound in which the hydrogen of the alcohol functionality of the compound of formula (I) is substituted by -P (= O) (OH) ₂ or -P ( = O) (ONa) ₂ or -P (= O) (O-) ₂ Ca ²⁺ ;

(v) wherein the compound of formula (I) contains a primary or secondary amino functionality (—NH2 or —NHR, where R ^ H). an amide thereof, for example a compound in which, as the case may be, one or both of the hydrogen of the amino functionality of the compound of formula (I) is (s) substituted by (CyDalkanoyl, —COCH2NH2, or the amino group is an amino acid derivative;

(vi) wherein the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or -NHR, where R ^ H), an amine thereof, for example a compound in which, as the case may be, one or both hydrogen of the amino functionality of the compound of formula (I) is (s) substituted by

- 7 035363

-CH2OP (= O) (OH) 2.

Certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). In addition, it is possible for two compounds of formula (I) to be linked together as a prodrug. In certain cases, a prodrug of a compound of formula (I) can be generated by internal linking of two functional groups in a compound of formula (I), for example, by forming a lactone.

As used herein, the term formula I may be referred to herein as the compound (s) of the invention, the compound (s) of the present invention, the invention, and the compound of the formula (I). Such terms are used interchangeably. In addition, it is contemplated that the embodiments that are discussed herein with reference to formula (I) also encompass compounds of formula (Ia) or formula (Ib). Such terms are further defined to include all forms of the compound of formula (I), including their hydrates, solvates, clathrates, isomers, crystalline (including co-crystals) and non-crystalline forms, isomorphs, polymorphs, tautomers and metabolites. For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, can exist in unsolvated and solvated forms. When the solvent or water is firmly bound, the complex will have a well-defined stoichiometry, independent of moisture. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on the moisture and dryness conditions. In such cases, the non-stoichiometric ratio will be the norm.

The currently accepted classification system for organic hydrates is that defining an isolated site, channel, or metal ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are released by direct contact with each other by inverting organic molecules. In channel hydrates, water molecules lie in a lattice of channels where they sit next to other water molecules. In metal ion coordinated hydrates, water molecules are bound to a metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry regardless of moisture. When, however, the solvent or water is weakly bound, like channel solvates and hygroscopic compounds, the water / solvent content will depend on moisture and drying conditions. In such cases, non-stoichiometry will be the norm.

In addition, multicomponent complexes (other than salts and solvates) are included within the scope of the invention, wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts.

Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are generally defined as crystalline complexes of neutral molecular composition that are linked together through non-covalent interactions, but can also be a complex of a neutral molecule with a salt. Co-crystals can be obtained by crystallization from melt, recrystallization from solvents, or physical grinding of the components together - see Chem Commun, 17, 1889-1896, O. Almarsson and M. J. Zaworotko (2004). For a general overview of multicomponent complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975).

The compounds of the invention may contain asymmetric or chiral centers, and thus exist in various stereoisomeric forms. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, are intended to form part of the present invention. In addition, the invention encompasses all geometric and positional isomers. For example, if a compound of the invention comprises a double bond or an annelated ring, both cis and trans forms, as well as mixtures, are within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting an enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral excipients such as a chiral alcohol or Mosher acid chloride), separating the diastereoisomers and converting (e.g. hydrolyzing) the individual diastereoisomers into the corresponding pure enantiomers ... Enantiomers can also be separated using a chiral HPLC column. Alternatively, specific stereoisomers can be synthesized using an optically active starting material by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer to another by asymmetric transformation.

When compounds of the present invention have one or more stereogenic centers and no stereochemistry is provided in the name or structure, it should be understood that the name or structure is intended to encompass all forms of the compound, including the racemic form. When connect

- 8 035363 values according to the presented invention have two or more stereogenic centers and the absolute or relative stereochemistry is given in the title, the designation R and S refer, respectively, to each stereogenic center in numerological order (1, 2, 3, etc.) in according to the usual IUPAC numbering schemes of each molecule. The stereogenic centers of molecules can be represented by numerous alternative combinations of solid and dotted wedges. Many examples given in this document may include a 3.1.0 ring system with meso-stereochemistry as defined by the IUPAC naming conventions or the Cahn-lngold-Prelog conventions that were used in naming the examples and intermediates, and using the ChemBioDraw software Ultra 14.0.0.117 and / or ACD / Name Software v12.0. It should be noted that bonds can be solid or dashed, reflecting the same stereochemistry, for example, compare examples 1 and 54, due to rotation on the bond between the nitrogen of the 3.1.0 fragment and the nuclear fragment, which can also occur between the bond with the nuclear fragment and R ¹ , where the moiety is pyridinyl, pyrimidinyl, or triazinyl depending on the definitions of X, Y and Z.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, in admixture with at least one pharmaceutically acceptable excipient.

The presented invention also contemplates any one or a combination of:

a method of treating a disease for which a KHK inhibitor is indicated in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof;

the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease for which a KHK inhibitor is indicated;

a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament;

a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease for which a KHK inhibitor is indicated;

a pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient;

a pharmaceutical composition for the treatment of a disease for which a KHK inhibitor is indicated, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

As used herein, treatment of a disease for which a KHK inhibitor is indicated means that at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a patient in need for treatment, or is used to prepare a medicament. means for treating a patient in need, by inhibiting KHK and further metabolizing fructose, for the treatment of a disease, disorder, condition, or a related concomitant condition (which is generally referred to herein as a disease), selected from any one or more of the following: T1D, T2D, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease, acute renal disorder, tubular dysfunction and, pro-inflammatory changes in the proximal tubule, diabetic retinopathy, adipocytic dysfunction, visceral fat, obesity, eating disorders, excessive sugar cravings, dyslipidemia, hyperlipidemia, hypertriglyceridemia, high total cholesterol, high LDL cholesterol, low cholesterol, low cholesterol, low cholesterol, low cholesterol steatosis, NASH, fibrosis, liver cirrhosis, hepatocellular carcinoma, HFI, coronary arterial disease, peripheral vascular disease, essential hypertension, endothelial dysfunction, vascular elasticity disorders, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, pulmonary hypertension restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cat aracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorders, conditions of impaired fasting glucose levels, hyperuricemia, gout, erectile disorders connective tissue, foot ulcers, ulcerative colitis, hyper-apo-B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome.

In another embodiment, the invention provides a method of treating diseases selected from any one or a combination of the following: T1D, T2D, insulin resistance, renal disease, acute renal disorder, tubular dysfunction, pro-inflammatory

- 9,035363 changes in proximal tubules, adipocytic dysfunction, visceral body fat, obesity, eating disorders, excessive sugar cravings, dyslipidemia, hyperlipidemia, hypertriglyceridemia, high total cholesterol, high LDL cholesterol, low HDL cholesterol, NASH stebosis, NAFL , liver cirrhosis, hepatocellular carcinoma, HFI, essential hypertension, endothelial dysfunction, metabolic syndrome, hyperuricemia, and gout.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, for use in the treatment of any one or more of the diseases discussed herein. ...

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, in admixture with at least one pharmaceutically acceptable excipient.

In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, in admixture with at least one other therapeutic agent described in this document.

The expression therapeutically effective amount means an amount of a compound of the invention that (i) treats or prevents a particular disease, (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, described in this document.

The term mammal refers to warm-blooded animals, including humans (male or female) and domestic animals (such as dogs, cats, horses, etc.), and other animals, including guinea pigs, mice, rats, pygmy gerbils, cattle , goats, sheep, monkeys and chimpanzees.

The term patient is an alternative reference to a mammal.

The expression “pharmaceutically acceptable” indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients contained in the preparation and / or the mammal to be treated.

The terms treat, treat, or treat are intended to encompass preventive, i.e. preventive and palliative care, i.e. weakening, alleviating, or slowing the progression of the disease in the patient or any tissue damage associated with the disease.

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of formula (I) in which one or more atoms are replaced by an atom having the same atomic number, but atomic mass or mass number other than the atomic mass or mass number normally found in nature. ...

Examples of isotopes suitable for inclusion in compounds of the invention include τ> ζ \ ΤΤΖ \ ΤΆΖ \ TTO TPU / Tyu ΛЮΛ ² ^ L T! ³ ^ J 'TLT ^ Tyu ΤΛΟΤΛ ^{11 13} ^^ ¹⁴ ^ -GAGP' TLT ^ Tyu ΤΛΟΤΛ ³ ^^ 1 O 'GLT / Tyu ΤΛΟΤΛ ¹⁸ 1h' hydrogen such as h and n, carbon such as c, c and c, chlorine such as ci, fluorine such as f, 1 123 _t 125t 13 ^ 1. ^ T 15L 17L 18L iodine such as I and I, nitrogen such as N and N, oxygen such as O, O and O.

Certain isotopically labeled compounds of formula (I), for example those into which a radioactive isotope has been incorporated, are useful in drug and / or substrate tissue distribution studies. Radioactive isotopes of tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C are particularly preferred for this purpose in terms of ease of administration and detection capability.

Substitution with heavier isotopes such as deuterium, i.e. ² H, may confer certain therapeutic benefits resulting from higher metabolic stability, for example, increased in vivo half-life or reduced required dose, and therefore may be beneficial in some situations.

Substitutions with positron-active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies to study substrate receptor occupancy.

Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to one of ordinary skill in the art, or using methods analogous to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of unlabeled reagents. which were previously used.

Combined agents

The compounds of the present invention can be used alone or in combination with other therapeutic agents in the treatment of various conditions or diseases. The compound (s) of the present invention and the other therapeutic (s) agent (s) may be administered simultaneously (or in the same dosage form or in separate dosage forms) or sequentially.

The introduction of two or more compounds in combination means that the two compounds are administered sufficiently

- 10 035363 exactly close in time, and the presence of one changes the biological actions of the other. Two or more connections can be entered simultaneously, in parallel or in series. In addition, simultaneous administration can be accomplished by mixing the compounds prior to administration, or by administering the compounds at the same time point, but in different dosage forms at the same or different administration sites.

In another embodiment, the compounds of this invention are co-administered with any one or more additional therapeutic agent (s) as described herein. The combination agents are administered to the mammal in a therapeutically effective amount to treat the diseases described herein.

The expression parallel administration, co-administration, simultaneous administration, and co-administration means that the compounds are administered in combination.

In another embodiment of the present invention, a compound of formula (I) can be co-administered with an antiobesity agent, wherein the antiobesity agent is selected from the group consisting of an enteric MTP inhibitor (e.g., dirlotapid, mitratapid and implitapid, R56918 (CAS No. 403987 and CAS No. 913541-47-6)), cholecystokinin-A (CCK-A) agonists (for example, N-benzyl-2- [4- (1H-indol-3-ylmethyl) -5-oxo-1-phenyl- 4,5-dihydro-2,3,6,10b-teraαza-benzo [e] azulene-6yl] -N-isopropylacetamide described in PCT Publication No. WO 2005/116034 or US Publication No. 2005-0267100 A1), 5HT2c agonists (e.g. lorcaserin), MCR4 agonist (e.g. compounds described in US 6,818,658), lipase inhibitor (e.g. cetylistat), PYY _3-36 (as used herein, PYY _3-36 includes analogs such as pegylated PYY _{3- 36} , for example, those described in US publication 2006/0178501), opioid antagonists (for example, naltrexone), combinations of naltrexone with buproprion, oleoyl-estrone ( CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensin (NS2330), leptin, liraglutide, bromocriptine, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), Exenatide (Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine.

Other antiobesity agents include 11β-hugroxysteroug dehydrogenase-1 inhibitors (11βHSD type 1), stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β3 agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, melanin-concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat) , anorectic agents (such as bombesin agonist), neuropeptide-Y antagonists (for example, NPY Y5 antagonists), thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-like peptide agonists ( such as Axokine ™, available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), inhibits human agouti-linked protein (AGRP) pores, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP / ApoB inhibitors (eg enteric MTP inhibitors), orexin antagonist, combination of naltrexone with bupropion, etc.

In another embodiment of the present invention, a compound of formula (I) can be co-administered with an antidiabetic agent, the antidiabetic agent being selected from the group consisting of an acetyl CoA carboxylase (ACC) inhibitor (for example, described in WO 2009144554, WO 2003072197, WO 2009144555 and WO 2008065508), a diacylglycerol Oacyltransferase 1 (DGAT-1) inhibitor (for example, as described in WO 09016462 or WO 2010086820, AZD7687 or LCQ908), monoacylglycerol O-acyltransferase activator (AMP) inhibitors, AMP10 , acetohexamide, chlorpropamide, diabinesis, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, glychidon, glisolamide, tolazamide and tolbutamide), meglitinide, an α-amylase inhibitor (such as tendamistat and AL36, glupentidine inhibitor, trestatine 88 , acarbose), an α-glucosidase inhibitor (for example, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimi cin-Q and salbostatin), PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pilglitazone and rosiglitazone), PPAR α / γ agonist (e.g. CLX-0940, GW-1536, GW-2433, GW-1929, GW-1929 , KRP-297, L796449, LR-90, MK-0767, SB-219994, and saroglitazar), biguanide (e.g. metformin), glucagon receptor antagonist, glucagon-like peptide 1 (GLP-1) modulator, such as agonist (e.g. Exendin-3, Exendin-4, ZYOG-1 and TTP273), liraglutide (Victoza®), albiglutide, exenatide (Byetta®, Bydureon®), albiglutide, lixisenatide, dulaglutide, semaglutide (NN-054), TTP-9924 protein tyrosine phosphatase-III (PTP-1B) (e.g. trodusquemin, hirtiosal extract and compounds described by Zhang, S., et al., Drug Discovery Today, 12 (9/10), 373-381 (2007)), SIRT activator -1 (e.g. resveratol, GSK2245840 or GSK184072), a dipeptidyl peptidase IV (DPP-IV) inhibitor (e.g. from WO 2005116014, sitagliptin, vildagliptin, alogliptin, dutoglipti on, linagliptin and saxagliptin), stimulants of insulin production, an inhibitor of fatty

- 11 035363 acids, A2 antagonist, c-jun amino terminal kinase (JNK) inhibitor, glucokinase activators (GKa) (for example, those described in WO 2010103437, WO 2010103438, WO 2010013161, WO 2007122482, TTP-399, TTP -355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, or GKM001), insulin and insulin analogs, insulin mimetic, glycogen phosphorylase inhibitor (e.g. GSK1362885), VPAC2 receptor agonist, SGLT2 inhibitors (e.g. in EC Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010), including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626 and LX4211, as well as described in WO 2010023594), a glucagon receptor modulator such as described in Demong, DE et al. Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators (e.g., partial agonists such as those described in WO 2010140092, WO 2010128425, WO 2010128414, WO 2010106457, Jones, RM et al. In Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821)), derivatives or analogs of FGF21 (e.g. described in Kharitonenkov, A. Et al. Et al., Current Opinion in Investigational Drugs 2009, 10 (4) 359 -364, TGR5 receptor modulators (also called GPBAR1) (e.g. INT777 and agonists such as those described by Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10 (4), 386-396), GPR40 agonists (e.g. , those described in Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, in particular agonists, highly related activators of the nicotinic acid receptor (HM74A ), and SGLT1 inhibitors such as GSK1614235 (list of antidiabetic agents (e.g. WO 20 11005611, in particular, which is on page 28, line 35 to page 30, line 19), inhibitors or modulators of carnitine palmitoyltransferase enzymes, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, and / or CCR2 inhibitors CCR5, PKC isoform inhibitors (e.g. PKCa, PKCβ, PKCy), fatty acid synthetase inhibitors, serine palmitoyltransferase inhibitors, modulators GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor , SSTR1, SSTR2, SSTR3 and SSTR5), PDHK2 or PDHK4 inhibitors or modulators, MAP4K4 inhibitors, IL1 family modulators including Hybeta, RXR-alpha modulators, acceptable antidiabetic agents including mechanisms cited by Carpino, PA, Goodwin, B. Expert Opin ... Ther. Pat 2010,20 (12) 1627-51.

In another embodiment of the present invention, the compound of formula (I) can be co-administered with agents that are typically used by those with diabetes, for example, thyroid hormone (such as Synthroid), an agent for diabetic neuropathy ( for example, gabapentin, amitriptyline) or an agent or agents for treating any type of depression (eg, fluoxetine, sertraline, paroxetine, escitalopram, citalopram, duloxetine, levomilnacipran, venlafaxine, desvenlafaxine, bupropion, tricyclic, prototypylinetine, amytriptirapinit, including n doxepin, tripriamine and desipramine).

In another embodiment of the present invention, a compound of formula (I) can be co-administered with a cholesterol / lipid modulating agent, wherein the cholesterol / lipid modulating agent is selected from the group consisting of LMWH-CoA reductase inhibitors (e.g. pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin or nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin or atavastatin or visastatin)); an inhibitor of LMWH-CoA reductase gene expression; squalene synthetase inhibitors; squalene epoxidase inhibitors; a squalene cyclase inhibitor; a combined squalene epoxidase / squalene cyclase inhibitor, or a CETP inhibitor; fibrates; niacin, ion exchange resin, antioxidant; substances that enhance the excretion of bile acids (such as questran); ACAT inhibitors; inhibitors of MTP / APO β secretion; lipoxygenase inhibitors; inhibitors of cholesterol absorption; cholesterol ester transport protein inhibitors; an agent such as mipomersen; and or atherosclerotic agents including PCSK9 modulators.

In another embodiment, a compound of formula (I) can be co-administered with agents for treating NASH and / or NAFLD such as obeticholic acid (OCA, Intercept), GFT505 (elafibranor), caspase inhibitors (e.g. emricasan), glutathione transferase inducers (e.g. , oltipraz), adenosylmethionine decarboxylase inhibitors (e.g. SAMe), fatty acid / bile acid conjugate (FABAC) such as aramhol, FGF21 analogs including long-acting pegylated FGF-21 (BMS-986036), dual CCR2 / CCR5 receptor antagonist (e.g. cenicrivirok or TAK652), galectin-3 inhibitor (e.g. GR-MD-02), apoptosis-stimulating kinase-1 inhibitor (e.g. GS-4997), 5-lipoxygenase inhibitor (e.g. tipelukast), anti-HSP 47 siRNA (e.g. ND-L02-s0201), orlistat, TZDs and other insulin sensitizing agents, metformin, omega-3 acid ethyl esters (e.g. Lovaza), fibrates, LMWH CoA reductase inhibitors, ezetimibe, probucol, ursodeoxycholic acid TGR5, FXR agonists, FXR agonists, vitamin E, betaine, pentoxifylline, CB1 antagonists, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, naltrexone / buproprion combination, SGLT2 inhibitors, phentermine, topiramate and GLIP analogs and angiotensin receptors.

Additional therapeutic agents include anticoagulant or coagu inhibitor agents

- 12 035363 drugs, inhibitor of antiplatelet or platelet agents, thrombin inhibitor, thrombolytic or fibrinolytic agents, antiarrhythmic agents, antihypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diuretics, mineralocorticoid receptor antagonists, donor corticosteroids such as organic nitrates, NO stimulating agents such as phosphodiesterase inhibitors, cholesterol / lipid-lowering agents and lipid-profile agents, anti-inflammatory agents (steroidal and non-steroidal), anti-osteoporotic agents, hormone replacement therapy agents, oral contraceptives, antiproliferative agents agents, antineoplastic agents, antiulcer agents, and gastroesophageal reflux agents, growth hormone and / or growth hormone secretion, thyroid mimics (including thyroid hormone receptor antagonists), anti-infective agents, antiviral agent s, antibacterial agents and antifungal agents.

Included are agents used in the ICU setup, for example, dobutamine, dopamine, epinephrine, nitroglycerin, nitropruside, and the like.

Included are combination preparations suitable for the treatment of vasculitis, for example azathioprine, cyclophosphamide, mycophenolate, mofetil, rituximab, and the like.

In another embodiment, the present invention provides a combination in which the second agent is at least one agent selected from a factor Xa inhibitor, an anticoagulant agent, an antiplatelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent. Illustrative factor Xa inhibitors include apixaban and rivaroxaban. Examples of suitable anticoagulants for use in combination with compounds of the invention include warfarin, synthetic pentasaccharide, and heparin (eg, unfractionated and low molecular weight heparins such as enoxaparin and dalteparin).

The term antiplatelet agents (or platelet inhibiting agents) as used herein means agents that inhibit platelet function, for example, by inhibiting platelet aggregation, adhesion, or granular secretion. Agents include, but are not limited to, various known non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Aspirin (acetylsalicylic acid, or ASA) and COX-2 inhibitors such as CELEBREX or piroxicam are preferred NSLPS. Other acceptable platelet inhibitory agents include IIb / IIIa antagonists (e.g. tirofiban, eptifibatide and abciximab), thromboxane A2 receptor antagonists (e.g. ifetroban), thromboxane A2 synthetase inhibitors, PDE-III inhibitors (e.g. cilostazol), dipyridamol and their pharmaceutically acceptable salts or prodrugs.

The term anti-platelet agents (or platelet inhibitors are agents), as used herein, is also intended to include ADP receptor antagonists, preferably antagonists of purinergic receptors P ₂ Y1 and P ₂ Y _12, are preferred where P ₂ Y _12. Preferred P ₂ Y ₁₂ receptor antagonists include ticagrelor, prasugrel, ticlopidine, and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds as they are known to be gastrointestinal when used.

The term thrombin inhibitors (or antithrombin agents), as used herein, means serine protease thrombin inhibitors. By inhibiting thrombin, various thrombin-mediated processes are disrupted, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation, and / or granular secretion of plasminogen activator inhibitor-1 and / or serotonin), and / or fibrin formation. A number of thrombin inhibitors are known to those skilled in the art, and these inhibitors are contemplated to be used in combination with the disclosed compounds. Such inhibitors include, but are not limited to, argatroban, boroarginine derivatives, boropeptides, dabigatran, heparins (eg, unfractionated and low molecular weight heparins), hirudin, argatroban, and melagatran, including their pharmaceutically acceptable salts and prodrugs. Boroarginine derivatives and boropeptides include N-acetyl and peptide boric acid derivatives such as the C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and their corresponding isothyouronium analogs. The term hirudin, as used herein, includes acceptable derivatives or analogs of hirudin as referred to herein, surgeons such as disulfatohirudin.

The term thrombolytic or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, refers to agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and its modified forms, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase

13 035363 (nPA), factor Vila inhibitors, PAI-1 inhibitors (i.e., tissue plasminogen activator inhibitor inactivators), alpha-2-antiplasmin inhibitors, and anisolated plasminogen activator streptokinase complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to an anisolated complex of a plasminogenic streptokinase activator as described, for example, in EP 028489, the disclosure of which is incorporated herein by reference. The term urokinase, as used herein, is intended to mean both double and single chain urokinase, the latter also referred to herein as prourokinase.

Non-limiting examples of suitable anti-arrhythmic agents include class I agents (e.g. propafenone) class II agents (such as metoprolol, atenolol, carvadiol, and propranolol) class III agents (such as sotalol, dofetilide, amiodarone, azimilide, and ibutilide) class IV agents ( such as dithiazem and verapamil) K + channel openers such as I _Ach inhibitors and I _Kur inhibitors (eg compounds such as those described in WO 01/40231).

The compounds of the invention can be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (eg, blood pressure measurement). Examples of suitable antihypertensive agents include alpha-blockers; beta-blockers; calcium channel blockers (eg diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (eg, hydralazine), diuretics (eg, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, tricrinaphen, ethacrylorthenemidonemidone) renin inhibitors; ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); antagonists of AT-1 receptors (eg losartan, irbesartan, valsartan); ET receptor antagonists (eg, sitaxentan, atrsentan, and compounds described in US Pat. Nos. 5,612,359 and 6,043,265.); dual ET / AII antagonist (eg compounds described in WO 00/01389) neutral endopeptidase (NEP) inhibitors vasopepsidase inhibitors (dual NEP-ACE inhibitors) (eg hematopatrilate and nitrates). An illustrative antianginal agent is ivabradine.

Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine, and mibefradil.

Examples of suitable cardiac glycosides include digitalis and ouabain.

In another embodiment, a compound of formula (I) may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (eg LASIX ™), torasemide (eg DEMADEX ™), bemethanide (eg BUMEX ™) and ethacrynic acid (eg EDECRIN ™); (b) thiazide-type diuretics such as chlorothiazide (eg DIURIL ™, ESIDRIX ™ or HYDRODIURIL ™), hydrochlorothiazide (eg MICrOzIDE ™ or ORETIC ™), benzothiazide, hydroflumethiazide (eg SALURON ™), bendroflumethiazide, polythenyl thiazide trichloromethiazide and indapamide (eg LOZOL ™); (c) phthalimidine-type diuretics such as chlorthalidone (eg HYGROTON ™) and metolazone (eg ZAROXOLYN ™); (d) quinazoline-type diuretics such as quinetasone; and (e) potassium-sparing diuretics such as triamterene (eg, DYRENIUM ™) and amiloride (eg, MIDAMOR ™ or MODURETIC ™).

In another embodiment, a compound of formula (I) may be co-administered with loop diuretics. In yet another embodiment, the loop diuretic is selected from furosemide and torasemide. In yet another embodiment, one or more compounds of formula (I) may be co-administered with furosemide. In yet another embodiment, one or more of the compounds of formula (I) may be co-administered with torasemide, which may optionally be in controlled or modified release torasemide form.

In another embodiment, a compound of formula (I) may be co-administered with thiazide-type diuretics. In yet another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of formula (I) may be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of formula (I) may be co-administered with hydrochlorothiazide.

In another embodiment, one or more of the compounds of formula (I) may be co-administered with a phthalimide-type diuretic. In another embodiment, the phthalimide-type diuretic is chlorthalidone.

Examples of a suitable combination of mineralocorticoid receptor antagonists include sprionolactone and eplerenone.

Examples of a suitable combination of phosphodiesterase (PDE) inhibitors include: PDE III inhibitors (eg, cilostazol); and PDE V inhibitors (such as sildenafil).

The qualified specialist in this field will understand that the compounds according to this

- 14 035363 of the invention may also be used in combination with other cardiovascular or cerebrovascular therapies, including PCI, stenting, drug elution stents, stem cell therapy, and medical devices such as pacemakers, defibrillators, or cardiac resynchronization therapy.

In another embodiment, the invention provides a combination of therapeutic agents in which the compounds of this invention can also be used in combination with other pharmaceutical agents to treat diseases, conditions and / or disorders described herein. Thus, further contemplated are methods of treatment comprising administering the compounds of the invention in combination with other pharmaceutical agents.

Administration and dosing

Typically, a compound of the invention is administered in an amount effective to treat a disease as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route of administration and in a dose effective for the treatment indicated. The therapeutically effective doses of the compounds required to treat disease progression are readily established by one of skill in the art using preclinical and clinical approaches known in the medical industry.

The compounds of the invention can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, which allows the compound to enter the bloodstream directly from the oral cavity.

In another embodiment, the compounds of the invention can also be administered directly into the bloodstream, into muscle, or into an internal organ. Acceptable routes of parenteral administration include intravenous, intra-arterial, intra-abdominal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedles) syringes, needleless syringes, and infusion techniques.

In another embodiment, the compounds of the invention can also be administered topically to the skin or mucous membrane, i. E. dermal or transdermal. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention can be administered rectally or vaginally. In another embodiment, the compounds of the invention can also be administered directly to the eye or ear.

The dosage regimen for compounds and / or compositions containing the compounds is based on many factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; route of administration; and the activity of the specific compounds that are used. Thus, the dosage regimen can vary widely. Dosage levels of the order of about 0.01 to about 100 mg per kilogram of body weight per day are acceptable in the treatment of the above conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg / kg. In another embodiment, the total daily dose of a compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg (i.e., mg of a compound of the invention per kg of body weight). In one embodiment, the dosage is from 0.01 to 10 mg / kg / day. In another embodiment, the dosage is 0.1 to 1.0 mg / kg / day. The dosage unit of the compositions may contain such amounts, or partial units thereof, constituting a daily dose. In many cases, administration of the compound will be repeated many times a day (usually no more than 4 times). Usually several doses per day can be used to increase the total daily dose if necessary.

For oral administration, the compositions can be presented in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25 , 0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 mg for symptomatic adjustment of patient dosage. A medicament typically contains from about 0.01 mg to about 500 mg of active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenous, doses can range from about 0.1 to about 10 mg / kg / min during infusion at a constant rate.

Suitable subjects in accordance with the present invention include mammalian subjects. Mammals of the present invention include dog, cat, cow, goat, horse, sheep, pig, rodent, lagomorph, primate, etc., and include mammals in utero. In one embodiment, humans are acceptable subjects. Human subjects can be of any gender and at any stage of development.

- 15 035363

Pharmaceutical compositions

For the treatment of the diseases mentioned above, the compound of the invention may be administered as the compound per se. Alternatively, pharmaceutically acceptable salts are acceptable for medical applications as they can have greater water solubility than the parent compound.

In another embodiment, the present invention includes pharmaceutical compositions. Such pharmaceutical compositions contain a compound of the invention provided with a pharmaceutically acceptable carrier. The carrier can be solid, liquid, or both, and can be formulated with the compound as a unit dosage composition, eg, a tablet, which can contain from 0.05 to 95% by weight of the active compounds. The compound of the invention can be combined with suitable polymers as useful carriers in a drug. In addition, other pharmacologically active substances may be present.

The compounds of the present invention can be administered by any suitable route, advantageously in the form of a pharmaceutical composition adapted to that route of administration and in a dose effective for the treatment contemplated. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, or topically.

Oral administration of a solid dosage form may, for example, be presented as discrete units such as hard or soft capsules, dragees, cachets, troches, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as, for example, lozenges. In such solid dosage forms, the compounds of the invention are typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled release composition. In the case of capsules, tablets and dragees, the dosage forms may also contain buffering agents or may be prepared with an enteric coating.

In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also contain adjuvants, such as moisturizing, emulsifying, suspending, flavoring (eg, sweetening) and / or flavoring agents.

In another embodiment, the present invention includes a parenteral dosage form. Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusions. Injectable preparations (eg, sterile injectable aqueous or oily suspensions) can be formulated in accordance with those known in the art using suitable dispersing, wetting and / or suspending agents.

In another embodiment, the presented invention includes a topical dosage form. Topical administration includes, for example, transdermal administration, such as using transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Topical compositions also include, for example, topical gels, sprays, ointments and creams. Topical preparations may include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered using a transdermal device, administration will be performed using a patch or reservoir, or a porous membrane type, or various solid matrices. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, implant capsules, implants, sponges, fibers, bandages, and microemulsions. In addition, liposomes can be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration amplifiers can be included; see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., Vol. 88, p. 955-958,1999.

Formulations suitable for topical administration to the eye include, for example, eye drops, wherein a compound of this invention is dissolved or suspended in an appropriate carrier. A typical formulation suitable for ophthalmic or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline solution. Other formulations suitable for ophthalmic and aural administration include ointments that are biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, implant capsules, lenses and particle systems or vesicles such as niosomes or liposomes. Polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymer such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose, or heteropolysac

- 16 035363 a read polymer such as gellan gum may be included together with a preservative such as benzalkonium chloride. Such drugs can also be administered using iontophoresis.

For intranasal or inhalation administration, the active compounds of the invention are generally administered in the form of a solution or suspension from a spray pump container that is compressed or inflated by the patient, or as an aerosol spray from a pressurized container or nebulizer using an appropriate propellant. Compositions suitable for intranasal administration are generally administered as a dry powder (or separately, as a mixture, for example, in a dry mix with lactose, or as mixed component particles, for example, mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, nebulizer (preferably an electrohydrodynamic nebulizer to produce a fine mist) or nebulizer with or without an acceptable propellant such as 1,1,1,2-tetrafluoroethane or 1 , 1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent such as chitosan or cyclodextrin.

In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives can be used if necessary.

In addition, other carrier materials and routes of administration known in the pharmaceutical industry can be used. The pharmaceutical compositions of the invention may be prepared using any of the methods well known in the pharmaceutical arts, such as efficient formulation and administration procedures. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. Drug formulation is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients ( 3 ^{rd Ed.), American Pharmaceutical Association} , Washington, 1999.

Receiving

In the preparation of compounds of formula (I), it is noted that some of the preparation processes described herein may require protection of remote functionality (eg, primary amine, secondary amine, carboxyl, in the precursors of formula (I)). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the acquisition methods. The need for such protection is easily determined by a qualified person in this field. The use of such protection / override protection methods is also within the purview of one skilled in the art. For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

For example, some compounds contain primary amines or carboxylic acid functionalities that can interfere with reactions elsewhere in the molecule if left unprotected. Accordingly, such functional groups can be protected with an appropriate protecting group, which can be removed in the next step. Suitable protecting groups for protecting the amine and carboxylic acid include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and 9fluorenylmethyleneoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids), which are usually not chemically reactive under the described reaction conditions, and can usually be removed without chemical replacement of other functionalities in the compounds of formula (I).

The reaction schemes described below are intended to provide a general description of the methodology used to prepare the compounds of the present invention. Some of the compounds of the present invention contain one chiral center with the stereochemical designation (R). Those skilled in the art will understand that all synthetic transformations can be carried out in a similar manner, regardless of whether the materials are enanti-enriched or racemic. In addition, resolution of the desired optically active material can occur at any desired point in the sequence using known methods described herein and in the chemical literature.

1 2 t "3 4 C taN S

In the following reaction schemes, the variables X, Y, Z, R, R, R, R, R, R, R, L, m and n are as described herein for compounds of formula (I), unless otherwise indicated. For the schemes below, some leaving groups are identified as LG ¹ or LG ² , each of which can independently represent halogen, SO ^ tkm, SO ^ -ipum. S-alkyl, S-aryl, S (O) alkyl, S (O) -aryl, or oxygen linked to a moiety that contains phosphorus. Each LG ³ may independently represent a leaving group such as an alkyl or aryl sulfonate (eg mesylate, tosylate or triflate), or halogen, or some other group which may be substituted with an amine. Each alkyl is independent of the other and, as a rule, contains from 1

- 17,035363 to 6 carbon atoms. Aryl is typically phenyl. When the protecting group is identified as PG ¹ , it may be an alkylamine protecting group such as benzyl, benzhydryl or the like; a carbamate protecting group such as Boc, Cbz or the like; or an amide protecting group such as trifluoroacetamide.

Pyrimidinyl and cyanopyridinyl rings can be prepared as described in Scheme 1. Intermediates of Formula 6 can be purchased or synthesized in general by condensation reactions as shown in Scheme 1. Esters 1 (in which R ³ can be F, Cl, Br, alkyl and the like) can be deprotonated with a base such as potassium t-butoxide, lithium diisoproprylamide, sodium hydride and the like and reacted with esters 2 to give beta-keto esters 3. Alternatively, ketones of general formula 7 can be treated analogously bases and react with chloroformates 8 in order to obtain similar beta-keto esters 3.

The esters 3 can then condense with reagents such as ureas to form pyrimidines 5 with or without heating, or alternatively with an acidic or basic catalyst. The activation of the hydroxyl to the leaving group can be carried out with reagents such as phosphorus oxyhalides, phosphorus penthalide, alkyl or aryl thiols and their salts (with subsequent oxidation or not), BOP, PyBOP, or other similar activation reagents to obtain compounds of the general formula 6.

Scheme 1

R ⁴ '

O ^A o ^alkyl o o activation in

ОН splitting off _ν Α _ν group

LG ²

N '^ N

R ³ RIG

V OH

R ³ r ^ V-'LG '6 ^RJ έ ³

Oh oh ^j

01¼ -apkil | η ₂ ν7νη ₂ alkyl

OH activating group into a leaving _Ν '

LG ² _r uv; o ^{h κ} 10 ^R4 'and ^R

Compounds of general formula 11 can be purchased or synthesized starting from beta-ketosters 3, which can be reacted with cyanoacetamide 9 to give compounds of general formula 10. They can be converted to compounds of general formula 11 by a method similar to conversion of 5 to 6.

Scheme 2

NH ₃ source

activation of a split-off OH group in LG

O-alkyl

acid N

R ₁₇

HE

NH O

O-alkyl alkyl

O O / 1.base / 2.alkylation '0-alkyl

R ¹ '' 0-alkyl

[electrophilic aromatic substitution

LG ² activation in _Λ splitting off

Ν ’A group ν

---- l

21 ^{R3 R 21} 20 acid ν f 'ΌΗ''Λ R ^{3 R} alkyl

Oh oh

O-alkyl j O-alkyl

R ³

Intermediates 18 can be synthesized as shown in Scheme 2. Starting from beta-keto esters 12, treatment with an ammonium source such as ammonium acetate, ammonium chloride, ammonium hydroxide, ammonium in solvent solution, and the like. under various conditions, which include with or without heating or alternatively with an acidic or basic catalyst to give compounds of general formula 13. Treatment with acid chlorides 14 can then lead to compounds of general formula 15. Treatment with base can cyclize to pyridine and alkylate the resulting hydroxyl groups can lead to pyridines 16. Treatment with an acid such as hydrofluoric acid, chloride, bromide, iodide, or various Lewis acids, with or without heating, can lead to compounds of general formula 17. Activation of hydroxyl functional groups in splitting corpses, with the formation of intermediate compounds of the general formula 18 can proceed in a similar manner with the conditions described for the conversion of 5 to 6 in Scheme 1. Al-18 035363 Ternatively, pyridine can be obtained by substitution (where R ³ is F, Cl, Br, and alkyls, which can be introduced by electrophilic aromatic substitution by methods such and as Friedel-Crafts alkylation) by reacting compounds of Formula 16 with one of various electrophilic aromatic substitution conditions such as chlorine gas, bromine, selectFluor ™, N-fluorobenzenesulfonimide, N-halogenosuccinimides, or any other known sources of electrophilic halide , or alkyl halides in the presence of aluminum catalysts to obtain compounds of general formula 19. The resulting compound can then be converted into intermediate compounds of general formula 21 by analogous methods described for conversion of 16 to 18.

Scheme 3A

Amines of General Formula 26 can be purchased or synthesized in general as shown in Schemes 3A through 3D. Starting from protected [3.1.0] azabicyclohexanes 22 (purchased or synthesized by methods similar to Berliner, MA; et al. Org. Process Res. Dev. 2011, 15, 1052-1062), the hydroxyl moiety can be converted to LG ³ using standard procedures and is replaced by known carbon-containing homologation reagents such as sodium or potassium cyanides to give nitriles 24. The nitrile moiety can then be hydrolyzed to esters 25 (or carboxylic acid) under various standard conditions for acidic or basic catalysis, where PG ² is alkyl (eg, C _1-6 alkyl) or benzyl. Removal of PG ¹ can be accomplished by many of the methods described in the literature to give amino esters 26.

Scheme 3B

Alternatively, as depicted in Scheme 3B, the hydroxyl moiety 22 can be oxidized to aldehyde 27 and homologated using the Wittig reaction and hydrolysis to give homologous aldehydes 29. In addition, oxidation using various oxidizing agents such as sodium chlorite, calcium hypochlorite, potassium permanganate, or others, will then give carboxylic acids 30 or esters 26.

Scheme 3C

Alternatively, as depicted in Scheme 3C, aldehydes 27 can be converted to alkynes 31 using various conditions such as Gilbert-Seyfert reagent, Ohira-Bestman reagent, CBr4 with PPh ₃ , or others. The alkyne can then be converted to carboxylic acids 30 using Bronsted acid or Lewis acid, or with a metal catalysis such as gold catalysis. Alternatively, the hydroxyl group can be oxidized to acids 32 and treated to Arndt-Eistert homologation conditions (32 to 33 to 34 to 30) to give homologous acids 30. Alternatively, compounds of the general formula for intermediate 35A can be synthesized by functionalizing alcohols 22 under various conditions described in the literature (see, for example, WO 2010116328).

- 19 035363

3D scheme

Amines of formulas 35D, 35F, 35H, 35K, 35N can be synthesized as described in the literature or synthesized as described in Schemes 3D through 3F. Starting from 30, treatment with a reagent that replaces hydroxyl with chloride (such as phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride, thionyl chloride, sulfuryl chloride, and others, in the presence or absence of DMF) can lead to acid chlorides 35B. Subsequent treatment with an amine, HN (R ^N ) 2, in the presence of any base such as DIPEA, TEA, DBU, K2CO ₃ , NaHCO ₃ , or any others, can lead to amides 35C. Alternatively, 30 can be directly coupled to the amine using any amide coupling reagent to activate the carboxylic acid (such as EDC, HATU, T3P, COMU, DCC, and many others described in the literature) to provide 35C. The acid chloride 35B can be treated with the sulfonamide, H2NS (O) 2R ^S, to provide the acyl sulfonamides 35E. Alternatively, 30 can be converted to 35E using the sulfonamide, H2NS (O) 2R ^S , and conditions similar to those described for converting 30 to 35C.

Scheme 3E

Intermediate 24 can be converted to tetrazole 35G by adding an azide such as sodium, potassium azide, trimethylsilyl azide, tributyltin azide, or others, using heat or adding a catalyst to accelerate the reaction. Tetrazole 35H is then prepared using standard procedures regarding the removal of PG ¹ .

Scheme 3F

Intermediate 23 can be converted to sulfone 35J in a variety of ways such as replacing the leaving group with sulfinic acid or sodium, potassium, or other sulfinic acid salt, HOS (O) ^RS under neutral or basic conditions. Alternatively, intermediate 23 can be converted to 35J by a process consisting of displacement of the leaving group in intermediate 23 to a thiol or sodium, potassium or other thiol salt to form a thioether, which can then be oxidized to sulfone using an oxidizing agent. such as meta-chloroperbenzoic acid, hydrogen peroxide, potassium permanganate, or many other oxidizing agents. Alternatively, intermediate 23 can be converted to sulfonyl chloride 35L by treatment with thiourea followed by treatment with calcium hypochlorite; or a metal-halogen exchange reagent such as magnesium or butyllithium, followed by treatment with sulfur dioxide or a sulfur dioxide source such as DABCO-SO2 and then chlorination using NCS, thionyl chloride, phosphorus oxychloride, or other chlorinating reagents; or using other methods known in the literature. Intermediate 35L can be converted to 35J by treatment with an alkylating reagent such as an alkyllithium, an alkyl magnesium halide, an aluminum trialkyl, or some other nucleophilic source of alkyl groups. Intermediate 35L can be converted to acylsulfonamide 35M by treatment with amide, H2NC (O) R ^S in the presence of a base such as sodium hydride, lithium diisopropylamide, potassium carbonate, DBU, or other bases. Removal of protective groups from 35C, 35E, 35G, 35J, and 35M can be accomplished using acidic conditions, basic conditions, hydrolysis, or other conditions known in the literature to remove the provided protective

- 20,035363 groups to give 35D, 35F, 35H, 35K and 35N, respectively.

Scheme 4A

Azetidines 40 (in which G may be H or any C _1-3 alkyl) can be purchased, synthesized as described in the literature (such as in J. Med. Chem. 1994, 37, 4195), or synthesized, as described in diagrams 4A through 4C. Intermediate diol compounds 36 can be converted to intermediates 37 by activation with mesyl chloride or anhydride, triflate anhydride, or other sulfonate-forming reagents, or converted to a halide leaving group, thionyl chloride, carbon tetrabromide with triphenylphosphine, iodosulfine or other triphenylazole reagents ... Treatment of 37 with amine 38 can lead to azetidines 39. Standard deprotection processes provide intermediates of general formula 40 which eventually become R ^{1 of} compounds of formula (I), so R ^1Sub is H when R ¹ is unsubstituted or R ^1Sub represents - ^^ alkyl and -OH as defined in any embodiment of compounds of formula (I) for substituents at R ¹ .

Scheme 4B

Alternatively, as depicted in Scheme 4B, when J is hydrogen, oxidation can occur to give ketones 44 (in which G can be H or some Cc ^ zcyl). Treatment with any known metal hydride (JM, where J is hydrogen and M is a source of metal counterion such as lithium, magnesium, zinc, aluminum, boron, or others) can result in the azetidinyl of intermediate 40 for R ¹ by acting to the desired stereochemical result by choosing a reagent. Alternatively, the ketones 44 can be treated with metal alkylating agents (JM, where J is any C ^ malkyl and M is a metal counterion such as lithium, magnesium, zinc, aluminum, boron, or others) such as alkylmagnesium halides, alkyllithium, or many other sources of nucleophilic alkyl groups, providing compounds of general Formula 39 in which J is alkyl. The resulting compounds can then be converted to azetidines 40 as previously described. Alternatively, ketones 41 can be activated with a leaving group, (LG ³ ), by treatment with a base and an electrophilic halogen source to give ketones 42. Derivation can then be carried out in a similar manner to conversion of 44 to 39 to give compounds 43. The resulting compounds can be subjected to basic conditions to form azetidines 39, in which J is alkyl or hydrogen, which can then be converted to intermediates 40 as previously described. Alternatively, the esters 45 can be converted to ketones 42 by a leaving group insertion homologation reaction using reagents such as chloroacetic acid or dihalomethane in the presence of a salt base or sulfonium ylide, and many other reagents as described in the literature. Intermediate 42 can then be converted to 40 as previously described.

- 21 035363

Scheme 4C

Alternatively, alkenes 46 or 48 (in which J may be any alkyl or hydrogen; G may be H or any C1. ₃ alkyl); can be treated with various oxidizing agents such as m-CPBA (meta-chloroperbenzoic acid), hydrogen peroxide, tert-butyl hydroperoxide, Slopless epoxidation conditions, Si epoxidation conditions, or many other conditions known in the literature to obtain 47 or 49, respectively.

Epoxides 47 or 49 can be treated with amine by methods analogous to conversion of 37 to 39 to give azetidines 39, can be further converted to intermediates 40.

Scheme 5

Intermediates of formulas 56 and 57 can generally be synthesized as shown in Scheme 5. Starting from bis-hydroxyheteroaryls of general formula 50 (acquired, known in the literature, or described in previous schemes), conversion to intermediates of general formula 51 can occur in in a manner similar to that described for the conversion of intermediate 5 to 6 in Scheme 1. Amines of general formula 52 (acquired, found in the literature, or described in previous schemes such as 30 or 25, in which the protection must first be deprotected under acidic conditions , basic conditions, hydrolysis conditions, or other conditions as described in the literature for the provided protecting group) can be coupled to 51 under basic or acidic conditions via an S _N Ar reaction in the presence of bases such as carbonate, bicarbonate, hydroxide, sodium acetate, potassium or cesium, or organic amine bases such as triethylamine, diisopropylethylamine, DBU, and the like or under the conditions of palladium catalysis with various sources of palladium, ligands and bases, obtaining intermediate compounds 53. The resulting compounds can then be combined with amines of general formula 54 (purchased, found in the literature, or described in previous schemes, such as 40) similar the previous step in a manner, but often at higher temperatures to obtain intermediates 56. Alternatively, treatment of compounds 53 with an alkyl metal or metalloid complexes 55 such as alkyl zinc, alkyl boronic acid, boronate, trifluoroborate salts and the like under palladium catalysis conditions can give intermediate compounds 56. When R ² contains an ester (see. Scheme 3A), the carboxylic acid can be prepared using various conditions as indicated in the literature to provide intermediates 57.

