EA040901B1 - Alkoxy-Substituted Pyridinyl Derivatives as LPA1 Receptor Antagonists and Their Use in the Treatment of Fibrosis - Google Patents

Description

The present invention relates to LPA1 receptor antagonists of formula (I) and their use as active ingredients for the preparation of pharmaceutical compositions. The invention also relates to related aspects, including methods for preparing compounds, pharmaceutical compositions containing a compound of formula (I), and their use as drugs that suppress fibrotic processes or other disorders in which LPA1 receptors play a role, either alone or in combination with other active compounds or therapies.

Lysophospholipids are membrane bioactive lipid mediators, among which one of the most medically important is lysophosphatidic acid (LPA). LPA is not a single chemical compound, but a set of endogenous structural variants with fatty acids of various lengths and degrees of saturation (Fujiwara et al., J. Biol. Chem. 2005, 280, 35038-35050). The structural skeleton of LPA is derived from glycerol-based phospholipids such as phosphatidylcholine (PC) or phosphatidic acid (PA). LPAs are biologically active lipids (signaling lipids) that regulate various cellular signaling pathways by binding to the same class of G protein 7-transmembrane domain-coupled receptors (GPCR) (Chun, J., Hla, T., Spiegel, S. , Moolenaar, W., Ed., Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4; Zhao, Y. et al., Biochim. Biophys. Acta (BBA)-Mol Cell Biol Of Lipids, 2013, 1831, 86-92). The currently known LPA receptors are referred to as LPA1, LPA ₂ , LPA ₃ , LPA4, LPA5 and LPA ₆ (Choi, JW, Annu. Rev. Pharmacol. Toxicol. 2010, 50, 157-186). The nucleotide sequence and amino acid sequence of the human LPA ₁ receptor are known in the art and published (Hecht et al. 1996 J. Cell. Biol. 135:1071-83, An et al. 1997 Biochem. Biophys. Res. Comm. 231:619- 622).

LPAs have long been known as precursors for phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but it has only recently been discovered that LPAs serve as signaling molecules that are rapidly produced and released by activated cells, in particular platelets, to act on cells- targets by acting on specific cell surface receptors (see, for example, Moolenaar et al., BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc. Trans., 2003, 31, 1209-1212 ). In addition to being synthesized and processed to more complex phospholipids in the endoplasmic reticulum, LPAs can be produced by hydrolysis of pre-existing phospholipids after cell activation; for example, the sn-2 position typically does not contain a fatty acid residue due to deacylation, which leaves only the sn-1 hydroxyl esterified with the fatty acid. Moreover, the key enzyme in LPA production, autotaxin (lysoPLD/NPP2), may be an oncogene product, as many tumor types upregulate autotaxin (Brindley, D., J. Cell Biochem. 2004, 92, 900- 12). Determination of human plasma & serum LPA concentrations as well as human bronchoalveolar lavage fluid (BALF) has been reported, including determinations performed using sensitive and specific LC/MS & LC/MS/MS techniques (Baker et al., Anal. Biochem. 2001, 292, 287-295; Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).

LPA influences a wide range of biological responses, ranging from the induction of cell proliferation, stimulation of cell migration and axonal retraction, closure of intercellular gap junctions, and even mucosal chemotaxis (Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla, T., Spiegel, S., Moolenaar, W., eds., Lysophospholipid Receptors: Signaling and Biochemistry, 2013, Wiley; ISBN; 978-0470-56905-4). The body of knowledge about the biology of LPA continues to grow as more and more cell systems are tested for responsiveness to LPA. For example, it is now known that, in addition to stimulating cell growth and proliferation, LPAs promote the processes of cell tension and cell surface fibronectin binding, which are important events in wound healing and regeneration (Moolenaar et al., BioEssays, 2004, 26, 870 -881). Recently, LPA has also been attributed anti-apoptotic activity, and PPARy has also recently been reported to be a receptor/target for LPA (Simon et al., J. Biol. Chem., 2005, 280, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leading to excessive accumulation and insufficient resorption of the extracellular matrix (ECM), which ultimately leads to damage to the target organ (Rockey et al., New Engl. J. Med., 2015, 372, 1138 -1149). Recently it was reported that LPA ₁ receptors were overexpressed in patients with idiopathic pulmonary fibrosis (IPF). LPA1 receptor knockout mice were also protected from bleomycin-induced pulmonary fibrosis (Tager et al., Nature Med., 2008, 14, 45-54). Thus, LPA1 receptor antagonism may be useful in the treatment of fibrosis (Stoddard et al., Biomol. Ther., 2015, 23(1), 1-11; Rancoule et al., Expert. Opin. Inv. Drug 2011 , 20 (85), 657-667; Yang et al., IOVS 2009, 50 (3) 1290-1298; Pradere et al., J. Am. Soc. Nephro. 2007, 18, 3110-3118; Abu El- Asrar et al., Acta Ophthalmol. 2012, 90, e84-e89), such as pulmonary fibrosis, liver fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis and thus diseases that result from fibrosis (pulmonary fibrosis - idiopathic pulmonary fibrosis [IPF], liver fibrosis - non-alcoholic steatohepatitis [NASH], kidney fibrosis - diabetic nephropathy, systemic sclerosis - scleroderma) (Castellino et al., Arthritis Rheum. 2011, 63 (5), 1405-1415).

- 1 040901

IPF is treated with corticosteroids in combination with immunosuppressants, cytostatics, and antioxidants. When used for long-term treatment, corticosteroids may cause side effects. Pirfenidone is approved for the treatment of IPF, but its therapeutic mechanism of action is not known and, in addition, side effects have been associated with the use of pirfenidone. Thus, oral active compounds that specifically target fibrotic processes and have reduced side effects could greatly improve current treatments for uncontrolled fibrosing diseases.

The use of LPA1 receptor antagonists is not limited to fibrosis, in particular, they can be used in other disorders in which the LPA/LPA1 receptor axis plays a role in the pathology, such as pain, including acute pain, chronic pain, and neuropathic pain (Inoue et al., Nat. Med. 2004, 10 (7) 712-718; Kuner, Nat. Med. 2010, 16 (11), 1258-1266), including fibromyalgia resulting from the formation of fibrous scar tissue in contractile (skeletal) muscles, where fibrosis binds tissues and interferes with blood flow, which leads to pain, and cancer pain; malignant and benign proliferative diseases, including malignancy (Stoddard et al., Biomol. Ther., 2015, 23 (1), 1-11; Komachi et al., Cancer Sci. 2012, 103 (6), 1099-1104; Zeng et al., The Prostate 2009, 69, 283-292), and control of tumor cell proliferation, invasion and metastasis of carcinomas, and pleural mesothelioma (Yamada, Cancer Sci., 2008, 99 (8), 1603-1610), mesothelioma peritoneum or bone metastases (Boucharaba et al., J. Clin. Invest., 2004, 1 14(12), 1714-1725; Boucharaba et al., Proc. Natl. acad. Sci., 2006, 103(25) 9643-9648); inflammation (Li et al., Kidney International 2017, 91(6), 1362-1373; Lin et al., Am. J. Pathol. 2018, 188(2), 353-366; Watanabe et al., J. Clin Gastroenterol 2007, 41(6), 616-623; Watanabe et al., Life Sciences 2007, 81, 1009-1015); nervous system disorders (Stoddard et al., Biomol. Ther., 2015, 23(1), 1-11; Choi et al., Biochim. Biophys. Acta 2013, 1831, 20-32; Nagai et al., Molecular Pain 2010, 6, 78); and respiratory diseases, including allergic respiratory diseases and hypoxia (Georas et al., Clin. Exp. Allergy 2007, 37 (3), 311-322). LPA has been shown to have a contracting effect on bladder smooth muscle cells isolated from it and to promote the growth of prostate-derived epithelial cells (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000, 163, 1027-1032). In addition, LPA has been shown to cause contraction of the urinary tract and prostate in vitro and increase intraurethral pressure in vivo (WO 02/062389). LPA has also been associated with obesity and insulin resistance (K. D'Souza et al., Nutrients 2018, 10, 399).

WO 2013/096771 discloses a broad generic spectrum of TGR5 agonists claimed as active agents for the treatment of diabetes. US 2007/0078120 (WO 2005/037269) discloses a broad generic spectrum of piperidine derivatives claimed to be useful in lowering LDL cholesterol levels in the blood. WO 2003/088908 discloses a broad generic spectrum of potassium channel inhibitors, exemplified by certain piperidine derivatives, which, however, differ from the compounds of the present invention at least in the absence of an obligatory R ⁴ substituent present. WO 2012/078805 and WO 2009/135590 disclose structurally distant compounds that act as LPA ₁ receptor antagonists and are claimed to exhibit a distinct anti-fibrotic effect.

The present invention provides novel compounds of formula (I) which are G protein-coupled LPA1 receptor antagonists and may have potent and long-lasting anti-fibrotic effects, which may be mediated by inhibition of fluid leakage through vessels, inhibition of fibroblast to myofibroblast conversion, and/or inhibition of subsequent release of profibrotic cytokines by myofibroblasts. Thus, the compounds of the present invention may be useful in the treatment of, for example, uncontrolled fibrosing diseases and other diseases and disorders associated with LPA ₁ signaling.

1) The first aspect of the invention relates to compounds of formula (I)

^R1

Formula (I), where

W is N and Z is CH; or Z is N and W is

- 2 040901 CH;

R ¹ means hydrogen or fluorine;

R ² means hydrogen, halogen (especially chlorine), methyl, ethyl, methoxy or ethoxy;

R ³ is C _1-3 alkoxy (especially methoxy, isopropoxy) or C _1-3 fluoroalkoxy (especially difluoromethoxy);

Ar ¹ is phenyl, or a 6-membered heteroaryl containing one or two nitrogen atoms (especially pyridinyl); (namely, Ar ¹ is phenyl), where said Ar ¹ group is substituted by R ⁴ and R ⁵ , where

R ⁴ is n-propyl, isopropyl, C _3-6 cycloalkyl, optionally containing a ring oxygen atom (especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4yl) or cyclopent-1-en-1-yl; (where it is to be understood that said R ⁴ substituent is attached ortho to the attachment point of the rest of the molecule) and

R ⁵ is one substituent independently selected from hydrogen, fluorine, methyl, or methoxy (in a sub-embodiment, if Ar ¹ is phenyl, R ⁵ is especially hydrogen; fluorine at the 5 or 6 position; methyl at position 4, 5 or 6; or methoxy, at position 5 of said phenyl group; in particular, in such a case, R ⁵ represents one substituent independently selected from hydrogen, fluorine, methyl and methoxy, at position 5 of said phenyl group);

m and n are independently an integer 1 or 2; and the -LR ⁶ group is hydrogen;

- C ₁ . ₄ alkyl;

- Co- ₆ alkylene-C ₃ . ₆ cycloalkyl; where C ₃ . ₆ cycloalkyl is independently unsubstituted or monosubstituted with halogen (especially fluorine);

- DREAM;

- L'-CO-RC ¹¹ where R ^C11 independently represents hydroxy; -O-benzyl; -O-C1-6alkyl; C1fluoroalkyl; or -NR ⁿ¹¹ R ⁿ¹² ; where independently R ^N11 is hydrogen or C1-4 alkyl and R ^N12 is hydrogen, C1-4 alkyl, -SO2-C1.6 alkyl or -OR ⁰¹¹ , where R ⁰¹¹ is independently hydrogen, _C1-6 alkyl, or benzyl; And

- L ¹ - independently represents

- C ₁ - ₆ alkylene-, -C0-C ₁ -6 alkylene-, -SO ₂ -C ₁ _ ₆ alkylene-, -CO-O-C ₁ - ₆ alkylene-, -CO-NH-C ₁ _ ₆ alkylene - or -SO ₂ -NH-C ₁ _ ₆ alkylene-;

- C ₁ - ₆ alkylene-, -C0-C ₁ -6 alkylene- or -SO ₂ -C ₁ . ₆ alkylene-; where in the above groups, the specified C ₁ - ₆ alkylene is independently monosubstituted with hydroxy, C _1-3 alkoxy, -0-C0-C ₁ - ₄ alkyl or -NR ^N13 R ^N14 ; where independently RN ¹³ means hydrogen or C1-4alkyl, and RN ¹⁴ means hydrogen, C1-4alkyl or -C0-0-C ₁ - ₄ alkyl;

- C ₂ - ₆ alkylene-, -CO-C ₂ - ₆ alkylene - or -SO ₂ -C ₂ . ₆ alkylene-; where in the above groups, the specified C ₂ - ₆ alkylene is independently disubstituted, where the substituents are independently selected from hydroxy and -NR ^N15 R ^N16 ; where independently RN ¹⁵ means hydrogen or C1-4alkyl, and RN ¹⁶ means hydrogen, C1-4alkyl or -C0-0-C ₁ - ₄ alkyl;

- C _o . ₄ alkylene-C ₃ . ₈ cycloalkylene-C _o . ₄ alkylene-, -CO-Co. ₄ alkylene-C ₃ . ₈ cycloalkylene-Co. ₄ alkylene-, -S0 ₂ Co- ₄ alkylene-C ₃ . ₈ cycloalkylene-Co. ₄ alkylene-, -CO-NH-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene- or -CO-O-C _o-4 alkylene-C _3-8 cycloalkylene-C _o-4 alkylene-;

- C _o _ ₄ alkylene-Su ¹ -Co_4 alkylene-, -CO-Co_4 alkylene-Su ¹ -Co_ ₄ alkylene-, -CO-O-C _o _ ₄ alkylene-Su ¹ -Co_4 alkylene-, -CO-NH-C0. 4alkylene-Su ¹ -C0. ₄ alkylene-, -SO ₂ -C ₀ . ₄ alkylene-Cu ¹ -C0.4 alkylene- or -SO2-NH-C0.4 alkylene-Cu ¹ Co-4 alkylene-; where Cy ¹ independently represents C ₃ - ₆ heterocycloalkyl containing one ring oxygen atom or one ring nitrogen atom, where the specified ring nitrogen, if it has a free valence, is independently unsubstituted or monosubstituted with C _1-4 alkyl or -C0-0 -C ₁ - ₄ alkyl;

- From ₂ . ₄ alkylene-O-C ₂ . ₄ alkylene-O-C ₁ . ₄ alkylene- or -C0-C ₁ . ₄ alkylene-O-C ₂ . ₄ alkylene-O-C ₁ . ₄ alkylene-;

- C ₂ _ ₄ alkylene-X ¹¹ -C1_4 alkylene-, -CO-O-C2_4 alkylene-X ¹¹ -C1_ ₄ alkylene-, -CO-NH-C ₂ . ₄ alkylene-X ¹¹ C1-4 alkylene- or -SO2-NH-C2.4 alkylene-X ¹¹ -C1. ₄ alkylene-; where X ¹¹ independently represents an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C _1-4 alkyl, C ₃ - ₆ cycloalkyl or -C0-0-C ₁ - ₄ alkyl;

- CO-C ₁ _ ₄ alkylene-X ¹² -C1_4 alkylene-, -SO2-C1.4 alkylene-X ¹² -C1_ ₄ alkylene- or -CO-C ₁ - ₄ alkylene-X ¹² C _o . ₄ alkylene-C ₃ . ₆ cycloalkylene-C _o . ₄ alkylene-; where X ¹² is independently an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C _1-4 alkyl, C ₃ . ₆ cycloalkyl, -C0-0-C ₁ - ₄ alkyl or C ₁ _ ₃ alkoxy-C ₂ _ ₄ alkyl;

- C ₂ _ ₄ alkylene-X ¹³ -C1_4 alkylene-; where X ¹³ represents -NH-CO-, and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy;

- C ₁ _ ₄ alkylene-X ¹⁴ -C ₁ _ ₄ alkylene-; where X ¹⁴ represents -CO-NH-;

- CO-C ₂ - ₆ alkenylene- or -SO ₂ -C ₂ . ₆ alkenylene-; or

- CO-C ₂ - ₆ fluoroalkylene-;

- L ² -hydroxy; where -L ² - represents

- 3 040901

-CO-C _1- balkylene- or -SO ₂ -C _1- 6 alkylene-; where in the above groups said _C1-6 alkylene is independently unsubstituted or monosubstituted with hydroxy, C ₁ -fluoroalkyl or -NR ⁿ²¹ R ⁿ²² , where independently R ^N21 is hydrogen or _{C1_4} alkyl and RN ²² is hydrogen, _{C1_4} alkyl or -CO- _OC1 . ₄ alkyl;

- C ₂ _ ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-, where in the above groups, the specified C ₂ _ ₆ alkylene is independently unsubstituted or monosubstituted by hydroxy, C ₁ -fluoroalkyl or -NR ^N23 R ^N24 , where independently RN ²³ means hydrogen or C1.4αkyl, and RN ²⁴ means hydrogen, C1. ₄ alkyl or -CO-OC ₁ . ₄ alkyl;

- Co- ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene-;

- C ₀ - ₄ alkylene-Cu ² -C0-4 alkylene-, -CO-C0-4 alkylene-Cu ² -C0- ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ² -C0.4alkylene-; where Su ² is independently a C3.6 heterocycloalkylene group containing one ring oxygen atom or one ring nitrogen atom; where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted with C _1-4 alkyl or -C 0-0-C ₁ - ₄ alkyl;

- From ₂ . ₄ alkylene-(O-C ₂ . ₄ alkylene) _p - or -CO-C1_ ₄ alkylene-(O-C ₂ _ ₄ alkylene) _p -; where p is independently the integer 1 or 2;

- From ₂ . ₄ alkylene-X ²¹ -C2.4 alkylene-; where X ²¹ represents a nitrogen atom which is unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC ₁ . ₄ αkyl;

- CO-C ₁ . ₄ alkylene-X ²² -C2.4 alkylene-, -CO-C1.4 alkylene-X ²² -C1. ₄ alkylene-C ₃ . ₆ cycloalkylene- or -SO2C ₁ . ₄ αkylene-X ²² -C2.4alkylene-; where X ²² is a nitrogen atom that is independently unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC ₁ . ₄ αkyl;

- C ₂ . ₄ alkylene-X ²³ -C1.4alkylene-; where X ²³ represents -NH-CO-, and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy;

- C ₁ . ₄ alkylene-X ²⁴ -C2.4 alkylene-; where X ²⁴ represents -CO-NH-, and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy; or ,4-dioxocyclobut-1-en-1,2-diyl;

- L ³ -O-RO ³¹ where RO ³¹ means -C1_ ₄ alkyl, -C0-C1_ ₄ alkyl or -CO-C ₂ . ₄ alkenyl; And

- L ³ - independently represents

- C ₂ _ ₆ alkylene-, -C0-C1_ ₆ alkylene- or -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₂ . ₆ alkylenyl -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁴ -NR ^N1 R ^N2 , where independently R ^N1 means hydrogen or C1_4alkyl; and RN ² means hydrogen; C1. ₄ alkyl; _C1 . ₃ fluoroalkyl; C _3-6 cycloalkyl; _C1 . ₃ alkoxy-C ₂ . ₄ alkylene; -CO-Cl. ₄ alkyl; -SO ₂ -C ₁ . ₄ alkyl; or -SO2-C1fluoroalkyl; And

- L ⁴ - independently represents

- C ₂ .6alkylene-, -CO-C1- ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ - ₆ alkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-; or

- Cmalkylene-Su ⁴ -C0_4 alkylene-, -CO-C0_4 alkylene-Su ⁴ -C0_ ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ⁴ -C0-4 alkylene-; where Su ⁴ is independently a C3-6 heterocycloalkylene group containing one ring oxygen atom;

- L ⁵ -NR ^N3 R ^N4 , where RN ³ means hydrogen, C1_4alkyl or C1_3alkoxy-C2_4alkylene; and RN ⁴ means -C00-C1_4 alkyl; -CO-NR ^N51 R ^N52 where RN ⁵¹ and RN ⁵² are independently selected from hydrogen and C1_4 alkyl; or -SO2nr ^N53 r ^N54 where independently RN ⁵³ is hydrogen or C1_4 alkyl and RN ⁵⁴ is hydrogen, C1_ ₄ alkyl or -C0-C1_ ₄ alkyl;

and -L ⁵ - independently represents

- C ₂ balkylene-, -C0- _C1-6 alkylene- or -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ .balkylene-, -CO-NH-C ₂ . ₆ alkylenyl -SO ₂ -NH-C ₂ .6 alkylene-;

- L ⁶ -N(R ^N61 )-OR ^O61 where R ^N61 is hydrogen, -C0- _C1-4 alkyl or

- C0-0- _C1-4 alkyl; and R ⁰⁶¹ is independently hydrogen, _C1-6 alkyl, or benzyl;

and -L ⁶ - independently represents

- C ₂ _ ₆ alkylene-, -CO-C1_ ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ _ ₆ alkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁷ -NR ^N5 R ^N6 where RN ⁵ means hydrogen or C1_4alkyl (in particular hydrogen); R ^N6 is hydrogen, C1_4alkyl, _-C0 - _{C1_4} alkyl, _{C1_3} fluoroalkyl or _{C3_6} cycloalkyl (especially hydrogen); And

- L ⁷ - independently represents

- CO- or -SO ₂ -;

- L ⁸ -SO2-R ^S81 where RS ⁸¹ is independently -C1-6 alkyl; C1-fluoroalkyl; hydroxy; -nr ^N81 r ^N82 where independently RN ⁸¹ is hydrogen or C1-4 alkyl and RN ⁸² is hydrogen, C1-4 alkyl, _-C0C1-6 alkyl; And

- L ⁸ - independently represents

- _C1-6 alkylene-, -CO- _C1-6 alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ - ₆ alkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,

- 4 040901 oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl), wherein said NO is independently unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from C ₁ . ₄ alkyl (especially methyl); halogen; cyano; hydroxy; hydroxymethyl; _-C0 . ₂ alkylene-Cu ⁹¹ -COOR ^O91 where R ⁰⁹¹ is hydrogen or C1.4 alkyl and where Cy ⁹¹ is C3. ₆ cycloalkylene group; or _-C0 . ₂ αkylene-COOR ^O92 where RO ⁹² is hydrogen or C ₁ . ₄ alkyl; And

- L ⁹ - independently represents

_-C0 . ₆ alkylene-, -CO-C ₀ . ₆ alkylene-, -SO ₂ -C ₀ . ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- L ¹⁰ -C ₄ .6heterocyclyl, where C ₄ -heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, the specified C ₄ _ ₆ heterocyclyl is independently unsubstituted or mono-, di- or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom ( thus forming together with nitrogen an amide group, or in case an additional ring oxygen is adjacent, a carbamate group, or in case an additional second ring nitrogen is adjacent, a urea group); and/or two methyl substituents attached to the ring carbon atom in the alpha position to the ring nitrogen atom or the ring oxygen atom (thus forming together with nitrogen -C(CH ₃ ) ₂ -N- group, or with oxygen -C(CH ₃ ) ₂ -O- group); and/or two oxo substituents on the ring sulfur atom (thus forming a -SO2- group); and/or

C _1-4 alkyl, C ₁ . ₃ alkoxy-C ₂ . ₄ alkyl, C ₂ . ₃ fluoroalkyl or -CO-C ₁ . ₄ alkyl attached to a ring nitrogen atom having a free valence; And

- L ¹⁰ - independently represents

_-C0 . ₆ alkylene-, -CO-C ₀ . ₆ alkylene-, -SO ₂ -C ₀ . ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- L ¹¹ -cyano; where -L ¹¹ - represents -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene or -C ₀ . ₆ αkylene-;

- L12-NO2; where -L ¹² - represents -C ₂ . ₆ alkylene-; or

- L ¹³ -C ₁ . ₄ alkyl; where -L ¹³ - represents -CO-, -CO-O- or -SO2-.

In a sub-embodiment, the present invention particularly relates to compounds of formula (I) as defined in embodiment 1), wherein the linker L in the -LR ⁶ group is as defined above (or, mutatis mutandis, in any of the embodiments implementation below), where the length of such a linker is L (i.e. each of the individual linker groups -L ¹ -, -L ² -, -L ³ -, -L ⁴ -, -L ⁵ -, -L ⁶ -, - L ⁷ -, -L ⁸ -, -L ⁹ -, -L ¹⁰ -, -L ¹¹ -, -L ¹² -u -L ¹³ -) is such that the R ⁶ group is removed from the nitrogen atom to which L is attached , a maximum of 9 atoms (preferably it is removed by a maximum of 5 atoms).

It should be understood that the linker groups in the -LR ⁶ group (such as -L ¹ -, -L ² -, -L ³ -, -L ⁴ -, -L ⁵ -, -L ⁶ -, -L ⁷ -, - L ⁸ -, -L ⁹ -, -L ¹⁰ -, -L ¹¹ -, -L ¹² - and -L ¹³ -) must be read from left to right: for example, the linker group -CO-C ₀ . ₆ is alkylene-attached to the rest of the molecule via a -CO- group which is part of said linker.

The compounds of formulas (I), (II) and (III) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in the (R)-as well as ^-configuration. Compounds of formulas (I), (II) and (III) may further encompass compounds with one or more double bonds, which may be present in the Z-as well as E-configuration, and/or compounds with substituents in the ring system, which may be present. , relative to each other, in the cis-as well as the trans-configuration. Thus, the compounds of formulas (I), (II) and (III) may be present as mixtures of stereoisomers, or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated using a method known to the person skilled in the art.

Where a single compound (or generic structure) is designated as the (R)- or (S) enantiomer, such designation should be understood to refer to the corresponding compound (or generic structure) in enriched, especially substantially pure, enantiomeric form. Similarly, where a particular asymmetric center in a compound is designated as being in the (R)- or R-configuration, or as being in a certain relative configuration, such designation should be understood to refer to a compound that is in an enriched, especially substantially pure form, with regard to the appropriate configuration of said asymmetric center. By analogy, cis or trans designations are to be understood as referring to the corresponding stereoisomer of the corresponding relative configuration in an enriched, in particular substantially pure, form. Similarly, in the case where a single compound (or generic structure) is designated as the Z- or E-stereoisomer (or in the case where a particular double bond in a compound is designated as being in the Z- or E-configuration), such designation should be understood as referring to the corresponding compound (or generic structure) in an enriched, especially substantially pure stereoisomeric form (or to a compound that is in an enriched, in particular essentially pure form, as far as the corresponding double bond configuration is concerned).

The term enriched, when used in the context of stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a ratio of at least 70:30, in particular at least 90:10 (i.e. at least 70 pure). wt.%, in particular at least 90 wt.%), in relation to the corresponding other stereoisomer/set of the corresponding other stereoisomers.

The term substantially pure, when used in the context of stereoisomers, is to be understood within the scope of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, in particular at least 99% by weight, relative to the corresponding other stereoisomer /set of the corresponding other stereoisomers.

The present invention also includes isotopically labeled, especially ² H (deuterium) labeled compounds of formula (I) according to embodiments 1)-36), such compounds being identical to compounds of formula (I) except that one or each of a larger number of atoms has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Isotopically labeled, in particular ² H (deuterium) labeled compounds of formulas (I), (II) and (III) and their salts are included within the scope of the present invention. Replacement of hydrogen with the heavier isotope ² H (deuterium) may result in greater metabolic stability resulting, for example, in increased in-vivo half-life or reduced required dosage, or may result in reduced inhibition of cytochrome P450 enzymes, resulting in, for example, an improved profile security. In one embodiment of the invention, the compounds of formulas (I), (II) and (III) are not isotopically labeled, or they are labeled with only one or more deuterium atoms. In a sub-embodiment, the compounds of formulas (I), (II) and (III) are not isotopically labeled at all. Isotopically labeled compounds of formulas (I), (II) and (III) can be obtained by analogy with the methods described in this application below, but using a suitable isotopic variant of suitable reagents or starting materials.

In the present patent application, a bond drawn with a wavy line or a dotted line indicates the point of attachment of the drawn radical. For example, the radical is a 1 H-pyrrol-1 -yl group.

representing Whenever an R ⁵ substituent is provided at a particular position of the phenyl moiety to which it is attached, it should be understood that the point of attachment of the R ⁴ substituent is considered to be position 2 of said phenyl moiety.

In some cases, the compounds of formulas (I), (II) and (III) may include tautomeric forms. Such tautomeric forms are included within the scope of the present invention. In the event that tautomeric forms of a particular residue exist and only one form of such residue is disclosed or defined, the other(s) tautomeric form(s) are also intended to be encompassed in such disclosed residue. For example, the 3-hydroxy-1H-pyrazol-4-yl group is to be understood as also encompassing its tautomeric form 3-oxo-2,3-dihydro-1H-pyrazol-4-yl. Similarly, the 3-hydroxy-1H-pyrazol5-yl group is to be understood as also encompassing its tautomeric form 3-oxo-2,3-dihydro-1H-pyrazol5-yl; the 3-hydroxy-1H-1,2,4-triazol-5-yl group is to be understood as also encompassing its tautomeric forms 3-hydroxy-4H-1,2,4-triazol-5-yl, 3-hydroxy-3H- 1,2,4-triazol-5-yl, as well as 3-oxo-2,5-dihydro-1H-1,2,4-triazol-5-yl and 3-oxo-4,5-dihydro-1H-1, 2,4-triazol-5-yl; the 3-hydroxyisoxazol5-yl group is to be understood as also encompassing its tautomeric form 3-oxo-2,3-dihydroisoxazol-5-yl; the 5-hydroxy-[1,2,4]oxadiazol-3-yl group is to be understood as also encompassing its tautomeric form 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl and group 5 -hydroxy-[1,3,4]oxadiazol-2-yl is to be understood as also encompassing its tautomeric form 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl; the 4-oxo-4,5-dihydrooxazol-2-yl group is to be understood as also encompassing its tautomeric form 4-hydroxyoxazol-2-yl; the 2,4-dioxoimidazolidin-1-yl group is to be understood as also encompassing its tautomeric form 2,4-dihydroxyimidazolidin-1-yl; and the 2,5-dioxoimidazolidin-1yl group is to be understood as also encompassing its 2,5-dihydroxyimidazolidin-1-yl tautomeric form.

If for compounds, salts, pharmaceutical compositions, diseases, etc. the plural form is used, it also implies one single compound, salt, or the like.

Any reference to compounds of formulas (I), (II) and (III) according to embodiments 1)36) should be understood to refer also to salts (and in particular pharmaceutically acceptable salts) of such compounds, as appropriate and appropriate. .

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compound of the invention and exhibit minimal undesirable toxic effects. Such salts include addition salts with inorganic or organic acids and/or bases, depending on the presence of basic and/or acidic groups in the compound of the invention. For reference, see, for example, Handbook of Phramaceutical Salts. Properties, Selection and Use., P. Heinrich Stahl, Camille G. Wermuth (ed.), Wiley-VCH, 2008; and Pharmaceutical

Salts and Co-crystals, Johan Wouters and Luc Quere (eds.), RSC Publishing, 2012.

The definitions provided in this application are intended to apply equally to the compounds of formulas (I), (II) and (III) as defined in any of embodiments 1)-33) and, mutatis mutandis, to throughout the description and claims, unless otherwise expressly stated definition provides a broader or narrower definition. It is clear that the definition or preferred definition(s) of a term defines and may replace the corresponding term independently of (and in combination with) any definition(s) or preferred definition(s) of any or all other terms as defined in this application.

Whenever a substituent is indicated as optional, it should be understood that such a substituent may be absent (i.e., the corresponding residue is unsubstituted, if we talk about such an optional substituent), in which case all positions having a free valency (to which such an optional substituent could be attached, such as, for example, ring carbon atoms and/or ring nitrogen atoms in an aromatic ring which are of free valency) substituted with hydrogen if necessary. Similarly, when the term is optionally used in the context of (circular) heteroatom(s), the term means that either the corresponding optional heteroatom(s) or the like. absent(s) (i.e., the specific fragment does not contain heteroatom(s)/is a carbocycle/or the like), or the corresponding(e) optional(s) heteroatom(s), or the like, is present (yut) as clearly defined.

The term halogen means fluorine, chlorine or bromine, preferably fluorine or chlorine.

The term alkyl, alone or in combination, refers to a straight or branched chain saturated hydrocarbon group containing from one to six carbon atoms. The term C _x-y -alkyl (x and y are each an integer) refers to an alkyl group as defined above, containing from x to y carbon atoms. For example, C1. _{The 6} alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 3-methylbutyl, 2,2-dimethylpropyl and 3,3dimethylbutyl. To avoid misinterpretation, it should be noted that when a group is named, for example, propyl or butyl, it means n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl.

The term -C _x-y -alkylene-, used alone or in combination, refers to a divalently attached alkyl group as defined above, containing from x to y carbon atoms. The term -C0 _-y alkylene- refers to a direct bond, or to -( _{C1_y} )alkylene- as defined above. Preferably, the -C1_ attachment points _at the alkylene group correspond to the 1,1-diyl, 1,2-diyl or 1,3-diyl scheme. Preferably, the points of attachment of the -C _2-y -alkylene group correspond to the 1,2-diyl or 1,3-diyl scheme. When a C ₀ _ _y -alkylene group is used in combination with another substituent, the term means that either said substituent is attached via a C 1_ _y -alkylene group to the rest of the molecule, or it is attached directly to the rest of the molecule (i.e. The C ₀ -alkylene group is a direct bond that attaches the indicated substituent to the rest of the molecule). The alkylene group -C ₂ H ₄ - refers to -CH2-CH2- unless expressly stated otherwise. Examples of -C _0-4 alkylene groups are in particular methylene, ethylene and propane-1,3-diyl. Examples of _-C0-b alkylene groups are in particular methylene, ethylene, propane-1,3-diyl and 3-methylbutan-1,3-diyl (especially methylene, ethylene and propane-1,3-diyl). Examples of _-C1-6 alkylene groups are in particular methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, 2- methylpropan-1,2-diyl, 2methylpropan-1,1-diyl, 2,2-dimethylpropan-1,3-diyl, butane-1,4-diyl, 3-methylbutan-1,3-diyl and 4methylpentan-1, 4-dyl. Examples of _{-C1_4} alkylene groups are in particular methylene, ethylene, propane-2,2-diyl and 2-methylpropan-1,2-diyl (especially methylene). Examples of -C _2-6 alkylene groups are in particular ethylene, propane-1,3-diyl, propane-1,2-diyl, 2,2-dimethylpropan-1,3-diyl, 2-methylpropan-1,2-diyl , 3-methylbutan-1,3-diyl and 4-methylpentan-1,4-diyl (most preferably ethylene, propane-1,3-diyl, propane-1,2-diyl, 2-methylpropan-1,2-diyl , 3-methylbutan-1,3-diyl and 4methylpentan-1,4-diyl). Examples of -C _2-4 alkylene groups are in particular ethylene, propane 1,2-diyl and propane-1,3-diyl.

An example of a -L ² -hydroxy group, where -L ² - is a C _2-b alkylene which is monosubstituted with hydroxy, is 2,3-dihydroxypropyl.

The term alkenyl, used alone or in combination, refers to a straight or branched hydrocarbon chain containing two to five carbon atoms and one carbon-carbon double bond. The term C _x-y -alkenyl (x and y are each an integer) refers to an alkenyl group as defined above, containing x to y carbon atoms. For example, a C _2-5 alkenyl group contains two to five carbon atoms. An example of an alkenyl group is in particular prop-1-en-2-yl.

- 7 040901

The term C _x . _y -alkenylene-, alone or in combination, refers to a divalently attached alkenyl group as defined above, containing from x to y carbon atoms. Examples of -C _2-6 alkenylene groups are in particular ethene-1,2-diyl, prop-1ene-2,3-diyl and prop-1-en-1,3-diyl.

The term fluoroalkyl, used alone or in combination, refers to an alkyl group as defined above, containing from one to three carbon atoms, in which one or more (and possibly all) of the hydrogen atoms has been replaced by fluorine. The term C _x-y- fluoroalkyl (x and y are each an integer) refers to a fluoroalkyl group as defined above, containing x to y carbon atoms. For example, _C1 . _{The 3} fluoroalkyl group contains from one to three carbon atoms, and in it from one to seven hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. C ₁ -fluoroalkyl groups such as trifluoromethyl are preferred.

The term fluoroalkoxy, used alone or in combination, refers to an alkoxy group as defined above, containing from one to three carbon atoms, in which one or more (and possibly all) of the hydrogen atoms has been replaced by fluorine. The term C _x _ _y -fluoroalkoxy (x and y are each an integer) refers to a fluoroalkoxy group as defined above, containing x to y carbon atoms. For example, _C1 . _{The 3} fluoroalkoxy group contains one to three carbon atoms and has one to seven hydrogen atoms replaced by fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are C ₁ -fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy, as well as 2,2,2-trifluoroethoxy.

The term cycloalkyl, used alone or in combination, particularly refers to a saturated monocyclic, or fused, bridged or spiro-bicyclic hydrocarbon ring containing three to eight carbon atoms. The term C _x . _y -cycloalkyl (x and y are each an integer) refers to a cycloalkyl group as defined above, containing x to y carbon atoms. For example, C ₃ . _{The 6} cycloalkyl group contains three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as the bicyclic group bicyclo[1.1.1]pentane. Preferred are cyclopropyl, cyclobutyl and cyclopentyl; especially cyclopropyl.

The term Cx _-y- cycloalkyl optionally containing a ring oxygen atom refers to a cycloalkyl group as defined above, containing from x to y carbon atoms, where one ring carbon atom of said Cx-y-cycloalkyl may be replaced by an oxygen atom. Such groups are unsubstituted or substituted, as expressly defined. Examples are in particular C ₃ .6 cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; as well as oxetanyl, tetrahydrofuranyl and tetrahydropyranyl. Separately taken C ₃ . ₆ cycloalkyl, wherein said C ₃ .6 cycloalkyl contains one ring oxygen atom is tetrahydro-2H-pyran-4-yl.

The term -C _x - _y -cycloalkylene-, used alone or in combination, refers to a divalently attached cycloalkyl group as defined above, containing from x to y carbon atoms. Preferably, the points of attachment of any divalently attached cycloalkyl group correspond to the 1,1-diyl or 1,2-diyl pattern. An example of a -C ₃ .6cycloalkylene- group is in particular cyclopropan-1,1-diyl. Examples -C ₃ . _{The 8} cycloalkylene groups are in particular cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, cyclobutane-1,1-diyl, bicyclo[1.1.1]pentan-1,3-diyl, cyclohexane-1, 3-diyl and cyclohexane-1,4-diyl (especially cyclopropan-1,1-diyl, cyclopropan-1,2-diyl and cyclobutan-1,1-diyl).

The term alkoxy, alone or in combination, refers to an alkyl-O- group, where the alkyl group is as defined above. The term Cx-y-alkoxy (x and y is each an integer) refers to an alkoxy group, as defined above, containing x to y carbon atoms. For example, _C1 . ₄ αlkoxy group means a group of formula C ₁ . ₄ alkyl-O-, where the term C ₁ _ ₄ alkyl has the meaning given earlier. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Ethoxy and especially methoxy are preferred.

The term heterocyclyl, used alone or in combination, and unless explicitly defined more broadly or narrower, refers to a saturated or unsaturated non-aromatic monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen (especially one oxygen atom, one sulfur atom, one nitrogen atom, two nitrogen atoms, two oxygen atoms, one nitrogen atom and one oxygen atom). The term Cx-y-heterocyclyl refers to such a heterocycle containing from x to y ring atoms. Examples of heterocyclyl groups used in the -L ¹⁰ -C ₄ group. ₆ heterocyclyl, are in particular oxetan-3-yl, thietan-3-yl, imidazolidin-1-yl, 4,5-dihydrooxazol-2-yl, 1,3-dioxolan-4-yl, piperidin4-yl, piperazine -1-yl, piperazin-2-yl, morpholin-3-yl, morpholin-4-yl and morpholin-2-yl. Heterocyclyl groups are unsubstituted or substituted, as expressly defined.

- 8 040901

The term is C _x . _y -heterocycloalkylene-, used alone or in combination, refers to a divalently attached heterocyclyl group as defined above, containing from x to y ring atoms. Examples C ₃ . ₆ heterocycloalkylene containing one ring oxygen atom, or containing one ring nitrogen atom, used in the groups Cy ¹ , Cy ² , and, subject to appropriate modifications, Cy ⁴ , are, in particular, nitrogen-containing groups azetidine 1,3-diyl, azetidine-3 ,3-diyl, pyrrolidine-2,4-diyl, piperidine-1,4-diyl and piperidine-4,4-diyl; and oxygen-containing groups oxetane-3,3-diyl, tetrahydrofuran-3,3-diyl and tetrahydro-2H-pyran-4,4-diyl.

The term heteroaryl, used alone or in combination, means a 5-10 membered monocyclic or bicyclic aromatic ring containing from one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl , бензимидазолил, бензоксазолил, бензизоксазолил, бензотиазолил, бензоизотиазолил, бензотриазолил, бензоксадиазолил, бензотиадиазолил, хинолинил, изохинолинил, нафтиридинил, циннолинил, хиназолинил, хиноксалинил, фталазинил, пирролопиридинил, пиразолопиридинил, пиразолопиримидинил, пирролопиразинил, имидазопиридинил, имидазопиридазинил и имидазотиазолил. The above heteroaryl groups are unsubstituted or substituted as expressly defined. In the case of the Ar ¹ substituent, which is a 6-membered heteroaryl containing one or two nitrogen atoms, the term means the corresponding 6-membered groups mentioned above; especially pyridinyl or pyrazinyl; in particular pyridin-2-yl, pyridin-4-yl, or pyrazin-2-yl. In the case of the HET ¹ substituent, which is a 5- or 6-membered heteroaryl, the term means the aforementioned 5- or 6-membered groups. In particular, the term refers to a 5-membered heteroaryl containing from one to four heteroatoms, such as, in particular, furanyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl or tetrazolyl; or to a 6-membered heteroaryl containing one or two nitrogen atoms; such as, in particular, pyrimidinyl, pyrazinyl, pyridazinyl or pyridinyl. Some examples of 5-membered heteroaryl used for HET ¹ are furan-2-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-pyrrol-2-yl, 1H-pyrazol-3-yl , 1H-pyrazol-4-yl, 1H-pyrazol5-yl, oxazol-2-yl, oxazol-4-yl, isoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 2H-1,2 ,3-triazol-2-yl, 1H-1,2,3triazol-4-yl, 4H-1,2,4-triazol-4-yl, 1H-1,2,4-triazol-5-yl, 1H -tetrazol-1-yl and 1H-tetrazol-5-yl; and, in addition to those listed above, 1H-1,2,3-triazol-1-yl and 2H-tetrazol-2-yl. Some examples of 6-membered heteroaryl used for HET ¹ are pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyridazin -3-yl and pyrazin-2-yl.

For the avoidance of ambiguity, certain groups having tautomeric forms which may advantageously be considered aromatic (such as, for example, 3hydroxyisoxazolyl, 5-hydroxy-[1,2,4]oxadiazol-3-yl, 3-hydroxy-[1,2 ,4]oxadiazol-5yl, 3-hydroxy-1H-pyrazol-4-yl or 2-hydroxy-[1,3,4]oxadiazolyl group) are defined in this invention as heteroaryl groups NO ¹ even though their the corresponding tautomeric forms (3-oxo-2,3-dihydro-2H-isoxazolyl, respectively, 5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl, 3-oxo-4,5- dihydro-[1,2,4]oxadiazol-5-yl, 3-oxo-2,3-dihydro-1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-3H-[1,3, 4]oxadiazolyl) can also be considered as a non-aromatic heterocyclyl group. Likewise, certain groups having tautomeric forms that can advantageously be considered non-aromatic (such as 2,4-dioxoimidazolidin-1-yl, 4-oxo-4,5-dihydrooxazol-2-yl) as defined for the -L substituent ¹⁰ -C4.6heterocyclyl are defined herein as not being part of the substituted heteroaryl groups as defined for HET ¹ , even though their corresponding tautomeric form (4hydroxyoxazol-2-yl, respectively 2,4-dihydroxyimidazol-1- silt), can also be considered as a heteroaryl group NO ¹ . It should be understood that the respective tautomers are included within the respective scope of -L9-HET ¹ respectively -L ¹⁰ -C4. ₆ heterocyclyl as defined.

The term cyano refers to the -CN group.

The term oxo refers to a =O group which is preferably attached to a carbon or sulfur atom in the chain or ring, such as in the case of a carbonyl group -(CO)-, or a sulfonyl group -(SO ₂ )-.

In cases where the word between is used to describe a range of numerical values, it should be understood to mean that the endpoints of the specified range are explicitly included in such a range. For example, if a temperature range is described between 40 and 80°C, then this means that the endpoints of 40 and 80°C are included in the range; or if the variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

When not used in relation to temperatures, the term approximately before the numerical value of X in this invention refers to the range that extends from X minus 10% X to X plus 10% X, and preferably to the range that extends from X minus 5% X to X plus 5% X. In the particular case of temperatures, the term approximately before temperature Y in this invention refers to the range that extends from temperature Y minus 10°C to Y plus 10°C, and preferably to an interval that extends from Y minus 5°C to Y plus 5°C. In addition, the term room temperature, as used in this application, refers to a temperature of approximately 25°C.

Additional embodiments of the invention are presented below.

2) The second embodiment relates to compounds according to embodiment 1), where R ¹ is hydrogen.

3) Another embodiment relates to compounds according to embodiment 1) where R ¹ is fluoro.

4) Another embodiment relates to compounds according to any of embodiments 1)-3), where R ² is hydrogen, chlorine, methyl, ethyl, methoxy or ethoxy.

5) Another embodiment relates to compounds according to any of embodiments 1)-3), where

W is N, Z is CH; and R ² is hydrogen, methyl, methoxy or ethoxy (especially methyl); or

Z is N, W is CH; and R ² means chlorine, bromine, methyl or methoxy (especially chlorine).

6) Another embodiment relates to compounds according to any of embodiments 1)-5), where R ³ is methoxy, isopropoxy or difluoromethoxy (especially methoxy or difluoromethoxy).

7) Another embodiment relates to compounds according to any of embodiments 1)-5), where R ³ is C _1-3 alkoxy (namely methoxy, isopropoxy, especially methoxy).

8) Another embodiment relates to compounds according to any of embodiments 1)-5), where R ³ is C _1-3 fluoroalkoxy (especially difluoromethoxy).

9) Another embodiment relates to compounds according to embodiment 1), where the fragment

is where R ¹ means hydrogen or fluorine (especially hydrogen); R ² means hydrogen, chlorine, methyl, ethyl, methoxy or ethoxy (especially methyl); and R ³ means C _1-3 αlkoxy (especially methoxy, isopropoxy) or C _1-3 fluoroalkoxy (especially difluoromethoxy); or

where R ¹ means hydrogen; R ² means halogen (especially chlorine), methyl or methoxy; and R ³ is C _1-3 alkoxy (especially methoxy) or C _1-3 fluoroalkoxy (especially difluoromethoxy).

10) Another embodiment relates to compounds according to embodiment 1), where the fragment

is where R ¹ means hydrogen; R ² means hydrogen, methyl, methoxy (especially methyl); and R ³ is C _1-3 alkoxy (especially methoxy) or C _1-3 fluoroalkoxy (especially difluoromethoxy); or

- 10 040901

where R ¹ means hydrogen; R ² means halogen (especially chlorine); and R ³ is methoxy or difluoromethoxy.

11) Another embodiment relates to compounds according to embodiment 1), where the fragment

is a ring independently selected from the following groups A) or B):

where each of the above groups A) and B) form a separate sub-option of the invention.

12) Another embodiment relates to compounds according to any of embodiments 1)-11), where Ar ¹ is phenyl (where it is to be understood that said phenyl is substituted with R ⁴ and R ⁵ as clearly defined).

13) Another embodiment relates to compounds according to any of embodiments 1)-11), where Ar ¹ is a 6-membered heteroaryl containing one or two nitrogen atoms (especially pyridinyl, pyrimidinyl or pyrazinyl; in particular pyridine -2-yl, pyridin4-yl, or pyrazin-2-yl) (wherein it is to be understood that said heteroaryl is substituted with R ⁴ and R ⁵ as clearly defined).

14) Another embodiment relates to compounds according to any of the options

- 11 040901 implementation 1)-13) (especially in accordance with option 12)), where R ⁴ means n-propyl, isopropyl or monocyclic C ₃ . ₆ cycloalkyl (especially cyclobutyl or cyclopentyl).

15) Another embodiment relates to compounds according to any one of embodiments 1)-13) (especially according to embodiment 12) or 13)), where R ⁴ is n-propyl, isopropyl.

16) Another embodiment relates to compounds according to any of embodiments 1)-13) (especially according to embodiment 12)), where R ⁴ is monocyclic C _3-6 cycloalkyl (especially cyclobutyl, cyclopentyl).

17) Another embodiment relates to compounds according to any of embodiments 1)-16), where R ⁵ is hydrogen, fluorine, or methyl (namely, hydrogen, or fluorine at position 5 or 6 of the phenyl moiety, or methyl at position 5 of the phenyl moiety; especially hydrogen, or fluorine in position 5 or 6 of the phenyl moiety).

18) Another embodiment relates to compounds according to any of embodiments 1)-16), where R ⁵ is hydrogen.

19) Another embodiment relates to compounds according to any of embodiments 1)-11), where the fragment

^R4

R ⁵ is a ring independently selected from the following groups A) or B):

A) δ _: ί. $. _: ΐ. 6. 'έ _;

S'2δ

OR ; especially, ;

B) 'δ 'δ 'δ or , where each of the above groups A) and B) form a separate sub-variant of the invention.

20) Another embodiment relates to compounds according to any of embodiments 1)-19), where m and n are both 1 or m and n are both 2.

21) Another embodiment relates to compounds according to any of embodiments 1)-19), where m and n are both 1.

22) Another embodiment relates to compounds according to any of embodiments 1)-21), where the -LR ⁶ group is hydrogen;

- D-CO-RC ¹¹¹ where R ^C11 independently represents hydroxy; -O-benzyl; -OC _1-6 alkyl;

C ₁ -fluoroalkyl; or -NR ^N11 RN ¹² ; where independently RN ¹¹ is hydrogen or C1-4 alkyl and RN ¹² is hydrogen, C 1-4 alkyl, -SO ₂ -C _1-6 alkyl or -O-RO ¹¹ where R ^{O 11} is independently hydrogen, C _1-6 alkyl , or benzyl; And

- L - independently represents

- C _1-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-;

- C _1-6 alkylene-, -CO-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups, the specified C _1-6 alkylene is independently monosubstituted with hydroxy, C _1-3 alkoxy, -O-CO-C _1-4 alkyl or -NR ^N13 R ^N14 ; where independently RN ¹³ means hydrogen or C1-4 alkyl, and RN ¹⁴ means hydrogen, C 1-4 alkyl or —CO-OC _1-4 alkyl;

- 12 040901

-C _2- balkylene-, -CO-C ₂ . ₆ αkylene- or -SO ₂ -C _2- 6alkylene-; where in the above groups indicated

C _2-6 alkylene is independently disubstituted, where the substituents are independently selected from hydroxy and

-NR ⁿ¹⁵ R ⁿ¹⁶ ; where independently R ^N15 is hydrogen or C1-4alkyl and R ^N16 is hydrogen, C1-4αalkyl or

-CO-OC _1-4 alkyl;

_-C0 . ₄ alkylene-C ₃ . ₈ cycloαkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-, -SO ₂ C _0-4 αkylene-C _3-8 cycloalkylene-C _0-4 alkylene-, -CO-NH-C _0-4 αkylene-C _3-8 cycloalkylene-C _0-4 alkylene- or -CO-O-C _0-4 alkylene-C _3-8 cycloalkylene-C _0-4 alkylene-;

- C _0-4 αkylene-Su ¹ -C0-4αkylen-, -CO-C0-4alkylene-Su ¹ -C0-4alkylene-, -CO-O-C _0-4 alkylene-Su ¹ -C0-4alkylene-, - CO-NH-C0-4alkylene-Su ¹ -Co-4alkylene-, -SO ₂ -Co- ₄ alkylene-Su ¹ -Co-4alkylene- or -SO2-NH-Co-4αkilen-Su ¹ Co-4alkylene-; where Cy ¹ is independently C ₃ . ₆ heterocycloalkyl containing one ring oxygen atom or one ring nitrogen atom, where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted with C ₁ . ₄ alkyl or -CO-OC ₁ . ₄ alkyl;

- C ₂ . ₄ alkylene-O-C ₂ . ₄ alkylene-O-C ₁ . ₄ alkylene- or -C0-C ₁ . ₄ αkylene-0-C ₂ . ₄ alkylene-0-C ₁ . ₄ alkylene-;

- C _2-4 alkylene-X ¹¹ -C1.4 alkylene-, -CO-O-C2.4 alkylene-X ¹¹ -C1. ₄ alkylene-, -CO-NH-C ₂ . ₄ alkylene-X ¹¹ C1.4αlkulene- or -SO2-NH-C2.4 alkylene-X ¹¹ -C1. ₄ alkylene-; where X ¹¹ is independently an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted by C ₁ . ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC ₁ . ₄ alkyl;

- CO-C ₁ . ₄ alkylene-X ¹² -C1.4 alkylene-, -SO2-C1.4 alkylene-X ¹² -C1. ₄ alkylene- or -CO-C ₁ . ₄ alkylene-X ¹² C0-4 alkylene-C3.6 cycloalkylene-C0-4 alkylene-; where X ¹² is independently an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC _1-4 alkyl;

- C ₂ . ₄ alkylene-X ¹³ -C1.4 alkylene-; where X ¹³ represents -NH-CO-, and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy;

- C _1-4 alkylene-X ¹⁴ -C _1-4 alkylene-; where X ¹⁴ represents -CO-NH-;

- CO-C _2-6 alkenylene- or -SO ₂ -C _2-6 alkenylene-; or

- CO-C _2-6 fluoroalkylene-;

- L ² -hydroxy; where -L ² - represents

- CO-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups said C _1-6 αkylene is independently unsubstituted or monosubstituted by hydroxy, C ₁ -fluoroalkyl or -NR ^N21 R ^N22 , where independently R ^N21 is hydrogen or C1-4 alkyl and RN ²² is hydrogen, C1-4 alkyl or -CO -OC _1-4 alkyl;

- C _2-6 alkylene-, -CO-O-C _2-6 αkylene-, -CO-NH-C _2-6 alkylene- or -SO ₂ -NH-C _2-6 alkylene-, where in the above groups the indicated _C2 . ₆ alkylene is independently unsubstituted or monosubstituted with hydroxy, C1fluoroalkyl, or -NR ^N23 R ^N24 , where independently RN ²³ is hydrogen or C1.4 alkyl and RN ²⁴ is hydrogen, C1. ₄ αkyl or -CO-OC ₁ . ₄ alkyl;

- Co- ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C3-6 cycloalkylene-C ₀ . ₄ alkylene- or -SO ₂ -Co- ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene-;

- Co. ₄ αalkylene-Su ² -C0.4alkylene-, -CO-C0.4alkylene-Su ² -C0. ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ² -C0.4alkylene-; where Cy ² is independently C3. ₆ a heterocycloalkylene group containing one ring oxygen atom or one ring nitrogen atom; where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted by C ₁ . ₄ alkyl or -CO-OC ₁ . ₄ alkyl;

- C ₂ . ₄ alkylene-(O-C ₂ . ₄ alkylene)p- or -CO-C ₁ . ₄ alkylene-(O-C ₂ . ₄ alkylene)p-; where p is independently the integer 1 or 2;

- C ₂ . ₄ alkylene-X ²¹ -C2.4 alkylene-; where X ²¹ represents a nitrogen atom which is unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC ₁ . ₄ αkyl;

- CO-C ₁ . ₄ alkylene-X ²² -C2.4 alkylene-, -CO-C1.4 alkylene-X ²² -C1. ₄ alkylene-C ₃ . ₆ cycloalkylene- or

- SO ₂ -C ₁ . ₄ alkylene-X ²² -C2.4 alkylene-; where X ²² is a nitrogen atom that is independently unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . ₆ cycloalkyl or -CO-OC ₁ . ₄ αkyl;

- C ₂ . ₄ alkylene-X ²³ -C1.4alkylene-; where X ²³ represents -NH-CO- and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy;

- C ₁ . ₄ alkylene-X ²⁴ -C ₂ . ₄ alkylene-; where X ²⁴ represents -CO-NH-, and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy;

- L ³ -O-RO ³¹ where RO ³¹ means -CO-C ₁ . ₄ alkyl or -CO-C ₂ . ₄ alkenyl; and -L ³ - independently represents

- C ₂ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene- or -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₂ . ₆ alkylenyl -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁴ -NR ^N1 R ^N2 where independently R ^N1 means hydrogen or C1.4alkyl; and RN ² means hydrogen; C1. ₄ alkyl; _C1 . ₃ fluoroalkyl; _C3 . ₆ cycloalkyl; _C1 . ₃ alkoxy-C ₂ . ₄ alkylene; -CO-C ₁ . ₄ alkyl; -SO ₂ -C ₁ . ₄ alkyl; or -SO2-C1fluoroalkyl; And

- L ⁴ - independently represents

- C ₂ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-; or

_-C0 . ₄ alkylene-Su ⁴ -C0.4 alkylene-, -CO-C0.4 alkylene-Su ⁴ -C0. ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ⁴ -C ₀ . ₄ alkylene-;

- 13 040901 where Cy ⁴ independently represents C ₃ . ₆ a heterocycloalkylene group containing one ring oxygen atom;

- L ⁵ -NR ⁿ³ R ⁿ⁴ where RN ³ means hydrogen, C1-4alkyl or C1.3αlkoxy-C2.4αkylene; and RN ⁴ means -COO-C1-4alkyl; -CO-NR ^N51 R ^N52 where RN ⁵¹ and RN ⁵² are independently selected from hydrogen and C1-4alkyl; or -SO2nr ^N53 r ^N54 where independently RN ⁵³ is hydrogen or C1-4 alkyl and RN ⁵⁴ is hydrogen, C _1-4 αkyl or -CO-C _1-4 alkyl;

and -L ⁵ - independently represents

- C ₂ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene- or -SO ₂ -C _1-6 alkylene-, -CO-O-C ₂ . ₆ αalkylene-, -CO-NH-C ₂ _ ₆ alkylenyl -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁶ -N(R ^N61 )-OR ^O61 , where RN ⁶¹ means hydrogen, -CO-C1-4 alkyl or -CO-O-C1-4αkyl; and RO ⁶¹ is independently hydrogen, C1. ₆ alkyl, or benzyl;

and -L ⁶ - independently represents

- C ₂ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁷ -NR ^N5 R ^N6 , where RN ⁵ means hydrogen or C1_4alkyl (in particular hydrogen); RN ⁶ means hydrogen, C1. ₄ αlkyl, -CO-C ₁ . ₄ alkul, C ₁ . ₃ fluoroalkyl or C ₃ _ ₆ cycloalkyl (especially hydrogen); And

- L ⁷ - independently represents

- CO- or -SO ₂ -;

- L ⁸ -SO2-R ^S81 where RS ⁸¹ is independently -C1. ₆ αlkyl; C ₁ -fluoroalkyl; hydroxy; -nr ^N81 r ^N82 where independently RN ⁸¹ is hydrogen or C1_4αkyl and RN ⁸² is hydrogen, C1. ₄ alkyl, -COC ₁ . ₆ alkyl; And

- L ⁸ - independently represents

- C ₁ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-Cl. ₆ alkylene-;

- L ⁹ -HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl), where said NO ¹ is independently unsubstituted or mono- or disubstituted, where the substituents are independently selected from C1.4 alkyl (especially methyl), halogen, cyano, hydroxy, -C0.2αkylene-Su ⁹¹ -COOR ^O91 , where RO ⁹¹ is hydrogen or C1_ ₄ alkyl, and wherein Cy ⁹¹ is a C3.6 cycloalkylene group; or -C0.2alkylene-COOR ^O92 where RO ⁹² is hydrogen or C1_ ₄ alkyl; And

- L ⁹ - independently represents

- Co- ₆ alkylene-, -CO-Co- ₆ alkylene-, -SO ₂ -C ₀ . ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- L ¹⁰ -C ₄ . ₆ heterocyclyl, where C ₄ - ₆ heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, the specified C _4-6 heterocyclyl is independently unsubstituted, or mono-, di- or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom (thus forming with the nitrogen an amide group, or in case an additional ring oxygen is adjacent, a carbamate group, or in case an additional second ring nitrogen is adjacent, a urea group); and/or two methyl substituents attached to the ring carbon atom in the alpha position to the ring nitrogen atom or the ring oxygen atom (thus forming together with nitrogen -C(CH ₃ ) ₂ -N- group, or with oxygen -C(CH ₃ ) ₂ -O- group); and/or two oxo substituents on the ring sulfur atom (thus forming a -SO2- group); and/or

_C1 . ₄ alkyl, C ₁ . ₃ alkoxy-C ₂ . ₄ alkyl, C ₂ . ₃ fluoroalkyl or -CO-C ₁ . ₄ alkyl attached to a ring nitrogen atom having a free valence; And

- L ¹⁰ - independently represents

_-C0 . ₆ alkylene-, -CO-C ₀ . ₆ alkylene-, -SO ₂ -C ₀ _ ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ _ ₆ alkylene- or -SO ₂ -NH-C ₁ _ ₆ alkylene-;

- L ¹¹ -cyano; where -L ¹¹ - represents -CO-C ₁ _ ₆ alkylene-, -SO ₂ -C ₁ _ ₆ alkylene or -C ₀ _ ₆ αkylene-;

- L12-NO2; where -L ¹² - represents -C ₂ _ ₆ alkylene-; or

- L ¹³ -C ₁ . ₄ alkyl; where -L ¹³ - represents -CO-, or -CO-O-.

23) Another embodiment relates to compounds according to any of embodiments 1)-21), where the -LR ⁶ group is hydrogen;

- L1-CO-R ^Cn where RC ¹¹ is independently hydroxy; -O-benzyl; -O-C1.6 alkyl; C1-fluoroalkyl; or -NR ^N11 R ^N12 ; where independently RN ¹¹ means hydrogen or C1. ₄ alkyl and RN ¹² is hydrogen, C1.4 alkyl, -SO2-C1.6 alkyl or -O-RO ¹¹ where RO ¹¹ is independently hydrogen, C1. ₆ alkyl, or benzyl; And

- L ¹ - independently represents

- C ₁ . ₆ alkylene-, -CO-C ₁ _ ₆ alkylene-, -SO ₂ -C ₁ _ ₆ alkylene-, -CO-O-C ₁ . ₆ αalkylene-, -CO-NH-C ₁ _ ₆ alkylene- or

- 14 040901

-SO ₂ -NH-C ₁ . ₆ alkylene-;

-C _1- balkylene-, -CO-C1- ₆ alkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups indicated

C1_ ₆ alkylene is independently monosubstituted with hydroxy, C1_ ₃ alkoxy, -O-CO-C _1-4 alkyl or -NR ^N13 R ^N14 ; where independently R ^N13 means hydrogen or C1_4 alkyl, and RN ¹⁴ means hydrogen, C1_4 alkyl or -CO-O-C ^ alkyl;

- C ₂ _ ₆ alkylene-, -CO-C ₂ _ ₆ alkylene- or -SO ₂ -C ₂ . ₆ alkylene-; where in the above groups, the specified C ₂ _ ₆ alkylene is independently disubstituted, where the substituents are independently selected from hydroxy and -NR ^N15 R ^N16 ; where independently RN ¹⁵ means hydrogen or C1_4 alkyl, and R ^N16 means hydrogen, C1_4 alkyl or -CO-O-C1_ ₄ alkyl;

- C _o . ₄ alkylene-C ₃ . ₈ cycloalkylene-C _o . ₄ alkylene-, -CO-C _o . ₄ alkylene-C ₃ . ₈ cycloalkylene-C _o . ₄ alkylene-, -SO2Co- ₄ alkylene-C ₃ . ₈ cycloalkylene-Co. ₄ alkylene-, -CO-NH-C ₀ . ₄ αkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene- or -CO-O-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-;

- C _o-4 alkylene-Cu1-C _o . ₄ alkylene-, -CO-C _o _ ₄ alkylene-Cu1-C _o _ ₄ alkylene-, -CO-O-C _o _ ₄ alkylene-Su ¹ -Co_4 alkylene-, -CO-NH-C0.4 alkylene-Su ¹ -C0. ₄ alkylene-, -SO ₂ -C ₀ . ₄ alkylene-Su ¹ -C0.4alkylene- or -SO2-NH-C0.4αalkylene-Su ¹ Co-4alkylene-; where Cy ¹ independently represents C ₃ - ₆ heterocycloalkyl containing one ring oxygen atom or one ring nitrogen atom, where the specified ring nitrogen, if it has a free valence, is independently unsubstituted or monosubstituted with C 1_ ₄ alkyl or -CO-O-C ₁ _ ₄ alkyl;

- CO-C1. ₄ alkylene-X ¹² -C1.4 alkylene-, -SO2-C1.4 alkylene-X ¹² -C1. ₄ alkylene- or -CO-C1_ ₄ alkylene-X ¹² Co.4 alkylene-C3.8 cycloalkylene-Co.4 alkylene-; where X ¹² independently represents an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C1_ ₄ alkyl, C ₃ _ ₆ cycloalkyl, -CO-O-C ₁ _ ₄ alkyl, or C ₁ _ ₃ alkoxy-C ₂ _ ₄ alkyl;

- From ₂ . ₄ alkylene-X ¹³ -C1.4alkylene-; where X ¹³ represents -NH-CO-, and where the specified C2_ ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy;

- CO-C ₂ - ₆ alkenylene- or -SO ₂ -C ₂ . ₆ alkenylene-; or

- CO-C ₂ - ₆ fluoroalkylene-;

- L ² -hydroxy; where -L ² - represents

- CO-C1_ ₆ alkylene- or -SO ₂ -C ₁ . ₆ alkylene-; where in the above groups said _{C1_6} alkylene is independently unsubstituted or monosubstituted with hydroxy, C1-fluoroalkyl, or —NR ^N21 R ^N22 , where independently RN ²¹ is hydrogen or C1_4 alkyl and RN ²² is hydrogen, C1_4 alkyl or —CO—O— _{C1_4} alkyl;

- C ₂ _ ₆ alkylene-, -CO-O-C ₂ _ ₆ alkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-, where in the above groups, the specified C ₂ _ ₆ alkylene is independently unsubstituted or monosubstituted by hydroxy, C1-fluoroalkyl or -NR ^N23 R ^N24 , where independently RN ²³ means hydrogen or C1_4 alkyl, and RN ²⁴ means hydrogen, C 1-4 alkyl or - CO-O-C1_ ₄ alkyl;

- C _o . ₄ alkylene-C ₃ . ₆ cycloalkylene-C _o . ₄ alkylene-, -CO-C _o . ₄ alkylene-C ₃ . ₆ cycloalkylene-C _o . ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-C ₃ . ₆ cycloalkylene-C ₀ . ₄ alkylene-;

- C _o - ₄ alkylene-Su ² -Co ^ alkylene-, -CO-Co_4 alkylene-Su ² -Co_ ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ² -Co_4alkylene-; where Cy ² is independently a _{C3_6} heterocycloalkylene group containing one ring oxygen atom or one ring nitrogen atom; where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted C1_ ₄ alkyl or -CO-O-C ₁ _ ₄ alkyl;

- CO-C1_ ₄ alkylene-X ²² -C2_4 alkylene-, -CO-C1.4 alkylene-X ²² -C1.4 alkylene-C ₃ . ₆ cycloalkylene- or _{-SO2C1_4} alkylene-X ²² -C2_4alkylene-; where X ²² represents a nitrogen atom that is independently unsubstituted or monosubstituted with C1_4 alkyl, C ₃ _ ₆ cycloalkyl or —CO—O—C1_ ₄ alkyl; or

- From ₂ . ₄ alkylene-X ²³ -C1.4alkylene-; where X ²³ represents -NH-CO-, and where the specified C2_ ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy;

- L ⁴ -NR ^N1 R ^N2 , where independently R ^N1 means hydrogen or C1_4alkyl; and RN ² means hydrogen; C1-4alkyl; _{C1-3fluoroalkyl} ; C ₃ _ ₆ cycloalkyl; C1. ₃ alkoxy-C ₂ . ₄ alkylene; -CO-C1_ ₄ alkyl; -SO ₂ -C ₁ . ₄ alkyl; or -SO2-C1fluoroalkyl; And

- L ⁴ - independently represents

- C ₂ - ₆ alkylene-, -CO-C1_ ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ _ ₆ alkylene-, -CO-NH-C ₂ . ₆ alkylene- or -SO ₂ -NH-C ₂ . ₆ alkylene-; or

- Omalkylene-Su ⁴ -Co ^ alkylene-, -CO-Co_4 alkylene-Su ⁴ -Co_ ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ⁴ -C0.4alkylene-; where Su ⁴ independently represents a C3_ ₆ heterocycloalkylene group containing one ring oxygen atom;

- L ⁵ -NR ^N3 R ^N4 , where RN ³ means hydrogen, C1_4alkyl or C1_3alkoxy-C2_4alkylene; and RN ⁴ means -COO-C1_4alkyl; -CO-NR ^N51 R ^N52 where RN ⁵¹ and RN ⁵² are independently selected from hydrogen and C1_4 alkyl; or -SO2nr ^N53 r ^N54 where independently RN ⁵³ is hydrogen or C1_4 alkyl and RN ⁵⁴ is hydrogen, _C1-4 alkyl or -CO- _C1-4 alkyl;

and -L ⁵ - independently represents

- C ₂ - ₆ alkylene-, -CO-C1- ₆ alkylene- or -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₂ - ₆ alkylene-, -CO-NH-C ₂ . ₆ alkylenyl -SO ₂ -NH-C ₂ . ₆ alkylene-;

- L ⁶ -N(R ^N61 )-OR ⁰⁶¹ , where R ^N61 means hydrogen, -CO-C1-4 alkyl or -CO-O-C1-4 alkyl; and R ⁰⁶¹ is independently hydrogen, C1_6 alkyl, or benzyl;

and -L ⁶ - independently represents

- 15 040901

-C _2- balkylene-, -CO-C _1- balkylene-, -SO ₂ -C _1- 6 alkylene-, -CO-O-C ₂ - ₆ alkylene-, -CO-NH-C ₂ . ₆ αkylene- or

-SO ₂ -NH-C ₂ . ₆ alkylene-;

-L ⁷ -NR ^N5 R ^N6 where RN ⁵ is hydrogen or C1-4 alkyl (especially hydrogen); R ^N6 means hydrogen, C1-4alkyl, -CO-C ₁ . ₄ alkyl, C1_ ₃ fluoroalkyl or C ₃ . ₆ cycloalkyl (especially hydrogen); And

-L ⁷ - independently represents

- CO- or -SO ₂ -;

- L ⁸ -SO2-R ^S81 where RS ⁸¹ is independently -C1. ₆ alkyl; C ₁ -fluoroalkyl; hydroxy; -nr ^N81 r ^N82 where independently RN ⁸¹ is hydrogen or C1.4 alkyl and RN ⁸² is hydrogen, C1. ₄ alkyl, -COC _1-6 alkyl; And

- L ⁸ - independently represents

- C _1-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 αkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-;

- L ⁹ -HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl) wherein said NO ¹ is independently unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from C1.4 alkyl (especially methyl); halogen; cyano; hydroxy; hydroxymethyl; -C0.2αkilen-Sy ⁹¹ -COOR ^O91 , where RO ⁹¹ means hydrogen or C1. ₄ alkyl, and where Cy ⁹¹ represents a C3.6 cycloalkylene group; or -C0.2αkylene-COOR ^O92 where RO ⁹² is hydrogen or C1. ₄ alkyl; And

- L ⁹ - independently represents

- Co. ₆ alkylene-, -CO-C ₀ . ₆ alkylene-, -SO ₂ -C ₀ . ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-Cl. ₆ alkulen-;

- L ¹⁰ -C ₄ . ₆ heterocyclyl, where C _4-6 heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, the specified C ₄ _ ₆ heterocyclyl is independently unsubstituted, or mono-, di- or tri-substituted, where the substituents are independently selected from:

one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom (thus forming with the nitrogen an amide group, or in case an additional ring oxygen is nearby, a carbamate group, or in case next to it is an additional second ring nitrogen, the urea group); and/or two methyl substituents attached to the ring carbon atom in the alpha position to the ring nitrogen atom or the ring oxygen atom (thus forming together with nitrogen a C(CH ₃ )2-N- group, or with oxygen -C(CH ₃ ) ₂ -O- group); and/or two oxo substituents on the ring sulfur atom (thus forming a -SO2- group); and/or

_C1-4 alkyl, C1. ₃ alkoxy-C ₂ . ₄ alkyl, C ₂ - ₃ fluoroalkyl or -CO-C ₁ . ₄ alkyl attached to a ring nitrogen atom having a free valency; And

- L ¹⁰ - independently represents

- C ₀ _ ₆ alkylene- or -CO-C ₀ _ ₆ alkylene-;

- L ¹¹ -cyano; where -L ¹¹ - represents -CO-C1_ ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene or -C ₀ _ ₆ alkylene-; or

- L ¹³ -C ₁ . ₄ alkyl; where -L ¹³ - represents -CO-, -CO-O or -SO2.