- 22 035363

Scheme 6A

Alternatively, intermediates 60, 61, and 62 (Scheme 6A) can be synthesized in a manner analogous to those described for intermediates 53, 56 and 57, respectively, as shown in Scheme 5.

Scheme 6B

Intermediates 60, 61 and 62 can be subjected to electrophilic aromatic substitution reactions in a manner analogous to those described for converting intermediate 16 to 19 in Scheme 2 to provide intermediates 63, 64 and 65, respectively, where R ³ = F, Cl, Br , I or alkyls, which can be introduced by electrophilic aromatic substitution by methods such as Friedel-Crafts alkylation. Intermediates 63 and 64 can be further converted to compounds of formula 65 by methods similar to those already described.

Scheme 6C

Alternatively, as shown in Scheme 6C, compounds 63a, 64a and 65a (in which R ^3a = halogen) can be converted to compounds of general formulas 67, 68 and 69, respectively, (in which R ³ = Me, Et, iPr, cPr and OMe) by treating R ^{3 M} (with reagent 66 where M can be a metal or metalloid such as sodium, potassium, zinc, tin, boron, aluminum, magnesium or others) and palladium or copper catalysis in a manner similar to that described with respect to compounds 53 with 55 to form co

- 23 035363 unions 56 (Scheme 5).

Exemplary 2,4-dichloro-6- (difluoromethyl) pyrimidine Intermediates

Cl

Ν '^ Ν

A solution of ethyldifluoroacetate (250 g, 2.01 mol) and EtOAc (1070 g, 12.10 mol) was heated to 70 ° C and treated with a solution of sodium ethoxide (151 g, 2.22 mol) in anhydrous ethanol (2500 ml) for 2 h. The resulting yellow mixture was stirred at 70 ° C for 14 h. The cooled reaction mixture was acidified to pH 2-3 with 4M HCl in EtOAc, whereby solids precipitated. The mixture was filtered through a Celite® pad and the filter cake washed with EtOAc (4x30 mL). The filtrate was concentrated to give crude ethyl 4,4-difluoro-3-oxobutanoate (200 g, 59.8%) as a yellow oil, which was used in the next step without further purification.

To a solution of ethyl 4,4-difluoro-3-oxobutanoate (100 g, 602 mmol) in anhydrous toluene (1000 ml) was added urea (43.4 g, 722 mmol) and a 2 M solution of sodium ethoxide in ethanol (81, 7 g, 1.20 mol). The resulting yellow solution was stirred at rt. for 30 min and then stirred at 120 ° C for 16 hours. The yellow suspension was then stirred at 130 ° C for an additional 16 hours. The yellow suspension was cooled to rt. and concentrated to give 6 (difluoromethyl) pyrimidine-2,4-diol as a yellow solid (100 g, quantitative), which was used directly in the next step without further purification.

In two separate batches, a brown suspension of 6- (difluoromethyl) pyrimidine-2,4-diol (97.6 g, 602 mmol) and NN-dimethylaniline (67.8 g, 560 mmol) in acetonitrile (1000 ml) was cooled to 0 ° C and phosphorus oxychloride (231 ml, 2.48 mol) were added dropwise. After the addition was complete, the resulting mixture was heated to 95 ° C for 16 h. The reaction mixture was then cooled to 25 ° C, quenched with ice water (1000 ml), and extracted with methyl tert-butyl ether (8x500 ml ). The combined organic layers were washed with saturated brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a brown oil (100 g). The two batches were combined and purified using column chromatography (100: 0 to 98: 2 petroleum ether / EtOAc) to give 2,4-dichloro-6- (difluoromethyl) pyrimidine (92.0 g) as a light yellow oil.

1H NMR (400 MHz, CD3OD) δ: 7.87 (s, 1H), 6.72 (t, 1H).

2,4-Dichloro-6- (difluoromethyl) -5-methylpyrimidine

CH ₃

A solution of ethyl propionate (200 g, 1.96 mol) in THF (1250 ml) was treated portionwise with sodium hydride (60% in mineral oil, 78.3 g, 1.96 mol). The resulting liquid suspension was then treated dropwise with ethyl difluoroacetate (486 g, 3.92 mol) for 2 hours. The liquid suspension was heated at 50 ° C for 19 hours. The cooled reaction mixture was then treated with 10% sulfuric acid (600 ml) and extracted with EtOAc (4x500 ml). The combined organic layers were washed with saturated brine (1000 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified using column chromatography eluting with petroleum ether / EtOAc (100: 0 to 5: 1) to give ethyl 4,4-difluoro-2-methyl-3-oxobutanoate (260 g, 74%) as a red oil which was used directly in the next step.

In two separate batches, urea (52.0 g, 866 mmol) was added dropwise to a solution of 4,4-difluoro-2-methyl-3-oxobutanoate (130 g, 722 mmol) in anhydrous toluene (1.44 L) and 2 M solution of sodium ethoxide in ethanol (98.2 g, 1.44 mol). The resulting yellow solution was stirred at rt. for 30 min and then stirred at 130 ° C for 16 h. The cooled reaction mixtures were combined and concentrated to give 6- (difluoromethyl) -5-methylpyrimidine-2,4-diol (254 g) as a light yellow solid, which was used directly in the next step.

A mixture of 6- (difluoromethyl) -5-methylpyrimidine-2,4-diol (84.7 g, 481 mmol) and phosphorus pentachloride (401 g, 1.92 mol) was stirred at 140 ° C for 16 h. The cooled reaction mixture poured into ice water (5000 ml) and extracted with methyl tert-butyl ether (8x1000 ml). The organic phase was washed with brine (3000 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a dark brown oil (300 g crude). The crude product was separated into three runs and purified using column chromatography eluting with petroleum ether / EtOAc (100: 0 to 98: 2) to give 2,4-dichloro-6- (difluoromethyl) -6-methylpyrimidine as a red oil ( 92 g, 30%).

- 24 035363 ¹ H NMR (400 MHz, CD3OD) δ: 6.83 (t, 1H), 2.49 (s, 3H).

2,4-Dichloro-5-methyl-6- (trifluoromethyl) pyrimidine

Sodium hydride (60% in mineral oil, 13.7 g, 343 mmol) was added to a solution of ethyl propionate (35.0 g, 340 mmol) in THF (350 ml) at 25 ° C. The gray liquid suspension was heated to 50 ° C and ethyl trifluoroacetate (97.4 g, 685 mmol) was added dropwise to the mixture over 15 minutes. The reaction mixture was stirred at 50 ° C for 16 hours. The cooled reaction mixture was slowly added to 10% sulfuric acid at 0 ° C. The resulting yellow mixture was extracted with EtOAc (3x500 ml) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give ethyl 4,4,4 trifluoro-2-methyl-3-oxobutanoate (60 g) which was used directly at the next stage.

To a solution of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (60.0 g, 303 mmol) in anhydrous toluene (500 ml) was added portionwise urea (21.8 g, 363 mmol) and freshly obtained 2 M sodium ethoxide in ethanol (41.2 g, 606 mmol). The resulting yellow solution was stirred at rt. over 15 min and then heated to 130 ° C for 48 h. The reaction mixture was concentrated and the solvent removed to give crude 5-methyl-6- (trifluoromethyl) pyrimidine-2,4-diol (60 g) as a gum which was used in the next step without further purification.

5-Methyl-6- (trifluoromethyl) pyrimidine-2,4-diol (120 g, 480 mmol) was added to phosphorus oxychloride (371.0 g, 2.420 mmol) at 0 ° C and treated dropwise with NN-dimethylaniline (54, 6 g, 451 mmol). The resulting mixture was heated to 100 ° C for 16 h. The dark reaction mixture was cooled to rt. and poured into ice water. The aqueous layer was extracted with methyl tert-butyl ether (3x1000 ml) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give a dark yellow oil (80 g). The crude product was dissolved in n-hexane and some of the formed insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give 2,4-dichloro-5-methyl-6- (trifluoromethyl) pyrimidine (40 g, 36%) as a yellow oil with residual n-hexane present.

1H NMR (400 MHz, CD ₃ OD) δ: 2.53 (s, 3H).

2,4-Dichloro-6- (1,1-difluoroethyl) pyrimidine

Step 1: 6- (1,1-difluoroethyl) pyrimidine-2,4-diol.

A solution of lithium hexamethyldisilazide (217 ml, 1 M solution in THF, 217 mmol) in dry THF (400 ml) was cooled under argon to -78 ° C and treated dropwise with EtOAc (19.1 g, 217 mmol). The reaction mixture was stirred at -78 ° C for 1 h, then treated dropwise with ethyl 2,2 difluoropropionate (15.0 g, 110 mmol). Stirring was continued for 4 hours at -78 ° C. A saturated ammonium chloride solution (150 ml) was added dropwise. The mixture was warmed to rt, acidified with 1 M HCl (150 ml) and left to stand for 2 h. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with 1 M HCl, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified using column chromatography eluting with petroleum ether / EtOAc (100: 0 to 7: 3) to give ethyl 4,4-difluoro-3-oxopentanoate (27 g) as a yellow oil which was used directly in the next step. ...

To a solution of ethyl 4,4-difluoro-3-oxopentanoate (20.0 g, 111 mmol) and urea (8.00 mg, 133 mmol) in anhydrous toluene (400 ml) and ethanol (30 ml) was added solid sodium ethoxide ( 30200 mg, 222 mmol) at rt, then the mixture was heated to 125 ° C while boiling under reflux, equipped with a Dean-Stark trap. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was acidified to pH 4 using 4N HCl in EtOAc and extracted with EtOAc (3x100 ml). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product (20.0 g) as a yellow oil. The crude product was purified using EtOH: petroleum ether (1: 1) to afford the title compound (11.6 g, 59%) as a solid.

1H NMR (400 MHz, CDCl3) δ: 5.71 (s, 1H), 1.93 (t, 3H).

Stage 2.

To a solution of 6- (1,1-difluoroethyl) pyrimidine-2,4-diol (9.60 g, 54.5 mmol) in acetonitrile (120 ml) was added phosphorus oxychloride (41.8 g, 273 mmol) followed by the addition of Ν, Ν-diisopropylamine (704 mg, 5.45 mmol). The mixture was stirred at 80 ° C for 16 h. The reaction mixture was cooled to

- 25 035363

Ph.D. and poured into ice water (60 ml). The mixture was podslushivaet to pH 7-8 with saturated aqueous sodium carbonate solution and was extracted with EtOAc (3x30 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil. The crude product was purified using column chromatography eluting with DCM / petroleum ether to give 2,4-dichloro-6- (1,1 difluoroethyl) pyrimidine (6.5 g, 56%) as a clear oil.

1H NMR (400 MHz, CD3OD) δ: 7.85 (s, 1H), 1.97 (t, 3H).

2,4-Dichloro-6- (1,1-difluoroethyl) -5-methylpyrimidine

CI

Stage 1: ethyl 4,4-difluoro-2-methyl-3-oxopentanoate.

Sodium hydride (60% in mineral oil, 5.87 g, 147 mmol) was added portionwise to a solution of ethyl propionate (15.0 g, 147 mmol) in THF (70 ml). The resulting gray liquid suspension was then treated dropwise with ethyl 2,2-difluoropropionate (24.3 g, 176 mmol) over 15 minutes. The liquid suspension was heated to 50 ° C for 4 h, then stirred at 16 ° C for 60 h. The mixture was slowly poured into 10% sulfuric acid (60 ml) and extracted with EtOAc (2x50 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography eluting with EtOAc: petroleum ether (1:10) to give the title compound (18 g) as a brown oil.

¹ H NMR (400 MHz, CD3OD) δ: 3.76 (q, 2H), 3.52 (q, 1H), 1.32 (t, 3H), 0.98 (d, 3H), 0.83 (t, 3H).

Stage 2.

To a solution of ethyl 4,4-difluoro-2-methyl-3-oxopentanoate (18 g, 93 mmol) and urea (6.68 g, 111 mmol) in toluene (270 ml) was added a solution of sodium ethoxide (12.6 g, 185 mmol) in ethanol (90 ml). The solution was stirred at 130 ° C for 16 hours. The cooled reaction mixture was concentrated to give 6- (1,1-difluoroethyl) -5-methylpyrimidine-2,4-diol (19 g) as a gray solid, which was used in the next stages without additional purification.

A mixture of 6- (1,1-difluoroethyl) -5-methylpyrimidine-2,4-diol (7.5 g, 39 mmol) in phosphorus oxychloride (50 ml) and DMF (8 ml) was stirred at 100 ° C for 5 h. The cooled reaction mixture was carefully poured into ice water (150 ml) and was extracted with EtOAc (3x80 ml). The combined organic layers were washed with brine (2x100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography to give 2,4-dichloro-6- (1,1-difluoroethyl) -5-methylpyrimidine as a yellow oil (6.0 g, 67%).

1H NMR (400 MHz, CDCl3) δ: 2.59 (s, 3H), 2.01 (t, 3H).

(2S, 3R) -3-hydroxy-2-methylazetidine-1-iya [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1yl] methanesulfonate

Step 1: (2R) -2 - [(1R) -1-bromethyl] oxirane.

In three separate reaction vessels, a solution of (2E) -but-2-en-1-ol (967 g, 13.4 mol) in chloroform (10 L) was treated with bromine (2.15 kg, 13.4 mol) for 2 h at 0 ° C. The mixture was stirred at 15 ° C for 30 min. The mixtures were quenched with saturated sodium thiosulfate solution (500 ml) at 15 ° C. The three reaction mixtures were combined and extracted with DCM (3x5 L). The combined organic phases were concentrated in vacuo to give trans-2,3-dibromobutan-1-ol (10.5 kg, quantitative) as a yellow oil, which was taken to the next step without further purification. In three separate reaction vessels, a solution of KOH (711 g, 12.7 mol) in water (6 L) was added dropwise to a solution of trans-2,3 dibromobutan-1-ol (3.33 kg, 12.7 mol) in THF (9 L) at 15 ° C. The reaction mixture was stirred at rt. for 2 hours. The three reaction mixtures were combined and the organic layer was separated. The aqueous phase was extracted with EtOAc (3x5 L). The combined organic layers were washed with brine (5 L x3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (6.5 kg, quantitative) as a yellow oil which was taken to the next step without further purification ...

1H NMR (600 MHz, CD ₃ OD) δ: 3.86 (quinn, 1H), 3.19-3.22 (m, 1H), 2.94 (t, 1H), 2.76-2, 78 (m, 1H), 1.73 (d, 3H).

Step 2: (2S, 3R) -1- (diphenylmethyl) -2-methylazetidin-3-ol.

In two separate reaction vessels, a solution of (2R) -2 - [(1R) -1-bromethyl] oxirane (3.28 kg, 16.2

- 26,035363 mol) and benzhydrylamine (2.97 kg, 16.2 mol) in anhydrous ethanol (5.41 L) were treated with NaHCO3 (2.07 kg, 24.34 mol) and the mixture was stirred at rt. for 80 h, then the mixture was stirred at 65 ° C for an additional 24 h. The two reaction mixtures were cooled to rt, combined and filtered. The filtrate was concentrated. The residue was dissolved in DCM (10 L), washed with saturated aqueous ammonium chloride solution (2x5 L), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with petroleum ether / EtOAc (50: 1 to 1: 1) to give the title compound (3.18 kg, ~ 80% purity, 36.5% yield) as a yellow oil. ...

1H NMR (400 MHz, CDCl3) δ: 7.16-7.46 (m, 10H), 4.34 (s, 1H), 3.93 (q, 1H), 3.66 (t, 1H), 3.03 (q, 1H), 2.58 (t, 1H), 0.76 (d, 3H).

Step 3: (2S, 3R) -1- (diphenylmethyl) -3-hydroxy-2-methylazetidinium [(1H ^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate.

To a solution of [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl] methanesulfonic acid (2.7 kg, 12 mol) in ethanol (8 L) was added a solution (2S, 3R) -1- (diphenylmethyl) -2-methylazetidin-3-ol (3.18 kg, 11.7 mol) in ethanol (2 L). The resulting solution was evaporated to remove EtOH. The residue was treated with methyl tert-butyl ether (5 L) and evaporated to a residual solvent volume of ~ 1 L. The residue was treated with additional methyl tert-butyl ether (5 L) and filtered. The filter cake was dried in vacuo to give a white solid (3.5 kg) which was dissolved in DCM (7.6 L) and EtOAc (10.9 L) added. The mixture was stirred at rt. within 30 minutes, resulting in a precipitate of white solids, which were collected by filtration. The filter cake was suspended in DCM (10.6 L), stirred at rt. over 10 min, and then EtOAc (10.6 L) was added to the solution. The mixture was stirred at rt. for 30 minutes, and the resulting white precipitate was collected by filtration. The filter cake was dissolved in DCM (10.6 L), stirred at rt. over 10 min, then EtOAc (10.6 L) was added. The reaction mixture was stirred at rt. for 30 minutes and the precipitated solids were collected by filtration to give a white solid (1.3 kg, ee = 95.2% by chiral SFC). This material was dissolved in DCM (7 L) and heated to reflux for 40 minutes. EtOAc (3.5 L) was added and the mixture was stirred at 40 ° C for an additional 20 min and white solids precipitated. The solids were collected by filtration. The filter cake was dried in vacuo to afford the title compound (1.1 kg, 98.2% ee by chiral SFC, 62.9% yield of chiral separation) as a white solid.

¹ H NMR (600 MHz, CD3OD) δ: 7.44-7.59 (m, 10H), 5.66 (s, 1H), 4.35-4.41 (m, 1H), 4.25- 4.30 (m, 2H), 3.73-3.78 (m, 1H), 3.37 (d, 1H), 2.80 (d, 1H), 2.68-2.74 (m, 1H), 2.36 (dt, 1H), 2.02-2.09 (m, 2H), 1.91 (d, 1H), 1.60-1.66 (m, 1H), 1.40 -1.45 (m, 1H), 1.16 (s, 3H), 1.09 (d, 3H), 0.88 (s, 3H).

Stage 4.

Part of a solution of (2S, 3R) -1- (diphenylmethyl) -3-hydroxy-2-methylazetidinium [(1H ^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (18.96 g, 39.04 mmol) in methanol (60 ml) was treated with 10% palladium hydroxide on carbon (1.11 g) in a stainless steel reaction vessel. The reaction vessel was purged with nitrogen gas, then filled with hydrogen gas (60 psi). The reaction mixture was stirred at rt. for 17 hours, then re-pressurized with hydrogen gas (55 psi). After an additional 24 hours, the reaction mixture was purged with nitrogen gas and filtered through a Celite® pad, eluting with methanol (4x80 ml). The combined filtrates were evaporated to give a white oily semi-solid. This material was suspended in heptane (100 ml), the sides of the flask were rubbed with a spatula and the heptanes were decanted. This process was repeated twice and the solids were suspended in heptanes (200 ml) and stirred at rt. over 2.5 h. The solids were collected by filtration, suspended in heptanes (100 ml) and stirred at rt. for 1 h. The solids were collected by filtration, suspended in heptanes (120 ml) and vigorously stirred for 24 h. The solids were collected by filtration to give (2S, 3R) -3-hydroxy-2-methylazetidine-1-ia [( 1I ^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (11.8 g, 95%) as a white solid.

¹ H NMR (600 MHz, CD3OD) δ: 4.27-4.34 (m, 2H), 4.04-4.09 (m, 1H), 3.76-3.80 (m, 1H), 3.31 (d, 1H), 2.80 (d, 1H), 2.62-2.69 (m, 1H), 2.34-2.39 (m, 1H), 2.04-2, 09 (m, 2H), 1.92 (d, 1H), 1.63-1.68 (m, 1H), 1.54 (d, 3H), 1.41-1.47 (m, 1H) , 1.13 (s, 3H), 0.88 (s, 3H).

(2S, 3R) -3-hydroxy-2,3-dimethylazetidinium [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1yl] methanesulfonate

Stage 1: tert-butyl [^) - 4-chloro-3-oxobutan-2-yl] carbamate.

- 27 035363

Magnesium chips (120 g, 4.90 mol) and iodine (50 mg) were combined in a 250 ml three-necked round bottom flask equipped with a reflux condenser. A solution of tert-butyl chloride (22.5 g, 245 mmol) in THF (80 ml) was added followed by ethyl bromide (5 ml). The reaction mixture was heated to 60 ° C, and vigorous gas evolution was observed. Additional tert-butyl chloride (428 g, 4.65 mol) in THF (1.52 L) was added dropwise using a dropping funnel at such a rate to maintain a slight reflux. After the addition was complete, the dark Mg chip solution was heated at 60 ° C for 30 min, then cooled to 0 ° C. Triethylamine (120 g, 1.19 mol) and solid sodium chloroacetic acid (139 g, 1.19 mol) were added to the chilled Grignard solution. Then, a solution of Boc-L-alanine methyl ester (157 g, 0.77 mol) in toluene (900 ml) was added dropwise. The reaction mixture was heated to rt. and stirred for 16 hours. The reaction mixture was then cooled to 0 ° C. and acetic acid (320 g, 5.50 mol) in water (640 ml) was added dropwise. Was added aqueous 2M HCl (70 ml) to adjust the pH of the aqueous layer to pH ~ 4-5. The reaction mixture was stirred at rt. within 45 minutes until gas evolution ceases. The layers were separated and the aqueous layer was extracted with EtOAc (500 ml). The combined organic layers were washed with saturated aqueous NaHCO ₃ (60 ml) and brine (30 ml). The organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give a yellow oil. Heptane (300 ml) was added to the oil and stirred at rt. within 30 minutes. The resulting solid was filtered and washed with heptane to give the title compound (105 g, 61%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 5.08 (br s, 1H), 4.50-4.57 (m, 1H), 4.23-4.32 (m, 2H), 1, 44 (s, 9H), 1.36 (d, 3H).

Stage 2: tert-butyl [^^) - 4-chloro-3-hydroxy-3-methylbutan-2-yl] carbamate.

To a solution of tert-butyl [^) - 4-chloro-3-oxobutan-2-yl] carbamate (90 g, 0.40 mol) in DCM (2.0 L), cooled to -70 ° C, was added dropwise methylmagnesium bromide (460 ml, 1.38 mol, 3 M in diethyl ether). The mixture was stirred at -70 ° C for 1 h, and then heated to ~ -5 ° C, and stirred for 5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (500 ml), dropwise at such a rate that the internal the temperature did not rise above 10 ° C. The gray suspension turned milky white and then the pH was adjusted to ~ 2 with 2N aqueous HCl. The organic layer was separated and the aqueous layer was extracted with DCM (3x800 ml). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude product was dissolved in hexane / EtOAc (10/1, 200 ml). The yellow mixture was heated to 50 ° C, stirred for 10 min. and then slowly cooled to 0 ° C. The resulting solid was filtered to give the title compound (45 g, 47%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ: 4.72 (br s, 1H), 3.77-3.87 (m, 1H), 3.60 (d, 1H), 3.52 (d, 1H ), 1.46 (s, 9H), 1.30 (s, 3H), 1.21 (d, 3H).

Stage 3.

To a solution of tert-butyl [^^) - 4-chloro-3-hydroxy-3-methylbutan-2-yl] carbamate (55 g, 0.23 mmol) in DCM (20 ml) and methanol (100 ml) was added 4N HCl in dioxane (150 ml) at 0 ° C. The brown mixture was warmed to 20 ° C and stirred for 2.5 h. The brown mixture was concentrated to give a brown oil (40 g, 100%), which was dissolved in CH ₃ CN (300 ml) and treated with solid NaHCO ₃ (146 g, 1.74 mol). The white suspension was stirred at 70 ° C for 4 h, then cooled to rt, filtered through Celite® and washed with acetonitrile. The yellow filtrate was concentrated in vacuo to give (2S, 3R) -2,3-dimethylazetudin-3-ol (22 g, 75%) as a brown oil. The compound was used in the next step without further purification.

A yellow solution of (2S, 3R) -2,3-dimethylazetidin-3-ol (23.4 g, 0.23 mol) in acetonitrile (130 ml) was added in [(^^) - 7,7-dimethyl-2- oxobicyclo [2.2.1] hept-1-yl] methanesulfonic acid (48 g, 0.21 mol) and stirred at 15 ° C for 4 h. The resulting precipitate was collected by filtration to give (2S, 3R) -3-hydroxy- 2,3-dimethylazetudinium [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1yl] methanesulfonate (50 g, 65%) as a white solid.

1H NMR (400 MHz, CD3OD) δ: 4.36 (q, 1H), 3.89 (d, 1H), 3.76 (d, 1H), 3.32 (d, 1H), 2.80 ( d, 1H), 2.632.72 (m, 1H), 2.36 (dt, 1H), 2.02-2.10 (m, 2H), 1.93 (d, 1H), 1.60-1 , 68 (m, 1H), 1.42-1.48 (m, 7H), 1.16 (s, 3H), 0.88 (s, 3H).

^) - 2-methylazetidinium [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl] methanesulfonate

Step 1: (^) - 1- (diphenylmethyl) -2-methylazetidinium [(11 <^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate.

Solution of R - (-) - 1,3-butanediol (20.0 g, 222 mmol) and DIPEA (101.5 ml, 585.0 mmol) in acetonitrile

- 28 035363 (444 ml) was cooled to -30 ° C and treated dropwise with a dropping funnel with trifluoromethanesulfonic anhydride (81.2 ml, 480 mmol) for 90 min while maintaining the internal reaction temperature from -30 to -35 ° C. After the addition was complete, the reaction mixture was stirred for 10 minutes. at -30 ° C and then treated dropwise with additional trifluoromethanesulfonic anhydride (1.5 ml) and stirred at -30 ° C for an additional 15 minutes.

The reaction mixture was then treated with additional DIPEA (101.5 ml, 585.0 mmol) for 15 min while maintaining the internal temperature at -30 ° C. After an additional 10 min at -30 ° C, the reaction mixture was treated dropwise with a solution of benzhydrylamine (38 ml) in acetonitrile (40 ml) for 30 min using an addition funnel, keeping the internal reaction temperature below -30 ° C. The reaction mixture was stirred at -30 ° C for 20 min then placed in an ice water bath for 30 min. The reaction mixture was then stirred at rt. for 30 min, followed by heating at 45 ° C for 30 min. The reaction mixture was cooled to rt, poured into deionized water (900 ml) and extracted with toluene (1 L). The aqueous phase was again extracted with toluene (300 ml) and the combined organic layers were washed with water (2x250 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was dissolved in DCM (300 ml) and loaded onto a silica gel plug (300 ml SiO ₂ , washed 1: 1 heptane / EtOAc). The layer was washed with 1: 1 heptane / EtOAc (1.2 L) and the filtrate was evaporated to give a red oil (50.2 g). The crude product was dissolved in methanol (200 ml), placed in a water bath at 10 ° C, and treated with [(1K ^) - 7.7-dimethyl-2-oxobicyclo [2.2.1 | hept-1yl] methanesulfonic acid (49 g) in series of 5 min. The solution was stirred at rt. within 2 hours, the solvent was evaporated and the solids were dried under high vacuum for 15 hours to give a solid (99.2 g). The solid was dissolved in DCM (100 ml) and stirred at rt. within 10 min, getting a dark solution. EtOAc (850 ml) was added slowly with stirring and solids precipitated from solution after ~ 5 min. The suspension was stirred at rt. for 2 h and the solids were collected by filtration and washed with EtOAc (50 ml). The solids were dissolved in DCM (100 ml) and EtOAc (700 ml) was added. The mixture was stirred at rt, and solids precipitated from solution. The suspension was stirred at rt. over 15 h, then the solids were collected by filtration, washed with EtOAc (50 ml) and dried under reduced pressure to give the title compound (66.7 g, 65% yield) as a white solid.

1H NMR (500 MHz, CD3OD) δ: 7.54-7.59 (m, 4H), 7.43-7.53 (m, 6 h), 5.67 (s, 1H), 4.69- 4.76 (m, 1H), 3.97-4.02 (m, 2H), 3.36 (d, 1H), 2.81 (d, 1H), 2.70-2.75 (m, 1H), 2.58-2.64 (m, 1H), 2.31-2.39 (m, 2H), 2.03-2.09 (m, 2H), 1.91 (d, 1H) , 1.62-1.66 (m, 1H), 1.41-1.47 (m, 1H), 1.16 (s, 3H), 1.11 (d, 3H), 0.88 (s , 3H);

Elemental analysis: Calculated for C ₂₇ H ₃₅ NO ₄ S: C = 69.05%, H = 7.51%, N = 2.98%; Found: C = 68.90%, H = 7.59%, N = 2.91%.

Stage 2.

A solution of ^) - 1- (diphenylmethyl) -2methylazetidinium [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (29, 4 g, 62.6 mmol) in methanol (125 ml) and 20% Pd (OH) ₂ / C (1.78 g). The reactor was purged with nitrogen three times, then three times with hydrogen, and then pressurized to 60 psi with hydrogen and stirred at rt. over 16 hours. Hydrogen was vented and the reactor was purged with nitrogen. The reaction mixture was filtered through a pad of Celite® eluting with methanol (100 ml) and the filtrate was concentrated in vacuo to give a white solid. The white solid was suspended in EtOAc / methyl tert-butyl ether (1: 1, 200 ml) and stirred for 1 h at 60 ° C. After cooling to rt, the liquid suspension was stirred for an additional hour and the solids were collected by filtration. The resulting solids were suspended in methyl t-butyl ether (100 ml) and stirred at rt. over 16 hours. The solids were collected by filtration, washed with methyl tert-butyl ether (25 ml) and dried under reduced pressure to give (2S) -2-methyl azetidinium [(^^) - 7,7-dimethyl-2- oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (18.1 g, 95%) as a white solid.

1H NMR (500 MHz, CD ₃ OD) δ: 4.59-4.66 (m, 1H), 4.05 (q, 1H), 3.92 (dt, 1H), 3.32 (m, 1H ), 2.80 (d, 1H), 2.59-2.70 (m, 2H), 2.36 (dt, 1H), 2.25-2.32 (m, 1H), 2.03- 2.10 (m, 2H), 1.92 (d, 1H), 1.62-1.68 (m, 1H), 1.57 (d, 3H), 1.41-1.47 (m, 1H), 1.15 (s, 3H), 0.89 (s, 3H);

Elemental analysis: Calculated for Ci ₄ H ₂₅ NO ₄ S: C = 55.42%, H = 8.31%, N = 4.62%; Found: C = 55.59%, H = 8.41%, N = 4.49%.

^) - 2-methylazetidine hydrochloride

Step 1: (2R) -4 - [(methylsulfonyl) oxy] butan-2-yl methanesulfonate.

A solution of (3R) -butane-1,3-diol (3 g, 30 mmol) and triethylamine (10.1 g, 99.9 mmol) in DCM (60 ml) was cooled to 0 ° C and treated dropwise with methanesulfonyl chloride (11 , 4 g, 99.9 mmol) at 0 ° C. After 15 minutes. the ice water bath was removed and the mixture was stirred at rt. for 2 h. The mixture was diluted with

- 29 035363 n saturated solution of ammonium chloride (80 ml) and extracted with DCM (3x50 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified using column chromatography eluting with EtOAc / petroleum ether (1: 4 to 3: 2) to give the title compound (7.3 g, 89%) as a colorless oil.

1H NMR (400 MHz, CDCl3) δ: 5.00 (s, 1H), 4.35 (t, 2H), 3.07 (s, 3H), 3.06 (s, 3H), 2.05- 2.12 (m, 2H), 1.50 (d, 3H).

Stage 2.

(2R) -4 - [(methylsulfonyl) oxy] butan-2-yl methanesulfonate (7.20 g, 29.2 mmol) was dissolved in benzylamine (19.2 ml, 175 mmol) and stirred at 45 ° C for 16 The reaction mixture was cooled to rt, and a mixture of cyclohexane / methyl tert-butyl ether (1: 1) was added, resulting in a precipitate of white solids. The precipitate was removed by filtration, and the filtrate was evaporated under reduced pressure and purified using column chromatography eluting with DCM and 1% ammonium hydroxide / methanol, 100: 0 to 99.5: 0.5) to give a light yellow oil (2.5 d, 53%). This yellow oil (2.28 g, 14.1 mmol) was dissolved in methanol (50 ml) and treated with 10% palladium hydroxide on carbon (500 mg). The resulting slurry was heated to 50 ° C under an atmosphere of hydrogen gas (30 psi) for 20 hours, then heated to 60 ° C and stirred under an atmosphere of hydrogen (30 psi) for an additional 40 hours The cooled reaction mixture was filtered and the filtered was treated with 4N HCl in EtOAc (15 ml) and stirred at rt. within 30 minutes. The mixture was concentrated to give () - 2-methylazetidine hydrochloride (1.47 g, 96.6%) as a white gum.

¹ H NMR (400 MHz, CDCl3) δ: 4.50-4.60 (m, 1H), 3.97-4.04 (m, 1H), 3.75-3.90 (m, 1H), 2.58-2.65 (m, 1H), 2.26-2.35 (m, 1H), 1.54 (d, 3H).

Ethyl (1R, 5S, 6s) -3-azabicyclo [3.1.0] hex-6-yl acetate

Step 1: [(^^, 6d) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methyl methanesulfonate.

The preparation of [(1R, 5S, 6d) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol is described in Berliner, M. A .; et al. Org. Process Res. Dev. 2011, 15, 1052-1062.

In a solution of [(1R, 5S, 6r) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol (95.0 g, 396 mmol) in dry THF (1230 ml) and DMF (95 ml) was added triethylamine (241 g, 2.38 mol) at 0 ° C. The mixture was stirred at 0 ° C for 5 min. and treated with methanesulfonyl chloride (82.22 g, 717.8 mmol) dropwise over 5 min. The mixture was stirred at 10 ° C for 16 hours. The reaction mixture was quenched by the addition of saturated NaHCO3 (1000 ml) and then the mixture was extracted with methyl tert-butyl ether (5x500 ml). The organic phase was concentrated in vacuo to give the title compound (99 g, 89%) as a brown oil. MS (ES ⁺ ): 281.9 (M + H).

Step 2: [(1R, 5S, 6s) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetonitrile.

To a solution of [(1R, 5S, 6r) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methylmethanesulfonate (99 g, 352 mmol) in DMF (700 ml) was added sodium cyanide (18.49 d, 377.3 mmol) at 20 ° C. The mixture was stirred at 20 ° C for 16 h.

Saturated aqueous NaHCO3 was added to the reaction mixture (200 ml) and the mixture was extracted with methyl tert-butyl ether (2x150 ml). The organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil (50 g). The brown oil was purified using silica gel column chromatography eluting with petroleum ether / EtOAc (10: 1 to 5: 1) to give the title compound (37 g, 50%) as a yellow oil. MS (APCl): 213.1 (M + H).

Stage 3: ethyl [(^^^) - 3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetate.

Concentrated sulfuric acid (108 ml) was added to ethanol (215 ml) at 0 ° C. The mixture was stirred at 10 ° C for 5 min, then cooled back to 0 ° C. A solution of [(4I ^, 6A) -3-benzyl-3azabicyclo [3.1.0] hex-6-yl] acetonitrile (37 g, 170 mmol) in EtOH (95 ml) was added to a mixture of EtOH and sulfuric acid at 0 ° C ... The mixture was stirred at 80 ° C for 16 h. The mixture was adjusted to pH 9 using 5M NaOH at 0 ° C and the product was extracted with EtOAc (5x500 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil (45 g). The yellow oil was purified using column chromatography on silica gel eluting with petroleum ether / EtOAc (10: 1 to 5: 1 form) to give the title compound (37 g, 82%) as a yellow oil. MS (APCl) 260.1 (M + H).

Stage 4: ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate.

To a solution of ethyl [(^^^) - 3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetate (37 g, 140 mmol) in EtOH (1500 ml) was added 10% palladium hydroxide on carbon ( 5 g, 4 mmol). The mixture was degassed and re-filled with nitrogen three times and degassed, and then again filled with hydrogen gas three times. The mixture was stirred under a hydrogen atmosphere (50 psi) at 50 ° C for 16 hours.

- 30 035363 the reaction mixture was purged with nitrogen, filtered, and the filter cake was washed with MeOH (500 ml). The filtrate was concentrated in vacuo to give ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate (22 g, 91%) as a yellow oil. MS (EC +): 170.1 (M + H).

Ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate and trifluoroacetic acid salt

Step 1: tert-butyl (^^^) - 6- (2-ethoxy-2-oxoethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate.

To a solution of [(^^^) - 3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hex-6-yl] acetic acid (400 mg, 1.66 mmol, MFCD12198681) in DCM (12 ml) ethanol (0.4 ml), 4-dimethylaminopyridine (203 mg, 1.66 mmol) and NN-dicyclohexylcarbodiimide (342 mg, 1.66 mmol) were added at RT. The resulting colorless suspension was stirred at rt. over 16 h. The mixture was diluted with water (15 ml) and aqueous ammonium chloride (10 ml). The product was extracted with DCM (3x25 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue (650 mg) as a white solid which was purified using flash column chromatography eluting with EtOAc / petroleum ether (1 to 11% EtOAc) to give the title compound (350 mg, 78%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.15 (q, 2H), 3.53-3.64 (m, 2H), 3.29-3.37 (m, 2H), 2.17 -2.32 (m, 2H), 1.44 (s, 9H), 1.35-1.38 (m, 2H), 1.27 (t, 3H), 0.88-0.92 (m , 1H).

Stage 2.

To a solution of tert-butyl (^^^) - 6- (2-ethoxy-2-oxoethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (340 mg, 1.26 mmol) in DCM (6 ml ) was added TPO (5 ml). The mixture was stirred at rt. for 1 h. The mixture was concentrated to dryness to give ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate trifluoroacetic acid salt (400 mg, 99%) as a brown liquid.

1H NMR (400 MHz, CD3OD) δ: 4.13 (q, 2H), 3.37-3.45 (m, 4H), 2.35 (d, 2H), 1.72-1.77 (m , 2H), 1.25 (t, 3H), 1.06-1.12 (m, 1H).

Ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate hydrochloride

Step 1: tert-butyl (^^^) - 6- (bromomethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate.

To a solution of tert-butyl (^^, 6g) -6- (hydroxymethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (5.1 g, 23.91 mmol, MFCD14525755) in DCM (180 ml) added carbon tetrabromide (11.9 g, 35.9 mmol) and triphenylphosphine (9.41 g, 35.9 mmol) at 5 ° C. The reaction mixture was heated to rt. and stirred for 12 hours. The reaction mixture was evaporated to dryness and purified using column chromatography eluting with petroleum ether / EtOAc (100: 1 to 10: 1) to give the title compound (5.6 g, 85%) as a yellow oil.

1H NMR (400 MHz, CD3OD) δ: 3.54 (d, 2H), 3.32-3.43 (m, 4H), 1.61-1.64 (m, 2H), 1.46 (s , 9H), 1.03-1.05 (m, 1H).

Stage 2: tert-butyl (^^^) - 6- (cyanomethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate.

To a solution of tert-butyl (1R, 5S, 6d) -6- (bromomethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (6000 mg, 21.73 mmol) in DMF (150 ml) was added sodium cyanide (1600 mg, 32.6 mmol) at rt, and the reaction mixture was stirred for 16 h at rt. The yellow mixture was diluted with EtOAc (100 ml), washed with saturated brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give a yellow oil which was purified using column chromatography eluting with petroleum ether / EtOAc (100: 1 to 5: 1) to give the title compound (4.0 g, 83 %) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ: 3.58 (dd, 2H), 3.30-3.35 (m, 2H), 2.45-2.51 (m, 1H), 2.31- 2.36 (m, 1H), 1.49-1.52 (m, 2H), 1.41 (s, 9H), 0.88-0.91 (m, 1H).

Stage 3.

Acetyl chloride (300 mg, 3.82 mmol) was added to dry ethanol (2.5 ml) at 0 ° C and stirred at rt. for 1 h in a sealed flask. The solution was added tert-butyl (^^^) - 6- (cyanomethyl) -3azabicyclo [3.1.0] hexane-3-carboxylate (85 mg, 0.38 mmol), and the mixture was stirred at 70 ° C for 68 h The solution was cooled to rt. and concentrated to give ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6yl acetate hydrochloride (80 mg,> 99%) as a white solid.

- 31 035363

1H NMR (400 MHz, CD3OD) δ: 4.15-4.18 (m, 2H), 3.44-3.47 (m, 4H), 2.36-2.38 (m, 2H), 1 , 74-1.78 (m, 2H), 1.25-1.30 (m, 3H), 1.14-1.17 (m, 1H).

Methyl (1 R, 5S, 6s) -3-azabicyclo [3.1.0] hex-6-yl acetate hydrochloride

Step 1: (^^, 6d) -3-benzyl-6- (chloromethyl) -3-azabicyclo [3.1.0] hexane.

The preparation of [(1R, 5S, 6d) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol is described in Berliner, M. A .; et al. Org. Process Res. Dev. 2011, 15, 1052-1062.

To a stirred solution of [(1R, 5S, 6r) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol (620 g, 3.05 mol) in methanol (600 ml) was added 4 M HCl in methanol (6.2 L) at 10 ° C for 45 min and the mixture was stirred for 15 min. The reaction mixture was slowly warmed to 25-30 ° C for 2 hours. The solvent was evaporated under reduced pressure to give the crude product. The crude product was triturated with ether (1.5 L) to give [(1R, 5S, 6r) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol hydrochloride (703 g, 96% yield) as a light brown solid which was used directly in the next step.

To a stirred solution of [(1R, 5S, 6r) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methanol hydrochloride (699 g, 2.91 mol) in toluene (1.4 L) was added thionyl chloride (693 g, 5.83 mol) at 5 to 10 ° C for 30 min. and stirred for 15 minutes. The reaction temperature was slowly raised to 45 ° C and stirred for 30 minutes. The reaction mixture was cooled to rt. and concentrated under reduced pressure. The crude product was dissolved in EtOAc (5 L) and saturated NaHCO ₃ solution (3 L, pH ~ 8) was added and stirred for 1 h, then the layers were separated. The aqueous layer was further extracted with EtOAc (2x2 L). The combined organic layers were washed with brine (2.0 L), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the title compound (611 g, 95%) as a brown liquid.

1H NMR (600 MHz, DMSO-a6) δ: 7.30 (t, 2H), 7.20-7.25 (m, 3H), 3.51-3.56 (m, 4H), 2.87 (d, 2H), 2.29 (d, 2H), 1.54-1.57 (m, 1H), 1.43 (s, 2H).

Step 2: [(1R, 5S, 6s) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetonitrile.

Sodium cyanide was added to a stirred solution of (1R, 5S, 6r) -3-benzyl-6- (chloromethyl) -3-azabicyclo [3.1.0] hexane (664 g, 2.99 mol) in DMF (2.9 L) (191 g, 3.89 mol) at rt and the mixture was slowly heated to 50 ° C over 48 h. The reaction mixture was cooled to rt, quenched with water (10 L) and extracted with EtOAc (3x4 L) ... The combined organic layers were washed with water (5 L), brine (3 L), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified using column chromatography eluting with 20% EtOAc in petroleum ether to give the title compound (593 g, 93.2%) as a brown liquid.

1H NMR (600 MHz, DMSO-06) δ: 7.27-7.32 (m, 2H), 7.19-7.26 (m, 3H), 3.54 (s, 2H), 2.87 (d, 2H), 2.45 (d, 2H), 2.28 (d, 2H), 1.33-1.41 (m, 3H).

Step 3: methyl [(^^^) - 3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetate.

Acetyl chloride (2.21 kg, 28.3 mol) was added to methanol (3.77 L) at 0 ° C over 1 h. The reaction mixture was slowly heated to 45 ° C over 30 min. The reaction mixture was again cooled to 0 ° C, and a solution of [(^^^) - 3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetonitrile (400 g, 1.88 mol) in methanol ( 700 ml) for 2 h at 0 ° C. The resulting solution was slowly heated to 65 ° C over 4 h. The reaction mixture was cooled to rt. and concentrated under reduced pressure. The crude product was dissolved in EtOAc (6 L) and saturated NaHCO ₃ solution (4 L, pH ~ 8) was added and stirred for 1 h. The layers were separated and the aqueous layer was further extracted with EtOAc (2x1 L). The combined organic layers were washed with brine (2.0 L), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the title compound (377 g, 82%) as a brown liquid.

1H NMR (600 MHz, CDCl ₃ ) δ: 7.19-7.31 (m, 5H), 3.67 (s, 3H), 3.56 (s, 2H), 2.99 (d, 2H) , 2.34 (d, 2H), 2.18 (d, 2H), 1.50-1.54 (m, 1H), 1.23 (s, 2H).

Stage 4.

To a solution of methyl [(^^^) - 3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] acetate (542 g, 2.21 mol) in methanol (550 ml) was added 4 M HCl in methanol (5.4 L) at 10 ° C for 30 min. The reaction mixture was heated to rt. and stirred for 2 hours. The solvent was evaporated under reduced pressure. The crude product was triturated with ether (1.5 L) to give an almost white solid (545 g, 87.7% yield) which was used directly in the next step. The crude product (420 g, 149 mol) was dissolved in methanol (4 L) in an autoclave and treated with 10% Pd (OH) ₂ / C (41.4 g, 50% wet) under a nitrogen atmosphere, the autoclave was evacuated twice with nitrogen, and filled in an atmosphere of hydrogen gas (100 psi), and heated to 70 ° C for 8 h. The reaction mixture was cooled to rt. and mixed in

- 32 035363 for 4 hours. The reaction mixture was filtered through a pad of Celite®, rinsing with methanol (2x1 L). The filtrate was evaporated under reduced pressure. The crude product was triturated with ether (1 L) and the solids were collected by filtration to give methyl (^^^) - 3-azabicyclo [3.1.0] hex-6-yl acetate hydrochloride (345 g, 99% yield) as an off-white solid matter.

1H NMR (600 MHz, DMSO-d.) Δ: 9.25-9.80 (br s, 2H), 4.05-4.44 (br s, 1H), 3.2-3.4 (br s, 1H), 3.21 (s, 3H), 3.15 (s, 2H), 2.30 (d, 2H), 1.60 (s, 2H), 1.20-1.27 (m , 1H).

2,6-dichloro-4- (1,1-difluoroethyl) -5-fluoropyridine-3-carbonitrile

Step 1: 4- (1,1-difluoroethyl) -5-fluoro-2,6-dihydroxypyridine-3-carbonitrile.