24) Another embodiment relates to compounds according to any of embodiments 1)-21), where the -LR ⁶ group is hydrogen;

- L1-CO-R ^C11 where R ^C11 independently represents hydroxy; -O-C1-6alkyl; C1-fluoroalkyl; or -NR ^N11 R ^N12 ; where independently RN ¹¹ is hydrogen and RN ¹² is -SO2-C ₁ . ₆ alkyl; And

- L ¹ - independently represents

- _C1-6 alkylene-, -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C1- ₆ alkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- C1_ ₆ alkylene-, -CO-C ₁ . ₆ αkylene- or -SO ₂ -C ₁ . ₆ alkylene-; where in the above groups, the specified C1_ ₆ alkylene is independently monosubstituted with hydroxy;

- From ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-, -SO2С ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-or -CO-OC ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ αkylene-;

- C ₀ _ ₄ alkylene-Su ¹ -C0_4 alkylene-, -CO-C0_4 alkylene-Su ¹ -C0_ ₄ alkylene-, -CO-O-C ₀ _ ₄ alkylene-Su ¹ -C0_4 alkylenyl -SO2-C0.4 alkylene-Cu1- C0.4alkylene-; where Su ¹ independently represents C3_ ₆ heterocycloalkyl containing one ring oxygen atom;

- CO-C ₁ . ₄ alkylene-X ¹² -C1.4alkylene-; where X ¹² independently represents an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C 1-4 alkyl or C _3-6 cycloalkyl;

- CO-C ₂ - ₆ alkenylene- or -SO ₂ -C ₂ . ₆ alkenylene-; or

- CO-C ₂ - ₆ fluoroalkylene-;

- L ² -hydroxy; where -L ² - represents

- CO-C ₁ . ₆ alkylene-; where C1_ ₆ alkylene is unsubstituted or monosubstituted by C1-fluoroalkyl;

- C ₂ _ ₆ alkylene-, where C ₂ _ ₆ alkylene is unsubstituted or monosubstituted by hydroxy;

- 16 040901

-C _0-4 alkylene-C _3-6 cycloalkylene-C _0-4 alkylene- or -CO-C _0-4 alkylene-C ₃ . ₆ cycloalkylene-C _0-4 alkylene-;

-Co-4alkylene-Cu ² -C0-4alkylene- or -CO-C0-4alkylene-Cu ² -C0-4alkylene-; where Su ² independently represents a C _3-6 heterocycloalkylene group containing one ring oxygen atom;

-CO-C _1-4 alkylene-X ²² -C2-4 alkylene-; where X ²² represents a nitrogen atom that is independently unsubstituted or monosubstituted with C 1-4 alkyl or C _3-6 cycloalkyl; or

- C _2-4 alkylene-X ²³ -C 1-4 alkylene-; where X ²³ represents -NH-CO-, and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy;

- L ⁴ -NR ⁿ¹ R ⁿ² , where independently R ^N1 means hydrogen or C1-4 alkyl; and R ^N2 is hydrogen; C1-4alkyl; C _1-3 fluoroalkyl; C _3-6 cycloalkyl; C _1-3 alkoxy-C _2-4 alkylene; -CO-C _1-4 alkyl; -SO ₂ -C _1-4 alkyl; or -SO2-C1fluoroalkyl; And

- L ⁴ - independently represents

- C _2-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-b alkylene-, -L ⁵ -NR ⁿ³ R ⁿ⁴ , where R ^N3 means hydrogen or C 1-4 alkyl; and R ^N4 is -SO2-NR ^N53 R ^N54 , where independently R ^N53 is hydrogen or C1-4 alkyl and R ^N54 is hydrogen or C1-4 alkyl;

and -L ⁵ - independently represents

- C _2-6 alkylene-, -CO-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-;

- L ⁶ -N(R ⁿ⁶¹ )-OR ⁰⁶¹ , where R ^N61 means -CO-C _1-4 alkyl; and RO ⁶¹ is hydrogen;

and -L ⁶ - independently represents

- C _2-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-b alkylene-;

- L ⁷ -NR ^N5 R ⁿ⁶ , where R ^N5 means hydrogen or C1-4 alkyl (especially hydrogen); R ^N6 is hydrogen, C1-4 alkyl or C _3-6 cycloalkyl; And

- L ⁷ - independently represents

- CO- or -SO2-;

- L ⁸ -SO2-R ^S71 where RS ⁸¹ is independently -C1-6 alkyl; C1-fluoroalkyl; hydroxy; -NR ⁿ⁸¹ R ⁿ⁸² where independently R ⁿ⁸¹ is hydrogen or C1-4 alkyl and R ^N82 is hydrogen, C1-4 alkyl, -CO-C _1-6 alkyl; And

- L ⁸ - independently represents

- C _1-6 alkylene-, -CO-C _1-6 αkylene- or -SO ₂ -C _1-6 alkylene-;

- L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl , pyrazinyl), where said NO ¹ is independently unsubstituted or mono- or disubstituted, where the substituents are independently selected from C1-4 alkyl (especially methyl); halogen; cyano; hydroxy; hydroxymethyl; -C0-2alkylene-Cy ⁹¹ -COOR ^O91 where RO ⁹¹ is hydrogen or C1-4 alkyl, and where Cy ⁹¹ is a C3-6 cycloalkylene group; or -C0-2alkylene-COORO ⁹² where RO ⁹² is hydrogen or C1-4alkyl; And

- L ⁹ - independently represents

- C _0-6 alkylene-, -CO-C _0-6 alkylene-, -SO ₂ -C _0-6 alkylene- or -CO-NH-C _1-6 alkylene-;

- L ¹⁰ -C _4-6 heterocyclyl, where C _4-6 heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups said C _4-6 heterocyclyl is independently unsubstituted, or mono- or disubstituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom (thus forming together with nitrogen an amide group, or in case an additional ring oxygen is located nearby, a carbamate group, or in case an additional second ring nitrogen is located nearby, a urea group); and/or two oxo substituents on the ring sulfur atom (thus forming a -SO ₂ - group); and/or

C1-4alkyl attached to a ring nitrogen atom having a free valence; And

- L ¹⁰ - independently represents

- C _0-6 alkylene- or -CO-C _0-6 alkylene-;

- L ¹¹ -cyano; where -L ¹¹ - represents -C _0-6 alkylene-; or

- L ¹³ -C _1-4 alkyl; where -L ¹³ - represents -CO-.

25) Another embodiment relates to compounds according to any of embodiments 1)-21), where the -LR ⁶ group is

- L1-COOH; where -L ¹ - represents

- C _1-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-;

- CO-C _1-6 alkylene-; where the specified C _1-6 alkylene monosubstituted by hydroxy;

- C0-4alkylene-C3-8cycloalkylene-C0-4alkylene-, -CO-C0-4alkylene-C3-8cycloalkylene-C0-4alkylene-,

-SO ₂ -C _0-4 alkylene-C _3-8 cycloalkylene-C _0-4 alkylene- or -CO-OC _0-4 alkylene-C _3-8 cycloalkylene-C _0-4 alkylene-;

- CO-C _0-4 alkylene-Cu1-C _0-4 alkylene-; where Su ¹ is independently C _3-6 heterocycloalkyl containing one ring oxygen atom;

- 17 040901

-CO-C _1-4 alkylene-X ¹² -C 1-4 alkylene-; where X ¹² is independently a nitrogen atom that is unsubstituted or monosubstituted with C1-4 alkyl;

-CO-C _2-6 alkenylene- or -SO ₂ -C _2-6 alkenylene-; or

-CO-C _2-6 fluoroalkylene-;

-L ² -hydroxy; where -L ² - represents

- C _2-6 alkylene-, where C _2-6 alkylene is unsubstituted or monosubstituted by hydroxy; or

- CO-C _1-4 alkylene-X ²² -C2-4 alkylene-; where X ²² represents a nitrogen atom that is independently unsubstituted or monosubstituted with C 1-4 alkyl or C _3-6 cycloalkyl;

- L ⁷ -NR ^N5 R ^N6 where R ^N5 means hydrogen; R ^N6 means hydrogen or C _3-6 cycloalkyl; And

- L ⁷ - independently represents -CO - or -SO ₂ -; or

- L ⁹ -HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl (especially pyrrolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl), wherein said NO ¹ is independently unsubstituted or mono- or disubstituted, where the substituents are independently selected from C1-4alkyl (especially methyl); halogen; cyano; hydroxy; hydroxymethyl; -C0-2alkylene-Cy ⁹¹ -COOR ^O91 where R ^O91 is hydrogen or C1-4 alkyl and where CY ⁹¹ is a C3-6 cycloalkylene group; or -C0-2alkylene-COOR ^O92 where R ^O92 is hydrogen or C1-4alkyl; And

- L ⁹ - independently represents

- C _0-6 alkylene-, -CO-C _0-6 alkylene-.

26) Another embodiment relates to compounds according to any of embodiments 1)-21), where the -LR ⁶ group is

- L1-COOH; And

- L ¹ - represents

- sn ₂ -sn ₂ -, -sn ₂ -sn ₂ -sn ₂ -, -sn ₂ -s (sn ₃ ) ₂ -sn ₂ -, * -sn ₂ -sn ₂ -s (sn ₃ ) ₂ -, * -CH ₂ -CH ₂ -CH ₂ -s (CH ₃ ) ₂ -, *-CO-CH2-CH2-, *-CO-CH (CH3) -CH2-, *-CO-CH2-C (OH) (CH3)-, *-CO-CH2-CH2-CH2-, *-CO-CH2-C(CH3)2-, *-CO-C(CH3)2-CH2-, *-SO2-CH2-, * -SO2-CH2-CH2-, *-SO2-CH2-CH2-CH2-, *-SO2-CH2-C(CH3)2-, *-co-oCH ₂ -, *-CO-O-CH(CH3) -, *-CO-O-CH2-C(CH3)2-, *-CO-NH-C(CH3)2-CH2-, *-CO-NH-CH2-C(CH3)2-, *-CONH -CH ₂ -CH ₂ -C(CH ₃ ) ₂ -, *-SO ₂ -NH-CH ₂ -; *-CH ₂ -CH ₂ -CH ₂ -cyclopropane-1,1-diyl-, *-CO-cyclopropan-1,2yl-, *-CO-CH ₂ -cyclopropane-1,1-diyl-, *-CO -CH ₂ -cyclobutane-1,1-diyl-, *-SO ₂ -cyclopropan-1,1-diylCH ₂ -, *-CO-O-cyclopropane-1,1 -diyl-, *-CO-O-CH ₂ -cyclopropane-1,1-diyl-;

*-CO-CH ₂ -(tetrahydro-2H-pyran-4,4-diyl)-;

* -CO-CH2-N(n-butyl)-CH2-;

*-SO2-CH=CH-, *-CO-C(CH2)-CH2-; or *-CO-CF2-CH2-;

- L ² -hydroxy; where -L ² - represents * -CH ₂ -CH(OH)-CH ₂ -; or *-CO-CH2-NH-CH2-CH2-, *-CO-CH2-NH-CH(CH3)-CH2-, *-CO-CH2-NH-CH2-CH(CH3)-;

- L ⁷ -NH ₂ ; where -L ⁷ - represents

- SO2-; or

- L9-HET ¹ where -L9-HET ¹ is

^m ^^coon _; or, in addition to the above groups, the -LR ⁶ group is

- L ⁷ -NH-cyclopropyl; Where

- L ⁷ - represents

-CO-;

where in the above groups, asterisks indicate a bond that is attached to the rest of the molecule.

- 18 040901

7) The invention thus relates to compounds of formula (I) as defined in embodiment 1), or to such compounds further limited by the features of any of embodiments 2)-26), when considering their respective dependencies; to their pharmaceutically acceptable salts; and to the use of such compounds as further described below. For the avoidance of misinterpretation, it should be noted in particular that the following embodiments relating to compounds of formula (I) are thus possible and implied and are hereby specifically disclosed in individualized form:

1, 2+1, 5+1, 5+2+1, 6+1, 6+2+1, 6+5+1, 6+5+2+1, 8+1, 8+2+1, 8+5+1, 8+5+2+1, 9+1, 11+1, 12+1, 12+2+1, 12+5+1, 12+5+2+1, 12+6+ 1, 12+6+2+1, 12+6+5+1, 12+6+5+2+1, 12+8+1, 12+8+2+1, 12+8+5+1, 12+8+5+2+1, 12+9+1, 12+11 + 1, 14+1, 14+12+1, 14+12+2+1, 14+12+5+1, 14+ 12+5+2+1, 14+12+6+1, 14+12+6+2+1, 14+12+6+5+1, 14+12+6+5+2+1, 14+ 12+8+1, 14+12+8+2+1,

14+12+8+5+1, 14+12+8+5+2+1, 14+12+9+1, 14+12+11+1, 18+1, 18+12+1,

18+12+2+1, 18+12+5+1, 18+12+5+2+1, 18+12+6+1, 18+12+6+2+1, 18+12+6+ 5+1, 18+12+6+5+2+1, 18+12+8+1, 18+12+8+2+1, 18+12+8+5+1, 18+12+8+ 5+2+1, 18+12+9+1, 18+12+11+1, 18+14+1, 18+14+12+1, 18+14+12+2+1, 18+14+ 12+5+1, 18+14+12+5+2+1, 18+14+12+6+1, 18+14+12+6+2+1, 18+14+12+6+5+ 1,

18+14+12+6+5+2+1, 18+14+12+8+1, 18+14+12+8+2+1, 18+14+12+8+5+1,

18+14+12+8+5+2+1, 18+14+12+9+1, 18+14+12+11 + 1, 19+1, 19+2+1, 19+5+1, 19+5+2+1, 19+6+1, 19+6+2+1, 19+6+5+1, 19+6+5+2+1, 19+8+1, 19+8+ 2+1, 19+8+5+1, 19+8+5+2+1, 19+9+1, 19+11 + 1, 21 + 1, 21+2+1, 21+5+1, 21+5+2+1, 21+6+1, 21+6+2+1, 21+6+5+1, 21+6+5+2+1, 21+8+1, 21+8+ 2+1, 21+8+5+1, 21+8+5+2+1, 21+9+1, 21+11+1, 21+12+1, 21+12+2+1, 21+ 12+5+1, 21+12+5+2+1, 21+12+6+1, 21+12+6+2+1, 21+12+6+5+1, 21+12+6+ 5+2+1, 21+12+8+1,

21+12+8+2+1, 21+12+8+5+1, 21+12+8+5+2+1, 21+12+9+1, 21+12+11+1, 21+ 14+1, 21+14+12+1, 21+14+12+2+1, 21+14+12+5+1, 21+14+12+5+2+1, 21+14+12+ 6+1, 21+14+12+6+2+1, 21+14+12+6+5+1, 21+14+12+6+5+2+1, 21+14+12+8+ 1,

21+14+12+8+2+1, 21+14+12+8+5+1, 21+14+12+8+5+2+1, 21+14+12+9+1,

21+14+12+11+1, 21+18+1, 21+18+12+1, 21+18+12+2+1, 21+18+12+5+1,

21+18+12+5+2+1, 21+18+12+6+1, 21+18+12+6+2+1, 21+18+12+6+5+1,

21+18+12+6+5+2+1, 21+18+12+8+1, 21+18+12+8+2+1, 21+18+12+8+5+1,

21+18+12+8+5+2+1, 21+18+12+9+1, 21+18+12+11+1, 21+18+14+1,

21+18+14+12+1, 21+18+14+12+2+1, 21+18+14+12+5+1, 21+18+14+12+5+2+1, 21+ 18+14+12+6+1, 21+18+14+12+6+2+1, 21+18+14+12+6+5+1,

21+18+14+12+6+5+2+1, 21+18+14+12+8+1, 21+18+14+12+8+2+1,

21+18+14+12+8+5+1, 21+18+14+12+8+5+2+1, 21+18+14+12+9+1,

- 19 040901

21+18+14+12+11+1, 21+19+1, 21+19+2+1, 21+19+5+1, 21+19+5+2+1, 21+19+6+ 1 21+19+6+2+1, 21+19+6+5+1, 21+19+6+5+2+1, 21+19+8+1, 21+19+8+2+1 21 + 19+8+5+1, 21 + 19+8+5+2+1, 21 + 19+9+1, 21 + 19+11 + 1, 25+1, 25+2+1, 25+ 5+1 25+5+2+1, 25+6+1, 25+6+2+1, 25+6+5+1, 25+6+5+2+1, 25+8+1, 25 +8+2+1 25+8+5+1, 25+8+5+2+1, 25+9+1, 25+11+1, 25+12+1, 25+12+2+1, 25+12+5+1 25+12+5+2+1, 25+12+6+1, 25+12+6+2+1, 25+12+6+5+1, 25+12+6 +5+2+1 25+12+8+1, 25+12+8+2+1, 25+12+8+5+1, 25+12+8+5+2+1, 25+12+ 9+1 25+12+11+1, 25+14+1, 25+14+12+1, 25+14+12+2+1, 25+14+12+5+1 25+14+12+ 5+2+1, 25+14+12+6+1, 25+14+12+6+2+1, 25+14+12+6+5+1 25+14+12+6+5+2 +1, 25+14+12+8+1, 25+14+12+8+2+1, 25+14+12+8+5+1 25+14+12+8+5+2+1, 25+14+12+9+1, 25+14+12+11+1, 25+18+1, 25+18+12+1 25+18+12+2+1, 25+18+12+5 +1, 25+18+12+5+2+1, 25+18+12+6+1 25+18+12+6+2+1, 25+18+12+6+5+1, 25+ 18+12+6+5+2+1, 25+18+12+8+1 25+18+12+8+2+1, 25+18+12+8+5+1, 25+18+12 +8+5+2+1, 25+18+12+9+1 25+18+12+11+1, 25+18+14+1, 25+18+14+12+1, 25+18+ 14+12+2+1 25+18+14+12+5+1, 25+18+14+12 +5+2+1, 25+18+14+12+6+1 25+18+14+12+6+2+1, 25+18+14+12+6+5+1, 25+18+ 14+12+6+5+2+1 25+18+14+12+8+1, 25+18+14+12+8+2+1, 25+18+14+12+8+5+1 25+18+14+12+8+5+2+1, 25+18+14+12+9+1, 25+18+14+12+11+1, 25+19+1 25+19+2 +1, 25+19+5+1, 25+19+5+2+1, 25+19+6+1, 25+19+6+2+1, 25+19+6+5+1 25+ 19+6+5+2+1, 25+19+8+1, 25+19+8+2+1, 25+19+8+5+1, 25+19+8+5+2+1 25 +19+9+1, 25+19+11+1, 25+21+1, 25+21+2+1, 25+21+5+1, 25+21+5+2+1 25+21+ 6+1, 25+21+6+2+1, 25+21+6+5+1, 25+21+6+5+2+1, 25+21+8+1 25+21+8+2 +1, 25+21+8+5+1, 25+21+8+5+2+1, 25+21+9+1, 25+21+11+1 25+21+12+1, 25+ 21+12+2+1, 25+21+12+5+1, 25+21+12+5+2+1, 25+21+12+6+1 25+21+12+6+2+1 , 25+21+12+6+5+1, 25+21+12+6+5+2+1, 25+21+12+8+1 25+21+12+8+2+1, 25+ 21+12+8+5+1, 25+21+12+8+5+2+1, 25+21+12+9+1 25+21+12+11+1, 25+21+14+1 , 25+21+14+12+1, 25+21+14+12+2+1 25+21+14+12+5+1, 25+21+14+12+5+2+1, 25+ 21+14+12+6+1 25+21+14+12+6+2+1, 25+21+14+12+6+5+1, 25+21+14+12+6+5+2 +1 25+21+14+12+8+1, 25+21+14+12+8+2+1, 25+21+14+12+8+5+1 25+21+14+12+8 +5+2+1, 25+21+14+12+9+1, 25+21+14+12+11+1, 25+21+18+1 25+21+18+12+1, 25+21+18+12+2+1, 25+21+18+12+5+1, 25+21+18+12+5 +2+1 25+21+18+12+6+1, 25+21+18+12+6+2+1, 25+21+18+12+6+5+1

- 20 040901

25+21+18+12+6+5+2+1, 25+21+18+12+8+1, 25+21+18+12+8+2+1, 25+21+18+12+ 8+5+1, 25+21+18+12+8+5+2+1, 25+21+18+12+9+1, 25+21+18+12+11+1, 25+21+ 18+14+1, 25+21+18+14+12+1, 25+21+18+14+12+2+1, 25+21+18+14+12+5+1, 25+21+ 18+14+12+5+2+1, 25+21+18+14+12+6+1, 25+21+18+14+12+6+2+1, 25+21+18+14+ 12+6+5+1, 25+21+18+14+12+6+5+2+1, 25+21+18+14+12+8+1, 25+21+18+14+12+ 8+2+1, 25+21+18+14+12+8+5+1, 25+21+18+14+12+8+5+2+1, 25+21+18+14+12+ 9+1, 25+21+18+14+12+11+1, 25+21+19+1, 25+21+19+2+1, 25+21+19+5+1, 25+21+ 19+5+2+1, 25+21+19+6+1, 25+21+19+6+2+1, 25+21+19+6+5+1, 25+21+19+6+ 5+2+1, 25+21+19+8+1, 25+21+19+8+2+1, 25+21+19+8+5+1, 25+21+19+8+5+ 2+1, 25+21+19+9+1, 25+21 + 19+11 + 1, 26+1, 26+2+1, 26+5+1, 26+5+2+1, 26+ 6+1, 26+6+2+1, 26+6+5+1, 26+6+5+2+1, 26+8+1, 26+8+2+1, 26+8+5+ 1, 26+8+5+2+1, 26+9+1, 26+11 + 1, 26+12+1, 26+12+2+1, 26+12+5+1, 26+12+ 5+2+1, 26+12+6+1, 26+12+6+2+1, 26+12+6+5+1, 26+12+6+5+2+1, 26+12+ 8+1, 26+12+8+2+1, 26+12+8+5+1, 26+12+8+5+2+1, 26+12+9+1, 26+12+11+ 1, 26+14+1, 26+14+12+1, 26+14+12+2+1, 26 +14+12+5+1, 26+14+12+5+2+1, 26+14+12+6+1, 26+14+12+6+2+1, 26+14+12+6 +5+1, 26+14+12+6+5+2+1, 26+14+12+8+1, 26+14+12+8+2+1, 26+14+12+8+5 +1, 26+14+12+8+5+2+1, 26+14+12+9+1, 26+14+12+11+1, 26+18+1, 26+18+12+1 , 26+18+12+2+1, 26+18+12+5+1, 26+18+12+5+2+1, 26+18+12+6+1, 26+18+12+6 +2+1, 26+18+12+6+5+1, 26+18+12+6+5+2+1, 26+18+12+8+1, 26+18+12+8+2 +1, 26+18+12+8+5+1, 26+18+12+8+5+2+1, 26+18+12+9+1, 26+18+12+11+1, 26 +18+14+1, 26+18+14+12+1, 26+18+14+12+2+1, 26+18+14+12+5+1, 26+18+14+12+5 +2+1, 26+18+14+12+6+1, 26+18+14+12+6+2+1, 26+18+14+12+6+5+1, 26+18+14 +12+6+5+2+1, 26+18+14+12+8+1, 26+18+14+12+8+2+1, 26+18+14+12+8+5+1 , 26+18+14+12+8+5+2+1, 26+18+14+12+9+1, 26+18+14+12+11+1, 26+19+1, 26+19 +2+1, 26+19+5+1, 26+19+5+2+1, 26+19+6+1, 26+19+6+2+1, 26+19+6+5+1 , 26+19+6+5+2+1, 26+19+8+1, 26+19+8+2+1, 26+19+8+5+1, 26+19+8+5+2 +1, 26+19+9+1, 26+19+11+1, 26+21+1, 26+21+2+1, 26+21+5+1, 26+21+5+2+1 , 26+21+6+1, 26+21+6+2+1, 26+21+6+5+1, 26+21+6+5+2+1, 26+21+8+1, 26 +21+8+2+1, 26+21+8+5+1, 26+21+8+5+2+1, 26+21+9 +1, 26+21+11+1, 26+21+12+1, 26+21+12+2+1, 26+21+12+5+1, 26+21+12+5+2+1 , 26+21+12+6+1, 26+21+12+6+2+1, 26+21+12+6+5+1, 26+21+12+6+5+2+1, 26 +21+12+8+1, 26+21+12+8+2+1, 26+21+12+8+5+1, 26+21+12+8+5+2+1, 26+21 +12+9+1,

- 21 040901

26+21+12+11+1, 26+21+14+1, 26+21+14+12+1, 26+21+14+12+2+1,

26+21+14+12+5+1, 26+21+14+12+5+2+1, 26+21+14+12+6+1,

26+21+14+12+6+2+1, 26+21+14+12+6+5+1, 26+21+14+12+6+5+2+1,

26+21+14+12+8+1, 26+21+14+12+8+2+1, 26+21+14+12+8+5+1,

26+21+14+12+8+5+2+1, 26+21+14+12+9+1, 26+21+14+12+11+1, 26+21+18+1,

26+21+18+12+1, 26+21+18+12+2+1, 26+21+18+12+5+1, 26+21+18+12+5+2+1, 26+ 21+18+12+6+1, 26+21+18+12+6+2+1, 26+21+18+12+6+5+1, 26+21+18+12+6+5+ 2+1, 26+21+18+12+8+1, 26+21+18+12+8+2+1, 26+21+18+12+8+5+1, 26+21+18+ 12+8+5+2+1, 26+21+18+12+9+1, 26+21+18+12+11+1, 26+21+18+14+1, 26+21+18+ 14+12+1, 26+21+18+14+12+2+1, 26+21+18+14+12+5+1, 26+21+18+14+12+5+2+1, 26+21+18+14+12+6+1, 26+21+18+14+12+6+2+1, 26+21+18+14+12+6+5+1, 26+21+ 18+14+12+6+5+2+1, 26+21+18+14+12+8+1, 26+21+18+14+12+8+2+1, 26+21+18+ 14+12+8+5+1, 26+21+18+14+12+8+5+2+1, 26+21+18+14+12+9+1, 26+21+18+14+ 12+11+1,

26+21+19+1, 26+21+19+2+1, 26+21+19+5+1, 26+21+19+5+2+1, 26+21+19+6+1,

26+21+19+6+2+1, 26+21+19+6+5+1, 26+21+19+6+5+2+1, 26+21+19+8+1,

26+21+19+8+2+1, 26+21+19+8+5+1, 26+21+19+8+5+2+1, 26+21+19+9+1,

26+21+19+11+1.

In the above list, the numbers refer to the embodiments according to their numbering provided above, while + indicates a dependency on another embodiment. Various individualized embodiments are separated by commas. In other words, 26+21+11+1, for example, refers to Embodiment 26) dependent on Embodiment 21) dependent on Embodiment 11) dependent on Embodiment 1), i.e. variant 26+21+11+1 corresponds to compounds of formula (I) as defined in embodiment 1), further limited by all structural features of embodiments 11), 21) and 26).

8) The second aspect of the invention relates to compounds of formula (I), which are also compounds of formula (II)

Formula (II) wherein R ¹ , R ² , R ³ , Ar ¹ , R ⁴ , R ⁵ , m, n and -LR ⁶ are as defined in Embodiment 1);

wherein the features disclosed in embodiments 2)-27) are intended to be applied, mutatis mutandis, also to compounds of formula (II) according to embodiment 28); where, in particular, the following embodiments are thus possible and implied and are hereby specifically disclosed in an individualized form:

- 22 040901

28+2, 28+5+2, 28+5, 28+6+2, 28+6+5+2, 28+6+5, 28+6, 28+8+2, 28+8+5+ 2, 28+8+5, 28+8, 28+12+2, 28+12+5+2, 28+12+5, 28+12+6+2, 28+12+6+5+2, 28+12+6+5, 28+12+6, 28+12+8+2, 28+12+8+5+2, 28+12+8+5, 28+12+8, 28+12, 28+14+12+2, 28+14+12+5+2, 28+14+12+5, 28+14+12+6+2, 28+14+12+6+5+2, 28+ 14+12+6+5, 28+14+12+6, 28+14+12+8+2, 28+14+12+8+5+2, 28+14+12+8+5, 28+ 14+12+8, 28+14+12, 28+14, 28+18+12+2, 28+18+12+5+2, 28+18+12+5, 28+18+12+6+ 2, 28+18+12+6+5+2, 28+18+12+6+5, 28+18+12+6, 28+18+12+8+2, 28+18+12+8+ 5+2, 28+18+12+8+5, 28+18+12+8, 28+18+12, 28+18+14+12+2, 28+18+14+12+5+2, 28+18+14+12+5, 28+18+14+12+6+2, 28+18+14+12+6+5+2, 28+18+14+12+6+5, 28+ 18+14+12+6, 28+18+14+12+8+2, 28+18+14+12+8+5+2, 28+18+14+12+8+5, 28+18+ 14+12+8, 28+18+14+12, 28+18+14, 28+18, 28+21+2, 28+21+5+2, 28+21+5, 28+21+6+ 2, 28+21+6+5+2, 28+21+6+5, 28+21+6, 28+21+8+2, 28+21+8+5+2, 28+21+8+ 5, 28+21+8, 28+21+12+2, 28+21+12+5+2, 28+21+12+5, 28+21+12+6+2, 28+21+12+ 6+5+2, 28+21+12+6+5, 28+21+12+6, 28+21+12+8+2, 28+21+12+8+5+2, 28+21+ 12+8+ 5, 28+21+12+8, 28+21+12, 28+21+14+12+2, 28+21+14+12+5+2, 28+21+14+12+5, 28+ 21+14+12+6+2,

- 23 040901

28+21+14+12+6+5+2, 28+21+14+12+6+5, 28+21+14+12+6, 28+21+14+12+8+2, 28+ 21+14+12+8+5+2, 28+21+14+12+8+5, 28+21+14+12+8, 28+21+14+12, 28+21+14, 28+ 21+18+12+2, 28+21+18+12+5+2, 28+21+18+12+5, 28+21+18+12+6+2, 28+21+18+12+ 6+5+2, 28+21+18+12+6+5, 28+21+18+12+6, 28+21+18+12+8+2, 28+21+18+12+8+ 5+2, 28+21+18+12+8+5, 28+21+18+12+8, 28+21+18+12, 28+21+18+14+12+2, 28+21+ 18+14+12+5+2, 28+21+18+14+12+5, 28+21+18+14+12+6+2, 28+21+18+14+12+6+5+ 2, 28+21+18+14+12+6+5, 28+21+18+14+12+6, 28+21+18+14+12+8+2, 28+21+18+14+ 12+8+5+2, 28+21+18+14+12+8+5, 28+21+18+14+12+8, 28+21+18+14+12, 28+21+18+ 14, 28+21 + 18, 28+21, 28+22+2, 28+22+5+2, 28+22+5, 28+22+6+2, 28+22+6+5+2, 28+22+6+5, 28+22+6, 28+22+8+2, 28+22+8+5+2, 28+22+8+5, 28+22+8, 28+22+ 12+2, 28+22+12+5+2, 28+22+12+5, 28+22+12+6+2, 28+22+12+6+5+2, 28+22+12+ 6+5, 28+22+12+6, 28+22+12+8+2, 28+22+12+8+5+2, 28+22+12+8+5, 28+22+12+ 8, 28+22+12, 28+22+14+12+2, 28+22+14+12+5+2, 28+22+14+12+5, 28+22+14+12+6+ 2, 28+22+14+12+6+5+2, 28+22+14+12+6+5, 28+22+14+12+6, 28+22+ 14+12+8+2, 28+22+14+12+8+5+2, 28+22+14+12+8+5, 28+22+14+12+8, 28+22+14+ 12, 28+22+14, 28+22+18+12+2, 28+22+18+12+5+2, 28+22+18+12+5, 28+22+18+12+6+ 2, 28+22+18+12+6+5+2, 28+22+18+12+6+5, 28+22+18+12+6, 28+22+18+12+8+2, 28+22+18+12+8+5+2, 28+22+18+12+8+5, 28+22+18+12+8, 28+22+18+12, 28+22+18+ 14+12+2, 28+22+18+14+12+5+2, 28+22+18+14+12+5, 28+22+18+14+12+6+2, 28+22+ 18+14+12+6+5+2, 28+22+18+14+12+6+5, 28+22+18+14+12+6, 28+22+18+14+12+8+ 2, 28+22+18+14+12+8+5+2, 28+22+18+14+12+8+5, 28+22+18+14+12+8, 28+22+18+ 14+12, 28+22+18+14, 28+22+18, 28+22+21+2, 28+22+21+5+2, 28+22+21+5, 28+22+21+ 6+2, 28+22+21+6+5+2, 28+22+21+6+5, 28+22+21+6, 28+22+21+8+2, 28+22+21+ 8+5+2, 28+22+21+8+5, 28+22+21+8, 28+22+21 + 12+2, 28+22+21 + 12+5+2, 28+22+ 21+12+5, 28+22+21+12+6+2, 28+22+21+12+6+5+2, 28+22+21+12+6+5, 28+22+21+ 12+6, 28+22+21+12+8+2, 28+22+21+12+8+5+2, 28+22+21+12+8+5, 28+22+21+12+ 8, 28+22+21+12, 28+22+21+14+12+2, 28+22+21+14+12+5+2, 28+22+21+14+12+5, 28+ 22+21+14+12+6+2, 28+22+21+14+12+6+5+2, 28+22+21+14+12 +6+5, 28+22+21+14+12+6, 28+22+21+14+12+8+2, 28+22+21+14+12+8+5+2, 28+22 +21+14+12+8+5, 28+22+21+14+12+8, 28+22+21+14+12, 28+22+21+14, 28+22+21+18+12 +2, 28+22+21+18+12+5+2, 28+22+21+18+12+5, 28+22+21+18+12+6+2, 28+22+21+18 +12+6+5+2, 28+22+21+18+12+6+5,

- 24 040901

28+22+21+18+12+6, 28+22+21+18+12+8+2, 28+22+21+18+12+8+5+2,

28+22+21+18+12+8+5, 28+22+21+18+12+8, 28+22+21+18+12,

28+22+21+18+14+12+2, 28+22+21+18+14+12+5+2, 28+22+21+18+14+12+5,

28+22+21+18+14+12+6+2, 28+22+21+18+14+12+6+5+2,

28+22+21+18+14+12+6+5, 28+22+21+18+14+12+6, 28+22+21+18+14+12+8+2,

28+22+21+18+14+12+8+5+2, 28+22+21+18+14+12+8+5, 28+22+21+18+14+12+8, 28+ 22+21 + 18+14+12, 28+22+21 + 18+14, 28+22+21 + 18, 28+22+21, 28+22, 28+26+2, 28+26+5+ 2, 28+26+5, 28+26+6+2, 28+26+6+5+2, 28+26+6+5, 28+26+6,

28+26+8+2, 28+26+8+5+2, 28+26+8+5, 28+26+8, 28+26+12+2, 28+26+12+5+2, 28+26+12+5, 28+26+12+6+2, 28+26+12+6+5+2, 28+26+12+6+5, 28+26+12+6, 28+ 26+12+8+2, 28+26+12+8+5+2, 28+26+12+8+5, 28+26+12+8, 28+26+12,

28+26+14+12+2, 28+26+14+12+5+2, 28+26+14+12+5, 28+26+14+12+6+2,

28+26+14+12+6+5+2, 28+26+14+12+6+5, 28+26+14+12+6, 28+26+14+12+8+2, 28+ 26+14+12+8+5+2, 28+26+14+12+8+5, 28+26+14+12+8, 28+26+14+12,

28+26+14, 28+26+18+12+2, 28+26+18+12+5+2, 28+26+18+12+5,

28+26+18+12+6+2, 28+26+18+12+6+5+2, 28+26+18+12+6+5, 28+26+18+12+6, 28+ 26+18+12+8+2, 28+26+18+12+8+5+2, 28+26+18+12+8+5, 28+26+18+12+8, 28+26+ 18+12, 28+26+18+14+12+2, 28+26+18+14+12+5+2, 28+26+18+14+12+5, 28+26+18+14+ 12+6+2, 28+26+18+14+12+6+5+2, 28+26+18+14+12+6+5,

28+26+18+14+12+6, 28+26+18+14+12+8+2, 28+26+18+14+12+8+5+2,

28+26+18+14+12+8+5, 28+26+18+14+12+8, 28+26+18+14+12, 28+26+18+14,

28+26+18, 28+26+21+2, 28+26+21+5+2, 28+26+21+5, 28+26+21+6+2,

28+26+21+6+5+2, 28+26+21+6+5, 28+26+21+6, 28+26+21+8+2, 28+26+21+8+5+ 2, 28+26+21+8+5, 28+26+21+8, 28+26+21 + 12+2, 28+26+21 + 12+5+2, 28+26+21 + 12+ 5, 28+26+21+12+6+2, 28+26+21+12+6+5+2, 28+26+21+12+6+5, 28+26+21+12+6, 28+26+21+12+8+2, 28+26+21+12+8+5+2, 28+26+21+12+8+5, 28+26+21+12+8, 28+ 26+21+12, 28+26+21+14+12+2, 28+26+21+14+12+5+2, 28+26+21+14+12+5, 28+26+21+ 14+12+6+2, 28+26+21+14+12+6+5+2, 28+26+21+14+12+6+5,

28+26+21+14+12+6, 28+26+21+14+12+8+2, 28+26+21+14+12+8+5+2,

28+26+21+14+12+8+5, 28+26+21+14+12+8, 28+26+21+14+12, 28+26+21+14,

28+26+21+18+12+2, 28+26+21+18+12+5+2, 28+26+21+18+12+5,

28+26+21+18+12+6+2, 28+26+21+18+12+6+5+2, 28+26+21+18+12+6+5,

28+26+21+18+12+6, 28+26+21+18+12+8+2, 28+26+21+18+12+8+5+2,

28+26+21+18+12+8+5, 28+26+21+18+12+8, 28+26+21+18+12,

28+26+21+18+14+12+2, 28+26+21+18+14+12+5+2, 28+26+21+18+14+12+5,

28+26+21+18+14+12+6+2, 28+26+21+18+14+12+6+5+2,

28+26+21+18+14+12+6+5, 28+26+21+18+14+12+6, 28+26+21+18+14+12+8+2,

28+26+21+18+14+12+8+5+2, 28+26+21+18+14+12+8+5, 28+26+21+18+14+12+8, 28+ 26+21 + 18+14+12, 28+26+21 + 18+14, 28+26+21 + 18, 28+26+21, 28+26.

In the above list, the numbers refer to the embodiments according to their numbering provided above, while + indicates the limitations set out above.

9) The third aspect of the invention relates to compounds of formula (I), which are also compounds of formula (III)

- 25 040901

wherein the features disclosed in embodiments 2)-27) are intended to be applied, mutatis mutandis, also to the compounds of formula (III) according to embodiment 29); where, in particular, the following embodiments are thus possible and implied and are hereby specifically disclosed in an individualized form:

29+8, 29+11, 29+12+8, 29+12+11, 29+12, 29+15+8, 29+15+11, 29+15+12+8,

29+15+12+11, 29+15+12, 29+15, 29+18+8, 29+18+11, 29+18+12+8, 29+18+12+11, 29+18+ 12, 29+18+15+8, 29+18+15+11, 29+18+15+12+8, 29+18+15+12+11, 29+18+15+12, 29+18+ 15, 29+18, 29+21+8, 29+21+11, 29+21+12+8, 29+21+12+11, 29+21+12, 29+21+15+8, 29+ 21+15+11, 29+21+15+12+8, 29+21+15+12+11, 29+21+15+12, 29+21+15, 29+21+18+8, 29+ 21+18+11, 29+21+18+12+8, 29+21+18+12+11, 29+21+18+12, 29+21+18+15+8, 29+21+18+ 15+11, 29+21+18+15+12+8, 29+21+18+15+12+11, 29+21+18+15+12, 29+21+18+15,

29+21+18, 29+21, 29+26+8, 29+26+11, 29+26+12+8, 29+26+12+11, 29+26+12, 29+26+15+ 8, 29+26+15+11, 29+26+15+12+8, 29+26+15+12+11, 29+26+15+12, 29+26+15, 29+26+18+ 8, 29+26+18+11, 29+26+18+12+8, 29+26+18+12+11,

29+26+18+12, 29+26+18+15+8, 29+26+18+15+11, 29+26+18+15+12+8,

29+26+18+15+12+11, 29+26+18+15+12, 29+26+18+15, 29+26+18, 29+26+21+8, 29+26+21+ 11, 29+26+21+12+8, 29+26+21+12+11, 29+26+21+12, 29+26+21+15+8, 29+26+21+15+11, 29+26+21+15+12+8, 29+26+21+15+12+11, 29+26+21+15+12, 29+26+21+15, 29+26+21+18+ 8, 29+26+21+18+11, 29+26+21+18+12+8,

29+26+21 + 18+12+11, 29+26+21 + 18+12, 29+26+21 + 18+15+8, 29+26+21 + 18+15+11, 29+26+ 21+18+15+12+8, 29+26+21+18+15+12+11, 29+26+21+18+15+12,

29+26+21 + 18+15, 29+26+21 + 18, 29+26+21, 29+26, 29.

In the above list, the numbers refer to the embodiments according to their numbering provided above, while + indicates the limitations set forth above.

0) Another embodiment relates to compounds of formula (III) in accordance with option 29), where

R ² means halogen (especially chlorine), methyl, ethyl, methoxy or ethoxy;

R ³ is C _1-3 alkoxy (especially methoxy) or C _1- sfluoroalkoxy (especially difluoromethoxy);

Ar ¹ is phenyl, or a 6-membered heteroaryl containing one or two nitrogen atoms (especially pyridinyl); (namely, Ar ¹ is phenyl), where said Ar ¹ group is substituted by R ⁴ and R ⁵ , where

R ⁴ is n-propyl, isopropyl, or C _3-6 cycloalkyl, optionally containing a ring oxygen atom (especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4yl); (wherein it is to be understood that said R ⁴ substituent is attached ortho to the point of attachment of the rest of the molecule) (wherein R ⁴ is in particular isopropyl) and

R ⁵ is hydrogen or fluorine (wherein R ⁵ is in particular hydrogen);

m and n are independently the integer 1 or 2 (in particular both m and n are the integer 1); and the -LR ⁶ group is hydrogen;

- 26 040901

-L'-CO-RC ¹¹ where R ^C11 is independently hydroxy; -O-benzyl; -O-C _1-6 alkyl;

Ci-fluoroalkyl; or -NR ⁿ¹¹ R ⁿ¹² ; where independently R ^N11 is hydrogen or C1-4 alkyl and R ^N12 is hydrogen, C1-4 alkyl, -SO ₂ -C _1-6 alkyl or -OR ⁰¹¹ where R ⁰¹¹ is independently hydrogen, C _1-6 alkyl, or benzyl; And

-L ¹ - independently represents

- C _1-6 alkylene-, -C0-C _1-6 alkylene-, -80 ₂ -C ₁ . ₆ alkylene-, -CO-O-C _1-6 alkylene-, -C0 ^ H-C _1-6 alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-;

- C _o-4 alkylene-C _3-8 cycloalkylene-C _o-4 alkylene-, -CO-C _o-4 alkylene-C _3-8 cycloalkylene-C _o-4 alkylene-, -S02Co _-4 alkylene-C _{3 -8} cycloalkylene-Co _-4 alkylene-, -CO-NH-C _0-4 alkylene-C _3-8 cycloalkylene-C _0-4 alkylene- or -CO-O-C _0-4 alkylene-C _3-8 cycloalkylene -C _0-4 alkylene-;

- L ² -hydroxy; where -L ² - represents

- C0-C _1- balkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups said C _1-6 alkylene is independently unsubstituted or monosubstituted by hydroxy, C ₁ -fluoroalkyl or -NR ^N21 R ^N22 , where independently R ^N21 is hydrogen or C1-4 alkyl and R ^N22 is hydrogen, C 1-4 alkyl or -CO -O-C _1-4 alkyl;

- C _2-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _2-6 alkylene- or -SO2-NH-C _2-6 alkylene-, where in the above groups the indicated C _2-6 alkylene is independently unsubstituted or monosubstituted with hydroxy, C ₁ -fluoroalkyl or -NR ^N23 R ^N24 , where independently R ^N23 is hydrogen or C1-4 alkyl and R ^N24 is hydrogen, C1-4 alkyl or -C0-0-C _{1- 4} alkyl;

- C _o-4 alkylene-C _3-6 cycloalkylene-C _o-4 alkylene-, -CO-C _o-4 alkylene-C _3-6 cycloalkylene-C _o-4 alkylene- or -SO ₂ -C _0-4 alkylene-C _3-6 cycloalkylene-C _0-4 alkylene-;

- L ⁷ -NR ^N5 R ^N6 , where RN ⁵ is hydrogen or C1-4 alkyl (especially hydrogen); RN ⁶ is hydrogen, C1-4 alkyl, -C0-C _1-4 alkyl, C _1-3 fluoroalkyl or C _3-6 cycloalkyl (especially hydrogen); And

- L ⁷ - independently represents

- CO- or -S02-;

- L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl (especially pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl; thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl , pyrazinyl), wherein said NO ¹ is independently unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from C1-4 alkyl (especially methyl), halogen, cyano, hydroxy, hydroxymethyl, and —Co-2-alkylene-Cy ⁹¹ —COOR ^O91 where R ⁰⁹¹ is hydrogen or C1-4 alkyl and where Cy ⁹¹ is a C3-6 cycloalkylene group; or -C0-2alkylene-COOR ^O92 where R ⁰⁹² is hydrogen or C1-4alkyl; And

- L ⁹ - independently represents

- C _o-6 alkylene-, -CO-C _o-6 alkylene-, -SO ₂ -C _0-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-; or

- L ¹⁰ -C _4-6 heterocyclyl, where C _4-6 heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, the specified C _4-6 heterocyclyl is independently unsubstituted, or mono-, di- or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom (thus forming with the nitrogen an amide group, or in case an additional ring oxygen is adjacent, a carbamate group, or in case an additional second ring nitrogen is adjacent, a urea group); and/or two methyl substituents attached to the ring carbon atom in the alpha position to the ring nitrogen atom or the ring oxygen atom (thus forming together with nitrogen a C(CH ₃ ) ₂ -N- group, or with oxygen -C(CH ₃ ) ₂ -O- group); and/or two oxo substituents on the ring sulfur atom (thus forming a -SO2- group); and/or

C _1-4 alkyl, C _1-3 alkoxy-C _2-4 alkyl, C _2-3 fluoroalkyl, or —CO—C _1-4 alkyl attached to a free valence ring nitrogen atom; And

- L ¹⁰ - independently represents

- C _o-6 alkylene-, -CO-C _o-6 alkylene-, -SO ₂ -C _0-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-.

31) Another embodiment relates to compounds of formula (III) according to option 29) or 3o), where R ² means halogen (especially chlorine), methyl or methoxy.

32) Another embodiment relates to compounds of formula (III) according to any one of embodiments 29)-31), where R ⁴ is isopropyl.

33) Another embodiment relates to compounds of formula (III) according to any one of embodiments 29)-32), where the -LR ⁶ group is hydrogen;

- L ¹ -CO-R ^C11 where R ^C11 independently represents hydroxy; -O-benzyl; or -0-C _1-6 alkyl; And

- L ¹ - independently represents

- C _1-6 alkylene-, -C0-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene or

- 27 040901

-SO ₂ -NH-C ₁ . ₆ alkylene-;

-C ₀ . ₄ alkylene-C ₃ .8 cycloalkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C ₃ .8 cycloalkylene-C ₀ . ₄ alkylene-, -SO ₂ C ₀ . ₄ alkylene-C ₃ .8 cycloalkylene-C ₀ . ₄ alkylene-, -CO-NH-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene or

-CO-O-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-;

- L ⁷ -NR ^N5 R ⁿ⁶ , where RN ⁵ is hydrogen or C1.4 alkyl (especially hydrogen); RN ⁶ means hydrogen, C1.4alkyl, -CO-C ₁ . ₄ alkyl, C ₁ . ₃ fluoroalkyl or C ₃ . ₆ cycloalkyl (especially hydrogen); And

- L ⁷ - is independently -CO- or -SO2-; or

- L ¹⁰ -C ₄ . ₆ heterocyclyl, where C ₄ . ₆ heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups specified With ₄ . ₆ heterocyclyl is independently unsubstituted, or mono-, di-, or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon at the alpha position to the ring nitrogen (thus forming, together with the nitrogen, an amide a group, or in case an additional ring oxygen is adjacent, a carbamate group, or in case an additional second ring nitrogen is adjacent, a urea group); And

- L ¹⁰ - independently represents

_-C0 . ₆ alkylene-, -CO-C ₀ . ₆ alkylene-, -SO ₂ -C ₀ . ₆ alkylene-, -CO-O-C ₁ . ₆ alkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-C ₁ . ₆ alkylene-.

34) Another embodiment relates to compounds of formula (I) according to option 1), which are selected from the following compounds:

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-4-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)pyrrolidine-3-carboxamide;

I-(2-aminoethyl)-M-(2-(difluoromethoxy)-6-methyl pyride in-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormethoκci)-6-methylpyridin-3-yl)-l-(2-hydroxiethyl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormethoκci)-6-methylpyridin-3-yl)-l-(3-hydroxipropyl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

1-cyano-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

1-(3-(1H-tetrazol-5-yl)propyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-1-(3-hydroxy-3-methylbutyl)3-(2-isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l-(2-(lhydroxycyclopropyl)ethyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

- 28 040901

I-(2-aminopropyl)-1H-(2-(difluoromethoxy)-6-methyl pyride in-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)propanoic acid;

1-(2-cyanoethyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

(R)-N-(2-(fl ifluoromethoxy)-6-methyl pyride in-3-yl)-1-(2,3dihydroxypropyl)-3-(2-isopropylphenyl)azetide in-3-carboxamide ;

(K)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2,3dihydroxypropyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l(oxetan-3-yl)azetidine-3-carboxamide;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)butanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3,3-dimethylbutanoic acid;

5-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)-1H-pyrrole-2-carboxylic acid;

5-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)furan-2-carboxylic acid;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-l-(4-hydroκci-4methylpentyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethylpentanoic acid;

-(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)propyl)cyclopropan-1-carboxylic acid;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(2(methylsulfonamido)ethyl)azetide in-3-carboxamide;

(8)-1H-(2-(d ifluoromethoxy)-6-methyl pyride in-3-yl)-1-(2-hydroxy-3-(2hydroxyacetamido)propyl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide;

1-(cyanomethyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

- 29 040901

1-(2-(1H-tetr-azol-5-yl)ethyl)-T4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)azetidine-3-carboxamide;

1-(4-cyanobutanoyl)^-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

1-acetyl-T4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(3sulfamoylpropanoyl)azetidine-3-carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2(N-methylcylφamoyl)acetyl)azetidine-3-carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1((methylsulfonyl)glycyl)azetidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(Nmethyl-M-sulfamoyl glycyl)azetide in-3-carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1(5,5,5-trifluoro-4-oxopentanoyl)azetidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-4-(2-isopropylφenyl)-l(5,5,5-trifluoro-4-oxopentanoyl)piperidine-4-carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxyoxetan-3yl)acetyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-l-(3-hydroκciisoκcasol-5carbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide [tautomeric form: N-(2-( diφτopmetoκci)-6-methylpyridin-3-yl)-l-(3-oκco-2,3-dihydroisoκcazol-5carbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide];

-(2-(1H-tetr azol-1-yl)acetyl)-M-(2-(difluoromethoxy)-6-methyl pyrid in-3yl)-4-(2-isopropylphenyl)piperidine-4-carboxamide;

1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-M-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3- carboxamide;

1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-M-(2-(difluoromethoxy)-6methylpyridin-3-yl)-4-(2-isopropylphenyl)piperidine-4- carboxamide;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1H-pyrazol5-yl)acetyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide [ and its tautomeric forms such as N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-30 040901 (2-(3-oxo-2,3-dihydro-1H-pyrazol-5-yl )acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide];

T4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1H-pyrazol4-yl)acetyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide [ and its tautomeric forms such as X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-oxo-2,3dihydro-1H-pyrazol-4-yl)acetyl)- 3-(2-isopropylphenyl)azetidine-3carboxamide];

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1H-pyrazol4-yl)acetyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide [ and its tautomeric forms such as X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1(2-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetyl) -4-(2isopropylphenyl)piperidine-4-carboxamide];

1-(E-alanyl)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)-1-((2methoxyethyl)glycyl)piperidine-4-carboxamide;

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2-hydroxyethyl)glycyl)4-(2-isopropylphenyl)piperidine-4-carboxamide;

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2-hydroxyethyl)glycyl)3-(2-isopropylphenyl)azetidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-((2methoxyethyl)glycyl)azetide in-3-carboxamide;

(K)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((K)-(2hydroxypropyl)glycyl)-3-(2-isopropyl phenyl)azetidine-3-carboxamide;

(8)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((8)-(2hydroxypropyl)glycyl)-3-(2-isopropyl phenyl)azetidine-3-carboxamide;

(K)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((K)-(1-hydroxypropan2-yl)glycyl)-3-(2-isopropylphenyl)azetidine-3- carboxamide;

(8)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((K)-(1-hydroxypropan2-yl)glycyl)-3-(2-isopropylphenyl)azetidine-3- carboxamide;

3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3-oxopropanoic acid;

3-(4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)-3-oxopropanoic acid;

- 31 040901

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-4-oxobutanoic acid;

4-(4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)-4-oxobutanoic acid;

(8)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-methyl-4-oxobutanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

1-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)cyclopropane-1-carboxylic acid;

1-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)cyclobutane-1-carboxylic acid;

(K)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3-methyl-4-oxobutanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3,3-dimethyl-4-oxobutanoic acid;

3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)but-3-enoic acid;

(18.2K)-2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1-carboxylic acid;

(1K,28)-2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1-carboxylic acid;

5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-5-oxopentanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3,3-difluoro-4-oxobutanoic acid;

(8)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-hydroxy-2-methyl-4- oxobutanoic acid;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1(5,5,5-trifluoro-4-hydroxypentanoyl)azetidine-3-carboxamide;

4-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)tetrahydro-2H-pyran-4 - carboxylic acid;

- 32 040901

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1(sulfamoylglycyl)azetidine-3-carboxamide;

1-(N-acetyl-N-hydroxyglycyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)acetic acid;

2-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)sulfonyl)acetic acid;

3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)propanoic acid;

3-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)sulfonyl)propanoic acid;

3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)-2,2-dimethylpropanoic acid;

2-(1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)cyclopropyl)acetic acid;

4-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)butanoic acid;

(E)-3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)acrylic acid;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((3-(hydroxyamino)-3oxopropyl)sulfonyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)acetic acid;

2-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidine-1-carbonyl)oxy)acetic acid;

(K)-2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)propanoic acid;

1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)cyclopropane-1-carboxylic acid;

3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)-2,2-dimethylpropanoic acid;

- 33 040901

1-(((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)methyl)cyclopropane-1-carboxylic acid;

((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)glycine;

N-(2-(diφtormethoκci)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-1sulfamoyl azetidine-3-carboxamide;

N-(2-(diφtormetoκci)pyridin-3-yl)-3-(2-isopropylphenyl)-1sulfamoyl-azetidine-3-carboxamide;

N-(2,6-dimethoκcypyridin-3-yl)-3-(2-isopropylφenyl)-l-sulfamoyl azetidine-3-carboxamide;

N-(6-etoksi-2-methokocypiridin-3-yl)-3-(2-isopropylφenyl)-l-sulfamoylazetidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(Nmethylsulfamoyl)azetidine-3-carboxamide;

l-(N-cyclopropylcyl-phamoyl)-N-(2-(diφτopmetoksi)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(2(sulfamoylamino)ethyl)azetide in-3-carboxamide;

N-(2-(diφtormetoκci)-5-φtorpyridin-3-yl)-3-(2-isopropylφenyl)-l-sulfamoylazetidine-3-carboxamide;

3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)-3-methylbutanoic acid;

M1-((1H-imidazol-4-yl)methyl)-X4-(2-(difluoromethoxy)-6-methylpyridin-3yl)-4-(2-isopropylphenyl)piperidine-1,4-carboxamide;

3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)-2,2-dimethylpropanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)-2,2-dimethylbutanoic acid;

N4-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-1,4-dicarboxamide;

N4-(2-(diφtormethocy)-6-methylpyridin-3-yl)-Nl-(2-hydroxiethyl)-4-(2isopropylphenyl)piperidine-1,4-dicarboxamide;

- 34 040901

6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)nicotinic acid;

6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)picolinic acid;

2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine-5-carboxylic acid;

6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyridazine-3-carboxylic acid;

5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrazine-2-carboxylic acid;

1-(5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidin-2-yl)cyclopropan-1-carboxylic acid ;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l-(4-φtorpyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-l-(3-φtorpyridin-4-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-l-(5-φtorpyrimidin-4-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)pyridin-3-yl)-l-(5-φtorpyrimidin-4-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

1-(5-cyanopyridin-2-yl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide;

I-(5-cyanopyride in-2-yl)-1H-(2-(difluoromethoxy) pyride in-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

1-(5-cyanopyrimidin-2-yl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)azetidine-3-carboxamide;

1-(5-cyanopyrimidin-2-yl)-PM-(2-(difluoromethoxy)pyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-4-carboxylic acid;

N-(2-(diφtormethoκci)-6-methylpyridin-3-yl)-l-(5-φtorpyrimidin-2-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide;

- 35 040901

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(2methylpyrimidin-4-yl)azetidine-3-carboxamide;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4oxo-4,5-dihydrooxazol-2-yl)azetidine-3-carboxamide [tautomeric form: N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4hydroxyoxazol-2-yl)azetidine-3-carboxamide];

[ tautomeric form: N-(2-(diφτopmetoksi)-6-methylpyridin-3-yl)-3-(2-isopropylφenyl)-l-(5oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)azetidine-3-carboxamide];

3-(2-cyclopentylphenyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide;

3-(2-cyclohexylphenyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide;

4-(3-(2-cyclobutylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-(2-cyclopentylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-(2-cyclohexylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2propylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-3-(2-φtor-6isopropylphenyl)azetidine-3-carboxamide;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropyl-5-methylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid ;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-fluoro-6isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid ;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(5-fluoro-2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid ; And

X-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-]H-propyl glycine .

35) In addition to the compounds listed in embodiment 33), additional compounds of formula (I) according to embodiment 1) are selected from the following compounds:

- 36 040901 methyl K-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-M- (2-methoxyethyl)glycinate;

M-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-M-(2-methoxyethyl) )glycine;

methyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)glycinate;

(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)glycine;

M-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-M-ethylglycine;

3-(2-isopropylphenyl)-M-(6-methyl-2-propoxypyridin-3-yl)-1sulfamoyl-azetidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2yl)az ethidine-3-carboxamide;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(3isopropylpyridin-2-yl)azetidin-1-yl)-4-oxobutanoic acid;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2yl)-1-sulfamoylaz etidine-3-carboxamide;

K1-cyclopropyl-K3-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3isopropylpyridin-2-yl)azetidine-1,3-dicarboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-fluoro-2-methylpyrimidin4-yl)-3-(3-isopropylpyridin-2-yl)az ethidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-fluoro-6-methylpyridin-2yl)-3-(3-isopropylpyridin-2-yl)az ethidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4yl)az ethidine-3-carboxamide;

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4yl)-1-sulfamoylaz etidine-3-carboxamide;

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(3-isopropyl pyrazin-2yl)azetidine-3-carboxamide; And

M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyrazin-2-yl)1-sulfamoylazetidine-3-carboxamide.

36) In addition to the compounds listed in options 33) and 34), additional compounds of formula (I) according to option 1) are selected from the following compounds:

- 37 040901

N-(5-chloro-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3 carboxamide;

N-(5-bromo-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;

M-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

M-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

M-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide;

M-(3,5-dimethoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide;

M-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2cyclopentylphenyl)azetidine-3-carboxamide;

M-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(3-isopropylpyridin-2yl)azetidine-3-carboxamide;

methyl 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoate;

4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid;

methyl 4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoate;

4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

- 38 040901

4-(3-((5-chloro-3-methoxypyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((5-bromo-3-methoxypyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

1-(2-(3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)cyclobutane-1-carboxylic acid;

benzyl 3-((3-((3-(d iffluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)propanoate;

3-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)sulfonyl)propanoic acid;

N-(5-chloro-3-methoκcypyridin-2-yl)-3-(2-isopropylφenyl)-l-sulfamoyl-azetidine-3-carboxamide;

N-(5-bromo-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)-1sulfamoyl-azetidine-3-carboxamide;

N-(5-chloro-3-(diφτopmetoκci)pyridin-2-yl)-3-(2-isopropylφenyl)-1sulfamoyl azetidine-3-carboxamide;

N-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-3-(2-isopropylphenyl)-1sulfamoyl-azetidine-3-carboxamide;

N-(3,5-dimethoκcypyridin-2-yl)-3-(2-isopropylφenyl)-l-sulfamoyl azetidine-3-carboxamide;

N-(5-chloro-3-(diφτopmetoκci)pyridin-2-yl)-3-(2-cyclopentylphenyl)-1sulfamoyl-azetidine-3-carboxamide;

N-(5-chloro-3-(diφτopmetoκci)pyridin-2-yl)-3-(3-isopropylpyridin-2-yl)1-sulfamoylazetidine-3-carboxamide;

N ³ -(5-chloro-3-(difluoromethoxy) pyride and η-2-ηπ)-N'-cyclopropyl-3-(2isopropylphenyl)azetidine-1,3-dicarboxamide;

N ³ -(5-bromo-3-(difluoromethoxy) pyride and n-2-yl)-M'-cyclopropyl-3-(2isopropylphenyl)azetidine-1,3-dicarboxamide;

2-methoxy-2-oxoethyl 3-((3-(difluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate;

2-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)acetic acid;

1-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)oxy)cyclopropane-1-carboxylic acid;

And

M-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2-isopropylphenyl)-1-(4oxo-4,5-dihydrooxazol-2-yl)azetidine-3-carboxamide.

The compounds of formulas (I), (II) and (III) according to embodiments 1)-36) and their pharmaceutically acceptable salts can be used as drugs, for example in the form of pharmaceutical compositions for enteral (such as, in particular oral , for example, in the form of a tablet or capsule) or parenteral administration (including topical application or inhalation).

The manufacture of pharmaceutical compositions can be carried out in a manner known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy,

- 39 040901

21st Edition (2005), Part 5, Pharmaceutical Manufacturing (published by Lippincott Williams & Wilkins)) by introducing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenic dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier substances and, if appropriate, conventional pharmaceutical excipients.

The present invention also relates to a method for preventing/preventing or treating a disease or disorder mentioned in this application, comprising administering to a subject a pharmaceutically active amount of a compound of formulas (I), (II) or (III) in accordance with embodiments 1)-36).

For the avoidance of misinterpretation, where compounds are described as being useful in the prevention/prevention or treatment of certain diseases, such compounds are also suitable for use in the preparation of a medicament for the prevention/prevention or treatment of said diseases. Likewise, such compounds are also useful in a method of preventing/preventing or treating such diseases, comprising administering to a subject (mammalian, especially a human) in need thereof an effective amount of such a compound.

The compounds of formulas (I), (II) and (III) according to embodiments 1)-36) are useful in the prevention and/or treatment of fibrosis (and diseases or disorders associated with fibrosis), or other disorders mediated by signaling with the participation of LPA1 receptors.

The term fibrosis refers to conditions that are associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased recruitment of fibroblasts in an organ; including fibrosis of specific organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal tissue, and gastrointestinal tract.

The term fibrosis in particular can be defined as including all forms of pulmonary fibrosis, including fibrosis-related lung diseases, including idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory disease such as rheumatoid arthritis, scleroderma, lupus; cryptogenic fibrosing alveolitis; pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; silicosis; asbestos-induced pulmonary fibrosis; and fibrosis of the pleura;

fibrosis of the kidneys; including renal fibrosis associated with CKD, chronic renal failure, tubulointerstitial nephritis and/or chronic nephropathies such as (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, focal segmental glomerulosclerosis, IgA- nephropathy, hypertension, renal allograft, and Alport's syndrome;

fibrosis of the gastrointestinal tract, including fibrosis of the gastrointestinal tract secondary to scleroderma, and radiation-induced fibrosis of the gastrointestinal tract;

all forms of liver fibrosis, including cirrhosis, alcoholic liver fibrosis, non-alcoholic steatohepatitis, bile duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infection- or virus-induced liver fibrosis (eg, chronic HCV infection), and autoimmune hepatitis;

fibrosis of the head and neck, including radiation-induced fibrosis of the head and neck;

corneal scarring, including the effects of LASIK (laser specialized keratomileusis), corneal transplants and trabeculectomy;

hypertrophic scarring and keloids, including burn-induced hypertrophic scarring or postoperative hypertrophic scarring, and keloids;

and other fibrosing diseases, eg endometriosis, spinal cord fibrosis, myelofibrosis, myocardial fibrosis, perivascular fibrosis; as well as scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis, and fibroblast-mediated fibrosis.

The term fibrosis prevention/prevention includes preventing fibrosis in a subject who has been exposed to one or more environmental conditions known to increase the risk of organ or tissue fibrosis, especially the risk of lung, liver, or kidney fibrosis; or in a subject who has a genetic predisposition to develop organ or tissue fibrosis; and preventing or minimizing scarring after trauma, including surgery.

Other disorders mediated by LPA1 receptor signaling include, in particular, dermatological disorders, pain, malignant and benign proliferative diseases, respiratory diseases, nervous system disorders, cardiovascular diseases, and inflammatory diseases, obesity, and insulin resistance.

The term dermatological disorder refers to a disease of the skin. Such dermatological disorders include proliferative or inflammatory skin diseases such as systemic

- 40 040901 sclerosis, atopic dermatitis, bullous disorders, collagenosis, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, Sjögren-Larsson syndrome; especially systemic sclerosis.

The term pain refers to acute pain, chronic pain and neuropathic pain. A single example is fibromyalgia, in particular fibromyalgia, which is a consequence of the formation of fibrous scar tissue in the contractile muscles, and cancer pain.

The term malignant and benign proliferative disease specifically refers to malignancy and the control of tumor cell proliferation, invasion and/or metastasis of carcinomas.

The term malignant neoplasm refers to all types of malignant neoplasms such as carcinomas; adenocarcinomas; leukemia; sarcomas; lymphomas; myeloma; metastatic types of malignant neoplasms; brain tumors; neuroblastomas; malignant neoplasms of the pancreas; malignant neoplasms of the gastrointestinal tract; malignant neoplasms of the lung; malignant neoplasms of the breast; malignant neoplasms of the prostate; malignant neoplasms of the endometrium; malignant neoplasms of the skin; malignant neoplasms of the bladder; malignant neoplasms of the head and neck; neuroendocrine tumors; malignant neoplasms of the ovary; malignant neoplasms of the cervix; tumors of the oral cavity; tumors of the nasopharynx; thoracic malignant neoplasms; and virus-induced tumors. In particular, the term refers to pleural mesothelioma, peritoneal mesothelioma and bone metastases, as well as brain tumors, including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningioma; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; malignant neoplasms of the gastrointestinal tract, including colon carcinoma, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; Kaposi's sarcoma; leukemias, including acute myeloid leukemia, adult T-cell leukemia; lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, MALT-type lymphoma, and primary intraocular B-cell lymphoma; lung cancer, including non-small cell lung cancer; breast cancer, including triple negative breast carcinoma; rhabdomyosarcoma; prostate cancer, including castration-resistant prostate cancer; squamous cell carcinoma of the esophagus; squamous cell carcinoma (oral cavity); endometrial cancer; thyroid carcinoma, including papillary thyroid carcinoma; metastatic types of malignant neoplasms; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer, including cancer of the bladder itself, urothelial cell carcinoma; multiple myeloma; osteosarcoma; head and neck cancer; and carcinomas of the kidney, including renal cell carcinoma, clear cell renal cell carcinoma, metastatic renal cell carcinoma, metastatic clear cell renal cell carcinoma; as well as neuroendocrine tumors; ovarian cancer; cervical cancer; tumors of the oral cavity; tumors of the nasopharynx; thoracic cancer; choriocarcinoma; Ewing's sarcoma; and virus-induced tumors.

The term respiratory disease refers to diseases that affect the organs that are involved in the breathing process, such as the nose, pharynx, larynx, Eustachian tubes, trachea, bronchi, lungs, related muscles (eg, diaphragm and intercostal muscles), and nerves. Respiratory diseases include interstitial pneumonia, asthma, referring to any lung disorder characterized by variations in gas flow in the lungs that is associated with airway constriction caused by any cause (intrinsic, extrinsic, or both; allergic or non-allergic), including adult respiratory distress syndrome and allergic (exogenous) asthma, non-allergic (endogenous) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise asthma, isocapnic hyperventilation, childhood-onset asthma, asthma, adult-onset, cough asthma, occupational asthma, steroid-resistant asthma, seasonal asthma; rhinitis, including seasonal allergic rhinitis, perennial allergic rhinitis; chronic obstructive pulmonary disease (COPD), including chronic bronchitis or emphysema; airway inflammation, sarcoidosis, cystic fibrosis, hypoxia, and acute lung injury and acute respiratory distress (including those caused by bacterial pneumonia, trauma, viral pneumonia, mechanical ventilation, nonpulmonary sepsis, and aspiration).

The term nervous system disorder refers to conditions that alter the structure or function of the brain, spinal cord, or peripheral nervous system, including, but not limited to, Alzheimer's disease, cerebral edema, multiple sclerosis, neuropathies, Parkinson's disease, neurological disorders nervous system as a result of blunt or

- 41 040901 surgical trauma (including postoperative cognitive dysfunction and damage to the spinal cord or brain stem, and head trauma), migraine, as well as neurological aspects of disorders such as degenerative disease of the spine and sciatica.

The term cardiovascular disease, as used herein, refers to diseases affecting the heart or blood vessels, or both, including, but not limited to, arrhythmia (atrial or ventricular, or both); atherosclerosis and its consequences; cerebral ischemia, stroke, angina pectoris; heart rhythm disturbances; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessels, including aortic aneurysm; retinal ischemia; reperfusion injury due to ischemia of the brain, heart, or other organ or tissue; restenosis; peripheral obstructive arteriopathy of a limb, organ or tissue; endotoxic, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including those associated with migraine); vascular disorders, thrombosis, insufficiency limited to one organ or tissue.

The term inflammatory disease includes psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, inflammatory muscle disease, vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic or xenogeneic transplant rejection (organ, bone marrow, stem cells, and other cells). and tissues), graft-versus-host disease, mixed connective tissue disease, lupus erythematosus, type I diabetes, dermatomyositis, phlebitis, Sjögren's syndrome, granulomatosis with angiopathy (GPA, Wegener's granulomatosis), thyroiditis (eg, Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis gravis, autoimmune hemolytic anemia, chronic relapsing hepatitis, allergic conjunctivitis, atopic dermatitis, sinusitis, and neutrophil-mediated inflammation.

Other disorders in which the LPA1 receptor plays a role include, in particular, prostate and bladder disorders such as benign prostatic hyperplasia, diseases associated with eosonophilic and/or basophilic and/or dendritic cells, and/or neutrophil recruitment and/or monocytes and / or T cells, cardiomyopathy, myocardial remodeling, vascular remodeling, vascular permeability disorders, kidney disease, papillary necrosis of the kidney, renal failure, tumor growth, metabolic diseases, pruritus, eye diseases, macular degeneration, endocrine disorders, hyperthyroidism, osteoporosis, diabetes-related diseases (nephropathy, retinopathy).

The present invention further relates to compounds of formulas (I), (II) and (III) for use in the treatment of diseases and disorders mentioned in this application (especially for the treatment of fibrosis), where the compound of formulas (I), (II) and ( III) is intended for use in combination (either in the same pharmaceutical composition or as a separate treatment) with one or more antifibrotic agents. Examples of such antifibrotic agents include corticosteroids, immunosuppressants, B-cell antagonists, and uteroglobin.

Preparation of compounds of formulas (I), (II) and (III).

Compounds of formulas (I), (II) and (III) can be obtained using well known literature methods, using the methods below, using the methods given in the experimental section below, or using similar methods. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization techniques. In some cases, the order of the following reaction schemes and/or steps of a particular reaction may be varied in order to promote the reaction or avoid unwanted reaction products. In the general sequence of reactions set forth below, the generic groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L are as defined for formula (I). Other abbreviations used in this application are clearly defined, or are as defined in the experimental section. In some cases, the generic groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and L may not be compatible with the set of other groups illustrated in the diagrams below, and therefore will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, Wiley-Interscience, 1999; PJ Kocienski, Protecting Groups, Thieme Stuttgart, 1994). For the purposes of this discussion, it will be assumed that such protecting groups are in place when necessary. In some cases, the end product can be further modified, such as by manipulating substituents to produce a new end product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal-catalyzed cross-coupling reactions, which are well known to those skilled in the art. The resulting compounds can also be converted into salts, in particular pharmaceutically acceptable salts, by a method known per se.

The compounds of formulas (I), (II) and (III) can be produced using the methods below, using the methods given in the experimental section, or using similar methods. Optimum reaction conditions may vary depending on the specific reagents used.

- 42 040901 tov or solvents, but such conditions can be determined by a person skilled in the art using routine optimization techniques.

Compounds of formulas (I), (II) and (III) of the present invention can be obtained in accordance with the general sequence of reactions set forth below. Only some of the possible synthetic routes leading to the compounds of formulas (I), (II) and (III) are described.

Compounds of formula (I) are prepared by reacting a compound of structure 1a or structure 1b with a compound of structure 2 in a solvent such as DMF, THF, DCM, EtOAc, etc. in the presence of one or more carboxylate activating agents such as SOCl ₂ , (COCl) ₂ , POCl ₃ , EDC, HOBt, HBTU, TBTU, DCC, CDI, T3P, etc., and in the presence or absence of a base such as TEA, DIPEA, NaH, K ₂ CO ₃ , etc. d. (Montalbetti CA., Falque V. Tetrahedron 2005 (46) 10827-10852; Valeur E., Bradley M. Chem. Soc. Rev. 2009 (389) 606-31). The R ⁴ residue may be present at the coupling step, or may be introduced at a later stage by replacing Br with an alkyl group under Negishi reaction conditions or by performing a Suzuki reaction/hydrogenation sequence as known to one skilled in the art. (Matsushita LH., Negishi EJ Org. Chem. 1982 (47) 4161-4165; Kerins, F. et al. J. Org. Chem. 2002 (67) 4968-4971).

In the case of obtaining compounds of formula I, it is possible to carry out reactions of the combination of structure 1a and structure 1b with structure 2 with the side chain LR ⁶ =X already present, or with structure 2, where N carries a protective group = X. Then, after deprotection, a functional an R ⁶ group by formation of an amine, amide, sulfonamide, carbamate, urea or sulfamide linker (L), for example, using a method known to a person skilled in the art.

Compounds of structure 1a and structure 1b may be commercially available or may be prepared by reducing a compound of structure 3a or structure 3b in a solvent such as THF, MeOH, EtOH, iPrOH, etc. in the presence of H ₂ /Pd/C or H ₂ /Pt+V/C or Fe, etc. (Dolle V. et al. Tetrahedron 1997 (53) 12505-12524; Mobus K. et al. Top. Catal. 2010 (53), 1126-1131; WO 2012/055995). If R1=H and ^R2 =Cl or Br, structure 1a and structure 1b can also be obtained by chlorination or bromination of the compound of structure 3c and structure 3d with N-chlorosuccinimide or N-bromosuccinimide using a method known to a person skilled in the art.

Compounds of structure 2 can be prepared by reacting a compound of structure 4 with 25% NaOH or concentrated H ₂ SO ₄ /AcOH or concentrated HCl at elevated temperature in a solvent such as water, EtOH, etc. (US 20120232026; WO 2005/049605; US 20080319188). Compounds of structure 2 can also be obtained by hydrolysis of a compound of structure 5 with an aqueous solution of NaOH or LiOH, etc. in a solvent such as water, MeOH, EtOH, THF, etc.

- 43 040901

Structure 6a Structure 6b Structure 7a Structure 7b

Compounds of structure 3a, structure 3b, structure 3c and structure 3d may be commercially available and may be prepared by reaction of structure 6a or structure 6b (wherein R ¹ is H or F and R ² is H, halogen, C _1-2 alkyl , OMe or OEt) with sodium chlorodifluoroacetate or 2,2-difluoro-2-(fluorosulfonyl)acetic acid at 60°C or higher in a solvent such as DMF, MeCN, etc., and in the presence of Na ₂ SO ₄ or a base such as Cs ₂ CO ₃ , K ₂ CO ₃ , etc. (Thomoson CS et al. J. Fluorine. Chem. 2014 (168) 34-39; Sperry J. B. et al. Org. ProcessRes. Dev. 2011 (15) 721-725; WO 2012/055995). Compounds of structure 3a, structure 3b, structure 3c and structure 3d can also be prepared by reacting compounds of structure 7a or structure 7b with an alcoholate such as NaOMe, NaOiPr in a solvent such as THF, DMF, etc. (WO 2010/023181). In the case of structure 3c and structure 3d, the nitro group is reduced in the next step using, for example, H ₂ and Pd/C. The remainder R ³ can also be introduced at a later stage, after the amide coupling.