Sodium hydride (60% in mineral oil, 3.19 g, 79.6 mmol) was added to a solution of ethyl 2,2-difluoropropanoate (10.0 g, 72.4 mmol) in THF (10.0 ml), and the mixture heated to 50 ° C. Ethyl fluoroacetate (15.4 g, 145 mmol) was added dropwise over 1 min and the reaction mixture was stirred at 50 ° C for 2 h. The solution was poured into aqueous ammonium chloride (100 ml) at 0 ° C. The mixture was extracted with EtOAc (3x150 ml), washed with saturated brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil (13 g). The crude product was dissolved in ethanol (200 ml) and treated with 2 cyanoacetamide (5.52 g, 65.6 mmol) and piperidine (5.59 g, 65.6 mmol). The resulting colorless solution was stirred at 50 ° C for 16 hours. The product precipitated from solution and was collected by filtration to give the title compound (10 g, 70%) as a white solid.

¹ H NMR (400 MHz, DMSO-06) δ: 8.20 (br s, 2H), 1.89 (t, 3H).

Stage 2.

A mixture of 4- (1,1-difluoroethyl) -5-fluoro-2,6-dihydroxypyridine-3-carbonitrile (10.0 g, 45.8 mmol) and phosphorus pentachloride (95.5 g, 458 mmol) was stirred at 130 ° C for 32 h. The reaction mixture was cooled to rt. and poured into aqueous NaHCO ₃ (750 ml) at 0 ° C. The product was extracted with EtOAc (3x150 ml), washed with brine (150 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil. The crude product was purified using column chromatography (EtOAc / petroleum ether 0: 100 to 3:97) to give 2,6-dichloro-4- (1,1-difluoroethyl) -5fluoropyridine-3-carbonitrile (6.0 g, 51%) as a yellow oil.

1H NMR (400 MHz, DMSO-06) δ: 2.10 (t, 3H).

2,4-Dichloro-6- (1,1-difluoroethyl) pyridine

Step 1: 6- (1,1-difluoroethyl) pyridine-2,4-diol.

A suspension of ethyl 6- (1,1-difluoroethyl) -2,4-dihydroxypyridine-3-carboxylate (10.5 g, 42.5 mmol) in 6N HCl (100 ml) was stirred at 100 ° C for 16 h. the mixture was cooled to rt. and evaporated under reduced pressure to give the title compound (8.0 g, 90%) as a white solid.

1H NMR (400 MHz, DMSOC ₆ ) δ: 7.9-8.6 (m, 2H), 6.62 (s, 1H), 6.27 (s, 1H), 1.95 (t, 3H) ...

Step 2: 2,4-dichloro-6- (1,1-difluoroethyl) pyridine.

A mixture of 6- (1,1-difluoroethyl) pyridine-2,4-diol (7.0 g, 33 mmol) and phosphorus pentachloride (34.4 g, 165 mmol) was stirred at 125 ° C for 20 h. The mixture quenched with ice water (200 ml) and extracted with EtOAc (2x100 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography eluting with petroleum ether to give 2,4-dichloro-6- (1,1-difluoroethyl) pyridine (2.5 g, 36% yield) as a light yellow oil. MS (EC +): 211.6 (M + H).

Examples of

Example 1: [(1R, 5S, 6R) -3- {5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -4 (trifluoromethyl) pyridin-2-yl } -3-azabicyclo [3.1.0] hex-6-yl] acetic acid

- 33 035363

Step 1: Ethyl {(^^^) - 3- [6-chloro-5-cyano-4- (trifluoromethyl) pyridin-2-yl] -3azabicyclo [3.1.0] hex-6-yl} acetate.

Suspension of 2,6-dichloro-4- (trifluoromethyl) pyridine-3-carbonitrile (2.4 g, 9.8 mmol), ethyl (^^^) - 3-azabicyclo [3.1.0] hex-6-ylacetate ( 1.7 g, 9.8 mmol) and NaHCO ₃ (2.6 g, 31 mmol) in ethanol (25 ml) were stirred at rt. during the night. The reaction mixture was concentrated, diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (3x25 ml). The combined organic phases were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using silica gel chromatography (10-35% EtOAc in n-heptane) to afford the title compound as an off-white solid (2.2 g, 57%).

MS (EC +): 374.2 (M + H), ¹ H NMR (600 MHz, DMSO-d6) δ: 6.90 (s, 1H), 4.07 (q, 2H), 3.79 (m , 2H), 3.67-3.53 (m, 2H), 2.43-2.21 (m, 2H), 1.75-1.57 (m, 2H), 1.19 (t, 3H ), 0.81 (dt, 1H).

Stage 2: ethyl [(1R, 5S, 6R) -3- {5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetugin-1-yl] -4 (trifluoromethyl) pyridin-2- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

Ethyl {(^^^) - 3- [6-chloro-5-cyano-4- (trifluoromethyl) pyridin-2-yl] -3-azabicyclo [3.1.0] hex-6yl} acetate (2.1 g, 5.7 mmol), (2S, 3R) -3-hydroxy-2-methylazetudin-1-ia | (1H ^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (2 , 0 g, 6.2 mmol), NaHCO ₃ (1.7 g, 20 mmol) was suspended in ethanol and stirred at 80 ° C for 18 h. The reaction mixture was diluted with saturated NaHCO ₃ solution (200 ml) and extracted with EtOAc ( 3x100 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The resulting white solid was transferred to the next step without purification. MS (EC ⁺ ): 447.0 (M + Na).

Stage 3.

Sodium hydroxide (40 ml, 1 M aq.) Was added to the suspension of ethyl [(1R, 5S, 6R) -3- {5-cyano-6 [(2S, 3R) -3-guroxy-2-methylazetugin-1-yl ] -4- (trifluoromethyl) pyrugin-2-yl} -3-azabicyclo [3.1.0] hex-6yl] acetate (2.5 g, 5.9 mmol) in ethanol (80 ml) and the reaction mixture was stirred at Ph.D. for 1 h. The reaction mixture was concentrated, diluted with water (25 ml), acidified with 1 N HCl to pH 2, and was extracted with EtOAc (3x25 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid. The white solid was combined with the product from another preparation using the same conditions to give 1.1 g for purification. The white solid was suspended at reflux for 3 h in MTBE / n-heptane and then at rt. within 5 days. The slurry was then filtered and the filter cake was washed with nheptane to give Example 1 as a white solid (2.4 g, 73%). (MP = 193.2-195.8 ° C). The solid was then dissolved in boiling EtOAc and filtered hot. The filtrate was concentrated and recrystallized from ethyl acetate / n-heptane. The solid was collected using vacuum filtration and dried in a vacuum oven at 50 ° C for 2 hours to give Example 1 as a white solid (1.4 g, 44%). MP = 189.9-196.8 ° C. MS (EC ⁺ ): 397.1 (M + H).

1H NMR (600 MHz, DMSO-d6) δ: 12.10 (br s, 1H), 6.22 (s, 1H), 5.63 (br s, 1H), 4.54 (t, 1H), 4.20 (quinn, 1H), 4.06 (br s, 1H), 3.94-3.60 (m, 3H), 3.51 (br s, 2H), 2.24 (d, 2h) , 1.60 (br d, 2H), 1.40 (d, 3H), 0.74 (br s, 1H).

Example 2: [(1R, 5S, 6R) -3- {3-chloro-5-cyano-6 - [(2S, 4R) -3-hydroxy-2-methylazetugin-1-yl] -4 (trifluoromethyl) pyridine -2-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid

HE

Stage 1: ethyl [(1R, 5S, 6R) -3- {3-chloro-5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -4 (trifluoromethyl) pyridin-2-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

Ethyl [(1R, 5S, 6R) -3- {5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -4- (trifluoromethyl) pyridin-2-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate (60 mg, 0.14 mmol) in DMF (2.5 ml) was treated with N-chlorosuccinimide (28.3 mg, 0.212 mmol) at RT, and the mixture was stirred for 16 h at 25 ° C. The mixture was diluted with water (15 ml) and saturated aqueous ammonium chloride (5 ml), then extracted with EtOAc (15 ml x 3). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (80 mg, quantitative) as an almost yellow solid which was used directly in the next step.

Stage 2.

Example 2 was prepared in a manner analogous to example 1, step 3, using ethyl [(1R, 5S, 6R) -3- {3-chloro-5-cyano-6 - [(2S, 3R) -3-guroxy-2- methylazetugin-1-yl] -4- (trifluoromethyl) pyridine

- 34 035363

2-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate and purified using preparative reverse phase HPLC to give Example 2 (30 mg, 49%) as a white solid.

MS (EC +): 431.1 (M + H).

1H NMR (400 MHz, CD3OD) δ: 4.70 (yes, 1H), 4.39-4.25 (m, 2H), 4.24-4.08 (m, 2H), 3.86-3 , 67 (m, 3H), 2.30 (d, 2H), 1.59 (br s, 2H), 1.48 (d, 3H), 0.90-0.74 (m, 1H).

Example 3: methyl [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} 3 -azabicyclo [3.1.0 ] hex-6-yl] acetate

I ^< V ^>

N ^ N

A-vw θ F 4 / II _Η * ^S> * ^x ^ OMe

Step 1: methyl {(^^^) - 3- [2-chloro-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex6-yl} acetate.

To a solution of methyl (^^^) - 3-azabicyclo [3.1.0] hex-6-ylacetate hydrochloride (120.2 g, 627.2 mmol) in DCM (1250 ml) was added 2,4-dichloro-6 - (trifluoromethyl) pyrimidine (145.7 g, 671.5 mmol) in DCM (50 ml) at -72 ° C; the dropping funnel was rinsed with DCM (50 ml) and the washes were added to the reaction flasks. DIPEA (273 ml, 1570 mmol) was added over 10 min while the reaction temperature was kept from -70 to -60 ° C. The mixture was stirred at -65 to -63 ° C for 1 hour and then heated to 25 ° C for 3 hours. The resulting clear solution was concentrated to ~ 1/5 of the original volume. To the resulting heavy suspension were added MTBE (700 ml) and heptane (700 ml) and the resulting liquid suspension was stirred at 25 ° C. for 10 minutes, then the solids were filtered off and washed with MTBE-heptane (4: 1). The combined mother liquor was concentrated in vacuo to an oil, which was combined with heptane (1200 ml). The resulting heterogeneous mixture was stirred at 25 ° C for 2.5 days. A white solid formed. The liquid was decanted and the solid was washed with heptane (200 ml) and dried under a stream of nitrogen.

The resulting title product was used for the next step without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ: 6.47 (s, 1H), 4.07 (d, 1H), 3.71 (s, 3H), 3.53-3.68 (m, 3H ), 2.36-2.49 (m, 1H), 2.21-2.34 (m, 1H), 1.60-1.73 (m, 2H), 0.88-0.97 (m , 1H).

Stage 2.

Methyl {(^^^) - 3- [2-chloro-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex-6yl} acetate from step 1 was dissolved in acetonitrile (1500 ml) , and (2S) -2-methylazetidinium [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (223.0 g, 735 mmol) was added. The mixture was stirred at 60 ° C, and DIPEA (77.0 ml, 442 mmol) was added over 3 h. The mixture was stirred for 3 h and then DIPEA (180 ml, 1.03 mol) was added over 3 h, and the mixture was stirred at 60 ° C for 18 h. An additional ^) - 2-methylazetidinium | (1H ^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (18.0 g, 59 mmol) and the mixture was stirred at 60 ° C for an additional 18 hours. The mixture was concentrated to ~ 1/4 of the original volume and the resulting yellow oil was partitioned between 500 ml of water, 400 ml of heptane and 400 ml of MTBE. The aqueous phase was separated and back extracted with MTBE-heptane (1: 1) (2x150 ml). The combined organic extract was washed with 120 ml of saturated NaHCO ₃ solution (120 ml) and then stirred with SiO ₂ (70 g) and anhydrous MgSO ₄ (70 g). The solids were filtered off and the clear solution was concentrated to give 216.6 g of Example 3 as a colorless oil. MS (EC ⁺ ): 371.1 (M + H).

1H NMR (400 MHz, CDCl ₃ ) δ: 5.91 (s, 1H), 4.37-4.48 (m, 1H), 3.87-4.05 (m, 3H), 3.70 ( s, 3H), 3.50-3.64 (m, 1H), 3.41-3.50 (m, 2H), 2.33-2.42 (m, 1H), 2.31 (d, 2H), 1.88-1.99 (m, 1H), 1.52-1.59 (m, 2H), 1.49 (d, 3H), 0.88-0.96 (m, 1H) ...

Example 4: [(1R, 5S, 6R) -3- {2 - [(2 S) -2-methylazetidin-1 -yl] -6 - (trifluoromethyl) pyrimidin-4-yl} -3 azabicyclo [3.1.0 ] hex-6-yl] acetic acid

I ^< V ^> N ^ N о ^F ^. / \ And

To a stirred solution of crude methyl [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3-azabicyclo [3.1. 0] hex-6-yl] acetate in methanol (650 ml), a solution of sodium hydroxide (35.1 g, 877 mmol) in water (70 ml) was added in small portions with stirring at 5 to 15 ° C. The mixture became clear after 30 minutes. The clear solution was stirred at rt. over 3 h, then concentrated to ~ 1/3 of the original volume and the residue was diluted with water (750 ml) and brine (250 ml), then washed with a mixture of MTBE (260 ml) and hep

- 35 035363 tana (130 ml). The organic washes were discarded. The aqueous phase was washed with MTBE-heptane (2: 1) (2x300 ml) and the organic layers were discarded. The aqueous layer was then combined with MTBE (250 ml) and heptane (250 ml) and cooled to 0 ° C. Slowly with stirring at 0 to 4 ° C, 6 M aq. HCl (130 ml), followed by the addition of 1 M aq. KHSO4 (150 ml) and the resulting mixture was stirred for 15 minutes. The organic phase was separated and the aqueous phase was further extracted with a mixture of MTBE (170 ml) and heptane (170 ml). The combined organic extract was washed with water-saturated brine (1: 1) (150 ml), dried over anhydrous MgSO ₄ (60 g) and SiO ₂ (60 g), filtered, and concentrated to give a colorless oil. This was combined (as a concentrated solution in MTBE) with another batch that was prepared using identical conditions on the same scale. The combined MTBE solution was concentrated in vacuo, then heptane (2000 ml) was added and the suspension was concentrated again by gradually increasing the vacuum to give the desired product (406.0 g). A portion of this material (196 g) was dissolved in MTBE (220 ml) at 60 to 63 ° C, stirred slowly and heptane (1500 ml) was added at 55 to 60 ° C. The mixture was seeded with crystalline title compound (50 mg). The mixture was stirred at 60 ° C for 30 min, then additional heptane (1700 ml) was added over 20 min. The heterogeneous mixture was stirred at 60 ° C for 2 h and then slowly cooled to 25 ° C and stirred for 20 h. A small amount of solid adhered to the walls of the flask and easily moved into the liquid phase with a spatula, and the mixture was additionally stirred at 25 ° C for 24 h. The solids were filtered, washed with 5% MTBE in heptane, and dried in vacuo at 50 ° C for 48 h to give Example 4 as a white crystalline solid (178.2 g, 73% over 3 stages). The crystalline solid from Example 4 was also prepared using similar purification conditions without the addition of seeding.

Melting point: 122-123 ° C, [a] _D + 86.3 ° (CDCl ₃ , c = 1.37). MS (EC +): 357.3 (M + H).

¹ H NMR (400 MHz, CDCl ₃ ) δ: 10.84 (br s, 1H), 5.92 (s, 1H), 4.38-4.51 (m, 1H), 3.89-4, 10 (m, 3H), 3.533.66 (m, 1H), 3.41-3.53 (m, 2H), 2.30-2.46 (m, 3H), 1.94 (ddt, 1H) , 1.55-1.63 (m, 2H), 1.50 (d, 3H), 0.94 (m, 1H).

Powder X-ray diffraction analysis was performed using a Broker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. The slit divergence was set at 0.6 mm, while the secondary optics used variable slits. Diffracted radiation was detected using

PSD-Lynx Eye detector. The X-ray tube voltage and current were set at 40 kV and 40 mA, respectively. Data were collected in a theta-2theta goniometer at a wavelength of Cu Κα1 = 1.54056 A from 3.0 to 40.0 ° 2-theta using a step size of 0.020 ° and a step time of 0.3 s. Samples were prepared by placing them on a silicone low background sample holder and rotated during collection. Data was collected using Bruker DIFFRAC Plus software and analysis was performed using EVA diffraction plus software.

The VDP data file was not processed until the peak search. Using the peak search algorithm in the EVA software, peaks were sampled with a cutoff of 1 and a width of 0.3 was used to pre-assign the peaks. The derivation of the automated assignments was visually checked to ensure validity and, if necessary, manual adjustments were made. In general, peaks with relative intensities> 3% were selected. Peaks that did not separate or were comparable to noise were also discarded. Typical errors associated with the position of the PRD, stated in the USP and JP, were up to ± 0.2 °.

The characteristic peaks for the crystalline free acid of Example 4 include 2θ (°) angles of approximately 9.0, 10.4, 15.0 and 21.4 ± 0.2 °. Yet another embodiment of the crystalline free acid of Example 4 is such that the characteristic peaks include 2θ (°) angles of about 9.0, 15.0 19.6, 21.4 and 26.5 ± 0.2 °. Yet another embodiment of the crystalline free acid of Example 4 is such that the characteristic peaks include 2θ (°) angles of about 9.0, 10.4, 11.5, 15.0, 16.5, 19.6, 21, 4 and 26.5 ± 0.2 °. Yet another embodiment of the crystalline free acid of Example 4 is such that the characteristic peaks include 2θ (°) angles of about 10.4, 11.5, 15.0, 19.6, and 26.5 ± 0.2 °. Tab. 1 is a listing of the SDP peaks for the crystalline free acid of Example 4, ± 0.2 ° should be applied to said peaks. FIG. 1 provides an X-ray powder diffractogram of the crystalline free acid of Example 4.

- 36 035363

Table 1

List of SDP peaks for crystalline free acid from example 4

Angle 2Θ (°) * Intensity (%) Angle 2Θ (°) * Intensity (%) Angle 2Θ (О) * Intensity (%) 9.0 37 18.3 85 25.9 20 10.4 17 18.8 17 26.5 thirty 11.5 sixteen 18.9 7 27.1 nine 13.5 ten 19.6 one hundred 27.6 five 13.9 five 21.4 36 28.1 nine 15.0 45 22.8 22 29.1 6 16.5 23 22.9 15 30.1 ten 17.3 4 23.3 55 30.5 6 17.7 fourteen 23,7 6 31.6 4 18.1 40 25.7 7

Example 5: [(1R, 5 S, 6R) -3 - {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} - 3-azabicyclo [3.1.0] hex-6-yl] acetic acid

Stage 1: methyl [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3 -azabicyclo [3.1.0] hex-6-yl] acetate.

A solution of methyl {(^^^) - 3- [2-chloro-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex-6yl} acetate (1.55 g, 4.60 mmol), (2S, 3R) -3-hydroxy-2-methylazetidin-1-i [(^^) - 7,7-dimethyl-2oxobicyclo [2.2.1] hept-1-yl] methanesulfonate (1.62 g , 5.10 mmol), triethylamine (1.6 ml, 12.0 mmol) and acetonitrile (15.4 ml) were heated at 60 ° C for 16 h. The reaction mixture was cooled to rt. and concentrated. Water (15 ml) was added and the reaction mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were concentrated and purified using flash chromatography (EtOAc / heptane, 0 to 100%) on a silica gel column to give the title compound (1.3 g, 73%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ: 5.98 (s, 1H), 4.31 (ddd, 1H), 4.23 (t, 1H), 4.21-4.11 (m, 1H) , 4.09-3.89 (m, 1H), 3.76 (dd, 1H), 3.72 (s, 3H), 3.67-3.54 (m, 1H), 3.53-3 , 41 (m, 2H), 2.34 (d, 2H), 1.61-1.58 (m, 2H), 1.54 (d, 3H), 0.98-0.88 (m, 1H ).

Stage 2.

In a solution methyl [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3- azabicyclo [3.1.0] hex-6-yl] acetate (1.30 g, 3.36 mmol) in methanol (5 ml) was added 2M aqueous NaOH (4.2 ml, 8.4 mmol). After 3 hours at room temperature. the reaction mixture was quenched with 1M aqueous potassium hydrogen sulfate (10 ml), extracted with tert-butyl methyl ether (10 ml x 3) and concentrated to give Example 5 (1.2 g, 96%). The crystalline form of the sodium salt was obtained by mixing example 5 (500 mg, 1.34 mmol) with 1 M NaOH (1.34 ml, 1.34 mmol). The solution was stirred at rt. for 5 minutes then dried under reduced pressure to give a white solid. EtOAc (3 ml), heptane (0.5 ml) and water (0.1 ml) were added and the suspension was stirred at rt. over 16 hours. Allocate the resulting white solid and dry to give Example 5 as a crystalline sodium salt.

MS (AP +): 373.4 (M + H).

1H NMR (400 MHz, CDCl ₃ ) δ: 5.96 (s, 1H), 4.34-4.25 (m, 1H), 4.25-4.17 (m, 1H), 4.17- 4.10 (m, 1H), 4.063.88 (m, 1H), 3.74 (dd, 1H), 3.65-3.53 (s, 1H), 3.53-3.43 (m, 2H), 2.45-2.27 (m, 2H), 1.62-1.55 (m, 2H), 1.52 (d, 3H), 0.97-0.87 (m, 1H) ...

Powder X-ray diffraction analysis was performed using a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. Slit divergence was set at 0.6 mm while the secondary optics used variable slits. Diffracted radiation was detected using a PSD-Lynx Eye detector. The X-ray tube voltage and current were set at 40 kV and 40 mA, respectively. Data were collected in a theta-2theta goniometer at a wavelength of Cu Κα1 = 1.54056 A from 3.0 to 40.0 ° 2-theta using a step size of 0.020 ° and a step time of 0.3 s. Samples were prepared by placing them on a silicone low background sample holder and rotated during collection. Data was collected using Bruker DIFFRAC Plus software and analysis was performed using EVA diffraction plus software.

The VDP data file was not processed until the peak search. Using a peak search algorithm in EVA software, peaks were sampled with a cutoff of 1 and a width of 0.3 using

- 37 035363 vali for preliminary assignment of peaks. The derivation of the automated assignments was visually checked to ensure validity and, if necessary, manual adjustments. In general, peaks with relative intensities> 3% were selected. Peaks that did not separate or were comparable to noise were also discarded. Typical errors associated with the position of the PRD, stated in the USP and JP, were up to ± 0.2 °.

The characteristic peaks for the crystalline sodium salt of Example 5 include 2Θ (°) angles of approximately 5.9, 11.5, 11.8, 13.3, 21.5 ± 0.2 °. Yet another embodiment of the crystalline sodium salt of Example 5 is such that the characteristic peaks include 2Θ (°) angles of about 5.9, 10.3, 11.5, 11.8, 13.3, 16.5, 21, 5 and 22.6 ± 0.2 °. Yet another embodiment of the crystalline sodium salt of Example 5 is such that the characteristic peaks include 2Θ (°) angles of about 5.9, 10.3, 11.8, 16.5 and 21.5 ± 0.2 °. Tab. 2 is a listing of the SDP peaks for the crystalline sodium salt of Example 5, ± 0.2 ° should be applied to said peaks. FIG. 2 provides an X-ray powder diffractogram of the crystalline sodium salt of Example 5.

table 2

List of SDP peaks for crystalline sodium salt from example 5 Angle 2Θ (°) * Intensity (%) Angle 2Θ (°) * Intensity (%) Angle 2Θ (°) * Intensity (%) 5.9 81 17.7 6 23,7 eleven 6.8 27 18.3 eleven 23.9 20 7.6 eleven 19.0 five 25.0 3 10.3 26 19.2 4 25.8 4 11.5 92 19.9 15 26.7 6 11.8 one hundred 20.4 7 27.0 8 13.3 48 20.7 28 28.6 3 13.7 five 21.1 4 30.8 8 15.3 20 21.5 21 31.5 3 16.5 33 22.6 18 34.3 3 17.0 22 23.1 4 36.0 3

Example 6: {(^^^) - 3- [2-cyclobutyl-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex6-yl} acetic acid

Step 1: Ethyl {(^^^) - 3- [2-cyclobutyl-6- (trifluoromethyl) pyrimidin-4-yl] -3azabicyclo [3.1.0] hex-6-yl} acetate.