Structure 8 Structure 9 Structure 10 Structure 11 Structure 12

Compounds of structure 4 and structure 5 may be commercially available (for n and/or m > 1) by the reaction of 2-(2-haloaryl)acetonitrile (structure 8) or methyl 2-(2haloaryl)acetate (structure 9), respectively, with N-benzyl-N,N-bis(2-chloroethyl)amine or N-bocN,N-bis(2-chloroethyl)amine at 60° C. or higher in a solvent such as THF and in the presence of base such as NaOH, NaH, etc. Compounds of structure 4 and structure 5 can also be prepared by the reaction of 2-(2-bromophenyl)acetonitrile with paraformaldehyde in a solvent such as DMF in the presence of a base such as K ₂ CO ₃ followed by a TFA-catalyzed 1,3-dipolar cycloaddition commercially available N-(methoxymethyl)-N(trimethylsilylmethyl)benzylamine in DCM (lit.: JP 2008110971). For n=m=1, compounds of structure 4 can be synthesized by reacting a compound of structure 10, 11, or 12 with a 1,2-dihaloaryl such as 1-bromo-2-fluorobenzene in a solvent such as THF in the presence of a base such as as KHMDS (WO 2012/017359). Alternatively, the bromo substituent can be replaced by R ⁴ = alkyl in the next step under Negishi reaction conditions or by following the sequence Suzuki reaction-hydrogenation as known to one skilled in the art.

Depending on the nature of the functional groups present at the R ⁶ residue in formulas (I), (II) and (III), these functional groups may require temporary protection. Suitable protecting groups are known to those skilled in the art and include, for example, a benzyl, acetyl, or trialkylsilyl group for alcohol protection, a ketal group for diol protection, an ester group for acid protection, and the like. These protecting groups can be used in accordance with standard procedures.

In cases where the compounds of formulas (I), (II) or (III) are obtained as a mixture of stereoisomers, such as, in particular, enantiomers, stereoisomers can be separated using methods known to the person skilled in the art, for example, by formation and separation of diastereomeric salts, or by HPLC on a chiral stationary phase, such as a Daicel ChiralPak AD-H column (5 µm), a Daicel ChiralCel OD-H column (5 µm), a Daicel ChiralCel OD column (10 µm), a Daicel ChiralPak IA column, or IB or IC or ID or IE (5 µm), Daicel ChiralPak AS-H column (5 µm) or (R,R)-Whelk-01 column (5 µm). Typical chiral HPLC conditions are an isocratic mixture of eluent A (EtOH, in the presence or absence of a base such as TEA and/or diethylamine or an acid such as TFA) and eluent B (heptane). Under supercritical liquid chromatography (SCLC) conditions, eluent A is CO ₂ and eluent B is isopropanol.

Experimental section

The following examples illustrate the invention but do not limit its scope in any way.

- 44 040901

All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise indicated, all reactions were carried out under nitrogen or argon. Compounds were purified by silica gel flash chromatography (Biotage), using prep. TLC (TLC plates from Merck, silica gel 60 F254), or by preparative HPLC. The compounds described in the invention were characterized by 'H-NMR (400 MHz or 500 MHz Bruker; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet , quint = quintuplet, hex = hexet, hept = heptet, m = multiplet, br = broad, coupling constants are in Hz), and/or by LCMS (retention time t _R is given in min; molecular weight derived from mass spectrum, given in g/mol) using the conditions listed below.

LCMS with acid medium.

JHMS-1. Waters Acquity Binary, Solvent Manager, MC: Waters SQ Detector, DMD: Acquity UPLC PDA Detector, IDSR: Acquity UPLC ELSD. Columns: Acquity UPLC CSH C18 1.7 µm 2.1x50 mm from Waters, thermostated in Acquity UPLC Column Manager at 60°C. Eluents: A: H ₂ O + 0.05% formic acid; B: AcCN + 0.045% MK. Method: Gradient: 2% B 98% B in 2.0 min. Flow: 1.0 ml/min. Detection: UV 214 nm and IDSR.

JHMS-2. Aligent 1100 series with mass spectrometric detection (MC: Finnigan, single quadrupole). Column: Zorbax RRHD SB-Aq (1.8 µm, 3.0x50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B^5% B over 5 min (flow: 4.5 ml/min)

Preparative HPLC with acid medium.

Prep-HPLC-1: Column: Waters XBridge C18 (10 µm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B]. Gradient: 95% B^5% B over 5 min (flow: 75 ml/min). Detection: UV/Visible. + MS.

Prep-HPLC-2: Column: Waters Zorbax SB-Aq (5 µm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% formic acid [eluent B]. Gradient: 95% B^5% B over 5 min (flow: 75 ml/min). Detection: UV/Visible. + MS.

Preparative HPLC with basic medium.

Prep HPLC-3. Column: Waters XBridge C18 (10 µm, 75x30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH [eluent B]. Gradient: 90% B^5% B over 6.5 min (flow: 75 ml/min). Detection: UV/Visible. + MS.

The racemates can be separated into their enantiomers, for example by preparative HPLC (column: ChiralPaK AS-H 30x250 mm, 5 μm, 20% iPrOH in supercritical CO ₂ ).

Abbreviations (in the context of the present invention):

Ac acetyl

AcOH acetic acid, aq. water

- 45 040901

BINAP 2,2'-bis(diphenylphosphino)-1,G-binaphthyl Vos tert-butoxy carbonyl Boc-D-Glu-OtBu complex 1-t/?et-butyl ester Boc-b-glutamine

acids Vp benzyl BSA bovine serum albumin In and butyl, such as in m/?em-Bu (= tertiary butyl) CDI carbonyldiimidazole _{Cs2CO3 _} cesium carbonate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexyl carbodiimide DXM dichloromethane DIPEA diisopropylethylamine, Hunig's base, ethyldiisopropylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DMF DMSO EDC dimethylformamide dimethyl sulfoxide X-(3-dimethylaminopropyl)-X'-ethylcarbodiimide equiv. equivalent(s) Et ethyl (e.g. in OEt: ethoxy) EtOAc ethyl acetate EtOH ethanol approx. example(s) h watch) HATU hexafluorophosphate 1-[bis(dimethylamino)methylene]-1R- 1,2,3-triazolo[4,5-b\pyridinium 3-oxide HBTU hexafluorophosphate O-(benzotriazol-1-yl)-X,X,X',X'- tetramethyluronium HC1 hydrochloric acid (hydrochloric acid) HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography _{H2SO4 _} sulfuric acid IPr isopropyl

- 46 040901

KHMDS bis(trimethylsilyl)potassium amide K ₂ CO ₃ potassium carbonate HCMS liquid chromatography - mass spectrometry lit. literature LPA lysophosphatidic acid LPARi lysophosphatidic acid receptor 1 Me methyl (e.g. in OM: methoxy) MeCN acetonitrile Meon methanol _NaBH4 sodium borohydride NaH sodium hydride NaOtBu otreot-butoxide sodium _{Na2SO4 _} sodium sulfate NMM N-methylmorpholine POC1 ₃ phosphoryl chloride Pd ₂ (dba) ₃ tris(dibeisylideneacetone)dipalladium(0) Pd(OH) ₂ /C palladium hydroxide on carbon Pd(OAc) ₂ palladium acetate prey. preparative k.t. room temperature sat. saturated TBME ot/?ot-butyl methyl ether TBTU tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,2,3,3- tetramethyluronium TEA triethylamine TFU trifluoroacetic acid THF tetrahydrofuran those thin layer chromatography T3P propylphosphonic anhydride tR Hold Time

Preparation of intermediate compounds.

Intermediate 1.A: 2-methoxy-6-methylpyridine-3-amine.

Step 1. To a stirred suspension of NaH (60% oil dispersion, 256 mg, 6.39 mmol) in anhydrous THF (10 mL) at 0°C, methanol (256 μL, 6.39 mmol) was added dropwise, and the resulting solution was stirred in for 0.5 h. To this solution was added dropwise a solution of 2-fluoro6-methyl-3-nitropyridine (1.0 g, 6.09 mmol) in anhydrous THF (5 ml). After the addition is complete, the solution is stirred at 0°C for 0.5 h, after which it is allowed to warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h, quenched with water (30 ml) and the aqueous layer was extracted with EtOAc (3x50 ml). The combined organic extracts are washed with brine (30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. 2-Methoxy-6-methyl-3-nitropyridine, after purification by prep-HPLC (prep-HPLC-3), was obtained as a yellow oil (539 mg, 53% yield). 1H NMR (400 MHz, DMSO D6) δ: 8.34 (d, J=8.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 4.01 (s, 3H), 2.51 (s, 3H).

Step 2 To a degassed solution of 2-methoxy-6-methyl-3-nitropyridine (539 mg, 3.21 mmol) in methanol (10 mL) was added Pd(OH) ₂ /C (255 mg) followed by ammonium formate. The reaction mixture was stirred at 50° C. for 20 h and then filtered through a Whatman filter and evaporated. The residue was dissolved in EtOAc (30 ml) and the organic solution was washed with sat. NaHCO ₃ solution (15 ml) followed by brine (15 ml) washing. The organic phase is dried over MgSO ₄ , filtered and evaporated to give 2-methoxy-6-methylpyridine-3-amine 1-1.A as yellow

- 47 040901 oils (199 mg, 45% yield). LCMS-2: t _R =0.38 min, [M+1]+ 139.13; 1H NMR (400 MHz, DMSO D ₆ ) δ: 6.78 (d, J=7.5 Hz, 1H), 6.54 (d, J=7.5 Hz, 1H), 4.65 (s, 2H), 3.82 (s, 3H), 2.23 (s, 3H).

Intermediate 1.B: 2-isopropoxy-6-methylpyridin-3-amine.

2-Isopropoxy-6-methylpyridin-3-amine I-1.B was synthesized using the procedure described for I1.A starting from commercially available 2-fluoro-6-methyl-3-nitropyridine and isopropanol. 1H NMR (400 MHz, DMSO D6) δ: 6.77 (d, J=7.5 Hz, 1H), 6.49 (d, J=7.5 Hz, 1H), 5.22 (m, 1H), 4.53 (s, 2H), 2.21 (s, 3H), 1.27 (d, J=6.2 Hz, 6H).

Intermediate 1.C: 2-(difluoromethoxy)-6-methylpyridin-3-amine.

Stage 1. A suspension of 6-methyl-3-nitropyridin-2-ol (10 g, 61.6 mmol) and Na ₂ SO ₄ (21.89 g, 15.4 mmol) in MeCN (250 ml) is heated to 60°C and 2 ,2-difluoro-2(fluorosulfonyl)acetic acid (8.8 ml, 80 mmol) for 10 min. The reaction mixture was stirred for an additional hour and then quenched with 3 M NaOH solution (250 ml) and the acetonitrile was removed in vacuo. The remaining aqueous part is extracted with EtOAc (3x200 ml). The combined organic extracts are washed with water (50 ml) followed by brine (100 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The yellow oil was purified by column chromatography (Biotage, heptane:EtOAc 1:0 to 1:1) to give 2-(difluoromethoxy)-6-methyl-3-nitropyridine as a yellow oil which crystallized on standing (10.9 g, 85% yield). %). 1H NMR (400 MHz, DMSO D ₆ ) δ: 8.51 (d, J=8.2 Hz, 1H), 7.82 (t, J=71.3 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 3.37 ( s), 2.55 (s, 3Н).

Step 2 To 2-(difluoromethoxy)-6-methyl-3-nitropyridine (4.65 g, 22.8 mmol) in degassed methanol (100 mL) was added 10% palladium on charcoal with 50% wet. (350 mg) and the reaction mixture was hydrogenated at atmospheric pressure for 18 hours. The mixture was filtered through a pad of celite. The packing was washed with THF (3x10 ml) and the organic solution was concentrated in vacuo to give 2(difluoromethoxy)-6-methylpyridin-3-amine T-1.C as a pale yellow oil which crystallized on standing (4.1 g, yield 92%). LCMS-2: t _R =0.75 min, no mass; 1H NMR (400 MHz, CDCl ₃ ) δ: 7.52 (t, J=73.5 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 2.36 (s , 3H).

Intermediate 2: 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid.

Step 1 To a solution of commercially available 1-bromo-2-fluorobenzene (5 g, 28.6 mmol) in THF (60 mL) was added 1-benzhydrylazetidine-3-carbonitrile (10.6 g, 42.9 mmol) and 95% KHMDS (10.3 mL, 42.9 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was then concentrated in vacuo to an oil, diluted with EtOAc (100 ml) and washed with water (2x50 ml). The organic phase is dried over MgSO ₄ and concentrated in vacuo. The crude material is purified with prep. HPLC (prep-HPLC-2 conditions) afforded 1-benzhydryl-3-(2bromophenyl)azetidine-3-carbonitrile as a beige solid (7.64 g, 66% yield). 1H NMR (400 MHz, DMSO D ₆ ) δ: 7.70 (d, J=7.9 Hz, 1H), 7.47-7.42 (m, 6H), 7.36-7.31 (m, 5H), 7.25-7.21 (m, 2H) , 4.56 (s, 1H), 3.98 (d, J=8.0 Hz, 2H), 3.49-3.42 (m, 2H).

Step 2 To a solution of 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonitrile (7.2 g, 17.9 mmol) in ethanol (80 ml) was added 25% NaOH (40 ml). The reaction mixture is stirred at 80°C for 3-4 days (the reaction is monitored using LCMS) and then cooled to 0°C and acidified with 2 M aq. HCl solution. The mixture is extracted with EtOAc (2x200 ml), dried over MgSO ₄ , filtered and evaporated. The crude material was purified by column chromatography (eluent: DCM/MeOH 9:1) to give 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid I-2 as a yellow foam (6.37 g, 84% yield). ). LCMS-2: tR = 0.83 min, [M+1] ⁺ 423.99; ¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.54 (d, J=7.8 Hz, 1H), 7.43-7.41 (m, 4H), 7.37 (d, J=4.2 Hz, 2H), 7.29 (t, J=7.3 Hz, 4H), 7.21-7.17 (m, 3H), 4.47 (s, 1H), 3.88 (d, J=7.8 Hz, 2H), 3.36 (d, J=7.7 Hz, 2H).

Intermediate 3: 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride.

1-Benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylic acid I-3 (538 mg, 1.38 mmol) was dissolved in DCM (10 ml). Three drops of DMF are added followed by thionyl chloride (0.5 ml, 6.9 mmol) and the reaction mixture is stirred at 50° C. for 1 h (reaction monitored by LCMS). The reaction mixture was then evaporated to give crude 1-benzhydryl-3-(2-bromophenyl)azetidine-3carbonyl chloride I-3 as a wax (620 mg), which was used as such below.

Intermediate 4: 1-(tert-Butoxycarbonyl)-4-(2-isopropylphenyl)piperidine-4carboxylic acid.

Step 1 A mixture of commercially available 2-bromophenylacetonitrile (10 g, 51 mmol) and tetrabutylammonium hydrogen sulfate (1.77 g, 5.1 mmol) in 60 ml of THF and 90 ml of 50% aqueous NaOH solution is refluxed for 10 minutes. Then N-benzyl-N,N-bis(2chloroethyl)amine hydrochloride (15 g, 56.1 mmol) was added at rt. and the mixture is heated at reflux overnight. Perform cooling to k.t. followed by dilution with water (120 ml) and extraction with EtOAc (2x200 ml). The combined organic extracts are washed with brine (100 ml), dried with MgSO4, and concentrated in vacuo. The crude compound was crystallized from acetonitrile to give 1-benzyl-4-(2-bromophenyl)piperidine-4-carbonitrile (12.6 g, 69% yield) as white

- 48 040901 crystalline substance. 1H NMR (500 MHz, DMSO D ₆ ) δ: 7.75 (dd, J ₁ =1.3 Hz, J2=7.9 Hz, 1H), 7.55 (dd,

J1=1.6Hz, _J2 =8.1Hz, 1H), 7.48(td, J1=1.3Hz, J2=7.4Hz, 1H), 7.35-7.32(m, 5H), 7.30-7.25(m, 1H), 3.58 (s,

2Н), 3.01-2.98 (m, 1Н), 2.98-2.95 (m, 1Н), 2.54-2.52 (m, 2H), 2.43-2.39 (m, 2Н), 2.00 (td, J1=3.4 Hz, J2= 12.8

Hz, 2H).

Step 2 A mixture of 1-benzyl-4-(2-bromophenyl)piperidine-4-carbonitrile (29.4 g, 82.9 mmol), acetic acid (75 ml) and concentrated sulfuric acid (75 ml) in water (75 ml) was stirred with reflux for 4 days (reaction monitored by LCMS). The reaction mixture was then diluted with water (50 ml) and 25% aqueous HCl (50 ml) and stirred for 15 minutes. TBME (100 ml) is added. The mixture is stirred for another 15 min and kept at 4°C overnight. The white precipitate was filtered off, washed with TBME and dried in vacuo to give 1-benzyl-4-(2-bromophenyl)piperidine-4-carboxylic acid (22.1 g, 71% yield) as a white powder. LCMS-2: tR=0.72 min, [M+1]+ 374.17 and 376.18.

Step 3. 1-Benzyl-4-(2-bromophenyl)piperidine-4-carboxylic acid (10 g, 26.7 mmol) and isopropenylboronic acid pinacol ester (15.1 ml, 80.2 mmol) are dissolved in dioxane (120 ml) and water ( 60 ml). Tripotassium phosphate (29.9 g, 134 mmol) is then added followed by palladium acetate (300 mg, 1.34 mmol) and di(1-adamantyl)-n-butylphosphine (969 mg, 2.67 mmol). The degassed reaction mixture is heated at 100° C. overnight (reaction monitored by LCMS). The reaction mixture was diluted with EtOAc (200 ml) and extracted with 2N. HCl solution (20 ml). The acidic aqueous phase is extracted with EtOAc (3x150 ml). All organic phases are combined (650 ml), washed with brine (20 ml), dried over MgSO ₄ , filtered and evaporated to give the crude compound, which is purified with prep. HPLC (prep-HPLC-3 conditions) to give 1-benzyl-4-(2-(prop-1-en-2-yl)phenyl)piperidine-4-carboxylic acid 1-4 as a beige solid (8.4 g , 93% yield. 1H NMR (400 MHz, DMSO D ₆ ) δ: 12.70 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.33-7.18 (m, 7H), 7.01 (dd, J1=1.2 Hz, J ₂ = 7.3 Hz, 1H), 5.10 (s, 1H), 4.71 (s, 1H), 2.43-2.38 (m, 4H), 2.342.31 (m, 2H), 2.13-2.11 (m, 2H), 2.01 (s, 3H).

Step 4 Degassed mixture of 1-benzyl-4-(2-(prop-1-en-2-yl)phenyl)piperidine-4-carboxylic acid (8.4 g, 24.8 mmol) and Pd/C 10-50% wet. (2 g) in MeOH/THF 1:1 (200 ml) hydrogenated at rt. within 4 days (reaction monitored by LCMS). The mixture was degassed with argon, filtered through a pad of celite, washed with THF, dried over MgSO4 and evaporated to give 4-(2isopropylphenyl)piperidine-4-carboxylic acid (5.6 g, 92% yield) as a white solid. ¹ H NMR (400 MHz, DMSO) δ: 9.06 (s br, 1H), 7.38 (dd, J1=1.4 Hz, J ₂ =7.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.247.16 ( m, 1H), 3.44 (s br, 1H), 3.27-3.12 (m, 5H), 2.38 (m, 2H), 2.20-2.12 (m, 2H), 1.14 (d, J=6.7 Hz, 6H).

Step 5 A mixture of 4-(2-isopropylphenyl)piperidine-4-carboxylic acid (5.65 g, 23.2 mmol), DIPEA (13.6 ml, 79.7 mmol) and Boc ₂ O (4.8 g, 21.9 mmol) was stirred at rt. within 24 hours Then add water, followed by the addition of 1N. HCl to bring the pH to 1. The reaction mixture is extracted four times with DCM (4x200 ml). The combined extracts were dried over MgSO ₄ , filtered and evaporated to give 1-(tert-butoxycarbonyl)-4-(2isopropylphenyl)piperidine-4-carboxylic acid I-4 (9 g, quantitative) as a yellow oil. ¹ H NMR (400 MHz, DMSO D6) δ: 12.73 (s, 1H), 7.36-7.31 (m, 2H), 7.26-7.23 (m, 1H), 7.18-7.14 (m, 1H), 3.753.65 ( m, 2H), 3.32-3.25 (m, 3H), 2.28-2.20 (m, 2H), 1.89-1.77 (m, 2H), 1.41 (s, 9H), 1.14 (d, J=6.6 Hz, 6H ).

Alternatively, I-4 can be prepared from commercially available 4-(2-bromophenyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid.

Step 1. 1-(tert-Butoxycarbonyl)-4-(2-(prop-1-en-2-yl)phenyl)piperidine-4-carboxylic acid is prepared from commercially available 4-(2-bromophenyl)-1-( tert-butoxycarbonyl)piperidine-4carboxylic acid following the procedure described for 1-4, step 3 (59% yield). ¹ H NMR (400 MHz, DMSO D ₆ ) δ: 7.44 (dd, J1=1.5 Hz, J ₂ =8.0 Hz, 1H), 7.30-7.22 (m, 2H), 7.05 (dd, J1=1.8 Hz, J2 =7.2 Hz, 1H), 5.14 (t, J=1.6 Hz, 1H), 4.75 (d, J=1.0 Hz, 1H), 3.54-3.48 (m, 2H), 3.32-3.15 (m, 2H), 2.27 -2.23 (m, 2H), 2.06-2.00 (m, 5H).

Stage 2. Degassed mixture of 1-(tert-butoxycarbonyl)-4-(2-(prop-1-en-2-yl)phenyl)piperidine4-carboxylic acid (986 mg, 2.85 mmol) and Pd/C 10-50% wet (100 mg) in MeOH/THF 1:1 (60 ml) was hydrogenated at rt. within 1 h (the reaction is monitored using LCMS). The mixture is degassed with argon, filtered through a pad of celite, washed with THF, dried over MgSO ₄ and evaporated to give 1-(tert-butoxycarbonyl)-4-(2-isopropylphenyl)piperidine-4-carboxylic acid I-4 as a white foam (923 mg, 93% yield).

Intermediate 5: 1-benzyl-3-(2-bromophenyl)pyrrolidine-3-carboxylic acid.

Step 1 Paraformaldehyde (2.17 ml, 14.8 mmol) and K2CO3 (1.37 g, 9.9 mmol) are added to a solution of commercially available 2-bromophenylacetonitrile (1.32 ml, 9.9 mmol) in DMF (60 ml). The reaction mixture is stirred at 80°C for 1 night. After cooling to rt, water (100 ml) was added and the aqueous layer was extracted with EtOAc (150 ml, 50 ml). The combined organic extracts are washed with brine, dried over MgSO ₄ , filtered and evaporated. The crude compound is purified with prep. HPLC (prep-HPLC-3 conditions) to give 2-(2-bromophenyl)acrylonitrile (561 mg,

- 49 040901 27% yield as orange oil. 1H NMR (400 MHz, DMSO) δ: 7.77-7.74 (m, 1H), 7.53-7.48 (m, 2H),

7.42 (ddd, J1=2.9 Hz, J2=6.3 Hz, J3=8.0 Hz, 1H), 6.61 (s, 1H), 6.36 (s, 1H).

Step 2 2-(2-Bromophenyl)acrylonitrile (461 mg, 2.22 mmol) and N-(methoxymethyl)-N(trimethylsilylmethyl)benzylamine (1.18 ml, 4.43 mmol) are dissolved in DCM (10 ml). TFA (208 μl, 2.66 mmol) was added to this solution under ice-cooling. After returning to RT, the reaction mixture was stirred overnight. The reaction mixture was then poured into water (25 ml) and extracted with DCM (2x50 ml). The combined organic extracts are washed with NaHCO ₃ followed by brine, dried over MgSO ₄ , filtered and evaporated. The crude compound was purified by prep-HPLC (prep-HPLC-3 conditions) to give 1-benzyl-3-(2bromophenyl)pyrrolidine-3-carbonitrile (495 mg, 65% yield) as a yellow oil. LCMS-2: t _R =0.74 min, [M+1]+ 341.22 and 343.20.

Step 3 1-Benzyl-3-(2-bromophenyl)pyrrolidine-3-carbonitrile (495 mg, 1.45 mmol) is subjected to the hydrolysis conditions described for I-4 to give 1-benzyl-3-(2-bromophenyl)pyrrolidine -3 carboxylic acid I-5 as a beige solid (293 mg, 56% yield). LCMS-2: t _R =0.64 min, [M+1] ⁺ 360.16 and 362.16.

Intermediate 6: 1-(tert-butoxycarbonyl)-4-(2-isopropylphenyl)piperidine-4carboxylic acid.

Step 1. To a solution of I-2 (5.0 g, 11.8 mmol) in MeOH (30 ml) was added conc. sulfuric acid (10 ml). The reaction mixture is stirred at 75°C for 24 h and then evaporated. The residue was dissolved in EtOAc (100 ml) and washed with sat. NaHCO ₃ solution. The phases are separated and the organic phase is washed with brine (50 ml), dried over MgSO ₄ , filtered and evaporated. The crude compound was purified by chromatography (CombiFlash heptane/EtOAc 9:1) to give methyl 1-benzhydryl-3(2-bromophenyl)azetidine-3-carboxylate as a yellow oil (4.12 g, 80% yield). 1H NMR (400 MHz, CDCl ₃ ) δ: 7.54 (dd, J1=1.1 Hz, J ₂ =8.0 Hz, 1H), 7.49-7.41 (m, 4 H), 7.38-7.32 (m, 1H), 7.32- 7.26 (m, 5H), 7.247.19 (m, 2H), 7.17 (td, J1=1.9 Hz, J ₂ =7.9 Hz, 1H), 4.43 (s, 1H), 4.08 (d, J=8.3 Hz, 2Н), 3.74 (s, 3Н), 3.51 (d, J=8.2 Hz, 2Н).

Step 2 Methyl 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carboxylate (4.12 g, 9.44 mmol) is subjected to the Suzuki coupling conditions described for intermediate 3 to give methyl 1-benzhydryl-3-(2-(prop -1-en-2-yl)phenyl)azetidine-3-carboxylate as a yellow oil (3.64 g, 97% yield). ¹ H NMR (400 MHz, DMSO D6) δ: 7.40-7.38 (m, 4H), 7.30-7.23 (m, 7H), 7.21-7.17 (m, 2H), 7.12-7.10 (m, 1H), 5.06 ( s, 1H), 4.59 (s, 1H), 4.42 (s, 1H), 3.82 (d, J=7.7 Hz, 2H), 3.66 (s, 3H), 3.21 (d, J=7.7 Hz, 2H), 1.92(s, 3H).

Step 3 Methyl 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylate (3.64 g, 9.16 mmol) is subjected to the saponification conditions described for I-3 to give 1-Benzhydryl-3-(2-(prop1-en-2-yl)-phenyl)-azetidine-3-carboxylic acid as a beige solid (3.35 g, 95% yield). ^1H NMR (400 MHz, DMSO D6) δ: 7.39 (d, J=7.3 Hz, 4H), 7.28 (t, J=7.4 Hz, 4H), 7.23-7.17 (m, 5H), 7.11-7.09 ( m, 1H), 5.06 (s, 1H), 4.71 (s, 1H), 4.39 (s, 1H), 3.82 (d, J=7.6 Hz, 2H), 3.14 (d, J=7.5 Hz, 2H), 1.95 (s, 3H).

Stage 4. Mixture of 1-benzhydryl-3-(2-(prop-1-en-2-yl)phenyl)azetidine-3-carboxylic acid (3.35 g, 8.74 mmol), 25% HCl solution (18 ml) and Pd (OH) ₂ /C 20% (1.6 g) in MeOH (100 ml) is degassed and then hydrogenated at 1 bar for 18 hours (reaction monitored by LCMS). The reaction mixture is then degassed with argon and filtered on a Celite pad, which is washed with MeOH. The volatiles were evaporated and the residue was crystallized from MeCN to give 3-(2isopropylphenyl)azetidine-3-carboxylic acid hydrochloride as a white solid (1.17 g, 61% yield). ¹ H NMR (400 MHz, DMSO D6) δ: 13.55 (s br, 1H), 9.40 (s br, 1H), 9.15 (s br, 1H), 7.39 (d, J=6.9 Hz, 1H), 7.34 ( t, J=7.2 Hz, 1H), 7.24 (t, J=7.0 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 4.57-4.54 (m, 2H), 4.39-4.35 (m, 2H ), 1.13 (d, J=6.7 Hz, 6H).

Step 5 To a suspension of 3-(2-isopropylphenyl)azetidine-3-carboxylic acid hydrochloride (1.17 g, 4.57 mmol) in DCM (25 mL) was added DIPEA (5.9 mL, 34.4 mmol) followed by Boc ₂ O (1.1 g , 5.02 mmol). The mixture is stirred at room temperature for 24 hours. Add 1N. HCl to bring the pH to 1, and the reaction mixture is extracted with DCM (4 times). The combined organic extracts are dried over MgSO ₄ , filtered and evaporated. The residue was purified by chromatography (CombiFlash heptane/EtOAc 1.5:1) to give 1-(tert-butoxycarbonyl)-4-(2isopropylphenyl)piperidine-4-carboxylic acid I-6 as a white solid (0.85 g, 58% yield). ). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.36-7.31 (m, 2H), 7.26-7.21 (m, 1H), 7.18 (d, J=7.0 Hz, 1H), 4.64 (d, J=8.5 Hz , 2Н), 4.37 (d, J=8.5 Hz, 2Н), 2.61 (m, 1Н), 1.46 (s, 9Н), 1.19 (d, J=6.7 Hz, 6Н).

Intermediate 7: 1-benzhydryl-3-(2-bromo-6-methylphenyl)azetidine-3-carboxylic acid.

Intermediate I-7 is prepared from 3-bromo-2-fluorotoluene according to the method described for I-2. For cleaner hydrolysis of the nitrile group to the corresponding carboxylic acid, a two-step sequence is performed using first basic conditions (KOH) to form an amide intermediate, and then acid hydrolysis of the amide as described for I-4. LCMS-2: t _R =0.84 min, [M+1] ⁺ 435.86.

- 50 040901

Intermediate 8: 1-benzhydryl-3-(2-bromo-5-methylphenyl)azetidine-3-carboxylic acid.

Intermediate I-8 is prepared from 4-bromo-3-fluorotoluene according to the method described for I-2. LCMS-2: t _R =0.85 min, [M+1]+435.75.

Intermediate 9: 1-benzhydryl-3-(2-bromo-4-methylphenyl)azetidine-3-carboxylic acid.

Intermediate I-9 is prepared from 3-bromo-4-fluorotoluene according to the method described for I-2. For cleaner hydrolysis of the nitrile group to the corresponding carboxylic acid, a two-step sequence is performed using first basic conditions (KOH) to form an amide intermediate, and then acid hydrolysis of the amide as described for I-4. LCMS-2: tR=0.86 min, [M+1] ⁺ 435.93.

Intermediate 10: 1-benzhydryl-3-(2-bromo-6-fluorophenyl)-azetidine-3-carboxylic acid.

Intermediate I-10 is prepared from 1-bromo-2,3-difluorobenzene according to the method described for I-2. LCMS-2: t _R =0.83 min, [M+1] ⁺ 440.24.

Intermediate 11: 1-benzhydryl-3-(2-bromo-5-fluorophenyl)-azetidine-3-carboxylic acid.

Intermediate I-11 is prepared from 1-bromo-2,4-difluorobenzene according to the method described for I-2. LCMS-2: t _R =0.83 min, [M+1] ⁺ 440.21.

Intermediate 12: 1-benzhydryl-3-(2-bromo-5-methoxyphenyl)azetidine-3-carboxylic acid.

Intermediate I-12 is prepared from 4-bromo-3-fluoroanisole according to the method described for I-2. LCMS-2: t _R =0.84 min, [M+1] ⁺ 451.97.

Intermediate 13: 3-(carboxymethyl)oxetane-3-carboxylic acid.

The title compound I-13 was prepared from commercially available ethyl 2-(3cyanooxetan-2-yl)acetate according to the method described in US 20080207573.

Intermediate 14: 3-(2-(benzyloxy)-2-oxoethoxy)propanoic acid.

To a solution of benzyl glycolate (1.0 g, 6.02 mmol) in DMF (60 ml) was added a suspension of NaH (60% dispersion in oil, 433 mg, 10.8 mmol). After 1 h, a solution of 2-(3-bromopropoxy)-tetrahydro-2H-pyran (1.07 g, 4.81 mmol) in DMF (2 ml) was added and the reaction mixture was stirred at 80°C for 2 h. Water (23 ml) and the mixture was extracted with EtOAc (100 ml). The extract is washed with brine, dried over MgSO ₄ , filtered and evaporated. The yellow residue is purified with prep. HPLC (prep-HPLC-3 conditions) afforded benzyl 2-(3-((tetrahydro-2H-pyran-2yl)oxy)propoxy)acetate (192 mg) as a yellow oil. Then a solution of benzyl 2-(3-((tetrahydro-2Hpyran-2-yl)oxy)propoxy)acetate (138 mg, 0.46 mmol) and p-toluenesulfonic acid monohydrate (8.8 mg, 0.05 mmol) in MeOH (10 ml) was stirred at k.t. within 2 h (the reaction is monitored using LCMS). The reaction mixture was diluted with Et ₂ O (60 ml) and washed with NaHCO3 solution (10 ml). The organic phase is dried over MgSO ₄ , filtered and evaporated to give crude benzyl 2-(3-hydroxypropoxy)acetate which is dissolved in MeCN (5 ml). NaH ₂ PO ₄ buffer solution (0.1 mol/l, 0.5 ml), 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO, 7.3 mg, 0.05 mmol), aq. sodium chlorite solution (80 g/l, 1.1 ml) and sodium hypochlorite (50 μl), and the reaction mixture was stirred at 50°C overnight. The mixture was then quenched with saturated sodium sulfite solution (2 ml) and the volatiles were evaporated. The residue is dissolved in 3 ml of DMF/MeCN (1:1) and purified with prep. HPLC (prep-HPLC-3 conditions) to give the title compound I-14 as a beige wax (11 mg). LCMS-2: t _R =0.76 min, [M+1] ⁺ 239.18; 1H NMR (500 MHz, MeOD) δ: 7.38 (m), 7.42-7.30 (m, 5H), 5.20 (s, 2H), 4.19 (s, 2H), 3.81 (t, J=6.4 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H).

Intermediate 15: 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid.

The title compound I-15 is prepared from commercially available dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate according to the method described in J. Med. Chem. 2012, 55(7), 3414-3424 (Stepan, A. F. et al.).

Intermediate 16: 3-(methylsulfonamido)-3-oxopropanoic acid.

The title compound I-16 was prepared from commercially available methyl propiolate and methanesulfonyl azide according to the method described by X. Wang et al. in Tetrahedron 2011, 67, 62946299.

Intermediate 17: 4-ethoxy-3,3-difluoro-4-oxobutanoic acid.

Trifluoroacetic anhydride (108 µl, 0.78 mmol) was added to a solution of 2,2-difluorosuccinic acid (100 mg, 0.649 mmol) in isopropyl acetate (2 ml). The solution was stirred at 50°C for 1 hour to give 2,2-difluorosuccinic anhydride, which was dissolved with ethanol (200 µl) to give crude 3,3-difluoro-4-methoxy-4-oxobutanoic acid I-17 (160 mg ) as a yellow oil. ¹ H NMR (400 MHz, DMSO) δ: 13.20 (s br, 1H), 4.30 (q, J=7.2 Hz, 1H), 3.36 (t, J _H -F=14.9 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).

Intermediate 18: (S)-(+)-citramalic acid.

Intermediate I-18 is prepared from commercially available (R)-(+)-4-methyl-4(trichloromethyl)-2-oxetanone according to the method described in M. Gill et al., Aust. J. Chem. 2000

- 51 040901

53, 245-256.

Examples

Example 1: 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide.

Step 1. To a solution of 2-methoxy-6-methylpyridin-3-amine I-1.A (191 mg, 1.38 mmol) in THF (10 ml) was added a suspension of NaH (60% dispersion in oil, 120 mg, 2.76 mmol) . After the mixture was stirred for 30 min, a suspension of benzhydryl-3-(2-bromophenyl)azetidine-3-carbonyl chloride I-3 (608 mg, 1.38 mmol) in THF (10 ml) was added dropwise and stirring continued for 2 h (reaction monitored by LCMS). The reaction mixture was then diluted with DCM (50 ml) and washed with water (20 ml). The organic phase is dried over MgSO ₄ , filtered and evaporated. The crude compound was crystallized from MeCN to give 1-benzhydryl-3-(2-bromophenyl)-N-(2-methoxy-6methylpyridin-3-yl)azetidine-3-carboxamide as an off-white solid (278 mg, 37% yield). %). 1H NMR (400 MHz, DMSO D6) δ: 11.10 (s, 1H), 8.42 (d, J=7.9 Hz, 1H), 7.62-7.57 (m, 5H), 7.40-7.34 (m, 5H), 7.28- 7.18 (m, 4H), 6.88 (d, J=7.9 Hz, 1H), 4.73 (s, 1H), 4.17 (s, 3H), 4.01 (d, J=7.0 Hz, 2H), 3.52 (d, J =7.3 Hz, 2H), 2.42 (s, 3H).