In a solution of ethyl {(^^^) - 3- [2-chloro-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex-6yl} acetate (50 mg, 0.14 mmol ; which was obtained in a manner similar to that for the preparation of the compound from step 1 of example 3) in dry DMF (3 ml) was added (tBu ₃ P) ₂ Pd (7.3 mg, 0.014 mmol). The mixture was purged with nitrogen and a 0.5 M solution of cyclobutylzinc bromide in THF (0.86 mL, 0.43 mmol) was added. The resulting gray suspension was purged with nitrogen and then stirred in a covered container at 100 ° C for 1 hour. The mixture was poured into saturated aqueous NH4C1 (15 ml) and extracted with EtOAc (3x15 ml). The combined organic extract was washed with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified using preparative TLC eluting with EtOAc-petroleum ether (1: 5) to give the title compound as a colorless gum (45 mg, 85% yield). MS (EC ⁺ ): 369.9 (M + H).

Stage 2.

Example 6 was synthesized in a manner analogous to example 1, step 3, using ethyl {(^^^) - 3- [2-cyclobutyl-6- (trifluoromethyl) pyrimidin-4-yl] -3-azabicyclo [3.1.0] hex -6-yl} acetate and purified using preparative reverse phase HPLC to give 15 mg (36% yield) as a white solid. MS (EC ⁺ ): 342.1 (M + H).

1H NMR (400 MHz, CD3OD) δ: 6.57 (s, 1H), 4.04-4.18 (m, 1H), 3.46-3.76 (m, 4H), 2.20-2 , 50 (m, 6H), 1.98-2.14 (m, 1H), 1.85-1.96 (m, 1H), 1.57-1.76 (m, 2H), 0.79 -0.94 (m, 1H).

Example 7: [(1 R, 5S, 6R) -3 - {5-cyclopropyl-2 - [(2 S, 3R) -3-hydroxy-2-methylazetidin-1 -yl] -6 (trifluoromethyl) pyrimidine-4 -yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid

- 38 035363

HE

Stage 1: ethyl [(1R, 5S, 6R) -3- {5-cyclopropyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

In a mixture of ethyl [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3- azabicyclo [3.1.0] hex-6-yl] acetate (100 mg, 0.250 mmol; synthesized by a method similar to the method for preparing the compound in stage 1 of example 5) was added potassium cyclopropyl trifluoroborate (185 mg, 1.25 mmol), AgNO ₃ ( 8.5 mg, 0.050 mmol), K ₂ S ₂ O ₈ (338 mg, 1.25 mmol), EDC (5.0 ml) and water (5.0 ml), then TPO (57 mg, 0, 50 mmol). The reaction vessel was covered and the reaction mixture was stirred at 50 ° C for 16 h. The reaction mixture was diluted with aqueous ammonium chloride solution (10 ml), extracted with EtOAc (3x30 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , and concentrated to give the crude product as a yellow oil which was purified using preparative TLC with 10% MeOH in DCM to give the title compound (30 mg, 27%) in the form of a colorless oil. MS (EC +): 441.1 (M + H).

Stage 2.

Example 7 was synthesized in a manner analogous to example 1, step 3, using ethyl [(1R, 5S, 6R) -3- {5-cyclopropyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidine-1- yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate and purified using reverse phase preparative HPLC to give 10 mg (36% yield) as white solid.

MS (EC ⁺ ): 413.1 (M + H).

1H NMR (400 MHz, CD3OD) δ: 4.30-4.19 (m, 3H), 4.15-4.07 (m, 2H), 3.70-3.56 (m, 3H), 2 , 31 (d, 2H), 1.90-1.81 (m, 1H), 1.58-1.53 (m, 2H), 1.47 (d, 3H), 1.02-0.95 (m, 2H), 0.93-0.84 (m, 1H), 0.49-0.41 (m, 2H).

Example 8: [(1 R, 5S, 6R) -3- {5-ethyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1 -yl] -6 (trifluoromethyl) pyrimidine-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid OH

Stage 1: ethyl [(1R, 5S, 6R) -3- {5-bromo-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

In a solution cooled to 0 ° C, ethyl [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate (100 mg, 0.259 mmol; prepared in a similar manner to methyl [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate) in dry acetonitrile (10 ml) was added N α-bromosuccinimide (60 mg, 0.29 mmol, 85% purity) and the reaction mixture was stirred for 1 h at 0 ° C. The mixture was diluted with aqueous sodium bicarbonate solution, extracted with EtOAc (30 ml x3) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude material which was purified using silica gel chromatography (EtOAc in petroleum ether 0 to 40%) to afford the title compound (110 mg, 91% yield) as a light yellow solid.

Stage 2: ethyl [(1R, 5S, 6R) -3- {5-ethenyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

In a mixture of ethyl [(1R, 5S, 6R) -3- {5-bromo-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl } -3-azabicyclo [3.1.0] hex-6-yl] acetate (50 mg, 0.11 mmol), tributylvinyl tin (51 mg, 0.16 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (11 mg, 0.015 mmol) in dry dioxane (5.0 ml) was added tetrabutylammonium bromide (35 mg, 0.11 mmol). The red reaction mixture was stirred at 50 ° C for 16 hours. The black reaction mixture was diluted with aq. NH ₄ Cl, was extracted with EtOAc (20 ml) three times. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give the crude product as a red oil. The residue was purified using preparative TLC (petroleum ether: EtOAc = 1: 1) to give the crude product and purified again under the same conditions using preparative TLC (petroleum ether: EtOAc = 1: 1), semi

- 39 035363 tea, the title compound as a white solid (15 mg). MS (EC +): 427.1 (M + H).

Stage 3: ethyl [(1R, 5S, 6R) -3- {5-ethenyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate.

In a mixture of ethyl [(1R, 5S, 6R) -3- {5-ethenyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl } -3-azabicyclo [3.1.0] hex-6-yl] acetate (50 mg, 0.020 mmol, 17% purity) in dry ethanol (10.0 ml) was added Pd / C (2.1 mg, 0.0020 mmol). The black suspension was stirred at 25 ° C for 16.0 hours under a hydrogen atmosphere (30 psi). The catalyst was filtered off and the filtrate was concentrated to give the desired product 35 mg as a white solid.

Stage 4.

Example 8 was synthesized in a manner analogous to example 1, step 3 using ethyl [(1R, 5S, 6R) -3- {5-ethenyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl ] -6- (trifluoromethyl) pyrimidin-4yl} -3-azabicyclo [3.1.0] hex-6-yl] acetate and purified using preparative reverse phase chromatography to give 6 mg as a white solid.

MS (EC ⁺ ): 401.0 (M + H).

¹ H NMR (400 MHz, CD3OD) δ: 4.22 (dd, 1H), 4.16-4.08 (m, 2H), 4.03 (t, 2H), 3.75-3.64 ( m, 2H), 3.453.48 (m, 1H), 2.73 (q, 2H), 2.36-2.29 (d, 2H), 1.63-1.59 (br m, 2H), 1.49 (d, 3H), 1.03 (t, 3H), 0.91-0.83 (m, 1H).

Example 9: (2S, 3R) -2,3-dimethyl-1- [4 - {(1R, 5S, 6S) -6 - [(methylsulfonyl) methyl] -3azabicyclo [3.1.0] hex-3-yl} -6- (trifluoromethyl) pyrimidin-2-yl] azetidin-3-olno

Step 1: (^^, 6d) -3-benzyl-6- (iodomethyl) -3-azabicyclo [3.1.0] hexane.

[(^^, 6d) -3-benzyl-3-azabicyclo [3.1.0] hex-6-yl] methyl methanesulfonate (600 mg, 2.13 mmol) and NaI (639, 4.26 mmol) were suspended in MeCN ( 5 ml) and stirred for 16 h. The white suspension was diluted with NH ₄ Cl (20 ml) and extracted with EtOAc (30 ml × 3). The combined organic phases were concentrated to give a red oil which was purified using flash chromatography (petroleum ether / EtOAc 0 to 40%) on a silica gel column to give the title compound (500 mg, 75%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.36-7.18 (m, 5H), 3.57 (s, 2H), 3.12 (d, 2H), 2.98 (d, 2H) , 2.37-2.24 (m, 2H), 1.87-1.76 (m, 1H), 1.36-1.29 (m, 2H).

Step 2: (1R, 5S, 6d) -3-benzyl-6 - [(methylsulfonyl) methyl] -3-azabicyclo [3.1.0] hexane.

(1R, 5S, 6d) -3-Benzyl-6- (iodomethyl) -3-azabicyclo [3.1.0] hexane (500 mg, 1.60 mmol) was dissolved in EtOH (10 ml). Sodium methanesulfonate (489 mg, 4.79 mmol) was added in portions. The yellow solution was stirred at 80 ° C for 16 h, then at rt. over 48 h. The reaction mixture was diluted with water (50 ml) and was extracted with EtOAc (30 ml x 3). The combined organic phases were concentrated to give a colorless oil which was purified using flash chromatography (petroleum ether / EtOAc 50 to 80%) on a silica gel column to give the title compound (310 mg, 73%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.41-7.10 (m, 5H), 3.59 (s, 2H), 3.04 (d, 2H), 2.96-2.86 ( m, 5H), 2.44-2.33 (m, 2H), 1.75-1.65 (m, 1H), 1.53-1.41 (m, 2H).

Step 3: (1R, 5S, 6r) -6- [(methylsulfonyl) methyl] -3-azabicyclo [3.1.0] hexane.

(1R, 5S, 6d) -3-Benzyl-6 - [(methylsulfonyl) methyl] -3-azabicyclo [3.1.0] hexane (310 mg, 1.17 mmol) was dissolved in EtOH (10 ml) and 10 wt % Pd / C (249 mg, 0.234 mmol). The suspension was stirred under 50 psi H ₂ for 48 hours. The reaction mixture was filtered and the filtrate was concentrated to give a white solid (200 mg, 98%) and used directly in the next step without purification.

Stage 4.

Example 9 was prepared analogously to example 1, steps 1-2, starting from (1R, 5S, 6r) -6 [(methylsulfonyl) methyl] -3-azabicyclo [3.1.0] hexane (40 mg, 0.11 mmol). Upon completion, the reaction mixture was quenched with us. aq. NH ₄ Cl solution and extracted with EtOAc. The organic phases were concentrated and purified using preparative HPLC (Phenomenex Gemini C18 250x50 10 μm from 26% MeCN in water (0.225% formic acid) to 46% MeCN in water (0.225% formic acid)), isolating Example 9 (30 mg, 25 % overall yield over two steps) as a white solid.

MS (EC ⁺ ): 420.9 (M + H).

1H NMR (400 MHz, CD3OD) δ: 6.13 (s, 1H), 4.16 (q, 1H), 4.09-3.87 (m, 1H), 3.87-3.75 (m , 2H), 3.753.62 (m, 1H), 3.61-3.46 (m, 2H), 3.16 (d, 2H), 2.99 (s, 3H), 1.87 (s, 2H), 1.42 (d, 3H), 1.39 (s, 3H), 0.98 (tt,

- 40 035363

1H).

Example 10: 2 - [(1 R, 5S, 6R) -3- {2 - [^) - 2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0 ] hex-6-yl] -Hmethylsulfonyl) acetamide

[(1R, 5S, 6R) -3- {2 - [(2S) -2-Methylazetugin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6- yl] acetic acid (75 mg, 0.21 mmol) was dissolved in DCM (6 ml). Added carbonyldiimidazole (34 mg, 0.21 mmol). After 2 h, methanesulfonamide (22 mg, 0.23 mmol) and 1,8-diazabicycloundec-7-ene (38 mg, 0.25 mmol) was added. After stirring for 16 h, the reaction mixture was diluted with NH ₄ Cl solution (15 ml) and extracted with DCM (15 ml x 3). The combined organic phases were concentrated and the crude material was purified using preparative HPLC (Agela Durashell C18 150x255 μm), mobile phase: 43% MeCN in water (0.225% formic acid) to 63% MeCN in water (0.225% formic acid), isolating an example 10 as a white solid (32 mg, 35%).

MS (EC +): 434.0 (M + H).

1H NMR (400 MHz, CD3OD) δ: 6.05 (s, 1H), 4.50-4.35 (m, 1H), 4.04-3.83 (m, 3H), 3.71-3 , 40 (m, 3H), 3.24 (s, 3H), 2.45-2.36 (m, 1H), 2.34 (d, 2H), 2.00-1.86 (m, 1H ), 1.69-1.57 (m, 2H), 1.48 (d, 3H), 0.90-0.79 (m, 1H).

Example 11: (1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetudin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -6- (1Htetrazol-5-ylmethyl ) -3-azabicyclo [3.1.0] hexane

Step 1: tert-butyl (^^^) - 6- (1H-tetrazol-5-ylmethyl) -3-azabicyclo [3.1.0] hexane-3carboxylate.

tert-Butyl (^^^) - 6- (cyanomethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (50 mg, 0.22 mmol) was dissolved in toluene (2 ml) and tributyltin azide (224 mg, 0.675 mmol). The reaction mixture was boiled under reflux for 16 h, then cooled to rt. The reaction mixture was diluted with saturated aq. Na ₂ CO ₃ solution (5 ml) and water (5 ml) and washed with DCM (15 ml x 2). Aq. the layer was then acidified to pH 5 and extracted with 10: 1 CH ₂ Cl ₂ : MeOH (15 ml x 3). The combined organic phases were concentrated to give the title compound (50 mg, 84%) as a colorless oil. This compound was used without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ: 3.60-3.48 (m, 2H), 3.46-3.29 (m, 2H), 3.08 (dd, 1H), 2.90 ( dd, 1H), 1.651.50 (m, 2H), 1.43 (s, 9H), 1.13-1.02 (m, 1H).

Step 2: (^^^) - 6- (1H-tetrazol-5-ylmethyl) -3-azabicyclo [3.1.0] hexane trifluoroacetic acid salt.

tert-Butyl (^^^) - 6- (III-tetrazol-5-ylmethyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate (45 mg, 0.10 mmol) was dissolved in DCM (3 ml) and TPO (1.5 ml) was added. After 2 hours at room temperature. the reaction mixture was concentrated to dryness to give the title compound, which was used without further purification.

Stage 3.

Example 11 was prepared analogously to example 1, steps 1 and 2 from (^^^) - 6- (III-tetrazol-5-ylmethyl) -3azabicyclo [3.1.0] hexane (trifluoroacetate salt, 70 mg, 0.12 mmol). Upon completion, the reaction mixture was quenched with us. aq. NH ₄ Cl solution (20 ml), acidified to pH 5, and extracted with EtOAc (20 ml x3). The organic phases were concentrated and purified using preparative HPLC (Daiso 150x25 5 μm, 36% MeCN in water (0.225% formic acid) to 66% MeCN in water (0.225% formic acid)), isolating Example 11 (9 mg, 19% ) as a white solid. MS (EC ⁺ ): 381.0 (M + H).

¹ H NMR (400 MHz, CD3OD) δ: 6.07 (s, 1H), 4.50-4.35 (m, 1H), 4.09-3.84 (m, 3H), 3.72- 3.56 (m, 1H), 3.563.44 (m, 2H), 3.00 (d, 2H), 2.46-2.34 (m, 1H), 2.02-1.86 (m, 1H), 1.82-1.67 (m, 2H), 1.49 (d, 3H), 1.04-0.94 (m, 1H).

Example 12: [(1R, 5S, 6R) -3- {3-chloro-2- (1,1-difluoroethyl) -6 - [(2S, 3R) -3-guroxy-2-methylazetudine-1yl] pyridine- 4-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid

- 41 035363

Stage 1: ethyl 3-amino-4,4-difluoropent-2-enoate.

In two separate batches, sodium hydride (60% in mineral oil, 2.72 g, 68.1 mmol) was added portionwise to a solution of EtOAc (6.0 g, 70 mmol) in THF (50 mL). After the addition was complete, ethyl 2,2-difluoropropanoate (11.3 g, 81.7 mmol) was added dropwise over 15 minutes. The reaction mixture was heated at 50 ° C for 4 h, then stirred at rt. over 16 h. The reaction mixture was poured into 10% sulfuric acid solution (50 ml) and was extracted with EtOAc (2x50 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated. The crude products were combined and purified using column chromatography eluting with EtOAc / petroleum ether (1: 5) to give a yellow oil. The product was dissolved in ethanol (150 ml) and treated with ammonium acetate (42.8 g, 555 mmol). The mixture was heated at 80 ° C for 16 h. The solvent was removed under reduced pressure and the residue was diluted with aqueous NaHCO ₃ solution (100 ml) and extracted with DCM (2x100 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (22.5 g, 90.5%) as a brown oil.

1H NMR (400 MHz, CDCla) δ: 4.89 (s, 1H), 4.16 (q, 2H), 1.81 (t, 3H), 1.28 (t, 3H).

Step 2: ethyl 3 - [(3-ethoxy-3-oxopropanoyl) amino] -4,4-difluoropent-2-enoate.

Ethyl 3-chlorine was added dropwise to a solution of ethyl 3-amino-4,4-difluoropent-2-enoate (22.5 g, 126 mmol) and pyridine (11.9 g, 151 mmol) in DCM (250 ml) -3-oxopropanoate (18.9 g, 126 mmol) at 0 ° C. The solution was stirred at rt. for 16 h. The reaction mixture was washed with 1N HCl (250 ml) and saturated aqueous NaHCO ₃ (250 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography eluting with EtOAc / petroleum ether (1:10) to give the title compound (18.9 g, 51.3% yield) as a light yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ: 10.53 (br s, 1H), 5.77 (s, 1H), 4.18-4.28 (m, 4H), 3.45 (s, 2H ), 1.99 (t, 3H), 1.23-1.39 (m, 6 h).

Stage 3: ethyl 6- (1,1-difluoroethyl) -2,4-dihydroxypyridine-3-carboxylate.

Suspension of ethyl 3 - [(3-ethoxy-3-oxopropanoyl) amino] -4,4-difluoropent-2-enoate (18.9 g, 64.4 mmol) and potassium tert-butoxide (8.68 g, 77 , 3 mmol) in EtOH (100 ml) was stirred at 80 ° C for 4 h, then at 10 ° C for 16 h. The solvent was removed under reduced pressure, and the residue was poured into ice-water (150 ml). The resulting solution was acidified to pH 2 with aqueous 2N HCl solution. The product was extracted with EtOAc (2x200 ml). The combined organic layers were filtered and the white filter cake (13.0 g) was collected. The filtrate was concentrated to dryness and washed with MeOH to give additional white solids (1.5 g) which were combined with the filtered solids to give the title compound (14.5 g, 91% yield) as a white solid.

1H NMR (400 MHz, DMSO-de) δ: 11.82 (br s, 2H), 6.30 (s, 1H), 4.23 (q, 2H), 1.92 (t, 3H), 1 , 28 (t, 3H).

Step 4: ethyl 6- (1,1-difluoroethyl) -2,4-diethoxypyridine-3-carboxylate.

Into a mixture of ethyl 6- (1,1-difluoroethyl) -2,4-dihydroxypyridine-3-carboxylate (2.00 g, 8.09 mmol) and solid potassium carbonate (2.80 g, 20.2 mmol) in DMF (35 ml) iodoethane (2.52 g, 16.2 mmol) was added dropwise at 0 ° C. The mixture was stirred at 30 ° C for 16 h. The reaction mixture was diluted with water (100 ml) and was extracted with EtOAc (3x 35 ml). The combined organic layers were washed with brine (2x40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (2.51 g,> 100%) as a yellow oil, which was used directly in the next step.

1H NMR (400 MHz, CDCl ₃ ) δ: 6.87 (s, 1H), 4.36-4.44 (m, 4H), 4.15 (q, 2H), 1.94 (t, 3H) , 1.41 (t, 3H), 1.33-1.39 (m, 6 hours).

Step 5: ethyl 5-chloro-6- (1,1-difluoroethyl) -2,4-diethoxypyridine-3-carboxylate.

To a solution of ethyl 6- (1,1-difluoroethyl) -2,4-dihydroxypyridine-3-carboxylate (2.50 g, 8.24 mmol) in acetonitrile (30 ml) was added N-chlorosuccinimide (2.20 g, 16 , 5 mmol). The colorless reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (120 ml) and aqueous saturated NaHCO ₃ solution (30 ml). The product was extracted with EtOAc (3x40 ml). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated. The crude product was purified using column chromatography eluting with EtOAc / petroleum ether (0: 100 to 96: 4) to give the title compound (2.1 g, 75%) as a light yellow oil.

- 42 035363

1H NMR (400 MHz, CDCl ₃ ) δ: 4.33-4.34 (m, 4H), 4.21 (q, 2H), 2.02 (t, 3H), 1.35-1.46 ( m, 9H).

Step 6: 5-chloro-6- (1,1-difluoroethyl) pyridine-2,4-diol.

A solution of ethyl 5-chloro-6- (1,1-difluoroethyl) -2,4-diethoxypyridine-3-carboxylate (2.10 g, 6.21 mmol) in a 48% aqueous solution of hydrobromide acid (25 ml) was stirred at 110 ° C for 48 h. The reaction mixture was concentrated and treated with ammonium hydroxide (6 ml). The reaction mixture was concentrated to give the title compound (3.1 g,> 100%, 30% pure) as a light yellow solid.

1H NMR (400 MHz, DMSO-d ... i δ: 6.36 (s, 1H), 1.93 (t, 3H).

Step 7: 3,4,6-trichloro-2- (1,1-difluoroethyl) pyridine.

A mixture of 5-chloro-6- (1,1-difluoroethyl) pyridine-2,4-diol (1.80 g, 2.6 mmol, 30% purity) in phosphorus oxychloride (18 ml) and DMF (4.5 ml ) was stirred at 100 ° C for 16 h. The reaction mixture was poured into ice with water (80 ml) and was extracted with EtOAc (3x40 ml). The combined organic layers were washed with brine (2x50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography eluting with EtOAc / petroleum ether (0: 100 to 0.5: 99.5) to give the title compound (540 mg, 85%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.56 (s, 1H), 2.08 (t, 3H).

Step 8: ethyl {(^^^) - 3- [3,6-dichloro-2- (1,1-difluoroethyl) pyridin-4-yl] -3-azabicyclo [3.1.0] hex6-yl} acetate.

A mixture of 3,4,6-trichloro-2- (1,1-difluoroethyl) pyridine (50 mg, 0.2 mmol), ethyl (1R, 5S, 6s) -3azabicyclo [3.1.0] hex-6-yl acetate (34 mg, 0.20 mmol) and triethylamine (62 mg, 0.61 mmol) in DMF (2 ml) was stirred at 60 ° C for 16 h.The mixture was diluted with water (15 ml) and an aqueous solution of ammonium chloride (10 ml) and extracted with EtOAc (3x 15 ml). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using column chromatography eluting with EtOAc / petroleum ether (0: 100 to 7:93) to give the title compound (70 mg) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ: 6.84 (s, 1H), 4.13 (q, 2H), 4.02-4.08 (m, 2H), 3.45-3.54 (m , 2H), 2.33 (d, 2H), 1.97 (t, 3H), 1.57-1.62 (m, 2H), 1.25 (t, 3H), 0.99-1, 06 (m, 1H).

Stage 9.

In a solution of ethyl {(^^^) - 3- [3,6-dichloro-2- (1,1-difluoroethyl) pyridin-4-yl] -3-azabicyclo [3.1.0] hex6-yl} acetate (70 mg, 0.18 mmol) in dioxane (5 ml) was added (2S, 3R) -3-hydroxy-2-methylazetidin-1-ia [(^^) - 7,7-dimethyl-2-oxobicyclo [2.2.1 ] hept-1-yl] methanesulfonate (64.3 mg, 0.200 mmol), sodium tert-butoxide (71.0 mg, 0.738 mmol), chlorine (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl ) [2- (2aminoethylphenyl)] palladium (II) (6.73 mg, 0.00923 mmol) and 2-dicyclohexylphosphino-2 ', 6'diisopropoxybiphenyl (4.31 mg, 0.00923 mmol) under nitrogen. The reaction mixture was stirred at 70 ° C for 16 h, then at 80 ° C for 40 h. The cooled reaction mixture was diluted with water, acidified to pH 5 with 2N HCl, and extracted with EtOAc (3x25 ml), the combined organic phases were washed with brine , dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using preparative thin layer chromatography and then purified using preparative HPLC to give Example 12 (10.5 mg, 14%) as a white solid.

MS (EC +): 401.9 (M + H).

1H NMR (400 MHz, CD3OD) δ: 5.78 (s, 1H), 4.09-4.15 (m, 2H), 3.88-3.96 (m, 3H), 3.41-3 , 47 (m, 1H), 3.18-3.24 (m, 2H), 2.26 (d, 2H), 1.92 (t, 3H), 1.49-1.51 (m, 2H ), 1.46 (d, 3H), 1.14-1.18 (m, 1H).

Example 13: [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -5-methoxy-6 (trifluoromethyl) pyrimidin-4-yl } -3 -azabicyclo [3.1.0] hex-6-yl] acetic acid

To a solution of ethyl [(1R, 5S, 6R) -3- {5-6pOM-2 - [(2S, 3R) -3-rugpOKCu-2-MeTura3eTuguH-1-uT] -6 (trifluoromethyl) pyrimidin-4-yl } -3-azabicyclo [3.1.0] hex-6-yl] acetate (50 mg, 0.13 mmol) in methanol (5.0 ml) sodium methoxide (16.9 mg, 0.313 mmol) and copper (I ) bromide (2.2 mg, 0.016 mmol) and heated to 60 ° C for 16 h. Additional copper (I) bromide (2.2 mg, 0.016 mmol) was added and the reaction mixture was heated at 60 ° C for 16 h. The reaction mixture was diluted with aq. ammonium chloride solution and extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude

43 035363 product which was purified using reverse phase preparative HPLC to give 20 mg (48% yield) of Example 13 as a white solid.

MS (EC +): 403.0 (M + H).

¹ H NMR (400 MHz, CD3OD) δ: 4.19-3.97 (m, 5H), 3.64-3.57 (m, 3H), 3.57 (s, 3H), 2.30 ( br d, 2H), 1.57 (br s, 2H), 1.46 (s, 3H), 0.91-0.81 (m, 1H).

Biological data

The screening assay was developed for KNK, incorporating a conjugated enzyme system that used the KNK reaction product to kinetically drive the absorption signal. KNK takes fructose and ATP and converts it to F1P and ADP. ADP then serves as a substrate for pyruvate kinase, which converts PEP to pyruvate, which is then reduced to lactate using lactate dehydrogenase while oxidizing NADH to NAD +. The resulting NADH depletion was monitored by measuring absorbance at 340 nm.

Recombinant human KHK-C and KHK-A were expressed in E. coli as a His-tagged fusion protein and purified using Ni-NTA chromatography. cDNA was synthesized based on NCBI refseq NP_006479.1 along with sequences for the N-terminal His-tag and thrombin cleavage site and cloned into the pET28a (+) vector. Protein was expressed in BL-21 (DE3) using IPTG induction and purified using Ni-NTA column followed by Superdex 75. Purified KHK-C and KHK-A were treated with thrombin to remove His tag and final purification was performed using purification Ni-NTA / Strapovidine Affinity. The protein preparation was ~ 95% pure by SDS-PAGE and the molecular weight as confirmed by mass spectrometry was 32663 Da (expected 32667 Da).

One study, called Assay A, uses a 384-well format on a Corning 3653 assay plate and monitored using continuous CT ultraviolet-visible absorption electron spectroscopy. Compounds were prepared in DMSO as a 4 mM stock solution, diluted using a Biomek FX 11-point semi-logarithmic scheme (Beckman Coulter), and incubated at rt. for 30 min with a reaction mixture containing 50 mM HEPES, pH 7.4, 140 mM KCl, 3.5 mM MgCl ₂ , 0.8 mM fructose, 2 mM TCEP, 0.8 mM PEP, 0.7 mM NADH , 0.01% Triton X-100, 30 U / ml pyruvate kinase - lactate dehydrogenase, and 10 nM purified KHK-C. The concentration of the compound in each well ranged from 1 nM to 100 μM. The reaction was initiated by the addition of 0.2 mM ATP. The absorbance was measured for 30 minutes on a SpectraMax reader (Molecular Devices) after the addition of ATP. Concentrations quoted are based on a final volume of 40 μl mixture (referred to as final concentration).

Controls: N- (cyclopropylmethyl) -U4- (2- (methylthio) phenyl) -2- (piperazin-1-yl) pyrimido [5,4d] pyrimidine-4,8-diamine at a final concentration of 2 μM was used as a control high percentage effect (HPE), and 2.5% DMSO that was present in all reaction wells was used as a zero percentage effect (ZPE) control. Reaction indicators were obtained for a time window of 300-1800 s in units of 1000 * units. Abs / min (absorbance units per minute), and the mean values for the ZPE and HPE control of each of the 16 wells, AveZPE and AveHPE, were calculated, respectively.

Percent inhibition (% inhibition) was calculated for each well using this equation:

100 - 100 x (the value of the absorption compounds coefficient - Aue _H pp) (ΑνβζρΕ - ΑνβΗρε)% inhibition was then plotted on the graph relative log compound concentration using GraphPad Prism, and the data was adapted to relative to the response equation log [compound] - variable slope using nonlinear regression analysis to obtain IC ₅₀ values. For each test compound, the reported IC ₅₀ are mean values based on at least two separate analyzes performed on separate days.

Compounds having IC ₅₀ values less than 20 nM were investigated in a second KHK assay called assay B using 10 times the smaller enzyme and measuring the absorbance over 3 h to obtain IC ₅₀ values below the lower limit of 10 nM assay A Compounds were prepared in DMSO as 4 μM stock solutions, diluted using an 11-point 2-fold dilution scheme on Biomek FX, which spans a concentration range of 97 pM to 100 nM, and incubated with the reaction mixture prepared in a similar manner as and in assay A, but which contains 1 nM KHK-C. The reaction was initiated by the addition of 0.2 mM ATP and the absorbance was monitored for 3 hours at 340 nm. Response rates and IC ₅₀ values were calculated as described above.

The third KHK assay, called assay C, was performed at high fructose and ATP concentrations, conditions that would be more consistent with the physiological concentrations of natural KHK enzyme substrates. Assay C was performed as described above for Assay B except for the use of 8 mM fructose and 2 mM ATP, and the concentration of the compound was in the range of 10 pM to 1 μM or 50 pM to 5 μM using a half-log dilution scheme

- 44 035363 laziness.

A fourth assay, called Assay D, was performed using human KHK-A to evaluate the effectiveness of compounds for inhibiting activity of a given enzyme. Compounds were prepared in DMSO as 4 μM stock solutions, diluted using an 11-point 2-fold dilution scheme on Biomek FX, which spans a final concentration range of 0.25 to 250 nM, and incubated with a reaction mixture prepared in a similar manner, as in Assay A, but which contains 8 mM fructose and 1 nM KHK-A. The reaction was initiated by the addition of 0.2 mM ATP and the absorbance was monitored for 3 hours at 340 nm. Response rates and IC ₅₀ values were calculated as described above.

Table 3 Biological data for analyzes A, B, C and D +

Example No. 1C ₅₀ (nM) Assay A 10 nM KNK-S Analysis B 1 nM KNK-S Analysis C 1 nM KNK-S Analysis D 1 nM KNK-A 1 5.5 (6) 1.5 (2) 3.3 (6) 7.3 (2) 2 6.8 (2) 1.5 (2) 3.6 (2) 3 3.508 (2) 4 14.2 (16) 8.4 (2) 37.3 (10) 66.0 (2) five 24.7 (6) 13.6 (6) 58.8 (10) 95.5 (2) 6 169.5 (2) 7 110.9 (2) 8 53.8 (3) nine 14.361 (2) ten 682.1 (2) eleven 866.1 (2) 12 288.8 (2) 13 33.9 (2) 24 9.7 (4) 3.3 (2) 11.0 (4) 12.1 (2) 40 11.1 (4) 3.7 (2) 37.9 (2) 42 8.8 (4) 2.4 (4) 10.5 (2) 43 17.8 (4) 8.0 (4) 48.6 (2) 50 4.4 (2) 1.5 (2) 2.6 (2)

⁺ Ser. IC ₅₀ based on (#) number of runs per example.

The following examples are presented in table. 4 were obtained using conditions similar to those presented in the examples listed in the column identified as Reference Example #, making non-critical changes to the method. Tab. 4 also includes biological data from Analysis A for these examples. Data structures of examples from table. 4 are shown in FIG. 3.

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Table 4

Examples and biological data for analysis A

Etc. # Name NMR data / LC-MS data Link example # 1C ₅₀ (nM) analysis A ⁺ Etc. fourteen [(1R, 5S, 6R) -3- {6- (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.30 (t, 1H), 6.03 (s, 1H), 4.21 (dd, 1H), 4.15-4.03 (m, 2H), 3.90 (br s, 1H) 3.68-3.55 (m, 2H), 3.54-3.41 (m, 2H), 2.32 (d, 2H), 1.61 (br s, 2H), 1.49 (d, 3H), 0.86-0.79 (m, 1H). MS (EC +): 355.0 (M + H). Etc. 1 152.2 (2) Etc. 15 [(1R, 5S, 6R) -3- {5-xnop-6 (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] pyrimid in-4-yl} -3azabicyclo [3.1, 0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.75 (t, 1H), 4.26 (dd, 2H), 4.19 (dd, 1H), 4.13-4.00 (m, 2H) , 3.72 (t, 2H), 3.64 (dd, 1H), 2.26 (d, 2H), 1.56 (br s, 2H), 1.47 (d, 3H), 0.91 -0.74 (m, 1H). MS (EC +): 389.0 (M + H). Etc. 2 19.1 (2) Etc. sixteen [(1R, 5S, 6R) -3- {5-xnop-2 [(2S, 3R) -3-rnflpoKcn-2methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 4.27 (t, 2H), 4.21-4.14 (m, 1H), 4.14-4.00 (m, 2H), 3.74 ( br t, 2H), 3.65 (dd, 1H), 2.29 (d, 2H), 1.57 (br s, 2H), 1.47 (d, 3H), 0.87-0.78 (m, 1H). MS (EC +): 406.9 (M + H). Etc. 2 6.4 (4) Etc. 17 [(1R, 5S, 6R) -3- {6- (1,1- difluoroethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.00 (s, 1H), 4.26-4.15 (m, 1H), 4.14-3.99 (m, 2H), 3.88 ( br s, 1H), 3.62 (dd, 2H), 3.52-3.41 (m, 2H), 2.30 (d, 2H), 1.82 (t, 3H), 1.59 ( br s, 2H), 1.49 (d, 3H), 0.88-0.78 (m, 1H). MS (EC +): 369.1 (M + H). Etc. 1 131.4 (2)

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Etc. 18 [(1 R, 5S, 6R) -3- {5-xnop-6- (1,1 difluoroethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] pyrimid in-4-yl} - 3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 4.27 (t, 2H), 4.20 - 3.94 (m, 3H), 3.73-3.65 (m, 2H), 3, 62 (dd, 1H), 2.29 (d, 2H), 1.90 (t, 3H), 1.55 (br s, 2H), 1.47 (d, 3H), 0.87-0, 79 (m, 1H). MS (EC +): 403.2 (M + H). Etc. 2 16.7 (2) Etc. nineteen [(1R, 5S, 6R) -3- {5-nnaHO-4 (difluoromethyl) -6 - [(25) -2methylazetidin-1yl] pyridin-2-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.86 (t, 1H), 6.02 (s, 1H), 4.68-4.53 (m, 1H), 4.39 (dt, 1H) , 4.12-4.01 (m, 1H), 3.903.60 (br m, 2H), 3.57-3.41 (d, 2H), 2.51-2.36 (m, 1H), 2.31 (d, 2H), 2.051.93 (m, 1H), 1.61 (br s, 2H), 1.49 (d, 3H), 0.86-0.79 (m, 1H). MS (EC +): 363.1 (M + H) Etc. 1 7.2 (4) Etc. 20 [(1R, 5S, 6R) -3- {6- (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] -5-methyl pyrimid in-4yl} -3-azabicyclo [3.1.0] hex6-yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 7.03 (t, 1H), 4.53-4.43 (m, 1H), 4.41-4.29 (m, 1H), 4.29- 4.15 (m, 3H), 4.00-3.87 (m, 2H), 3.85 (dd, 1H), 2.37-2.30 (m, 5H), 1.70-1, 64 (br s, 2H), 1.52 (d, 3H), 0.88-0.80 (m, 1H). MS (EC +): 368.9 (M + H). Etc. 1 33.4 (2) Etc. 21 [(1R, 5S, 6R) -3- {3-xnop-5cyano-4- (difluoromethyl) -6 [(25, 3R) -3-hydroxy-2,3dimethylazetidin-1yl] pyridin-2-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 7.11 (t, 1H), 4.38-4.21 (m, 4H), 3.85 (d, 1H), 3.75 (dd, 2H) , 2.29 (d, 2H), 1.61 1.55 (m, 2H), 1.41 (s, 3H), 1.40 (d, 3H), 0.88-0.81 (m, 1H). MS (EC +): 427.0 (M + H). Etc. 2 8.7 (2)

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Etc. 22 [(1 R, 5S, 6R) -3- {2 - [(2S, 3R) -3hydroxy-2,3- dimethylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid MS (EC +): 387.1 (M + H). Retention time: 2.190 min; Column: Waters Atlantis dC18 4.6x50mm, 5um. Modifier: TPO 0.05%. Gradient: 95% water / 5% acetonitrile linear to 5% water / 95% acetonitrile over 4.0 minutes, retention at 5% water / 95% acetonitrile for a total run time of 5.0 minutes. Flow: 2.0ml / min. Etc. 1 702.8 (2) Etc. 23 [(1R, 5S, 6R) -3- {5-nnaHO-6 [(25,45) -4-hydroxy-2methylpyrrolidin-1-yl] -4 (trifluoromethyl) pyridin-2yl} -3-azabicyclo [3.1, 0] hex6-yl] acetic acid MS (AP +): 411.1 (M + H); Retention time = 1.62 minutes; Column: Waters XBridge C18 4.6x50, 5 μm Mobile Phase A: 0.03% NH ₄ OH in H ₂ O (v / v); Mobile phase B: 0.03% NH ₄ OH in acetonitrile (v / v) Gradient: 95.0% H ₂ O / 5.0% Acetonitrile linearly up to 5% H ₂ O / 95% Acetonitrile at 4.0 min., retention at 5% H ₂ O / 95% Acetonitrile for a total run time of 5.0 minutes. Flow: 2ml / min. Etc. 1 11.6 (2) Etc. 24 [(1 R, 5S, 6R) -3- {2 - [(2S, 3R) -3hydroxy-2-methylazetidin1-yl] -5-methyl-6- (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (600 MHz, CD3OD) b: 4.154.22 (m, 1H), 4.02-4.14 (m, 4H), 3.563.67 (m, 3H), 2.32 (br d, 2H ), 2.202.23 (m, 3H), 1.54-1.57 (m, 2H), 1.50 (d, 3H), 0.87-0.94 (m, 1H). MS (EC +): 387.8 (M + H). Etc. 1 9.7 (4)

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Etc. 25 [(1R, 5S, 6R) -3- {6- (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2,3- dimethylazetidin-1-yl] -5methylpyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.46 (m, 1H), 4.17-3.98 (m, 3H), 3.79 (d, 1H), 3.72 (d, 1H), 3.59 (dd, 2H), 2.29 (d, 2H), 2.23 (s, 3H), 1.53 (br s, 2H), 1.46-1.31 (m, 6 h), 0.93-0.84 (m, 1H). MS (EC +): 382.9 (M + H). Etc. 1 258.9 (2) Etc. 26 [(1 R, 5S, 6R) -3- {2 - [(2S, 3R) -3hydroxy-2,3- dimethylazetidin-1-yl] -5- methyl-6- (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 4.173.98 (m, 3H), 3.76 (dd, 2H), 3.58 (t, 2H), 2.28 (d, 2H), 2.19 (d, 3H), 1.53 (br s, 2H), 1.45-1.30 (m, 6 h), 0.940.81 (m, 1H). MS (EC +): 401.0 (M + H). Etc. 1 63.6 (2) Etc. 27 [(1 R, 5S, 6R) -3- {2 - [(2S, 3R) -3hydroxy-2-methylazetidin1-yl] -6- (trifluoromethyl) pyridin-4yl} -3-azabicyclo [3.1.0] hex6-yl] acetic acid ¹ H NMR (400MHz, CD3OD) b: 6.30 (d, 1H), 5.46 (s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08 (m , 1H), 4.00-3.90 (m, 1H), 3.57 (dd, 2H), 3.50 (dd, 1H), 3.41 3.32 (m, 2H), 2.31 (d, 2H), 1.67-1.62 (m, 2H), 1.48 (d, 3H), 0.93-0.82 (m, 1H). MS (EU +): 371.9 (M + H) Etc. 1 109.4 (2) Etc. 28 [(1R, 5S, 6R) -3- {2 - [(2S) -2- methylpyrrolidin-1-yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1,0] hex-6- sludge] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 5.97 (s, 1H), 4.26-4.18 (m, 1H), 3.93 (br s, 1H), 3.72 - 3.40 ( m, 5H), 2.32 (d, 2H), 2.15-1.94 (m, 2H), 1.94- 1.81 (m, 1H), 1.74- 1.64 (m, 1H), 1.60 (br s, 2H), 1.24 (d, 3H), 0.87-0.79 (m, 1H). MS (EU +): 371.0 (M + H) Etc. 1 119.8 (2)

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Etc. 29 [(1R, 5S, 6R) -3- {6- (difluoromethyl) -2 - [(28, 3R) -3hydroxy-2-methylazetidin1-yl] -5-methoxypyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.71 (t, 1H), 4.23-3.97 (m, 5H), 3.61-3.54 (m, 3H), 3, 58 (s, 3H), 2.30 (br d, 2H), 1.56 (br s, 2H), 1.47 (s, 3H), 0.90-0.82 (m, 1H). MS (EC +): 384.9 (M + H) Etc. 13 264.9 (2) Etc. thirty [(1 R, 5S, 6R) -3- {4 - [(2S, 3R) -3hydroxy-2-methylazetidin1 -yl] -6- (trifluoromethyl) 1,3,5-triazin-2-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400MHz, CD3OD) b: 4.32 4.22 (m, 1H), 4.22-4.10 (m, 2H), 3.97-3.85 (m, 2H), 3, 73 (dd, 1H), 3.55 -3.42 (m, 2H), 2.41-2.21 (m, 2H), 1.56 (br s, 2H), 1.50 (d, 3H ), 0.850.68 (m, 1H). MS (EC +): 373.9 (M + H) Etc. 1 509.2 (2) Etc. 31 {(1 R, 5S, 6s) -3- [5-qnaHO-6- cyclobutyl-4- (trifluoromethyl) pyridin-2yl] -3-azabicyclo [3.1.0] hex6-yl} acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.59 (s, 1H), 4.26-4.05 (m, 1H), 4.02-3.88 (m, 1H), 3.81- 3.53 (m, 3H), 2.39-2.52 (m, 2H) 2.39-2.28 (m, 4H), 2.16-2.03 (m, 1H), 1.99 -1.86 (m, 1H), 1.75-1.62 (m, 2H), 0.92-0.83 (m, 1H). MS (EC +): 365.9 (M + H). Etc. 6 30.0 (2) Etc. 32 [(1 R, 5S, 6R) -3- {6 - [(2S, 3R) -3hydroxy-2-methylazetidin1-yl] -2- (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400MHz, CD3OD) b: 5.18 (s, 1H), 4.25-4.18 (m, 1H), 4.18-4.12 (m, 1H), 4.11 -4 , 03 (m, 1H), 3.73 (br m ,, 2H), 3.57 (dd, 1H), 3.42 (br d, 2H), 2.31 (d, 2H), 1.59 (br s, 2H), 1.48 (d, 3H), 0.86-0.79 (m, 1H). MS (EC +): 372.9 (M + H) Etc. 1 1,760.4 (2) Etc. 33 [(1R, 5S, 6R) -3- {6- (1,1- difluoroethyl) -2 - [(28, 3R) -3hydroxy-2-methylazetidin1 -yl] -5-methyl pyrimid in-4yl} -3-azabicyclo [3.1.0] hex6-yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 4.243.91 (m, 5H), 3.68-3.44 (m, 3H), 2.27 (d, 2H), 2.20 (br s, 3H ), 1.90 (t, 3H), 1.58-1.41 (m, 5H), 0.91 (br s, 1H). MS (EC +): 382.9 (M + H). Etc. 1 113.6 (4)

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Etc. 34 [(1R, 5S, 6R) -3- {2- (1,1- difluoroethyl) -6 - [(25, 3R) -3hydroxy-2-methylazetidin1-yl] pyridin-4-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.27 (s, 1H), 5.40 (s, 1H), 4.19 (t, 1H), 4.09-4.14 (m, 1H), 3.91-3.98 (m, 1H), 3.54-3.58 (m, 2H), 3.48 (dd, 1H), 3.323.36 (m, 2H), 2.30 (d, 2H), 1.86 (t, 3H), 1.61-1.64 (m, 2H), 1.47 (t, 3H), 0.85-0.89 (m, 1H). MS (EC +): 368.0 (M + H). Etc. 12 331.4 (2) Etc. 35 [(1R, 5S, 6R) -3- {5-xnop-2 [(25,45) -4-hydroxy-2methylpyrrolidin-1-yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid MS (EC +): 421.32 (M + H). Retention time = 4.1336; SFC Column: Lux Cell 3 4.6 x 100 mm 5 μm. Modifier A: CO ₂ , Modifier B: Methanol with 0.2% NH ₄ OH. Gradient: 85:15 A: B, hold for 6 minutes. Column Temp. = 40 ° C. Back pressure: 120 bar. Flow: 1.5ml / min. Etc. 2 187.5 (2) Etc. 36 [(1R, 5S, 6R) -3- {5-xnop-6 (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2,3dimethylazetidin-1yl] pyrimidin-4-yl} -3azabicyclo [3.1.0 ] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.75 (t, 1H), 4.25 (dd, 2H), 4.14 (q, 1H), 3.88-3.65 (m, 4H) , 2.30 (d, 2H), 1.57 (br s, 2H), 1.47-1.31 (m, 6 h), 0.880.78 (m, 1 H). MS (EC +): 402.9 (M + H). Etc. 2 102.8 (2) Etc. 37 {(1 R, 5S, 6s) -3- [5-qnaHO-4- (difluoromethyl) -b- (pyrrolidin-1-yl) pyridine- 2-yl] -3- azabicyclo [3.1,0] hex-6yl} acetic acid MS (API +): 363 (M + H). Retention time: 3.218. Method D Etc. 1 58.3 (4)