Stage 2. 1-Benzhydryl-N-(2-methoxy-6-methylpyridin-3-yl)-3-(2-(prop-1-en-2-yl)phenyl)azetidine3-carboxamide is obtained from 1-benzhydryl- 3-(2-bromophenyl)-N-(2-methoxy-6-methylpyridin-3yl)azetidine-3-carboxamide following the procedure described for I-6 step 3 (216 mg, 84% yield). 1H NMR (400 MHz, DMSO D6) δ: 11.24 (s, 1H), 8.44 (d, J=7.9 Hz, 1H), 7.57 (d, J=7.5 Hz, 4 H), 7.36 (t, J=7.5 Hz, 4H), 7.26-7.15 (m, 5H), 7.00 (d, J=7.3 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.98 (s, 1H), 4.74 (s, 1Н), 4.68 (s, 1Н), 4.16 (s, 3Н), 3.87 (d, J=7.4 Hz, 2Н), 3.33 (d, J=7.4 Hz, 2Н), 2.42 (s, 3Н), 1.94 ( s, 3H).

Step 3. A mixture of 1-benzhydryl-M-(2-methoxy-6-methylpyridin-3-yl)-3-(2-(prop-1-en-2yl)phenyl)azetidine-3-carboxamide (216 mg, 0.43 mmol), 25% HCl solution (4.5 ml) and Pd(OH) ₂ /C 20 wt.% (300 mg) in MeOH (25 ml) are degassed and then hydrogenated at a pressure of 1 bar for 18 h (the reaction is monitored using JHMS). The reaction mixture was then degassed with argon and filtered on a pad of celite, which was washed with MeOH (10 ml). Volatiles are evaporated and the residue is dissolved in EtOAc (60 ml). The organic solution is washed with 5N. aq. NaOH solution (30 ml), dried over MgSO ₄ , filtered and evaporated. The crude material is purified with prep. TLC (eluent: DCM/MeOH: 9/1) to give 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide approx. 1 as a white solid (32 mg, 22% yield). LCMS-1: t _R =0.68 min, [M+1]+ 340.43; 1H NMR (400 MHz, CD3OD) δ: 8.34 (d, J=7.9 Hz, 1H), 7.46-7.35 (m, 4 H), 6.78 (d, J=7.9 Hz, 1H), 4.31 (d, J= 8.5 Hz, 2H), 4.17 (d, J=8.5 Hz, 2H), 3.72 (s, 3H), 2.49 (m, 1H), 2.36 (s, 3H), 1.13 (d, J=6.7 Hz, 6 H ).

Example 2: N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide is obtained from 2-isopropoxy-6-methylpyridin-3-amine 1-1.B (1.8 g) and benzhydryl-3-(2-bromophenyl)azetidine-3carbonyl chloride I-3 (4.36 g), following the procedure described for approx. 1 (1.29 g, white solid). LCMS-1: tR=0.80 min, [M+1] ⁺ 368.34; 1H NMR (400 MHz, CD3OD) δ: 8.45 (d, J=7.9 Hz, 1H), 7.49-7.47 (m, 2H), 7.43-7.40 (m, 2H), 6.74 (d, J=8.0 Hz, 1H ), 5.51 (s, 1H), 5.18-5.11 (m, 1H), 4.38 (d, J=8.2 Hz, 2H), 4.21 (d, J=8.0 Hz, 2H), 2.37-2.44 (m, 1H) , 2.33 (s, 3Н), 1.13 (d, J=6.7 Hz, 7Н), 1.02 (d, J=6.2 Hz, 6Н).

Example 3: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine I-1.C (229 mg) and benzhydryl-3-(2bromophenyl)azetidine-3-carbonyl chloride I-3 (608 mg), following the procedure described for approx. 1 (110 mg, yellow oil). LCMS-1: t _R =0.71 min, [M+1] ⁺ 376.22; 1H NMR (500 MHz, DMSO D6) δ: 9.90 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.63 (t, J=72.6 Hz, 1H), 7.33 (dd, Ji=1.3 Hz , J ₂ =7.8 Hz, 1H), 7.28 (td, Ji=1.2 Hz, J ₂ =7.3 Hz, 1H), 7.19 (m, J1=1.4 Hz, J ₂ =7.7 Hz, 1H), 7.14 (dd, J1=1.1 Hz, J ₂ =7.7 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.07 (m, 2H), 4.01 (m, 2H), 2.38 (s, 3H), 1.09 (d , J=6.7 Hz, 6H).

Example 4: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)piperidine-4-carboxamide; Example 4.1: tert-Butyl 4-((2-hydroxy-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidine-1-carboxylate.

Step 1. To a solution of 1-(tert-butoxycarbonyl)-4-(2-isopropylphenyl)piperidine-4-carboxylic acid I-4 (2 g, 5.76 mmol) and DMF (1 ml) in pyridine (20 ml) dropwise POCl ₃ (0.79 ml, 8.63 mmol) was added over 35 min (complete conversion to its acyl chloride was monitored by LCMS with MeOH quench). The reaction mixture is then evaporated to remove volatiles. The crude material is suspended in pyridine (20 ml) and added dropwise to a solution of 3-amino-6-methylpyridin2-ol (14.4 mmol, 1.79 g) in pyridine (10 ml). The reaction mixture was stirred at rt. for 2 h and then evaporated. The residue was dissolved in EtOAc (50 ml) and washed with water (20 ml) followed by a wash with sat. NaHCO ₃ solution (50 ml) and brine (50 ml). The organic phase is then dried over MgSO ₄ , filtered and evaporated. The crude product is purified with prep. HPLC (prep-HPLC-3 conditions) to give tert-butyl 4-((2-hydroxy-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidine-1-carboxylate (850 mg, 33% yield ) as a yellow oil. LCMS-1: tR=1.24 min, [M+1] ⁺ 454.07; 1H NMR (400 MHz, DMSO D6) δ: 11.88 (s, 1H), 8.12 (d, J=7.4 Hz, 1H), 7.81 (s,

- 52 040901

1Н), 7.52 (d, J=7.5 Hz, 1Н), 7.41 (dd, Ji=1.4 Hz, J ₃ =7.8 Hz, 1Н), 7.35 (t, J=7.0 Hz, 1Н), 7.29 (td, J1 =1.4 Hz,

J2=7.8 Hz, 1H), 5.99 (d, J=7.5 Hz, 1H), 3.49 (s br, 4H), 3.11-3.04 (m, 1H), 2.28-2.24 (m, 2H), 2.10 (s, 3Н), 1.991.95 (m, 2Н), 1.40 (s, 9Н), 1.02 (d, J=6.6 Hz, 6Н).

Step 2. To a solution of 4-((2-hydroxy-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidine-1-carboxylate (850 mg, 1.87 mmol) in DMF (20 ml) is added Cs ₂ CO ₃ (916 mg, 2.81 mmol) followed by the addition of sodium chlorodifluoroacetate (429 mg, 2.81 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The mixture was then diluted with EtOAc (50 ml) and washed with sat. NaHCO ₃ solution (25 ml) followed by brine (25 ml) washing. The organic phase is dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-3 conditions) to give tert-butyl 4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidine-1-carboxylate as a beige powder ( 709 mg) approx. 4-1, which contains approximately 15% of the regioisomer. LCMS-1: t _R =1.48 min, [M+1]+ 504.17. 1H NMR (400 MHz, DMSO D ₆ ) δ: 8.23 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.53 (t, J=72.6 Hz, 1H), 7.50-7.48 (m, 1H ), 7.41 (dd, J1=1.5 Hz, J2=7.8 Hz, 1H), 7.34 (d, J=6.1 Hz, 1H), 7.27 (m, 1H), 7.09 (d, J=8.0 Hz, 1H), 3.67-3.60 (m, 2H), 3.53-3.42 (m, 2H), 3.28-3.20 (m, 1H), 2.41-2.37 (m, 5H), 1.98-1.90 (m, 2H), 1.41 (s, 9H ), 1.09 (d, J=6.6 Hz, 6H).

Step 3 To a solution of 4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidine-1-carboxylate (709 mg, 1.41 mmol) in DCM (20 mL) was added TFA (1.1 ml, 14.1 mmol) at 10°C. The reaction mixture was stirred at rt. for 2 hours (reaction monitored by LCMS) and then evaporated. The residue is purified with prep. HPLC (prepHPLC-3 conditions) to give N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropyl-phenyl)piperidine4-carboxamide approx. 4 (416 mg, 73% yield) as a white solid. LCMS-1: t _R =0.74 min, [M+1] ⁺ 404.06. 1H NMR (400 MHz, DMSO D6) δ: 7.97 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.53-7.51 (m, 1H), 7.50 (t, J=72.5 Hz, 1H) , 7.39 (dd, J1=1.5 Hz, J2=7.7 Hz, 1H), 7.33-7.25 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 3.26-3.17 (m, 1H), 3.01- 2.96 (m, 2H), 2.75-2.71 (m, 2H), 2.36 (s, 3H), 2.34-2.27 (m, 2H), 1.95-1.89 (m, 2H), 1.06 (d, J=6.6 Hz, 6H).

Example 5: N-(6-chloro-2-methoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Step 1. To a solution of I-6 (40 mg, 0.125 mmol), commercial 6-chloro-2-methoxypyridine-3-amine (25 mg, 0.15 mmol) and pyridine (70 µl, 0.07 mmol) in EtOAc (1 ml) add 50% T3P solution in EtOAc (300 µl, 0.5 mmol). The reaction mixture is stirred at 65°C overnight. Then add water (5 ml) and the reaction mixture is extracted with EtOAc (3x10 ml). The combined organic extracts are dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give tert-butyl 3-((6-chloro-2-methoxypyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxylate as a yellow oil (54 mg , yield 62%). LCMS-2: t _R =1.22 min, [M+1] ⁺ 460.37. 1H NMR (400 MHz, CDCl ,) δ: 8.58 (d, J=8.2 Hz, 1H), 7.48-7.41 (m, 2H), 7.39-7.32 (m, 3H), 6.92 (d, J=8.2 Hz , 1Н), 4.80-4.54 (m, 2Н), 4.52-4.28 (m, 2Н), 3.75 (s, 3Н), 2.43 (m, 1Н), 1.48 (s, 9Н), 1.14 (d, J=6.6 Hz, 6H).

Step 2: tert-Butyl 3-((6-chloro-2-methoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine 1-carboxylate is subjected to the Boc deprotection conditions described for approx. 4, obtaining approx. 5 as a colorless oil (30 mg, 75% yield). LCMS-1: t _R =0.72 min, [M+1] ⁺ 360.30. 1H NMR (400 MHz, CDC13) δ: 8.62 (d, J=8.2 Hz, 1H), 8.38 (s, 1H), 7.41-7.36 (m, 2H), 7.34-7.29 (m, 1H), 7.17 (d , J=7.7 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.27 (s br, 4H), 3.85 (s, 3H), 2.51-2.41 (m, 1H), 1.14 (d, J =6.7 Hz, 6H).

Example 6 N-(2,6-dimethoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide hydrochloride; Example 6-1 tert-Butyl 3-((2,6-dimethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate

N-(2,6-dimethoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide hydrochloride approx. 6 and tert-butyl 3-((2,6-dimethoxypyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carboxylate approx. 6-1 is prepared from commercially available 3-amino-2,6-dimethoxypyridine hydrochloride (35 mg) and I-6 (46 mg) following the procedure described for approx. 5.

Note. 6 (65 mg, yellow wax). LCMS-1: t _R =0.70 min, [M+1] ⁺ 356.02.

Note. 6-1 (72 mg, white solid). LCMS-1: t _R =1.44 min, [M+1] ⁺ 456.24.

Example 7 N-(2-(difluoromethoxy)pyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide hydrochloride.

N-(2-(difluoromethoxy)pyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide hydrochloride approx. 7 was prepared from commercially available 2-(difluoromethoxy)pyridine-3-amine hydrochloride (32 mg) and I-6 (40 mg) following the procedure described for approx. 5 (31 mg, white solid). LCMS-1: t _R =0.68 min, [M+1]+ 362.33; 1H NMR (500 MHz, DMSO D6) δ: 8.63 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.05 (d, J=4.6 Hz, 1H), 7.58 (t, J=72.2 Hz , 1Н), 7.51 (d, J=7.7 Hz, 1Н), 7.48-7.40 (m, 2Н), 7.39-7.29 (m, 2Н), 4.74-4.61 (m, 2Н), 4.48-4.42 (m, 2Н ), 2.46-2.40 (m, 1Н), 1.12 (d, J=6.6 Hz, 6Н).

Example 8: N-(2-(difluoromethoxy)-5-fluoropyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-5-fluoropyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 8

- 53 040901 obtained from commercially available 3-amino-5-fluoropyridin-2-ol (89 mg) and I-6 (86 mg), following the procedure described for approx. 4 (13.5 mg, colorless oil). LCMS-1: tR=0.72 min, [M+1]+ 380.13.

Example 9: N-(6-ethoxy-2-methoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

N-(6-ethoxy-2-methoxypyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 9 was prepared from commercially available 6-ethoxy-2-methoxypyridine-3-amine (77 mg) and I-6 (70 mg) using the POCl ₃ procedure described for approx. 4 (88 mg, yellow oil). LCMS-1: tR=0.76 min, [M+1] ⁺ 470.10.

Example 10 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)pyrrolidine-3-carboxamide.

Step 1. 1-Benzyl-3-(2-bromophenyl)pyrrolidine-3-carboxylic acid I-5 (273 mg, 0.76 mmol) is combined with 2-(difluoromethoxy)-6-methylpyridine-3-amine hydrochloride I-1. C (319, 1.52 mmol), following the procedure described for approx. 1, step 1 to give 1-benzyl-3-(2-bromophenyl)-N-(2(difluoromethoxy)-6-methylpyridin-3-yl)pyrrolidin-3-carboxamide (317 mg, 81% yield) as pale yellow oil. LCMS-2: tR=0.89 min, [M+1] ⁺ 516.17 and 518.16.

Step 2 Following the procedure described for I-4, Step 3, 1-benzyl-3-(2-bromophenyl)-N-(2(difluoromethoxy)-6-methylpyridin-3-yl)pyrrolidin-3-carboxamide (307 mg, 0.60 mmol) is reacted with isopropenylboronic acid pinacol ester (0.56 ml, 2.97 mmol) to give 1-benzyl-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-( prop-1-en-2-yl)phenyl)pyrrolidine3-carboxamide (228 mg, 80% yield) as a colorless oil. LCMS-2: tR=0.94 min, [M+1] ⁺ 478.30.

Step 3. To a solution of 1-benzyl-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-(prop-1-en-2yl)phenyl)pyrrolidine-3-carboxamide (228 mg, 0.48 mmol) Pd/C 10% (100 mg, 0.03 mmol) is added to 10 ml of methanol/THF 1:1 mixture. The reaction mixture is degassed, hydrogenated at 1 bar and stirred for 2 hours (reaction monitored by LCMS). The mixture is filtered on celite and evaporated to dryness to give the title compound approx. 10 (138 mg, 74% yield) as a colorless oil. LCMS-1: tR=0.83 min, [M+1] ⁺ 390.29. 1H NMR (400 MHz, CDCl ₃ ) δ: 8.49 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.45-7.37 (m, 2H), 7.29 (m, J=76.8 Hz, 1H) , 7.32-7.26 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 3.81-3.68 (m, 1H), 3.47-3.25 (m, 2H), 3.15-2.94 (m, 2H), 2.90 -2.75 (m, 1H), 2.39 (s, 3H), 2.31-2.18 (m, 1H), 1.17 (d, J=6.6 Hz, 3H), 1.13 (d, J=6.6 Hz, 3H).

Example 11-1: 1-(2-aminoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Step 1 To a solution of N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine3-carboxamide approx. 3 (200 mg, 0.53 mmol) and TEA (222 μl, 1.60 mmol) in DCM (5 ml) NBoc-bromoethylamine (239 mg, 1.07 mmol) is added. The reaction mixture is stirred overnight. Then another portion of N-Boc-bromoethylamine (239 mg, 1.07 mmol) was added and stirring was continued for 24 h. The reaction mixture was diluted with DCM (20 ml) and washed with water (15 ml) followed by brine (10 ml) . The organic phase is dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-3 conditions) to give tert-butyl (2-(3((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl )ethyl)carbamate (180 mg, 0.35 mmol, 66% yield). LCMS-2: tR=0.99 min, [M+1] ⁺ 519.19.

Step 2. tert-Butyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)ethyl)carbamate is dissolved in DCM (10 ml) and add TFA (250 µl, 3.27 mmol). The reaction mixture was stirred overnight and then quenched with sat. NaHCO ₃ solution (5 ml). The organic phase is collected and the aqueous phase is extracted with DCM (2x10 ml). The combined organic phases are dried over MgSO ₄ , filtered and evaporated to give 1-(2-aminoethyl)-N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 11-1 (90 mg, 62% yield) as a wax. LCMS-1: t _R =0.64 min, [M+1] ⁺ 419.4.

Table 1. Examples 11-2 - 11-11.

Examples 11-2 - 11-11 were synthesized by nucleophilic substitution using the procedure described for example approx. 11-1, based on approx. 3 or approx. 4 and various haloalkanes. In step 1, bases other than TEA can be used, such as NaOAc or Cs ₂ CO ₃ . In step 1, DXM can be replaced with DMF, MeCN or MeOH.

Example Name Analytical data of LCMS-1 Note. 11-2 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2hydroxyethyl)-3-(2-isopropylphenyl)azetidine-3carboxamide [M+1] ⁺ 420.36 t _R 0.71

- 54 040901

Note. 11-3 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2hydroxyethyl)-4-(2-isopropylphenyl)piperidine-4carboxamide [M+1] ⁺ 448.38 t _R 0.73 Note. 11-4 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3hydroxypropyl)-3-(2-isopropylphenyl)azetidine-3carboxamide [M+1] ⁺ 434.17 t _R 0.73 Note. 11-5 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(oxetan-3-ylmethyl)azetidine-3 carboxamide [M+1] ⁺ 446.39 t _R 0.74 Note. 11-6 1-cyano-X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 401.43 t _R 1.26 Note. 11-7 1-(3-(1H-tetrazol-5-yl)propyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 486.44 t _R 0.80 Note. 11-8 1-((1H-tetrazol-5-yl)methyl)-X-(2-(difluoromethoxy)6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 458.10 t _R 0.92 Note. 11-9 M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3hydroxy-3-methylbutyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 462.03 t _R 0.84 Note. 11-10 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2(1-hydroxycyclopropyl)ethyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 460.04 t _R 0.83 Note. 11-11 1-(2-aminopropyl)-X-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 433.36 t _R 0.75

Example 11-12: 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)acetic acid.

Step 1. Cesium carbonate (87 mg, 0.27 mmol) and benzyl bromoacetate (33 µl, 0.2 mmol) are added to a solution of X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl) Azetidine-3-carboxamide approx. 3 (50 mg, 0.13 mmol) in DMF (2 mL). The reaction mixture was stirred at rt. overnight (reaction monitored by LCMS). The mixture was then diluted with water (10 ml) and extracted with EI Ac (2x15 ml). The combined extracts are dried over MgSO4, filtered and evaporated to give benzyl 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)acetate (16 mg, 23% yield) as a colorless oil, which is used as such in the next step. LCMS-2: t _R =l.01 min, [M+H] ⁺ =524.17.

Step 2. To a solution of benzyl 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)acetate (16 mg, 0.03 mmol) in Pd/C (4 mg, 0.03 mmol) was added to 1 ml of a 1:1 ethanol/THF mixture. The reaction mixture is degassed, hydrogenated at 1 bar and stirred overnight. The mixture is filtered on celite and evaporated to dryness to give the title compound approx. 11-12 (11 mg, 83% yield) as a white solid. LCMS-1: t _R =0.86 min, [M+1] ⁺ 434.30.

Example 11-13 Ethyl 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)propanoate and Example 11-14: 3- (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)propanoic acid.

Stage 1. Hydrochloride mixture approx. 3 (60 mg, 0.15 mmol), methyl acrylate (20 μl, 0.19 mmol) and Cs ₂ CO ₃ (71 mg, 0.22 mmol) in DMF (15 ml) were stirred at rt. within 18 h. The reaction mixture was evaporated and the residue was purified by prep-HPLC (prep-HPLC-3 conditions) to give approx. 1113 as a white solid (51 mg, 73% yield). LCMS-1: t _R =0.82 min, [M+1] ⁺ 476.33; 'H NMR (400 MHz, CDC1 ₃ ) δ: 9.89 (s, 1H), 8.60 (d, >8.1 Hz, 1H), 7.46 (t, >73.0 Hz, 1H), 7.35-7.33 (m, 2H), 7.26-7.21 (m, 1H), 7.03 (d, >7.4 Hz, 1H), 6.92 (d, >8.1 Hz, 1H), 4.22-4.11 (m, 4H), 3.70-3.55 (m, 2H), 2.88 (t, >7.4 Hz, 2H), 2.58-2.46 (m, 3H), 2.41 (s, 3H), 1.28 (t, >7.1 Hz, 3H), 1.18 (d, >6.8 Hz, 6H).

Step 2 Ethyl 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)propanoate approx. 11-13 (45 mg, 0.09 mmol) was dissolved in MeOH/THF 1:1 (5 ml) and treated with 2 M LiOH solution (1 ml, 2.0 mmol). The solution is stirred at rt. within 2 h (the course of the reaction is monitored using LCMS). The reaction mixture is filtered through a filter syringe and evaporated. The residue was purified by prep-HPLC (prep-HPLC-3 conditions) to give approx. 11-14 as a white solid (& mg, 25% yield). LCMS-1: t _R =0.77 min, [M+1] ⁺ 447.99; Ή NMR (400 MHz, CDC1 ₃ ) δ: 8.58 (d, >8.1 Hz, 1H), 7.56 (s, 1H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 1H), 7.30 (t , >72.8 Hz, 1H), 7.23 (d, >7.5 Hz, 1H), 6.94 (d, >8.1 Hz, 1H), 4.48-4.28 (m, 2H), 3.99-3.75 (m, 2H), 3.00 ( t, >6.1 Hz, 2H), 2.50–2.40 (m, 3H), 2.39 (s, 3H), 1.15 (d, >6.5 Hz, 6H).

Example 11-15: 1-(2-amino-2-oxoethyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2

-55040901 isopropylphenyl)azetidine-3-carboxamide.

To a solution of 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)acetic acid approx. 11-12 (11 mg, 0.025 mmol) in DCM (0.5 mL) at 0°C under nitrogen, isobutyl chloroformate (8 mg, 0.06 mmol) was added followed by TEA (8 μL, 0.06 mmol). The reaction mixture was stirred at 0°C for 30 min, and then ammonium hydroxide (8 µl, 0.05 mmol) was added. The mixture is allowed to warm up to rt. and stirred for 30 min. The volatiles are evaporated in vacuo and the residue is purified with Prep. HPLC (prep-HPLC-3 conditions) to give 1-(2-amino-2-oxoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide approx. 11-15 (10 mg, 80% yield) as a colorless oil. LCMS-1: tR=0.72 min, [M+H]+=433.33.

Example 11-16: 1-(2-cyanoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

1-(2-cyanoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide approx. 11-16 are obtained from approx. 3 and acrylonitrile following the procedure described for approx. 11-13 to give the title compound as a beige solid. LCMS-1: t _R =0.93 min, [M+H]+=529.14.

Example 11-17: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxy-2,2-dimethylpropyl)-3(2-isopropylphenyl)azetidine-3-carboxamide.

To a solution of N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3 carboxamide approx. 3 (68 mg, 0.18 mmol) and 3-hydroxy-2,2-dimethylpropanal (25 mg, 0.245 mmol) in MeOH (2 ml) sodium cyanoborohydride (18 mg, 0.29 mmol) is added under an inert atmosphere. The reaction mixture was stirred at 50° C. for 2 h (reaction monitored by LCMS) and then quenched with water (2 ml). The mixture was diluted with MeCN (2 ml) and then purified with prep. HPLC (prep-HPLC-3 conditions) to give the title compound approx. 11-17 (46 mg, 55% yield) as colorless glass. LCMS-1: t _R =0.79 min, [M+1] ⁺ 462.41; 1H NMR (500 MHz, CDC13) δ: 8.61 (d, J=8.1 Hz, 1H), 8.07 (s, 1H), 7.42-7.35 (m, 3H), 7.33-7.29 (m, 1H), 7.19 (d , J=7.7 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 4.25 (s br, 2H), 3.70 (s br, 2H), 3.50 (s, 2H), 2.60 (s, 2H) , 2.53-2.45 (m, 1Н), 2.39 (s, 3Н), 1.14 (d, J=6.7 Hz, 6H), 0.94 (s, 6Н).

Table 2. Examples 11-18 - 11-66.

Examples 11-18 - 11-66 were synthesized using the procedure described for Example approx. 11-17, based on approx. 3 or approx. 4 and various aldehydes using sodium cyanoborohydride or other reducing agents. Functional groups such as an alcohol or acid group may be protected with an appropriate protecting group. For example, esters are saponified with 2n. LiOH after the reductive amination step.

- 56 040901

Example Name Analytical data of LCMS-1 Note. 11-18 (B.)-1M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)1-(2,3-dihydroxypropyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 450.22 t _R 0.71 Note. 11-19 (K)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)1-(2,3-dihydroxypropyl)-4-(2isopropylphenyl)piperidine-4-carboxamide [M+1] ⁺ 478.39 t _R 0.72 Note. 11-20 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(oxetan-3-yl)azetidine-3carboxamide [M+1] ⁺ 432.35 t _R 0.84 Note. 11-21 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-((2-methyloxazol-4yl)methyl)azetidine-3-carboxamide [M+1] ⁺ 471.37 t _R 0.81 Note. 11-22 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-((1-methyl-1H-pyrazol-5yl)methyl)azetidine-3-carboxamide [M+1] ⁺ 470.37 t _R 0.86 Note. 11-23 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-((1-methyl-1H-pyrazol-4yl)methyl)azetidine-3-carboxamide [M+1] ⁺ 470.38 t _R 0.74 Note. 11-24 methyl 3-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylpropanoate [M+1] ⁺ 490.04 t _R 0.96 Note. 11-25 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylpropanoic acid [M+1] ⁺ 476.05 t _R 0.93 Note. 11-26 methyl 1-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)cyclopropan-1-carboxylate [M+1] ⁺ 488.29 t _R 0.82 Note. 11-27 1-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 474.02 t _R 0.85 Note. 11-28 methyl 4-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)butanoate [M+1] ⁺ 476.48 t _R 0.82

- 57 040901

Note. 11-29 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)butanoic acid [M+1] ⁺ 462.35 t _R 0.74 Note. 11-30 methyl 4-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoate [M+1] ⁺ 504.35 t _R 0.86 Note. 11-31 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoic acid [M+1] ⁺ 490.01 t _R 0.78 Note. 11-32 ethyl 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-3,3-dimethyl butanoate [M+1] ⁺ 518.02 t _R 0.99 Note. 11-33 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-3,3-dimethylbutanoic acid [M+1] ⁺ 490.33 t _R 0.91 Note. 11-34 ethyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)isoxazole-3-carboxylate [M+1] ⁺ 529.24 t _R 1.24 Note. 11-35 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)isoxazole-3-carboxylic acid [M+1] ⁺ 501.02 t _R 0.95 Note. 11-36 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(isoxazol-5ylmethyl)azetide in-3-carboxamide [M+1] ⁺ 457.00 t _R 0.88 Note. 11-37 methyl 4-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrazole-3-carboxylate [M+1] ⁺ 514.38 t _R 0.88 Note. 11-38 4-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrazole-3-carboxylic acid [M+1] ⁺ 500.22 t _R 0.88 Note. 11-39 ethyl 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrazole-4-carboxylate [M+1] ⁺ 528.10 t _R 0.84 Note. 11-40 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrazole-4-carboxylic acid [M+1] ⁺ 500.37 t _R 0.87 Note. 11-41 methyl 2-(2-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)-1H-pyrrol1-yl)acetate [M+1] ⁺ 527.41 t _R 0.87 Note. 11-42 2-(2-((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1 H-pyrrol-1-yl) acetic acid [M+1] ⁺ 513.03 t _R 0.97 Note. 11-43 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrrole-2-carboxylate [M+1] ⁺ 513.14 t _R 0.84

- 58 040901

Note. 11-44 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrrole-2-carboxylic acid [M+1] ⁺ 499.38 t _R 0.77 Note. 11-45 methyl 6-((3-((2-(diφtormetoksi)-6-methylpyridin3-yl)κarbamoyl)-3-(2-isopropylφenyl)azetidine-lyl)methyl)picolinate [M+1] ⁺ 525.31 ΐκ 0.84 Note. 11-46 6-((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)picolinic acid [M+1] ⁺ 511.05 t _R 0.84 Note. 11-47 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(oxazol-2-ylmethyl)azetidine3-carboxamide [M+1] ⁺ 457.24 ΐκ 0.96 Note. 11-48 methyl 2-(4-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)az etidin-1-yl)methyl)-1H-1,2,3 triazole -1 -yl)acetate [M+1] ⁺ 529.02 t _R 0.78 Note. 11-49 2-(4-((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1 Η-1,2,3 - triazol-1-yl)acetic acid [M+1] ⁺ 515.09 Ir 0.82 Note. 11-50 methyl 4-((3-((2-(diφtormetoksi)-6-methylpyridin3-yl)κarbamoyl)-3-(2-isopropylφenyl)azetidine-lyl)methyl)picolinate [M+1] ⁺ 525.04 t _R 0.97 Note. 11-51 4-((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)picolinic acid М+1] ⁺ 511.03 Ir 0.88 Note. 11-52 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)picolinate [M+1] ⁺ 525.08 t _R 0.92 Note. 11-53 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)picolinic acid [M+1] ⁺ 511.05 Ir 0.85 Note. 11-54 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)pyrazine-2-carboxylate [M+1] ⁺ 526.47 Ir 0.89 Note. 11-55 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)3-(2-isopropylphenyl)azetidin-1yl)methyl)pyrazine-2-carboxylic acid [M+1] ⁺ 512.08 tR 0.84 Note. 11-56 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)furan-2-carboxylate [M+1] ⁺ 514.42 t _R 0.97 Note. 11-57 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)az etidin-1 yl)methyl)furan-2-carboxylic acid [M+1] ⁺ 500.27 tR 0.87 Note. 11-58 ethyl 2-(2-((3-((2-(difluoromethoxy)-6- methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)oxazol-4yl)acetate [M+1] ⁺ 543.24 t _R 1.07

- 59 040901

Note. 11-59 2-(2-((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)oxazol-4-yl)acetic acid [M+1] ⁺ 515.27 t _R 0.90 Note. 11-60 1-(4-cyano-4-methylpentyl)-X-(2-(difluoromethoxy)6-methylpyridin-3-yl)-3-(2- isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 471.46 t _R 0.90 Note. 11-61 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(4-methyl-4nitropentyl)azetidine-3-carboxamide [M+1] ⁺ 505.50 t _R 0.94 Note. 11-62 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(2(methylamino)ethyl)azetidine-3-carboxamide [M+1] ⁺ 433.05 t _R 0.74 Note. 11-63 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2(ethylamino)ethyl)-3-(2-isopropylphenyl)azetidine3-carboxamide [M+1] ⁺ 447.31 t _R 0.77 Note. 11-64 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(2-methyl-2(methylamino)propyl)azetidine-3-carboxamide [M+1] ⁺ 461.20 t _R 0.91 Note. 11-65 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-methylpentan-2-yl acetate [M+1] ⁺ 510.08 t _R 0.95 Note. 11-66 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(4hydroxy-4-methylpentyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 476.50 t _R 0.85

Example 11-67: Methyl 2-(1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)cyclopropyl)acetate and Example 11-68: 2-(1-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)methyl)cyclopropyl)acetic acid.

Stage 1. Hydrochloride mixture approx. 3 (50 mg, 0.115 mmol), methyl 2-[1(bromomethyl)cyclopropyl]acetate (37.5 mg, 0.172 mmol) and Cs ₂ CO ₃ (150 mg, 0.46 mmol) in MeCN (1 ml) stirred at 50°C within 18 h. The reaction mixture was evaporated and the residue was purified by prep-HPLC (prep-HPLC-3 conditions) to give approx. 11-67 as a colorless oil (32 mg, 56% yield). LCMS-1: t _R =0.85 min, [M+1] ⁺ 502.06.

Step 2 Methyl 2-(1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)methyl)cyclopropyl)acetate approx. 11-67 (30 mg, 0.06 mmol) is dissolved in MeOH (2 ml) and treated with 2 M LiOH solution (1 ml, 2.0 mmol). The solution is stirred at rt. overnight (reaction progress is monitored by LCMS). The reaction mixture is cooled to 0°C and slowly acidified to pH 4 with 2N. HC1 solution. The aqueous solution is then extracted twice with EtOAc. The combined organic extracts are dried over MgSO ₄ , filtered and evaporated to give the hydrochloride salt of approx. 11-68 as a white solid (20 mg, 69% yield). LCMS-1: t _R =0.84 min, [M+1] ⁺ 488.04.

Table 3. Examples 11-69 - 11-76.

Examples 11-69 - 11-76 were synthesized using the procedure described for Example approx. 11-68, based on approx. 3 which is reacted with functionalized haloalkanes.

-60040901

Example Name Analytical data of LCMS-1 Note. 11-69 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylpentanoic acid [M+1] ⁺ 504.42 t _R 0.81 Note. 11-70 methyl 1-(3-(3-((2-(diφτopmetoksi)-6methylpyridin-3-yl)κarbamoyl)-3-(2isopropylphenyl)azetidin-1 yl)propyl)cyclopropane-1-carboxylate [M+1] ⁺ 516.07 t _R 0.87 Note. 11-71 1 -(3-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)propyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 502.07 t _R 0.81 Note. 11-72 1 -(2-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 488.08 t _R 1.14 Note. 11-73 1 -(2-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethyl)cyclobutane-1-carboxylic acid [M+1] ⁺ 502.09 t _R 1.20 Note. 11-74 ethyl 2-(2-(3-((2-(diφτopmetoksi)-6-methylpyridin3-yl)κarbamoyl)-3-(2-isopropylφenyl)azetidine-lyl)ethoxy)acetate [M+1] ⁺ 506.48 t _R 0.84 Note. 11-75 2-(2-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethoxy)acetic acid [M+1] ⁺ 478.04 t _R 0.80 Note. 11-76 3-(2-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethyl)tetrahydrofuran-3-carboxylic acid [M+1] ⁺ 518.12 t _R 1.22

Example 11-77: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2(methylsulfonamido)ethyl)azetidine-3-carboxamide.

To a solution of 1-(2-aminoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isonronylphenyl)azetidine-3-carboxamide approx. 11-1 (73 mg, 0.18 mmol) in DCM (10 mL) triethylamine (98 μL, 0.78 mmol) was added followed by methanesulfonyl chloride (27 μL, 0.35 mmol). The reaction mixture was stirred at rt. during the night. The volatiles are evaporated and the residue is purified with Prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 11-77 (18 mg, 21% yield) as a foam. LCMS-1: tR=0.73 min, [M+1]+ 497.06.

Example 11-78: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(dimethylamino)ethyl)-3-(2isopropylphenyl)azetidine-3-carboxamide.

2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethyl methanesulfonate is synthesized from approx. 11-2, following the procedure described for obtaining approx. 11-76. The mesylate (40 mg, 0.08 mmol) is then reacted with 1 M dimethylamine in THF (5 ml) and stirred at 60°C. The reaction mixture was evaporated and the residue was purified with prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 11-78 (8 mg, 22% yield) as a foam. LCMS-1: tR=0.80 min, [M+1] ⁺ 447.03.

Example 11-79 Ethyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethyl)glycinate.

Example 11-80: (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethyl)glycine.

Step 1 Methyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethyl)glycinate approx. 11-79 synthesized from approx. 11-1 and ethyl chloroacetate according to the protocol described for obtaining approx. 11-67. LCMS-1: t _R =0.87 min, [M+1] ⁺ 505.11.

Step 2. (2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethyl)glycine ca. 11-80 synthesized in accordance with the protocol described for obtaining approx. 11-14. LCMS-1: tR=0.76 min, [M+1] ⁺ 477.07.

Example 11-81 Ethyl N-(2-(3-((2-(difluoromethoxy)-6-methyl-pyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)ethyl)-N-methylglycinate and Example 11-82: N-(2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethyl)-N-methyl glycine.

Examples 11-81 and 11-82 are obtained from approx. 11-62 by analogy with approx. 11-79 and approx. 11-80.

Note. 11-81 LCMS-1: tR=0.94 min, [M+1] ⁺ 519.06. approx. 11-82 LCMS-1: tR=0.77 min, [M+1] ⁺ 491.12

Example 11-83: (S)-1-(3-amino-2-hydroxypropyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide .

- 61 040901

Step 1 To a solution of N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine3-carboxamide approx. 3 (450 mg, 1.2 mmol) in isopropanol (5 mL) 3 M NaOH aqueous solution (1.5 mL) was added followed by R-epichlorohydrin (282 μL, 3.6 mmol). The reaction mixture was stirred at rt. overnight, diluted with EtOAc (15 ml) and washed with water (10 ml). The organic phase is dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. TLC (eluent: heptane/ethyl acetate 4:1) to give (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(oxiran-2-ylmethyl) azetidine-3-carboxamide (245 mg, 47% yield) as an oil. LCMS-2: t _R =0.89 min, [M+H]+=432.10.

Step 2. To a solution of (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1(oxiran-2-ylmethyl)azetidine-3-carboxamide (50 mg, 0.12 mmol) in MeOH (1 ml) was added with 7 M NH3 in MeOH (10 µl, 0.35 mmol). The reaction mixture is stirred at 60° C. for 6 hours. The volatiles are then evaporated off and the residue is purified with prep. HPLC (prep-HPLC-3 conditions) to give the title compound approx. 11-83 (53 mg, 100% yield) as a glass. LCMS-1: t _R =0.53 min, [M+1] ⁺ 449.07.