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Etc. 38 {(1 Е, 55,6h) -3- [5-cyano-4 (difluoromethyl) -6- (2methylpyrrolidin-1yl) pyridin-2-yl] -3azabicyclo [3.1.0] hex-6yl} acetic acid MS (API +): 377 (M + H). Retention time: 3.325. Method 1 * Etc. 1 25.3 (4) Etc. 39 {(1R, 5S, 6s) -3- [2- (2methylpiperidin-1-yl) -6 (trifluoromethyl) pyrimidin4-yl] -3- azabicyclo [3.1,0] hex-6yl} acetic acid MS (API +): 385 (M + H). Retention time = 3.528. Method 2 ** Etc. 1 24.8 (2) Etc. 40 [(1R, 5S, 6R) -3- {5-xnop-6 (difluoromethyl) -2 - [(25) -2methylazetidin-1yl] pyrimidin-4-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.74 (t, 1H), 4.45-4.35 (m, 1H), 4.25 (t, 2H), 3.98 (dt, 1H), 3.89 (q, 1H), 3.72 (br t, 2H), 2.45-2.33 (m, 1H), 2.30 (d, 2H), 2.00-1, 89 (m, 1H), 1.61-1.53 (m, 2H), 1.47 (d, 3H), 0.87-, 080 (m, 1H). MS (EC +): 373.1 (M + H). Etc. 2 11.1 (4) Etc. 41 [(1R, 5S, 6R) -3- {6 (difluoromethyl) -5-ethyl-2 [(25, 3R) -3-hydroxy-2methylazetidin-1yl] pyrimidin-4-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.52 (t, 1H), 4.20-4.14 (m, 1H), 4.09 (q, 1H), 4.05 - 3.93 (m , ZN), 3.66 - 3.56 (m, ZN), 2.75 (q, 2H), 2.34-2.27 (w m, 2H), 1.57 (br s, 2H), 1.48 (d, 3H), 1.03 (t, 3H), 0.93-0.85 (m, 1H). MS (EC +): 382.9 (M + H). Etc. 8 110.7 (2) Etc. 42 [(1R, 5S, 6R) -3- {5-Me ™ n-2 [(25) -2-methylazetidine-1yl] -6- (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CDCl3) b: 4.344.43 (m, 1H), 3.95-4.09 (m, 3H), 3.863.95 (m, 1H), 3.48-3.61 ( m, 2H), 2.302.40 (m, ZN), 2.16 (s, ZN), 1.89-2.00 (m, 1H), 1.45-1.54 (m, 5H), 0 , 95-1.04 (m, 1H). MS (EC +): 371.1 (M + H). Etc. 1 8.8 (4)

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Etc. 43 [(1R, 5S, 6R) -3- {6- (difluoromethyl) -5-methyl-2 [(25) -2-methylazetidin-1yl] pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD ₃ OD) b: 6.45 (t, 1H), 4.43-4.28 (m, 1H), 4.06 (dd, 2H), 3.94 (dt, 1H), 3.85 (q, 1H), 3.64-3.50 (m, 2H), 2.36 (dtd, 1H), 2.28 (d, 2H), 2.21 (t, 3H ), 2.00-1.88 (m, 1H), 1.51 (br s, 2H), 1.47 (d, 3H), 0.99-0.81 (m, 1H). MS (EC +): 353.1 (M + H). Etc. 1 17.8 (4) Etc. 44 [(1R, 5S, 6R) -3- {6- (1,1difluoroethyl) -5-methyl-2 [(25) -2-methylazetidin-1yl] pyrimidin-4-yl} -3azabicyclo [3.1,0] hex -6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 4.434.21 (m, 1H), 4.02 (t, 2H), 3.94-3.77 (m, 2H), 3.49 (t, 2H) , 2.40-2.29 (m, 1H), 2.26 (d, 2H), 2.19 (br s, 3H), 1.93 (m, 4H), 1.47 (m, 5H) , 0.98-0.87 (m, 1H). MS (EC +): 367.3 (M + H). Etc. 1 51.4 (4) Etc. 45 [(1R, 5S, 6R) -3- {5cyclopropyl-6 (difluoromethyl) -2 - [(25, 3R) -3hydroxy-2-methylazetidin1 -yl] pyrimidin-4-yl} -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 7.04 (t, 1H), 4.27-4.18 (m, 3H), 4.11-4.03 (m, 2H), 3.65- 3.51 (m, 3H), 2.30 (d, 2H), 1.86-1.75 (m, 1H), 1.54-1.50 (m, 2H), 1.47 (d, 3H), 1.04-0.97 (m, 2H), 0.95-0.87 (m, 1H), 0.47-0.41 (m, 2H). MS (EC +): 395.0 (M + H). Etc. 7 237.8 (2) Etc. 46 {(1 P, 55.6h) -3- [6- (azetidine-1yl) -5-cyano-4- (trifluoromethyl) pyridin-2yl] -3-azabicyclo [3.1.0] hex6-yl} acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.07 (s, 1H), 4.29 (t, 4H), 4.04 - 3.56 (wm „2H), 3.51 (dd, 2H ), 2.41 - 2.27 (m, 4H), 1.62 (br s, 2H), 0.87 - 0.74 (m, 1H). MS (EC +): 366.8 (M + H). Etc. 1 21.5 (2) Etc. 47 {(1 P, 55.6h) -3- [2- (azetidine-1yl) -6- (trifluoromethyl) pyrimidine- 4-yl] -3- azabicyclo [3.1,0] hex-6yl} acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.30 (s, 1H), 4.18 (t, 4H), 4.05-3.93 (m, 1H), 3.79-3.70 ( m, 1H), 3.65-3.50 (m, 2H), 2.43-2.34 (m, 2H), 2.33 (d, 2H), 1.70-1.59 (m, 2H), 0.87-0.79 (m, 1H). MS (EC +): 342.9 (M + H). Etc. 1 619.1 (2)

- 53 035363

Etc. 48 (2S, 3R) -1- [5-xnop-4- {(1R, 5S, 6S) -6- [(methylsulfonyl) methyl] -3azabicyclo [3.1.0] hex-3-yl} 6- (trifluoromethyl) pyrimidin2-yl] -2,3-dimethylazetidin3-ol ¹ H NMR (400 MHz, CD ₃ OD) b: 4.424.27 (m, 2H), 4.21-4.10 (m, 1H), 3.893.70 (m, 4H), 3.17 (d, 2H), 3.01 (s, 3H), 1.86 (d, 2H), 1.50-1.33 (m, 6 hours), 1.06-0.93 (m, 1H). MS (EC +): 455.0 (M + H). Etc. 1 1,359 (2) Etc. 49 [(1R, 5S, 6S) -3- {2 - [(2S) -2methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 6.05 (s, 1H), 4.49-4.37 (m, 1H), 4.00 (dt, 1H), 3.95-3.85 (m , 1H), 3.77 - 3.54 (m, 3H), 3.42 (br, 1H), 2.40 (dddd, 1H), 2.12 (d, 2H), 2.01 - 1, 79 (m, 3H), 1.48 (d, 3H), 1.38-1.29 (m, 1H). MS (EC +): 356.9 (M + H). Etc. 1 2084 (4) Etc. 50 [(1R, 5S, 6R) -3- {5-nnaHO-4 (1,1-difluoroethyl) -3-fluoro-6 [(25, 3R) -3-hydroxy-2methylazetidin-1yl] pyridin-2-yl } -3azabicyclo [3.1,0] hex-6yl] acetic acid ¹ H NMR (400 MHz, CD3OD) b: 4.714.64 (m, 1H), 4.24-4.30 (m, 1H), 4.164.11 (m, 1H), 4.09-3.98 ( m, 2H), 3.783.62 (m, 3H), 2.35 (d, 2H), 1.99 (t, 3H), 1.66-1.60 (m, 2H), 1.47 (d , 3H), 0.92-0.87 (m, 1H). MS (EC +): 411.1 (M + H). Etc. 1 4.4 (2) Etc. 51 {(1 R, 5S, 6s) -3- [5-qnaHO-6 (cyclobutylamino) -4 (difluoromethyl) pyridin-2yl] -3-azabicyclo [3.1,0] hex6-yl} acetic acid MS (API +): 363 (M + H). Retention time = 3.226. Method 2 ** Etc. 1 150.4 (4) Etc. 52 3 - [(1 R, 5S, 6R) -3- {5-nnaHO-6 [(2S, 3R) -3-rnflpoKcn-2methylazetidin-1-yl] -4 (trifluoromethyl) pyridin-2yl} -3-azabicyclo [3.1,0] hex6-yl] propionic acid ¹ H NMR (400 MHz, CD3OD) b: 6.13 (s, 1H), 4.66 (ddd, 1H), 4.34 - 4.23 (m, 1H), 4.14 (dt, 1H), 4.01-3.78 (wm „1H), 3.78 (dd, 1H), 3.68-3.40 (m, 3H), 2.40 (t, 2H), 1.65 - 1 , 52 (m, 4H), 1.49 (d, 3H), 0.60 (tt, 1H). MS (EC +): 411.0 (M + H). Etc. 1; 82.5 (2)

- 54 035363

Etc. 53 [(1E, 55.6P) -3- {5-cyano-2 [(2S, 3R) -3-n / iflpoKcn-2methylazetide in-1 -yl] -6 (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid MS (EC +): 398.3 (M + H); Retention time: 2.1964. Method 3 *** Etc. 1 21.0 (2) Etc. 54 [(1R, 5S, 6R) -3- {5-unaHO-4 [(2S, 3R) -3-rnflpOKCn-2methylazetide in-1 -yl] -6 (trifluoromethyl) pyrimidin2-yl} -3- azabicyclo [3.1.0] hex-6yl] acetic acid MS (EC +): 398.2 (M + H); Retention time: 2.6397. Method 3 *** Etc. 1 19.0 (2) Etc. 55 [(1R, 5S, 6R) -3- {5-unaHO-4 (difluoromethyl) -6 - [(28, 3R) -3hydroxy-2,3- dimethylazetide in-1 yl] pyridin-2-yl} -3azabicyclo [3.1.0] hex-6yl] acetic acid ¹ H NMR (600 MHz, CD ₃ OD) b: 6.69 (t, 1H), 6.08 (s, 1H), 4.35 (q, 1H), 4.26 (d, 1H), 4 , 10-3.93 (br s, 1H), 3.87 (d, 1H), 3.74-3.43 (m, 3H), 2.32 (d, 2H), 1.69-1, 55 (m, 2H), 1.44-1.38 (m, 6 hrs), 0.87-0.81 (m, 1H). MS (EC +): 392.9 (M + H). Etc. 1 13.7 (2)

⁺ Ser. IC ₅₀ based on (#) number of runs per example.

* Examples 37 and 38 apply Method 1: Column: Xbridge C18 2.1x50 mm 5 μm. Temperature: 40 ° C. Mobile phase A: 0.0375% TPO in H ₂ O. Mobile phase B: 0.01875% TPO in acetonitrile. Initial conditions: B: 1%, A: 99%. Gradient: B: 1%, A: 99% to B: 5%, A: 95% from t = 0.00 to 0.60 min, then to B: 100% from t = 0.60 to 4.00 min , then to B: 1%, A: 99% of t = 4.00 to 4.30 min, hold to t = 4.70 min. Flow rate = 0.8 ml / min, injected sample volume -2 ml.

* * Examples 39 and 51 apply Method 2: Column: Xbridge C18 2.1x50 mm 5 μm. Temperature: 40 ° C. Mobile phase A: 0.0375% TPO in H ₂ O. Mobile phase B: 0.01875% TPO in acetonitrile. Initial conditions: B: 10%, A: 90%. Hold from t = 0.00 to θ, 5θ min. Gradient: B: 10%, A: 90% to B: 100%, A: 0% from t = 0.50 to 4.00 min, then to B: 10%, A: 90% of t = 4, 00 to 4.30 min, hold up to t = 4.70 min. Flow rate = 0.8 ml / min, injected sample volume -2 ml.

* ** Examples 53 and 54 apply method 3: column: OJ-H 4.6x100 mm, 5 μm; mobile phase A: methanol (v / v); mobile phase B: CO ₂ (v / v). Gradient: 80.0% CO2 / 20.0% methanol isocratic over 5 min. Flow: 1.5ml / min. Back pressure: 100 bar.

Claims (23)

CLAIM 1. Compound of formula (I) R ¹ (I) or a pharmaceutically acceptable salt thereof, in which Y is N or C-CN; Z is N or CH; X is N or CR ³ ; with the proviso that at least one of Y, Z or X is N; R ¹ is C ₃ . _{7 is a} cycloalkyl or 4-7 membered heterocyclic moiety, where the heterocyclic moiety contains from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents independently selected from -C ^ alkyl and -OH, provided that no more than one -OH substituent exists; or Ν (Ο _{1 3} 3λκκλ.) 2 OR ^^ adail) or NH ^ -dikloalkil), each C ₁ - ₃ alkul substituted with from 0 to 1 OH; R ² is - (L) m-CON (R ^N ) 2, - (L) _m -SO ₂ RS, -L- (CH ₂ ) _n SO ₂ R ^S , -L- (CH2) nCO2H, -L (CH2) nC (O) R ^C , -L- (CH2) _n CONHSO ₂ R ^S , -L- (CH2) nSO2NHCOR ^S , -L- (CH2) _n SO ₂ NHCONH ₂ or -L- (CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; R ⁿ represents H or -S1- ₃ alkyl; R ^S is H or -S1- ₃ alkyl; L is CH2, CHF or CF2; R ^C is ^^ alkyloxy, -C ^ alkyloxycarbonyloxy-C ^ alkyloxy or ^^ alkylcarbonyloxy-Ci- ₄ alkyloxy; R ³ is H, halogen, —CN, —C ^ alkyl, —OC1— ^ KM, ^^ alkyl substituted with 1 to 3 halogen atoms, or - ^ - dcycloalkyl; and R ⁴ is cyclopropyl, cyclobutyl or ^^ alkyl substituted with 0 to 5 halogen atoms, as valency allows. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N or C-CN; Z is N or CH; X is CR ³ ; with the proviso that at least one of Y or Z is N; R ¹ is a N-hoycloalkyl or a 4-7 membered heterocyclic moiety, the heterocyclic moiety having 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains 0 to 3 substituents independently selected from -C ^ alkyl and -OH, provided that no more than one -OH substituent exists; or N (C1- ^ KM) _2, NH (C ₁ - ₃ alkyl) or NH (C ₃ - ₄ cycloalkyl), wherein each C'l-gi.mKu.m substituted with from 0 to 1 OH; R ² represents - (L) m-CON (R ^N ) 2, - (L) _m -SO ₂ R ^S , -L- (CH ₂ ) _n SO ₂ R ^S , -L- (CH2) nCO2H, - L (CH2) nC (O) R ^C , -L- (CH2) _n CONHSO ₂ R ^S , -L- (CH2) nSO2NHCOR ^S , -L- (CH2) _n SO ₂ NHCONH ₂ or -L- (CH ₂ ) _n tetrazol-5-yl; m is 0 or 1; n is 0 or 1; RN is H or ^^ alkyl; R ^S is H or ^^ alkyl; L is CH2, CHF or CF2; R ^C represents ^^ alkyloxy, -C ₁ - ₄ alkuloksikarboniloksi-C ₁ - ₄ alkuloksi or alkylcarbonyloxy-C ^^ - ₄ alkyloxy; R ³ is H, halogen, —CN, —C ^ alkyl, —OC1— ^ KM, ^^ alkyl substituted with 1 to 3 halogen atoms, or - ^^ cycloalkyl; and R ⁴ is —C ^ alkyl substituted with 0 to 5 halogen atoms as valency allows. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is C-CN; Z is N; X is CR ³ ; R ¹ is a ^^ cycloalkyl or 4-7 membered heterocyclic moiety, the heterocyclic moiety having from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents independently selected from ^^ alkyl and —OH, with the proviso that not more than one —OH substituent exists; R ² represents - (L) m-CON (R ^N ) 2, - (L) _m -SO ₂ R ^S , -L- (CH ₂ ) _n SO ₂ R ^S , -L- (CH2) nCO2H, - L (CH2) nC (O) R ^C , -L- (CH2) _n CONHSO ₂ R ^S , -L- (CH ₂ ) _n SO ₂ NHCOR ^S or -L- (CH ₂ ) _n -tetrazol-5-yl ; m is 0 or 1; n is 0 or 1; RN is H or ^^ alkyl; R ^S is H or ^^ alkyl; L is CH2, CHF or CF2; R ^C represents ^^ alkyloxy, -C ₁ - ₄ alkuloksikarboniloksi-C ₁ - ₄ alkuloksi or -C1 ^ alkylcarbonyloxy-C - ₄ alkyloxy; R ³ is H, halogen, —CN, —C ^ alkyl, —OC1— ^ KM, ^^ alkyl substituted with 1 to 3 halogen atoms, or - ^^ cycloalkyl; and R ⁴ is —C ^ alkyl substituted with 0 to 5 halogen atoms as valent allows - 56 035363 ness. 4. A compound according to any one of claims 1, 2, or a pharmaceutically acceptable salt thereof, in which Y is N; Z is N; X is CR ³ ; R ¹ is a ^^ cycloalkyl or 4-7 membered heterocyclic moiety, the heterocyclic moiety having from 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and where the cycloalkyl or heterocyclic moiety contains from 0 to 3 substituents independently selected from ^^ alkyl and —OH, with the proviso that not more than one —OH substituent exists; R ² is - (L) _m -CON (RN) ₂ , - (L) _m -SO2RS, -L ^ CH ^ SO ^ ⁸ , -L-CCHjnCOzH, -L (CH2) nC (O) R ^C , -L- (CH2) nCONHSO2R ^S , -L- (CH2) nSO2NHCOR ^S or -b- (CH2) p-tetrazol-5-yl; m is 0 or 1; n is 0 or 1; RN is H or —C _1-3 alkyl; RS is H or —C _1-3 alkyl; L is CH ₂ , CHF or CF2; R ^C is ^^ alkyloxy, -C-dalkyloxycarbonyloxy-C-dalkyloxy, or ^^ alkylcarbonyloxy-C'i _-d alkyloxy; R ³ is H, halogen, —CN, —C ^ alkyl, —OC _1-3 alkyl, ^^ alkyl substituted with 1 to 3 halogen atoms, or - ^^ cycloal ^; and R ⁴ is —C ^ alkyl substituted with 0 to 5 halogen atoms as valency allows. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein RS is H or —CH ₃ . 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ² is —CH ₂ CO ₂ H, —CH ₂ CO ₂ CH ₃ or —CH ₂ CO ₂ CH ₂ CH ₃ ... 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ³ is H, —Cl, —CH ₃ , —CH ₂ CH ₃ , —O — CH3, cyclopropyl or CN. 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is —CF ₃ , —CHF2 or —CF2CH3. 9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in which R ¹ is a 4-7 membered heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl and piperidine- 1-yl having from 0 to 3 substituents independently selected from —CH ₃ and —OH, with the proviso that no more than one —OH substituent exists. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in which R ¹ is azetidin-1-yl having 1 to 2 -CH3 substituents and having 0 to 1 -OH substituents, and in which Y is C-CN and Z is N or Y and Z are each N. 11. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in which R ¹ is cyclobutyl having from 0 to 3 substituents independently selected from —CH ₃ and —OH, provided that there is no more than one -OH substituent. 12. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: [(1R, 5S, 6R) -3- {5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -D- (trifluoromethyl) pyridin-2yl} -3- azabicyclo [3.1.0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {3-chloro-5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -D (trifluoromethyl) pyridin-2- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid; methyl [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-D-yl} -3azabicyclo [3.1.0] hex-6 -yl] acetate; [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-D-yl} -3azabicyclo [3.1.0] hex-6- sludge] acetic acid; [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-D-yl} -3azabicyclo [3.1. 0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {5-cyclopropyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6 (trifluoromethyl) pyrimidin-4-yl} -3 -azabicyclo [3.1.0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {5-ethyl-2 - [(2S, 3R) -3-hydroxy-2-methylazetzdin-1-yl] -6- (trifluoromethyl) pyrimidine-Dyl} -3- azabicyclo [3.1.0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {3-chloro-2- (1,1-difluoroethyl) -6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] pyridine-Dyl } -3-azabicyclo [3.1.0] hex-6-yl] acetic acid and [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidine-1- yl] -5-methoxy-6- (trifluoromethyl) pyrimidin-4-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid. - 57 035363 13. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 14. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (2S, 3R) -2,3-dimethyl-1- [4 - {(1R, 5S, 6S) -6 - [(methylsulfonyl) methyl] -3-azabicyclo [3.1.0] hex-3-yl} - 6 (trifluoromethyl) pyrimidin-2-yl] azetidin-3-ol; 2 - [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0] hex- 6-yl] -Hmethylsulfonyl) acetamide and (1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -6- (1H-tetrazole-5ylmethyl) -3-azabicyclo [3.1.0] hexane. 15. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: [(1R, 5S, 6R) -3- {5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -4- (trifluoromethyl) pyridin-2yl} -3- azabicyclo [3.1.0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {3-chloro-5-cyano-6 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -4 (trifluoromethyl) pyridin-2- yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6- sludge] acetic acid; [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1. 0] hex-6-yl] acetic acid; [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -5-methyl-6- (trifluoromethyl) pyrimidin4-yl} -3- azabicyclo [3.1.0] hex-6-yl] acetic acid and [(1R, 5S, 6R) -3- {5-cyano-4- (1,1-difluoroethyl) -3-fluoro-6 - [(2S , 3R) -3-hydroxy-2-methylazetidin-1yl] pyridin-2-yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid. 16. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is [(1R, 5S, 6R) -3- {2 - [(2S) -2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6-yl] acetic acid. 17. A compound according to claim 16, wherein the compound is in crystalline form [(1R, 5S, 6R) -3- {2 [^) - 2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidin-4-yl } -3-azabicyclo [3.1.0] hex-6-yl] acetic acid. 18. A compound according to claim 17, wherein the crystalline form is characterized by substantially the following main peaks in the X-ray powder diffractogram, expressed in terms of 2θ angles, as measured using copper radiation, selected from 9.0, 10.4, 15.0 and 21.4 ± 0.2 °. 19. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] -6- (trifluoromethyl) pyrimidine-4yl} -3-azabicyclo [3.1.0] hex-6-yl] acetic acid. 20. A compound according to claim 19, wherein the compound is a crystalline form of the sodium salt [(1R, 5S, 6R) -3- {2 - [(2S, 3R) -3-hydroxy-2-methylazetidin-1-yl] - 6- (trifluoromethyl) pyrimidin-4-yl} -3azabicyclo [3.1.0] hex-6-yl] acetic acid. - 58 035363 21. A compound according to claim 20, wherein the crystalline form is characterized by substantially the following main peaks of the powder X-ray diffractogram, expressed in terms of 2θ angles, as measured using copper radiation, selected from 5.9, 11.5, 11.8, 13.3 and 21.5 ± 0.2 °. 22. A pharmaceutical composition for the treatment of a disease for which a KHK inhibitor is indicated, comprising a compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 23. A method of treating a disease for which a KHK inhibitor is indicated, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.