Table 4. Examples 11-84 and 11-85.

Examples 11-84 and 11-85 were synthesized using the procedure described for Example approx. 11-83 using methyl or dimethylamine as the nucleophile.__________________________________

Example Name Analytical data of LCMS-1 Note. 11-84 (8)-L1-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(2-hydroxy-3-(methylamino)propyl)-3-(2- [M+1] ⁺ 463.08 t _R 0.54 isopropylphenyl)azetidine-3-carboxamide Note. 11-85 (8)-X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(3-(dimethylamino)-2-hydroxypropyl)-3(2-isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 477.17 t _R 0.55

Example 11-86: (S)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-hydroxy-3-(2-hydroxyacetamido)propyl)-3-(2-isopropylphenyl) )azetidine-3-carboxamide.

(S)-1-(3-amino-2-hydroxypropyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 11-83 (52 mg, 0.12 mmol) is added to a solution of glycolic acid (0.14 mmol, 11 mg), EDC (33 mg, 0.17 mmol), HOBt (23.5 mg, 0.17 mmol) and DIPEA (40 µl, 0.23 mmol) in DMF (5 ml). The reaction mixture was stirred at rt. for 1 h, then evaporated to dryness and purified with prep. HPLC (prep-HPLC-2 conditions) to give the title compound approx. 11-86 (22 mg, 37% yield) as an oil. LCMS-1: t _R =0.68 min, [M+1] ⁺ 507.35; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.50 (d, J=8.1 Hz, 1H), 7.62-7.57 (m, 1H), 7.49-7.43 (m, 3H), 7.39-7.35 (m, 1H), 7.26 (t, J=83.8 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 5.70-5.01 (m, 4H), 4.19-4.05 (m , 3Н), 3.48-3.42 (m, 1H), 3.42-3.33 (m, 2Н), 3.29-3.20 (m, 1H), 2.38 (s, 3Н), 2.29-2.18 (m, 1H), 1.19 (d , J=6.1 Hz, 6H).

Example 11-87: X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(2-hydroxyacetamido)ethyl)-3-(2isopropylphenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(2-hydroxyacetamido)ethyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 11-87 (35 mg, solid) is prepared from 1-(2-aminoethyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 11-1 (73 mg, 0.17 mmol) following the procedure described for approx. 11-86. LCMS-1: t _R =0.69 min, [M+1] ⁺ 477.36; 1H NMR (400 MHz, CDCl3) δ: 8.56 (d, J=8.1 Hz, 1H), 8.48 (s, 1H), 7.24-7.43 (m, 5H), 7.16 (m, 1H), 6.94 (d, J =8.1 Hz, 1H), 4.32-3.14 (m, 2H), 4.11 (s, 2H), 3.79-3.57 (m, 2H), 3.44-3.42 (m, 2H), 2.79 (t, J=5.6 Hz, 2Н), 2.50-2.43 (m, 1Н), 2.40 (s, 3Н), 1.16 (d, J=6.6 Hz, 6Н).

Example 11-88: 1-(cyanomethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

To the hydrochloride solution approx. 3 (100 mg, 0.24 mmol) and bromoacetonitrile (19 μl, 0.27 mmol) in DMF (2 ml) add Cs ₂ CO ₃ (158 mg, 0.49 mmol). The reaction mixture was stirred at rt. for 1 h (reaction monitored by LCMS), then extracted with DCM (2x20 ml). The organic extracts are washed with water (10 ml) followed by brine (10 ml) and then dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 11-88 (50 mg, 50% yield) as a beige solid. LCMS-1: t _R =1.25 min, [M+1] ⁺ 415.37; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.60 (d, J=8.1 Hz, 1H), 8.17 (s, 1H), 7.42-7.38 (m, 2H), 7.32 (t, J=72.8 Hz, 1H) , 7.34-7.30 (m, 1H), 7.17 (d, J=6.6 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.30-4.21 (m, 2H), 3.96-3.85 (m, 2H ), 3.65 (s, 2Н), 2.56-2.47 (m, 1Н), 2.40 (s, 3Н), 1.16 (d, J=6.7 Hz, 6Н).

Example 11-89: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((3-(hydroxymethyl)oxetan-3yl)methyl)-3-(2-isopropylphenyl)azetidine-3- carboxamide.

To the hydrochloride solution approx. 3 (200 mg, 0.49 mmol) and (3-(bromo-methyl)oxetanyl-3-yl)methanol

- 62 040901 (88 µl, 0.49 mmol) Cs2CO ₃ (316 mg, 0.97 mmol) is added to MeCN (10 ml). The reaction mixture was stirred at 85° C. for 2 h (reaction monitored by LCMS). Water (20 ml) was added and the mixture was then extracted with EtOAc (2x50 ml). The organic extracts are washed with brine (10 ml), dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 11-89 (157 mg, 68% yield) as a beige solid. LCMS-1: t _R =0.75 min, [M+1]+ 476.37.

Example 11-90: methyl 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)methyl)oxetan-3- carboxylate and Example 11-91: 3-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)methyl)oxetane-3-carboxylic acid.

Methyl 3-(bromomethyl)oxetane-3-carboxylate (172 mg, 0.82 mmol) prepared from commercially available 3-(bromomethyl)oxetane-3-carboxylic acid and trimethylsilyldiazomethane is reacted with hydrochloride approx. 3 (150 mg, 0.36 mmol) following the procedure described for approx. 11-89 to give methyl 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)methyl)oxetan-3- carboxylate approx. 11-90. LCMS-1: t _R =1.02 min, [M+1] ⁺ 504.03. The methyl ester is then saponified with LiOH following the procedure described for approx. 11-14, obtaining Note. 11-91 (17 mg, 9% yield) as a beige wax. LCMS-1: t _R =0.90 min, [M+1] ⁺ 490.29.

Example 11-92: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3,3-dimethyl-4-(methylamino)-4oxobutyl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3,3-dimethyl-4-(methylamino)-4-oxobutyl)-3-(2isopropylphenyl)azetidine-3-carboxamide approx. 11-92 is prepared from 4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethylbutanoic acid approx. 11-31 and 2 n. methylamine in THF following the procedure described for approx. 11-86. Colorless oil. LCMS-1: tR=0.79 min, [M+1] ⁺ 503.52.

Example 11-93: 1-(4-amino-3,3-dimethyl-4-oxobutyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)azetidine-3 -carboxamide.

Note. 11-31 (60 mg, 0.114 mmol) is reacted with allylamine (10 µl, 0.125 mmol) according to the procedure described for approx. 11-86. The resulting allylamide was purified by prep-HPLC (prep-HPLC-2 conditions) and then injected (48 mg, 0.09 mmol) into a sealed tube containing tetrachlorobis(2,7-dimethyl-2,6-octadienylene)diruthenium (1.7 mg, 0.002 mmol ), KIO4 (21 mg, 0.09 mmol) and water (1 ml). The reaction mixture is heated at 100° C. for 2 hours under argon. Water is added and the mixture is extracted with EtOAc. The organic extract is dried over MgSO ₄ , dried, filtered and evaporated. The crude compound is purified with prep. HPLC (prep-HPLC-2 conditions) to give the title compound approx. 11-93 as a colorless oil (8 mg, 18%). LCMS-1: t _R =0.82 min, [M+1] ⁺ 489.12.

Example 11-94: 1-(4-amino-4-methylpentyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide.

For solution approx. 11-61 (82 mg, 0.16 mmol) in AcOH (5 ml) ZnBr (2.5 eq., 114 mg) was added and the mixture was stirred at 100°C for 2 h in a microwave oven. Add another portion of ZnBr (1.1 eq., 50 mg) and the reaction mixture is stirred at 100°C for 2 h. HPLC (prep-HPLC-1 conditions) gives the title compound approx. 11-94 as a beige wax (16 mg, 17% yield). LCMS-1: t _R =0.61 min, [M+1] ⁺ 475.15.

Example 11-95: 1-(2-(1H-tetrazol-5-yl)ethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide .

1-(2-(1H-tetrazol-5-yl)ethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 11-95 is prepared from 3-(2-isopropylphenyl)-N-(2-methoxy-6methylpyridin-3-yl)azetidine-3-carboxamide approx. 3 and 5-(2-bromoethyl)-1H-1,2,3,4-tetrazole, following the procedure described for approx. 11-1 - 11-11. Colorless oil. LCMS-1: t _R =0.80 min, [M+1] ⁺ 472.06.

Example 12-1: 1-(4-cyanobutanoyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

To a solution of 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)azetidine-3-carboxamide approx. 3 (72 mg, 0.19 mmol) and 4-cyanobutanoic acid (21.6 mg, 0.19 mmol) in DMF (2 ml) add EDC (55 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and DIPEA (65 µl, 0.49 mmol). The mixture is stirred at rt. for 1 h (the course of the reaction is monitored using LCMS), then it is diluted with sat. aq. NaHCO ₃ solution and extracted twice with EtOAc. United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product is purified with prep. HPLC (prep-HPLC-3 conditions) to give 1-(4-cyanobutanoyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide approx. 12-1 (52 mg, 58% yield) as a yellow oil; LCMS-1: t _R =1.17 min, [M+1] ⁺ 471.07.

Table 5. Examples 12-2 - 12-31.

Examples 12-2 - 12-31 were synthesized using the procedure described for approx. 12-1 above, based on approx. 3 or approx. 4. Standard coupling reagents such as EDC/HOBt, TBTU, HATU, T3P can be used.

- 63 040901

Reagents - carboxylic acids are commercially available or obtained in accordance with the literature protocols._______________________________________________________________

Example Name Analytical data of LCMS-1 Note. 12-2 1-acetyl-N-(2-(difluoromethoxy)-6-methylpyridin3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide [M+1] ⁺ 418.06 t _R 1.14 Note. 12-3 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethane-1-sulfonic acid [M+1] ⁺ 498.10 t _R 1.33 Note. 12-4 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(2sulfamoylacetyl)azetidine-3-carboxamide [M+1] ⁺ 497.10 t _R 1.07 Note. 12-5 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(3sulfamoylpropanoyl)azetidine-3-carboxamide [M+1] ⁺ 511.17 t _R 1.07 Note. 12-6 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(2-(Nmethylsulfamoyl)acetyl)azetidine-3carboxamide [M+1] ⁺ 511.30 t _R 1.12 Note. 12-7 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1((methylsulfonyl)glycyl)azetidine-3carboxamide [M+1] ⁺ 511.15 t _R 1.10 Note. 12-8 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(H-methyl-Hsulfamoylglycyl)azetidine-3-carboxamide [M+1] ⁺ 526.18 t _R 1.I Note. 12-9 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(3-(methylsulfonamido)3-oxopropanoyl)azetidine-3-carboxamide [M+1] ⁺ 539.20 t _R 1.11 Note. 12-10 1-(carbamoylglycyl)-H-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 476.44 t _R 0.99 Note. 12-11 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(5,5,5-trifluoro-4oxopentanoyl)azetidine-3-carboxamide [M+1] ⁺ 528.43 t _R 1.21 Note. 12-12 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4(2-isopropylphenyl)-1-(5,5,5-trifluoro-4oxopentanoyl)piperidine-4-carboxamide [M+1] ⁺ 556.28 t _R 1.28 Note. 12-13 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1(2-(3-hydroxyoxetan-3-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 490.02 tR 1.08 Note. 12-14 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1(2-(3-hydroxyoxetan-3-yl)acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide [M+1] ⁺ 518.36 t _R 1.15 Note. 12-15 H-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(1H-pyrazole-4carbonyl)azetidine-3-carboxamide [M+1] ⁺ 470.09 tR 1.08

- 64 040901

Note. 12-16 N-(2-(diφtormetoκci)-6-methylpyridin-3-yl)-l(3-hydroxyisoxazole-5-carbonyl)-3-(2isopropylphenyl)az etidine-3-carboxamide [tautomeric form: T\G-(2 -(difluoromethoxy)-6methylpyridin-3-yl)-1-(3-oxo-2,3dihydroisoxazole-5-carbonyl)-3-(2isopropylphenyl)az ethidine-3-carboxamide] [M+1] ⁺ 487.24 tR 1.16 Note. 12-17 [ and its tautomeric forms such as N-(2(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3oxo-4,5-dihydro-1H-1,2,4-triazole-5-carbonyl)3 -(2-isopropylphenyl)az etidine-3-carboxamide] [M+1] ⁺ 486.96 1r 1.05 Note. 12-18 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(1Н-tetrazol-5carbonyl)az etidine-3-carboxamide [M+1] ⁺ 472.09 t _R 1.30 Note. 12-19 1-(2-(1H-tetrazol-5-yl)acetyl)-T\G-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)az ethidine-3-carboxamide [M+1] ⁺ 486.06 t _R 1.07 Note. 12-20 1-(2-(1H-tetrazol-1-yl)acetyl)-M-(2(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-4-carboxamide [M+1] ⁺ 514.37 t _R 1.16 Note. 12-21 1-(2-(2H-1,2,3-triazol-2-yl)acetyl)^-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)az etidine-3-carboxamide [M+1] ⁺ 484.99 t _R 1.16 Note. 12-22 1 -(2-(2H-1,2,3-triazol-2-yl)acetyl)^-(2(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-4-carboxamide [M+1] ⁺ 513.06 t _R 1.21 Note. 12-23 1 - (2- (4H-1,2,4-triazol-4-yl) acetyl) -T\G- (2 (difluoromethoxy) -6-methylpyridin-3-yl) -3- (2isopropylphenyl)az etidine- 3-carboxamide [M+1] ⁺ 485.33 t _R 1.01 Note. 12-24 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l(2-(3-hydroxy-1H-pyrazol-5-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [and its tautomeric forms such as N-(2(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3oxo-2,3-dihydro-1H-pyrazol-5-yl)acetyl)-3- (2isopropylphenyl)az etidine-3-carboxamide] [M+1] ⁺ 500.11 t _R 1.01 Note. 12-25 N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l(2-(3-hydroxy-1H-pyrazol-5-yl)acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide [and its tautomeric forms such as N-(2(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3oxo-2,3-dihydro-1H-pyrazol-5-yl)acetyl)-4- (2isopropylphenyl)piperidine-4-carboxamide] [M+1] ⁺ 528.01 t _R 1.06

- 65 040901

Note. 12-26

Note. 12-27

Note. 12-28

Note. 12-29

Note. 12-30

Note. 12-31

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l(2-(3-hydroxy-1H-pyrazol-4-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [and its tautomeric forms such as N-(2(difluoromethoxy)-6-methylpyride in-3-yl)-1-(2-(3 oxo-2,3-dihydro-1H-pyrazol-4-yl)acetyl)- 3-(2isopropylphenyl)azetidine-3-carboxamide]

[ and its tautomeric forms such as N-(2(difluoromethoxy)-6-methylpyride in-3-yl)-1-(2-(3 oxo-2,3-dihydro-1H-pyrazol-4-yl)acetyl) -4-(2isopropylphenyl)piperidine-4-carboxamide] 1-(3-(4H-1,2,4-triazol-4-yl)propanoyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl )-3-(2isopropylphenyl)azetidine-3-carboxamide

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-l(3-(3-hydroxyisoxazol-5-yl)propanoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [tautomeric form: 18G- (2-(difluoromethoxy)-6methylpyridin-3-yl)-1-(3-(3-oxo-2,3 dihydroisoxazol-5-yl)propanoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide] 1-( 4-(1H-tetrazol-5-yl)butanoyl)-N-(2(diφτopmetoksi)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide

N-(2-(diφtormetoksi)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)-1-(2-(1-methylpiperidin-4yl)acetyl)azetidine-3-carboxamide

[M+1] ⁺ 500.32 t _R 1.03

[M+1] ⁺ 528.21 t _R 1.08

[M+1] ⁺ 499.36 t _R 1.00

[M+1] ⁺ 514.99 t _R 1.12

[M+1] ⁺ 514.17 t _R 1.08

[M+1] ⁺ 515.18 t _R 0.77

Example 12-32: tert-Butyl (1-(4-(2-isopropylphenyl)-4-((2-methoxy-4-methylphenyl)carbamoyl)piperidine-1-carbonyl)cyclopropyl)carbamate and Example 12-33: 1-(L-alanyl)-N-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Step 1. tert-Butyl (S)-(1-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-1 -oxopropan-2-yl) carbamate approx. 12-32 are obtained from approx. 3 (69 mg, 0.183 mmol) and commercially available Boc-alanine (35 mg, 0.183 mmol) following the method described for approx. 12-1. White solid (81 mg, 81% yield). LCMS-1: t _R =1.30 min, [M+1] ⁺ 547.02.

Step 2 1-(L-alanyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 12-33 are obtained from approx. 12-32 (75 mg, 0.137 mmol) following the reaction conditions of step 2 described for approx. 11-1: 44 mg, yield after prep. HPLC (prepHPLC-3 conditions) 72%. LCMS-1: t _R =0.74 min, [M+1] ⁺ 446.99; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.54 (d, J=8.1 Hz, 1H), 7.48-7.45 (m, 2H), 7.42-7.37 (m, 1H), 7.35-7.31 (m, 1H), 7.26 (d, J=72.8 Hz, 1H), 7.24 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 5.17-4.94 (m, 1H), 4.78-4.40 (m, 3H), 3.70 -3.50 (m, 1H), 2.46-2.39 (m, 4H), 1.40 (d, J=6.8 Hz, 1.5H), 1.27 (d, J=6.8 Hz, 1.5H), 1.23-1.09 (m, 6H ).

Table 6. Examples 12-34 - 12-51.

Examples 12-34 - 12-51 were synthesized using the procedure described for approx. 12-33, based on approx. 3 or approx. 4. Standard coupling reagents such as EDC/HOBt, TBTU, HATU, T3P can be used.

- 66 040901

Example Name Analytical data of LCMS-1 Note. 12-34 (8)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-hydroxy-4-oxobutanoic acid [M+1] ⁺ 492.14 t _R 1.05 Note. 12-35 (K)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-hydroxy-4-oxobutanoic acid [M+1] ⁺ 492.17 t _R 1.05 Note. 12-36 (8)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl)- 4-(2isopropylphenyl)piperidine-4-carboxamide [M+1] ⁺ 560.02 tR 1.31 Note. 12-37 (8)-4-(4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)-2-hydroxy-4-oxobutanoic acid [M+1] ⁺ 520.35 tR 1.11 Note. 12-38 1-(2-(3-aminooxetan-3-yl)acetyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 489.36 t _R 0.75 Note. 12-39 from/?et-butyl (8)-(1-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3-hydroxy-1 oxopropan-2-yl)carbamate [M+1] ⁺ 563.20 t _R 1.21 Note. 12-40 1-(L-seryl)-H-(2-(difluoromethoxy)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 463.36 t _R 0.72 Note. 12-41 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((48)4-hydroxypyrrolidin-2-carbonyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 489.37 t _R 0.73 Note. 12-42 Note. 12-43 Note. 12-44 Note. 12-45 Note. 12-46 Note. 12-47 Note. 12-48 Note. 12-49 Note. 12-50 Note. 12-51 (K)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(morpholine-2-carbonyl)azetidine3-carboxamide X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(morpholine-3-carbonyl)az etidine3-carboxamide (8)-X-(2-(difluoromethoxy)- 6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(morpholin-3yl)acetyl)azetide in-3-carboxamide (K)-X-(2-(difluoromethoxy)-6-methylpyridine- 3-yl)-3-(2isopropylphenyl)-1-(2-(morpholin-3yl)acetyl)azetide in-3-carboxamide X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(2-(3-oxopiperazin-2yl)acetyl)azetide in-3-carboxamide from/?et-butyl (2-(4-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)-2-oxoethyl)(2methoxyethyl)carbamate X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)-1 -((2methoxyethyl)glycyl)piperidine-4-carboxamide from/?et-butyl (2-(4-( (2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)-2-oxoethyl)(2hydroxyethyl)carbamate X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2hydroxyethyl)glycyl)-4-(2isopropylphenyl)piperidine-4-carboxamide T9-(2-(difluoromethoxy)-6-methylpyridine- 3-yl)-1-(3-(2(2-hydroxyethoxy)ethoxy)propanoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 489.38 t _R 0.76 [M+1] ⁺ 489.20 t _R 0.76 [M+1] ⁺ 503.37 t _R 0.76 [M+1] ⁺ 503.16 t _R 0.76 [M+1] ⁺ 516.17 t _R 0.73 [M+1] ⁺ 619.29 t _R 1.37 [M+1] ⁺ 519.40 t _R 0.80 [M+1] ⁺ 605.18 t _R 1.29 [M+1] ⁺ 505.34 t _R 0.78 [M+1] ⁺ 536.14 t _R 1.08

Example 12-52: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2-hydroxyethyl)glycyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Stage 1. To an ice-cold solution, approx. 3 (150 mg, 0.4 mmol) and DIPEA (205 µl, 1.2 mmol) in THF (10 ml) add chloroacetyl chloride (48 µl, 0.6 mmol). The reaction mixture was stirred at rt. for 18 h and then diluted with EtOAc. The organic solution is washed with water, dried over MgSO ₄ , filtered and evaporated to give the crude chloroacetamide intermediate, which is used as such in the next step.

Step 2: The chloroacetamide intermediate is dissolved in MeCN (10 ml). Ethanolamine (49 µl, 0.80 mmol) and K ₂ CO ₃ (221 mg, 1.6 mmol) are added and the reaction mixture is then stirred at 65° C. for 18 h (reaction progress is monitored by LCMS). The mixture was diluted with DCM (20 ml), washed with water (10 ml), dried over MgSO ₄ , filtered and evaporated. The residue is then purified with prep. TLC (DCM/MeOH 9:1) gave approx. 12-52 as a pale yellow foam (60 mg, 32% yield). LCMS-1: tR=0.73 min, [M+1]+ 477.15.

Table 7. Examples 12-53 - 12-60.

Examples 12-53 - 12-60 were synthesized using the procedure described above for approx. 12-52, based on approx. 3.

Example Name Analytical data of LCMS-1 Note. 12-53 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3 hydroxyazetidin-1-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 489.29 t _R 0.77 Note. 12-54 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-((2-methoxyethyl)glycyl)azetidine3-carboxamide [M+1] ⁺ 491.41 1r 0.76 Note. 12-55 (K)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1((K)-(2-hydroxypropyl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 491.38 t _R 0.75 Note. 12-56 (8)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1((8)-(2-hydroxypropyl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 491.07 tR 0.75 Note. 12-57 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(((1hydroxycyclopropyl)methyl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 503.38 tR 0.76 Note. 12-58 (K)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1((K)-(1-hydroxypropan-2-yl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 491.40 t _R 0.75 Note. 12-59 (8)-X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1((K)-(1-hydroxypropan-2-yl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 491.40 t _R 0.75 Note. 12-60 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-((2hydroxyethyl)amino)propanoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 491.39 t _R 0.74

Example 12-61 Methyl 4-(3-(2-isopropylphenyl)-3-((2-methoxy-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)-4-oxobutanoate and Example 12-62 : 4-(3-(2-isopropylphenyl)-3-((2-methoxy-6-methylpyridin3-yl)carbamoyl)azetidin-1-yl)-4-oxobutanoic acid.

Step 1 To a solution of 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)αzetidine-3carboxamide approx. 1 (30 mg, 0.088 mmol) and 4-methoxy-4-oxobutanoic acid (14.7 mg, 0.11 mmol) HATU (40.3 mg, 0.11 mmol) and DIPEA (45 µl, 0.26 mmol) are added. The mixture is stirred at rt. for 1 h (the course of the reaction is controlled by LCMS), then it is diluted with sat. aq. NaHCO ₃ solution and extracted twice with EtOAc. United org. the extracts are dried over MgSO ₄ , filtered and concentrated. The crude product is purified with prep. HPLC (prepHPLC-3 conditions) to give methyl 4-(3-(2-isopropylphenyl)-3-((2-methoxy-6-methylpyridin-3yl)carbamoyl)azetidin-1-yl)-4-oxobutanoate approx. 12-61 (20 mg, 50% yield) as a yellow oil. LCMS-1: t _R =1.18 min, [M+1] ⁺ 454.39; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.41 (d, J=7.8 Hz, 1H), 7.49-7.44 (m, 2H), 7.40-7.34 (m, 3H), 6.72 (d, J=8.0 Hz, 1Н), 5.08-4.96 (m, 1H), 4.72-4.62 (m, 1H), 4.58-4.45 (m, 2Н), 3.70 (s, 3Н), 3.69 (s, 3Н), 2.79-2.73 (m, 1H), 2.69-2.61 (m, 1H), 2.51-2.41 (m, 3H), 2.38 (s, 3H), 1.18 (d, Ji=6.7 Hz, 3H), 1.12 (d, Ji=6.7 Hz, 3H ).

Step 2. 4-(3-(2-Isopropylphenyl)-3-((2-methoxy-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)4-oxobutanoate (20 mg, 0.044 mmol) is dissolved in a mixture of MeOH/THF 1:1 (1 ml) and treated with 2 M LiOH (45 μl, 18.4 mmol). The solution is stirred at rt. within 2 h (the course of the reaction is monitored using LCMS). The reaction mixture is then diluted with water, acidified to pH 1 with 6N. HCl and extracted twice with EtOAc. The combined organic extracts are dried over MgSO ₄ , filtered and evaporated to give 4-(3-(2-isopropylphenyl)-3-((2-methoxy-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)-4 -oxobutanoic acid approx. 12-62 as a pale yellow oil (13 mg, 67% yield). LCMS-1: tR=1.07 min, [M+1] ⁺ 440.36; 1H NMR (400 MHz, CDQ3) δ: 8.40 (d, J=7.9 Hz,

- 68 040901

1Н), 7.51-7.43 (m, 2Н), 7.41-7.30 (m, 3Н), 6.73 (d, J=7.9 Hz, 1Н), 5.12-4.95 (m, 1Н), 4.69 (d, J=8.5 Hz , 1Н),

4.62-4.44 (m, 2H), 3.71 (s, 3H), 2.82-2.64 (m, 2H), 2.60-2.48 (m, 2H), 2.45-2.41 (m, 1H), 2.38 (s, 3H), 1.19(d,

J=6.6 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H).

Table 8. Examples 12-63 - 12-114.

Examples 12-63 - 12-114 were synthesized using the procedure described for approx. 12-62, based on approx. 2, approx. 3, approx. 4, approx. 5, approx. 6, approx. 7, approx. 8, or approx. 10. Standard coupling reagents such as EDC/HOBt, TBTU, HATU, T3P can be used. Reagents - carboxylic acids are commercially available or obtained in accordance with the literature protocols. If another functional group is present, an additional deprotection step is required, such as removal of the Boc from the amino group in an acidic medium.

Example Name Analytical data of LCMS-1 Note. 3-(3-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 462.01 t _R 1.09 12-63 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3-oxopropanoic acid Note. 1-(3-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 488.13 t _R 1.12 12-64 yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)cyclopropane-1-carboxylic acid Note. ethyl-3-(4-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 518.21 t _R 1.27 12-65 yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)-3-oxopropanoate Note. 3-(4-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 490.21 t _R 1.15 12-66 yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)-3-oxopropanoic acid Note. methyl 4-(3-((2-isopropoxy-6-methylpyridine-3- [M+1] ⁺ 482.42 ΐκ 1.33 12-67 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobutanoate Note. 4-(3-((2-isopropoxy-6-methylpyridine-3- [M+1] ⁺ 468.38 t _R 1.23 12-68 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobutanoic acid Note. methyl 4-(3-((6-chloro-2-methoxypyridine-3- [M+1] ⁺ 474.13 t _R 1.23 12-69 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobutanoate Note. 4-(3-((6-chloro-2-methoxypyridin-3-yl)carbamoyl)-3- [M+1] ⁺ 460.41 t _R 1.12 12-70 (2-isopropylphenyl)azetidin-1-yl)-4-oxobutanoic acid Note. 4-(3-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 475.97 12-71 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobutanoic acid t _R 1.09 Note. methyl 4-(4-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 518.05 t _R 1.25 12-72 yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)-4-oxobutanoate Note. 4-(4-((2-(difluoromethoxy)-6-methylpyridine-3- [M+1] ⁺ 504.20 t _R 1.15 12-73 yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)-4-oxobutanoic acid

- 69 040901

Note. 12-74 ethyl (E)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobut-2-enoate M+1] ⁺ 501.99 t _R 1.29 Note. 12-75 (E)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobut-2-enoic acid [M+1] ⁺ 474.13 t _R 1.13 Note. 12-76 ethyl (2)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobut-2-enoate [M+1] ⁺ 502.09 t _R 1.24 Note. 12-77 (2)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)4-oxobut-2-enoic acid [M+1] ⁺ 474.10 t _R 1.17 Note. 12-78 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-methyl-4-oxobutanoic acid [M+1] ⁺ 490.05 t _R 1.13 Note. 12-79 (8)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-methyl-4-oxobutanoic acid [M+1] ⁺ 490.00 t _R 1.13 Note. 12-80 (K)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-methyl-4-oxobutanoic acid [M+1] ⁺ 490.08 t _R 1.13 Note. 12-81 methyl 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoate [M+1] ⁺ 518.01 t _R 1.30 Note. 12-82 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 504.19 t _R 1.20 Note. 12-83 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)pyrrolidin-1yl)-2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 518.02 t _R 1.21 Note. 12-84 4-(3-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-3(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 490.14 t _R 1.14 Note. 12-85 methyl 4-(3-((2,6-dimethoxypyridin-3-yl)carbamoyl)3-(2-isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoate [M+1] ⁺ 498.15 t _R 1.28 Note. 12-86 4-(3-((2,6-dimethoxypyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 484.03 t _R 1.17 Note. 12-87 4-(3-((2-(difluoromethoxy)-5-fluoropyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 508.02 t _R 1.19 Note. 12-88 1 -(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)cyclopropan-1-carboxylic acid [M+1] ⁺ 502.32 t _R 1.15

- 70 040901

Note. 12-89 1 -(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)cyclobutan-1-carboxylic acid [M+1] ⁺ 516.00 t _R 1.22 Note. 12-90 (K)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3-methyl-4-oxobutanoic acid [M+1] ⁺ 490.35 t _R 1.13 Note. 12-91 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3,3-dimethyl-4-oxobutanoic acid [M+1] ⁺ 504.32 t _R 1.18 Note. 12-92 methyl 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)but-3-enoate [M+1] ⁺ 502.07 tR 1.24 Note. 12-93 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)but-3-enoic acid [M+1] ⁺ 488.11 t _R 1.15 Note. 12-94 methyl (lS,2R)-2-(3-((2-(diφτopmetokκci)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1 carboxylate [M+1] ⁺ 502.34 t _R 1.18 Note. 12-95 (lS,2R)-2-(3-((2-(diφτopmetoksi)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 488.08 t _R 1.10 Note. 12-96 methyl (1R,28)-2-(3-((2-(diφτopmetoksi)-6methylpyridin-3-yl)κarbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1 carboxylate [M+1] ⁺ 502.17 t _R 1.18 Note. 12-97 (1R, 2 8)-2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 488.02 t _R 1.10 Note. 12-98 3-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)oxetan-3-carboxylic acid [M+1] ⁺ 518.08 t _R 1.09 Note. 12-99 2-(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxetan-3-yl)acetic acid [M+1] ⁺ 518.02 t _R 1.09 Note. 12-100 ethyl (8)-3-amino-4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-4-oxobutanoate [M+1] ⁺ 505.19 t _R 0.75 Note. 12-101 (8)-3-amino-4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-4-oxobutanoic acid [M+1] ⁺ 491.06 t _R 1.19 Note. 12-102 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)5-oxopentanoic acid [M+1] ⁺ 490.05 t _R 1.10

- 71 040901

Note. 12-103 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-5-oxopentanoic acid [M+1] ⁺ 518.07 t _R 1.18 Note. 12-104 ethyl (K)-3-acetoxy-5-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-5-oxopentanoate [M+1] ⁺ 576.38 t _R 1.26 Note. 12-105 (K)-5-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3-hydroxy-5-oxopentanoic acid [M+1] ⁺ 506.09 t _R 1.05 Prim neil) Azeti Note. 12-106 Note. 12-107 Note. 12-108 Note. 12-109 Note. 12-110 Note. 12-111 Note. 12-112 Note. 12-113 Note. 12-114 ger 12-1 in-1-yl)-3 benzyl 2-(2-(2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2oxoethoxy)ethoxy)acetate 2-(2-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethoxy)ethoxy)acetic acid 2-(3-((2-(difluoromethoxy)-6-methylpyridine-3- yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)bicyclo[1.1.1]pentan-1-carboxylic acid benzyl 2-(3-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl )carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-3-oxopropoxy)acetate 2-(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3-oxopropoxy)acetic acid ethyl 4-(3- ((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-difluoro-4-oxobutanoate 4-(3-((2-(difluoromethoxy )-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-difluoro-4-oxobutanoic acid ethyl 3-(3-((2-(difluoromethoxy)-6- methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)azetidine-3-carboxylate 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2- isopropylphenyl)azetidine-1carbonyl)azetidine-3-carboxylic acid 15: 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carb 1,3-difluoro-4-oxobutanoic acid. [M+1] ⁺ 626.09 t _R 1.32 [M+1] ⁺ 536.00 t _R 1.08 [M+1] ⁺ 514.19 t _R 1.13 [M+1] ⁺ 596.01 t _R 1.33 [M+1] ⁺ 506.35 t _R 1 .I [M+1] ⁺ 539.98 t _R 1.32 [M+1] ⁺ 512.05 t _R 1.30 [M+1] ⁺ 531.11 t _R 0.81 [M+1] ⁺ 503.16 t _R 0.83 amoil)-3-(2- iso propylfe

4-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3,3-difluoro-4-oxobutanoic acid approx. 12-115 is obtained from hydrochloride approx. 3 (50 mg, 0.12 mmol) and 2,2-difluorosuccinic acid (23 mg, 0.15 mmol) following the amide coupling procedure described for step 1, approx. 12-1: white solid, 31 mg, 50% yield. LCMS-1: t _R = 1.21 min, [M+1]+ 511.97. ¹ H NMR (500 MHz, DMSO^) δ: 12.97 (s br, 1H), 8.36 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H) , 7.52 (t, J=72.5 Hz, 1H), 7.44 (m, 1H), 7.42-7.39 (m, 1H), 7.33-7.30 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 5.11 (d, J=9.3 Hz, 1H), 4.84 (d, J=9.4 Hz, 1H), 4.72 (d, J=10.2 Hz, 1H), 4.39 (d, J=10.2 Hz, 1H), 3.323. 18 (m, 2H), 2.38 (s, 3H), 1.12 (t, J=6.4 Hz, 6H).

Example 12-116: (R)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-hydroxy -2-methyl-4-oxobutanoic acid.

(R)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-hydroxy-2-methyl-4 -oxobutanoic acid approx. 12-116 is obtained from hydrochloride approx. 3 (50 mg, 0.12 mmol) and (R)-(-)-citramalic acid (22 mg, 0.15 mmol) following the amide coupling procedure described for step 1, approx. 12-1: white solid, 15 mg, 24% yield. LCMS-1: t _R =1.10 min, [M+1] ⁺ 506.03.

Example 12-117: (S)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-hydroxy -2-methyl-4-oxobutanoic acid.

(S)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-hydroxy-2-methyl-4 -oxobutanoic acid approx. 12-117 is obtained from hydrochloride approx. 3 (50 mg, 0.12 mmol) and (8)-(-)-citramalic acid (22 mg, 0.15 mmol) following the amide coupling procedure described for approx. 12-1 - stage 1: colorless oil, 18 mg, 29% yield. LCMS-1: t _R =1.11 min, [M+1] ⁺ 506.38.

Example 12-118: (2R,3R)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2

- 72 040901 isopropylphenyl)azetidin-1-yl)-2,3-dihydroxy-4-oxobutanoic acid.

For solution approx. 3 (20 mg, 0.05 mmol) in DCM (2 mL) diacetyl A-tartaric anhydride (13 mg, 0.06 mmol) was added followed by DIPEA (18 μL, 0.10 mmol). The reaction mixture was stirred at rt. for 15 min and then concentrated. The residue is dissolved in MeCN (1 ml) and treated with NaOMe. The reaction mixture is stirred for 30 min (reaction monitored by LCMS) and then quenched with ammonium chloride, concentrated and purified with prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 12-118 as an oil (15 mg, 56% yield). LCMS-1: t _R =1.03 min, [M+1]+ 508.11.

Example 12-119: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4(methylsulfonamido)-4-oxobutanoyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-(methylsulfonamido)-4oxobutanoyl)azetidine-3-carboxamide approx. 12-119 are obtained from approx. 12-71 (90 mg, 0.189 mmol) and methanesulfonamide (18 mg, 0.189 mmol) following the amide coupling procedure described for Step 1, Ex. 12-1: 4 mg, 4% yield. LCMS-1: t _R =1.11 min, [M+1] ⁺ 553.09.

Example 12-120: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(5,5,5trifluoro-4-hydroxypentanoyl)azetidine-3-carboxamide.

For solution approx. 12-11 (10 mg, 0.02 mmol) in MeOH (0.5 ml) NaBH ₄ (10 mg, 0.26 mmol) is added. The reaction mixture was stirred for 2 h, then quenched with water and extracted with DCM (2x10 ml). The combined extracts are dried over MgSO ₄ , filtered and evaporated. The residue is then purified with prep. HPLC (prep-HPLC-2 conditions) to give approx. 12-120 (1.5 mg, 15% yield). LCMS-1: t _R =1.22 min, [M+1] ⁺ 530.21.

Example 12-121: 2-(2-(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3-oxopropoxy )ethoxy)acetic acid.

For solution approx. 12-51 (32 mg, 0.06 mmol) in MeCN (5 ml) NaH ₂ PO ₄ buffer solution (0.1 mol/l, 0.5 ml), 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO , 1 mg, 0.006 mmol), aq. sodium chlorite solution (80 g/l, 0.5 ml) and sodium hypochlorite (50 µl). The reaction mixture is stirred at 50°C overnight. The mixture was then quenched with saturated sodium sulfite solution (2 ml) and the volatiles were evaporated. The residue is dissolved in 3 ml of DMF/MeCN (1:1) and purified with prep. HPLC (prep-HPLC-3 conditions) to give the title compound approx. 12-121 as a beige wax (14.7 mg, 45% yield). LCMS-1: t _R =1.08 min, [M+1] ⁺ 550.09.

Example 12-122: 4-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-oxoethyl) tetrahydro-2H-pyran-4-carboxylic acid.

To the hydrochloride solution approx. 3 (50 mg, 0.121 mmol) in DCM (2 mL) TEA (34 µL, 0.243 mmol) was added followed by commercially available 2,8-dioxaspiro[4.5]decan-1,3-dione dissolved in DCM (1 mL ). The reaction mixture was stirred at rt. for 1 h and then evaporated. The crude compound is purified with prep. HPLC (prep-HPLC conditions 2) to give the title compound approx. 12-122 as a white solid (41 mg, 62% yield). LCMS-1: t _R =1.13 min, [M+1] ⁺ 546.00.

Example 12-123: 3-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-oxoethyl) tetrahydrofuran-3-carboxylic acid.

-(2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)tetrahydrofuran-3-carboxylic acid Prim . 12-123 (12 mg, white solid) is obtained from approx. 3 and commercially available 2,7-dioxaspiro[4.4]nonane-1,3-dione following the procedure described for approx. 12-122. LCMS-1: t _R =1.10 min, [M+1] ⁺ 531.97.

Example 12-124: 4-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-oxoethyl) -1-methylpiperidine-4-carboxylic acid.

4-(2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)-1-methylpiperidine-4 -carboxylic acid approx. 12-124 (43 mg, white solid) is obtained from approx. 3 and commercially available 8-methyl-2-oxa-8-azaspiro[4.5]decane-1,3dione hydrochloride following the procedure described for approx. 12-122. LCMS-1: t _R =0.77 min, [M+1] ⁺ 559.10.

Example 12-125: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(3-(methoxyamino)-3-oxopropanoyl)azetidine-3-carboxamide.

For solution approx. 12-63 (60 mg, 0.13 mmol) in DCM (4 ml) add O-methylhydroxylamine (16 mg, 0.19 mmol), DIPEA (67 µl, 0.39 mmol) and T3P in DCM (50%, 0.16 mmol). The mixture is stirred at rt. for 18 h, concentrated in vacuo. The residue is purified with prep. HPLC (prepHPLC-1 conditions) to give the title compound approx. 12-125 (48 mg, 75% yield) as white solid; LCMS-1: t _R =1.05 min, [M+1] ⁺ 491.13.

Example 12-126: N-(2-(difluoromethoxy)-6-methylpyridin-3 -yl)-1 -(2-(2,4-dioxoimidazolidin-1 yl)acetyl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(2,4-dioxoimidazolidin-1-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide approx. 12-126 (7 mg, white solid) is obtained from approx. 3 and 2-(2,4-dioxoimidazolidin-1-yl)acetic acid, following the procedure described for approx. 12-73 040901

61. LCMS-1: t _R =1.06 min, [M+1]+ 515.99; ¹ H NMR (500 MHz, DMSO) δ: 10.92 (s, 1H), 8.32 (s, 1H), 8.00 (d,

J=8.0 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.52 (t, J=72.5 Hz, 1H), 7.44 (dd, J1=1.3 Hz, J ₂ =7.8 Hz, 1H), 7.40 (t, J=7.5

Hz, 1H), 7.32 (m, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.89 (d, J=8.5 Hz, 1H), 4.65 (d, J=8.5 Hz, 1H), 4.58 ( d, J=9.6 Hz,

1Н), 4.36 (d, J=10.1 Hz, 1Н), 4.05 (d, J=17.1 Hz, 1Н), 4.02 (d, J=17.1 Hz, 1Н), 3.90 (s, 2Н), 2.38 (s, 3Н), 1.13 (d, J=6.7 Hz, 3Н), 1.10 (d, J=6.7 Hz, 3Н).

Example 12-127: N-(2-(difluoromethoxy)-6-methylpyridin-3 -yl)-1 -(2-(2,5-dioxoimidazolidin-1 yl)acetyl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide.

N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(2,5-dioxoimidazolidin-1-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide approx. 12-127 (22.5 mg, white solid) is obtained from approx. 3 and (2,5-dioxoimidazolidin-1-yl)acetic acid, following the procedure described for approx. 5 with T3P as coupling reagent. LCMS-1: t _R =1.07 min, [M+1] ⁺ 515.96; 1H NMR (500 MHz, CDCl ₃ ) δ: 8.57 (d, J=8.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.42-7.39 (m, 1H), 7.34 (dd, J1=0.9 Hz, J ₂ =7.9 Hz, 1H), 7.27 (t, J=72.5 Hz, 1H), 7.24 (s, 1H), 6.96 (d, J=8.2 Hz, 1H), 5.46 (s, 1H), 5.08 (s br, 1H), 4.70 (s br, 1Н), 4.61 (s br, 2H), 4.30 (d, J=16.2 Hz, 1H), 4.13-4.09 (m, 3H), 2.42-2.37 (m, 4H) , 1.20 (d, J=6.6 Hz, 3H), 1.13 (d, J=6.5 Hz, 3H).

Example 12-128: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(sulfamoylglycyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(sulfamoylglycyl)azetidine3-carboxamide approx. 12-128 (25 mg, white solid) is obtained from approx. 3 and 2 (sulfamoylamino) acetic acid, following the procedure described for approx. 5 with T3P as coupling reagent. LCMS-1: tR=1.07 min, [M+1] ⁺ 512.30; ¹ H NMR (400 MHz, CDCl ,) δ: 8.52 (d, J=8.1 Hz, 1H), 7.56-7.46 (m, 2H), 7.41 (td, J=2.0 Hz and J=7.7 Hz, 1H) , 7.33-7.28 (m, 2H), 7.26 (t, J=72.8 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 5.11-4.99 (s br, 1H), 4.84-4.67 (s br , 1Н), 4.67-4.46 (s br, 2H), 3.97 (d, J=16.4 Hz, 1H), 3.75 (d, J=16.4 Hz, 1H), 2.40 (s, 3H), 2.38-2.33 (m , 1H), 1.20 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.5 Hz, 3H).

Example 12-129: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(1,1-dioxidothietan-3-carbonyl)-3(2-isopropylphenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(1,1-dioxidothietan-3-carbonyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 12-129 (21 mg, white solid) is obtained from approx. 3 and 1,1-thietane-3-carboxylic acid dioxide, following the procedure described for approx. 5 with EDC/HOBt as coupling reagents. LCMS-1: t _R =1.15 min, [M+1] ⁺ 508.32.

Example 12-130: N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-(N-hydroxyacetamido)propanoyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Stage 1. To the hydrochloride solution, approx. 3 (300 mg, 0.73 mmol) and DIPEA (822 µl, 4.79 mmol) in THF (30 ml) acryloyl chloride (89 µl, 1.09 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min (reaction monitored by LCMS), then diluted with Et ₂ O, washed with NaHCO ₃ solution (10 ml), dried over MgSO ₄ , filtered and evaporated to give the crude acrylamide intermediate , which is cleaned with prep. HPLC (prep-HPLC-1 conditions) to give a colorless glassy compound (259 mg, 83% yield). ¹ H NMR (500 MHz, CDC13) δ: 8.55 (d, J=8.1 Hz, 1H), 7.50-7.44 (m, 2H), 7.40-7.38 (m, 1H), 7.37-7.34 (m, 1H), 7.28 (t, J=72.6 Hz), 7.25 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.38 (dd, J1=1.8 Hz, J ₂ =17.0 Hz, 1H), 6.28 (dd , J1=10.3 Hz, J2=17.0 Hz, 1H), 5.74 (dd, J1=1.8 Hz, J ₂ =10.3 Hz, 1H), 5.13-5.04 (s br, 1H), 4.97-4.85 (br s, 1H ), 4.79-4.75 (s br, 1H), 4.59-4.48 (s br, 1H), 2.46-2.40 (m, 1H), 2.38 (s, 3H), 1.19 (d, J=6.6 Hz, 3H), 1.14 (d, J=6.5 Hz, 3H).

Step 2 To a solution of the acrylamide intermediate (250 mg, 0.58 mmol) and tert-butyl N-(benzyloxy)carbamate (569 mg, 1.16 mmol) in DMF is added Cs ₂ CO ₃ (569 mg, 1.75 mmol). The reaction mixture was stirred at 65° C. for 4 h (reaction monitored by LCMS), then diluted with EtOAc (50 ml), washed with water (20 ml) followed by brine (20 ml) and dried over MgSO ₄ . The organic solution is filtered, evaporated and purified with prep. HPLC (prep-HPLC-1 conditions) to give tert-butyl(benzyloxy)(3-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1 -yl)-3-oxopropyl)carbamate as a colorless wax (289 mg, 76% yield). ¹ H NMR (500 MHz, CDC13) δ: 8.54 (d, J=8.1 Hz, 1H), 7.49-7.43 (m, 2H), 7.42-7.36 (m, 3H), 7.34-7.30 (m, 3H), 7.28 (s, 1H), 7.26 (t, J=72.6 Hz, 1H), 7.22 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.95-4.79 (m, 3H), 4.71-4.60 (m, 1H), 4.54-4.30 (m, 2H), 3.80 (t, J=7.3 Hz, 2H), 2.47-2.42 (m, 2H), 2.40-2.34 (m, 4H), 1.50 (s, 9H ), 1.15 (d, J=6.6 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H).

Step 3. tert-Butyl(benzyloxy)(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-3-oxopropyl) carbamate (285 mg, 0.44 mmol) is subjected to the Boc deprotection conditions described for approx. 4, with receipt after prep. HPLC (prep-HPLC-3 conditions) approx. 12-130 as a white solid (231 mg, 96% yield). LCMS-1: t _R =1.30 min, [M+1] ⁺ 553.40. ¹ H NMR (500 MHz, CDCI3) δ: 8.55 (d, J=8.1 Hz, 1H), 7.50-7.45 (m, 2H), 7.39 (td, J1=1.9 Hz, J ₂ =7.8 Hz, 1H), 7.36-7.28 (m, 6H), 7.27 (t, J=72.9 Hz, 1H), 7.24 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 5.98 (s br, 1H), 5.03- 4.88 (m, 1H), 4.74-4.61 (m, 3H), 4.58-4.40 (m, 2H), 3.31-3.23 (m, 2H), 2.50-2.41 (m, 2H), 2.40-2.37 (m, 4H ), 1.17 (d, J=6.6 Hz, 3H), 1.14 (d, J=6.6 Hz, 3H).

- 74 040901

Example 12-131: 1-(3-(N-(benzyloxy)acetamido)propanoyl)-N-(2-(difluoromethoxy)-6-methylpyridin3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide and Example 12-132: N-(2-(difluoromethoxy)-6methylpyridin-3-yl)-1-(3-(N-hydroxyacetamido)propanoyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Step 1 To a solution of N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-(N-hydroxyacetamido)propanoyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 12-130 (225 mg, 0.41 mmol) in DCM (7 ml) DIPEA (105 µl, 0.61 mmol) and Ac ₂ O (58 µl, 0.61 mmol) are added sequentially. The solution is stirred at rt. within 1.5 h (the reaction is monitored using zhhms), then concentrated and purified using prep. HPLC (prep-HPLC-1 conditions) to give 1-(3-(N(benzyloxy)acetamido)propanoyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl) )azetidine-3-carboxamide approx. 12-131 as a white solid (228 mg, 94% yield). LCMS-1: t _R =1.29 min, [M+1]+ 595.26.

Step 2. 1-(3-(N-(benzyloxy)acetamido)propanoyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)azetidine-3-carboxamide (220 mg, 0.37 mmol) subjected to the hydrogenation conditions described for I-1.A to give the title compound approx. 12-132 as a white solid (114 mg, 60% yield). LCMS-1: t _R =1.08 min, [M+1] ⁺ 505.39; 1H NMR (500 MHz, CDCl ₃ ) δ: 8.54 (d, J=8.1 Hz, 1H), 7.52-7.47 (m, 2H), 7.43-7.39 (m, 1H), 7.32 (d, J=7.7 Hz, 1Н), 7.28 (m, 1H), 7.27 (t, J=72.5 Hz, 1Н), 6.95 (d, J=8.1 Hz, 1Н), 5-05-4.85 (s br, 1Н), 4.83-4.65 ( s br, 1H), 4.63-4.44 (s br, 2H), 4.04-3.96 (m, 1H), 3.94-3.88 (m, 1H), 2.71-2.64 (m, 1H), 2.61-2.54 (m, 1H ), 2.42-2.34 (m, 4H), 2.15 (s, 3H), 1.19 (d, J=6.5 Hz, 3H), 1.15 (d, J=6.1 Hz, 3H).

Example 12-133 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-(hydroxyamino)propanoyl)-3(2-isopropylphenyl)azetidine-3-carboxamide.

To a stirred solution of tert-butyl N-(benzyloxy)carbamate (45 mg, 0.20 mmol) in anhydrous DMF (5 mL) was added NaH (60 wt%, 9 mg, 0.22 mol) and the resulting mixture was stirred at rt . within 30 min. Add 1-(2-bromoacetyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)-azetidine-3-carboxamide (100 mg, 0.20 mmol) obtained from prim . 3 and 2 bromoacetyl bromide in accordance with stage 1 approx. 12-52 and the reaction mixture is stirred at rt. within 18 hours the Reaction mixture was then quenched with water (10 ml) and extracted with hexane (50 ml and 2 x 10 ml). The combined extracts are dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 12133 as a beige solid (65 mg, 51% yield). LCMS-1: t _R =1.45 min, [M+1] ⁺ 639.05.

Example 12-134: 1-((benzyloxy)glycyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Note. 12-133 (60 mg, 0.09 mmol) is subjected to the Boc deprotection conditions described for approx. 4, with receipt after prep. HPLC (prep-HPLC-3 conditions) approx. 12-134 as a beige solid (30 mg, 59% yield). LCMS-1: t _R =1.31 min, [M+1] ⁺ 539.49.

Example 12-135: 1-(N-acetyl-N-(benzyloxy)glycyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)3-(2-isopropylphenyl)azetidine-3-carboxamide and Example 12-136: 1-(N-acetyl-N-hydroxyglycyl)-N-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Examples approx. 12-135 and approx. 12-136 are obtained from approx. 12-134 in accordance with the procedure described for approx. 12-131 and approx. 12-132.

Note. 12-135: Beige solid. LCMS-1: t _R =1.29 min, [M+1] ⁺ 581.58.

Note. 12-136: white solid. LCMS-1: t _R =1.07 min, [M+1] ⁺ 491.42; 1H NMR (400 MHz, CDCl ,) δ: 8.54 (d, J=8.1 Hz, 1H), 8.44-8.05 (s br, 1H), 7.50-7.45 (m, 2H), 7.40 (m, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.28 (t, J=65.3 Hz, 1H), 7.26 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.98 (s br, 1H) , 4.73 (s br, 1H), 4.58-4.48 (m, 3H), 4.36 (d, J=16.7 Hz, 1H), 2.39 (s, 3H), 2.36 (m, 1H), 2.23 (s, 3H) , 1.19 (d, J=6.6 Hz, 3H), 1.14 (d, J=6.6 Hz, 3H).

Example 12-137: 1-(2-(1-acetylpiperidin-4-yl)acetyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3yl)-3-(2-isopropylphenyl)azetidine-3- carboxamide.

-(2-(1-Acetylpiperidin-4-yl)acetyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide approx. 12-137 (11 mg, colorless oil) is obtained from approx. 3 and commercially available 1-acetyl-4-piperidineacetic acid, following the procedure described for approx. 5 with EDC/HOBt as coupling reagents. LCMS-1: t _R =1.15 min, [M+1]+543.06.

Example 12-138: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(piperidin4-yl)acetyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(piperidin-4-yl)acetyl)azetidine-3-carboxamide approx. 12-138 (36 mg, colorless oil) is obtained from approx. 3 and commercially available 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid following the coupling procedure described for approx. 5 and performing Boc deprotection with HCl in dioxane. LCMS-1: t _R =0.82 min, [M+1] ⁺ 501.49.

Example 12-139: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(1-(2methoxyethyl)piperidin-4-yl)acetyl) Azetidine-3-carboxamide.

- 75 040901 N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-3-(2isopropylphenyl)azetidine-3 - carboxamide approx. 12-139 (16 mg, colorless oil) is obtained from approx. 3 and commercially available 2-bromoethyl methyl ether following the coupling procedure described for approx.

11-67. LCMS-1: tR=0.84 min, [M+1]+ 559.12.

Example 12-140: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-(2-hydroxyethyl)piperidin-4yl)acetyl)-3-(2-isopropylphenyl) Azetidine-3-carboxamide.

No.(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide prim . 12-140 (16 mg, colorless oil) is obtained from Approx. 3 and commercially available 2-bromoethanol, following the coupling procedure described for approx. 11-67 LCMS1: tR=0.81 min, [M+1] ⁺ 454.29

Example 12-141: N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-(2-fluoroethyl)piperidin-4yl)acetyl)-3-(2-isopropylphenyl)azetidine -3-carboxamide.

To the suspension of N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(piperidin4-yl)acetyl)azetidine-3-carboxamide approx. 12-138 (34 mg, 0.06 mmol), 1-fluoro-2-iodomethane (22 mg, 0.13 mmol) and B114NF (4 mg, 0.01 mmol) in acetone (1 ml) was added K2CO3 (43.7 mg, 0.32 mmol). The reaction mixture was stirred at rt. under nitrogen for 16 h. Two more portions of 1-fluoro-2-iodomethane (22 mg, 0.13 mmol) are added after 2 and 4 h to ensure complete conversion. The mixture is evaporated and the residue partitioned between EtOAc and water. The organic phase is collected, dried over MgSO4, filtered and concentrated. The crude product is purified by prep-HPLC (prep-HPLC-2 conditions) to give N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-(2-fluoroethyl)piperidine -4-yl)acetyl)3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 12-141 as a colorless oil (29 g, 84% yield). LCMS-1: tR=0.83 min, [M+1] ⁺ 547.03.

Example 12-142: N-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-N -methylglycine.

Example 12-142 receive in accordance with the procedure described for approx. 12-52 using bromoacetyl bromide, aminocarboxylic acid ester (sarcosine methyl ester), and approx. 3. Yellow oil. LCMS-1: t _R =0.93 min, [M+1] ⁺ 505.30.

Example 13-1: 2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)acetic acid.

Stage 1. To a solution of approx. 3 (90 mg, 0.239 mmol) and TEA (100 μl, 0.73 mmol, 3 eq.) in DCM (5 ml) chlorosulfonylacetic acid ethyl ester (44.6 mg, 0.239 mmol) was added dropwise. The reaction mixture was stirred at rt. overnight and then concentrated. The residue is purified with prep. HPLC (prep-HPLC-2 conditions) to give ethyl 2-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl) acetate (43 mg, 34% yield). LCMS-2: t _R =1.16 min, [M+1] ⁺ 526.20.

Step 2 Ethyl 2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)acetate solution (43 mg, 0.082 mmol) in a mixture of EtOH/THF (1:1, 1 ml) is treated with 2n. aq. LiOH solution (85 ml, 170 mmol). The reaction mixture was stirred at rt. for 2 h and then concentrated. The residue is dissolved in water. The resulting solution is acidified to pH 1 with 1N. aq. HCl solution and then extracted with EtOAc (2x10 ml). The combined extracts are dried over MgSO ₄ , filtered and evaporated to give approx. 13-1 (41 mg, 100% yield). LCMS-1: tR=1.19 min, [M+1] ⁺ 498.16; 1H NMR (400 MHz, CDCl ,) δ: 8.55 (d, J=8.1 Hz, 1H), 7.537.43 (m, 2H), 7.42-7.37 (m, 1H), 7.36 (s, 1H), 7.30 -7.23 (m, 2H), 6.95 (d, J=8.1 Hz, 1H), 5.32 (s, 2H), 4.81-4.58 (m, 2H), 4.25 (s, 2H), 2.40 (s, 3H), 2.38-2.31 (m, 1H), 1.16 (d, J=6.6 Hz, 6H).

Table 9. Examples 13-2 - 13-27.

Examples 13-2 - 13-27 were synthesized using the procedure described for approx. 13-1, based on approx. 3, approx. 4 or approx. 7. In the case of the benzyl ester, the hydrogenation is carried out as a second step to give the corresponding carboxylic acid.

- 76 040901

Example Name Analytical data of LCMS-1 Note. 13-2 methyl 2-((4-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidin1-yl)sulfonyl)acetate [M+1] ⁺ 539.93 t _R 1.27 Note. 13-3 2-((4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)sulfonyl)acetic acid [M+1] ⁺ 526.10 t _R 1.22 Note. 13-4 Benzyl 3-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1 yl)sulfonyl)propanoate [M+1] ⁺ 602.12 t _R 1.39 Note. 13-5 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoic acid [M+1] ⁺ 512.20 t _R 1.16 Note. 13-6 methyl 3-((4-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidine- 1-yl)sulfonyl)propanoate [M+1] ⁺ 554.03 t _R 1.30 Note. 13-7 benzyl 3-((4-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-4-(2isopropylphenyl)piperidin-1-yl)sulfonyl)propanoate [M+1] ⁺ 630.04 t _R 1.43 Note. 13-8 3-((4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)sulfonyl)propanoic acid [M+1] ⁺ 540.13 t _R 1.20 Note. 13-9 benzyl 3-((3-((2-(difluoromethoxy)pyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoate [M+1] ⁺ 588.02 t _R 1.35 Note. 13-10 3-((3-((2-(difluoromethoxy)pyridine-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoic acid [M+1] ⁺ 498.23 t _R su Note. 13-11 methyl 3 -((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-2,2-dimethylpropanoate [M+1] ⁺ 554.00 t _R 1.33 Note. 13-12 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-2,2-dimethylpropanoic acid [M+1] ⁺ 539.98 t _R 1.23 Note. 13-13 ethyl 2-(1-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1 yl)sulfonyl)cyclopropyl)acetate [M+1] ⁺ 566.58 t _R 1.38 Note. 13-14 2-(1-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)cyclopropyl)acetic acid [M+1] ⁺ 538.09 t _R 1.21 Note. 13-15 methyl 3-(((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2- [M+1] ⁺ 568.07 t _R 1.25

- 77 040901

isopropylphenyl)azetidin-1 yl)sulfonyl)methyl)oxetane-3-carboxylate Note. 13-16 3-(((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)methyl)oxetane-3-carboxylic acid [M+1] ⁺ 554.00 t _R 1.16 Note. 13-17 4-((3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)butanoic acid [M+1] ⁺ 526.18 t _R 1.16 Note. 13-18 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)pentanoate [M+1] ⁺ 554.02 t _R 1.30 Note. 13-19 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)pentanoic acid [M+1] ⁺ 540.01 tR 1.19 Note. 13-20 methyl (E)-3-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1 yl)sulfonyl)acrylate [M+1] ⁺ 524.44 t _R 1.32 Note. 12-21 (E)-3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)acrylic acid [M+1] ⁺ 509.96 t _R 1.25 Note. 13-22 methyl 4-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-1H-pyrazole-5-carboxylate [M+1] ⁺ 564.16 t _R 1.17 Note. 13-23 4-((3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-1H-pyrazole-5-carboxylic acid [M+1] ⁺ 550.22 t _R 1.13 Note. 13-24 ethyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-1H-pyrazole-4-carboxylate [M+1] ⁺ 578.13 t _R 1.22 Note. 13-25 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-1H-pyrazole-4-carboxylic acid [M+1] ⁺ 550.10 t _R 1.07 Note. 13-26 methyl 5-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)isoxazole-3-carboxylate [M+1] ⁺ 565.04 t _R 1.34 Note. 13-27 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)-3-methoxypropanoic acid [M+1] ⁺ 542.00 t _R 1.20

Example 13-28: 1-((3-((benzyloxy)amino)-3-oxopropyl)sulfonyl)-X-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine- 3-carboxamide and Example 13-29: N-(2(difluoromethoxy)-6-methylpyridin-3-yl)-1-((3-(hydroxyamino)-3-oxopropyl)sulfonyl)-3-(2isopropylphenyl)azetidine -3-carboxamide.

Step 1. To a solution of 3-chlorosulfonylpropionyl chloride (prepared from 1,2oxathiolan-5-one 2-dioxide: lit. US 6734184, Novartis AG) (28 mg, 0.15 mmol) and TEA (39 µl, 0.67 mmol) in DMF is added O-benzylhydroxylamine (18.6 mg, 0.15 mmol). The reaction mixture was stirred at rt. for 5 min and then add the hydrochloride approx. 3 (55 mg, 0.13 mmol) and stirring continued for 18 hours. Water was added and the reaction was purified with prep. HPLC (prep-HPLC-3 conditions) to give approx. 13-28 as a white solid (12.5 mg, 15% yield). LCMS-1: t _R =l.28 min, [M+1] ⁺ 618.10.

Stage 2. Approx. 13-28 (12 mg, 0.02 mmol) are hydrogenated according to the method described for approx. 11-12, obtaining approx. 13-29 as a pale yellow oil (8 mg, 76% yield). LCMS-1: t _R =1.08 min, [M+1] ⁺ 527.01; 'H NMR (400 MHz, MeOD) δ: 8.29 (d, J=8.1 Hz, 1H), 7.57 (s, 0.25H), 7.49-7.46 (m, 3H), 7.43-7.37 (m, 2H), 7.21 (s, 0.25H), 7.06 (d, J=8.1Hz, 1H), 4.64 (d, J=8.0Hz, 2H), 4.47 (d, J=8.0Hz, 2H), 3.45 (t, J=7.4 Hz, 2H), 2.61 (t, J=7.4 Hz, 2H), 2.52-2.44 (m, 1H), 2.41 (s, 3H), 1.17 (d, J=6.7 Hz, 6H).

Example 13-3 0:3 -((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)propan-1 -sulfonic acid.

Hydrochloride approx. 3 (50 mg) is subjected to reaction with commercially available 3(chlorosulfonyl)propane-!-sulfonyl fluoride (32 mg), adhering to the same conditions as in stage 1 approx. 13-1. The fluorosulfonyl product (32 mg, 0.057 mmol) is then hydrolyzed with 32% water, NaOH solution (1 mL) at 50°C for 18 hours to give the title compound approx. 13-30, which is isolated in accordance with stage 2 approx. 13-1 (19 mg, 28% yield over 2 steps, oil). ZhHMS-1:

t _R \u003d 1.35 min, [M + 1] + 562.10; 1H NMR (400 MHz, CD ₃ OD) δ: 8.31 (d, J=8.0 Hz, 1H), 7.51-7.42 (m, 3H), 7.39 (dd, J1=2.3 Hz, J ₂ =14.1 Hz, 1H) , 7.38 (t, J=72.8 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.66 (d, J=7.9 Hz, 2H), 4.46 (d,

J=7.9 Hz, 2H), 3.40-3.34 (m, 2H), 3.06-2.98 (m, 2H), 2.54-2.48 (m, 1H), 2.41 (s, 3H), 2.31 (m, 2H), 1.16 (d,

J=6.7 Hz, 6H).

Example 14-1: 2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)oxy)acetic acid.

Step 1. To a solution of methyl glycolate (500 mg, 1.18 mmol) and TEA (2.34 ml, 16.7 mmol) in MeCN (20 ml) was added N,N-disuccinimidyl carbonate (1.56 g, 6.11 mmol). The reaction mixture was stirred overnight, then diluted with EtOAc, washed with brine, dried over MgSO ₄ , filtered and concentrated to give methyl 2-((((2,5-dioxopyrrolidin-1yl)oxy)carbonyl)oxy)acetate ( 940 mg, 73% yield. Said compound is added to a solution of approx. 3 (50 mg, 0.133 mmol) and DIPEA (57 μL, 0.33 mmol) in DMF (5 mL). The reaction mixture was stirred for 18 hours, concentrated and purified by prep-HPLC (prep-HPLC-2 conditions) to give 2-methoxy-2-oxoethyl 3-((2-(difluoromethoxy)-6-methylpyridin-3-yl )carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxylate: 48 mg, 73% yield.

Stage 2. 2-Methoxy-2-oxoethyl 3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxylate (48 mg, 0.098 mmol) is dissolved in THF (3 ml) and treated with 2 M LiOH solution (130 μl). The reaction solution is stirred at rt. within 2 h (the course of the reaction is monitored using LCMS). The reaction mixture is then diluted with water, acidified to pH 1 with 6N. HCl and extracted twice with EtOAc. The combined organic extracts are dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-2 conditions) to give approx. 14-1 as a white solid (24 mg, 51% yield). LCMS-1: tR=1.18 min, [M+1] ⁺ 478.45.

Table 10. Examples 14-2 - 14-14.

Examples 14-2 - 14-14 were synthesized using the procedure described for approx. 14-1, based on approx. 3 or approx. 4.______________________________________________________________________

Example Name Analytical data of LCMS-1 Note. 14-2 2-((4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidine1-carbonyl)oxy)acetic acid [M+1] ⁺ 520.12 t _R 1.32 Note. 14-3 2-((4-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-4-(2-isopropylphenyl)piperidine- [M+1] ⁺ 506.07 t _R 1.23

- 79 040901

1-carbonyl)oxy)acetic acid Note. 14-4 (8)-2-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)propanoic acid [M+1] ⁺ 492.08 t _R 1.22 Note. 14-5 (K)-2-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)propanoic acid [M+1] ⁺ 492.00 t _R 1.22 Note. 14-6 1-methoxy-2-methyl-1-oxopropan-2-yl [M+1] ⁺ 520.08 t _R 1.42 Note. 14-7 1-(methoxycarbonyl)cyclopropyl 3-((2(difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carboxylate [M+1] ⁺ 534.26 t _R 1.32 Note. 14-8 1-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)cyclopropane-1-carboxylic acid [M+1] ⁺ 504.06 t _R 1.22 Note. 14-9 3-methoxy-2,2-dimethyl-3-oxopropyl 3-((2(difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carboxylate [M+1] ⁺ 534.26 t _R 1.37 Note. 14-10 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)-2,2-dimethylpropanoic acid [M+1] ⁺ 520.17 t _R 1.25 Note. 14-11 (1-(Methoxycarbonyl)cyclopropyl)methyl 3-((2(difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carboxylate [M+1] ⁺ 532.13 t _R 1.33 Note. 14-12 1-(((3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)methyl)cyclopropane-1-carboxylic acid [M+1] ⁺ 518.02 t _R 1.22 Note. 14-13 (3-(methoxycarbonyl)oxetan-3-yl)methyl 3-((2(difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carboxylate [M+1] ⁺ 548.09 t _R 1.27 Note. 14-14 3-(((3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)methyl)oxetane-3-carboxylic acid [M+1] ⁺ 534.10 t _R 1.17

Example 15-1 Ethyl ((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)glycinate.

Example 15-2: ((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)glycine.

Step 1. A solution of chlorosulfonyl isocyanate (42 µl, 0.48 mmol) in DCM (1 ml) is cooled to 0°C and 2-bromoethanol (35 µl, 0.48 mmol) in DCM (1 ml) is added. The reaction mixture was stirred for 1 h at 0° C., then ethyl 2-aminoacetate (52 mg, 0.48 mmol) in DCM (1 mL) was added followed by TEA (200 μL, 1.43 mmol, 3 eq.). The reaction mixture is stirred at 35°C for 14 h and then concentrated under reduced pressure. The residue is dissolved in DMF (1 ml) and added to the solution approx. 3 (51 mg, 0.14 mmol) and TEA (285 µl, 2.05 mmol) in DMF (1.5 ml). The reaction mixture is stirred at 95°C overnight. The reaction mixture is then concentrated and the residue is purified using prep. HPLC (prep-HPLC-3 conditions) to give approx. 15-1 as an off-white solid (32 mg, 43% yield). LCMS-1: tR=1.24 min, [M+1]+ 541.23; 1H NMR (500 MHz, CDCl ₃ ) δ: 8.55 (d, J=8.1 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.35 (m, 1H), 7.33 (s, I H), 7.28 (t, J _HF =72.5 Hz, 1H), 7.27 (dd, J1=0.9 Hz, J2=7.8 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 4.96 (s, 1H), 4.67- 4.52 (m, 2H), 4.51-4.36 (m, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.93 (s, 2H), 2.44-2.36 (m, 4H), 1.31 (s, 3H) , 1.14 (d, J=6.7 Hz, 6H).

Stage 2. Solution approx. 15-1 (28 mg, 0.052 mmol) in MeOH/THF (1:1, 1 ml) was treated with 2N. aq. LiOH solution (104 µl, 0.10 mmol). The reaction mixture was stirred at rt. for 18 h and the organic solvents are then evaporated. The residue is dissolved in water. The resulting solution is acidified to pH 1 with 1N. aq. HCl solution and then extracted with EtOAc

- 80 040901 (3x10 ml). The combined extracts are dried over MgSO ₄ , filtered and evaporated to give approx. 15-2 as a yellow oil (26 mg, 98% yield). LCMS-1: t _R =1.13 min, [M+1]+ 513.10; 1H NMR (400 MHz,

CDC13) δ: 8.56 (d, J=8.1 Hz, 1H), 7.48-7.42 (m, 3H), 7.39-7.35 (m, 1H), 7.27 (t, J _HF =72.5 Hz, 1H), 7.25 (d , J=7.7

Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 4.63-4.52 (m, 2H), 4.51-4.40 (m, 2H), 4.01 (s, 2H), 2.45-2.34 (m, 4H ), 1.15 (d,

J=6.6Hz, 6H).

Example 15-3: N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-O(2-hydroxyethyl)sulfamoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide.

Step 1. A solution of chlorosulfonyl isocyanate (12 µl, 0.14 mmol) in DCM (1 ml) is cooled to 0°C and 2-bromoethanol (10 µl, 0.13 mmol) in DCM (1 ml) is added. The reaction mixture is stirred for 1 hour at 0°C, then approx. 3 (57 mg, 0.14 mmol) in DCM (2 ml) followed by TEA (78 µl, 0.55 mmol, 4 eq.). The reaction mixture was stirred at rt. for 1.5 h and then concentrated under reduced pressure to give crude N(2-(difluoromethoxy)-6-methylpyridin3-yl)-3-(2-isopropylphenyl)-1-((2-oxooxazolidin-3-yl)sulfonyl) Azetidine-3-carboxamide. LCMS-2: t _R =1.12 min, [M+1] ⁺ 525.14.

Stage 2. N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-((2oxooxazolidin-3-yl)sulfonyl)azetidine-3-carboxamide (70 mg, 0.13 mmol) was dissolved in EtOH (1 ml) and 6N was added. NaOH (0.4 ml, 2.4 mmol). The reaction mixture was stirred for 2 h and then diluted with water (5 ml) and extracted with DCM (3x20 ml). The organic extracts are dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give approx. 15-3 as a beige solid (32 mg, 44% yield over 2 steps). LCMS-1: tR=1.12 min, [M+1] ⁺ 499.10. 1H NMR (400 MHz, CDCl ,) δ: 8.55 (d, J=8.1 Hz, 1H), 7.50-7.43 (m, 2H), 7.407.34 (s, 2H), 7.26 (t, J=71.8 Hz , 1Н), 7.25 (d, J=7.7 Hz, 1Н), 6.94 (d, J=8.1 Hz, 1Н), 4.55 (s, 2Н), 4.46 (s, 2Н), 3.84 (t, J=4.8 Hz , 2Н), 3.37 (t, J=4.8 Hz, 2Н), 2.39 (m, 4Н), 1.15 (d, J=6.6 Hz, 6 Н).

Example 15-4 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(N-(2-fluoroethyl)sulfamoyl)-3-(2isopropylphenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(N-(2-fluoroethyl)sulfamoyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide approx. 15-4 (3.5 mg, yellow solid) is obtained from approx. 3 and commercially available 2-fluoroethylamine, following the procedure described for approx. 15-3. LCMS-1: t _R =1.10 min, [M+1] ⁺ 501.00.

Example 15-5: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide.

For solution approx. 3 (50 mg, 0.12 mmol) and TEA (51 μl, 0.36 mmol) in dioxane (2 ml) add sulfamide (12 mg, 0.12 mmol). The reaction mixture is stirred at 100°C for 18 hours and then evaporated. The crude compound is purified with prep. HPLC (prep-HPLC 2) to give the title compound approx. 15-5 as a white solid (35 mg, 63% yield). LCMS-1: t _R =1.14 min, [M+1] ⁺ 455.39; 1H NMR (400 MHz, CDCI3) δ: 8.55 (d, J=8.1 Hz, 1H), 7.50-7.44 (m, 2H), 7.41-7.39 (m, 1H), 7.37-7.34 (m, 1H), 7.31 -7.27 (m, 2H), 6.95 (d, J=8.1 Hz, 1H), 4.78 (s, 2H), 4.72-4.59 (m, 2H), 4.53-4.37 (m, 2H), 2.44-2.33 (m , 4H), 1.15 (d, J=6.7 Hz, 6H).

Table 11. Examples 15-6 - 15-18.

Examples 15-6 - 15-18 were synthesized using the procedure described for approx. 15-5, based on approx. 1, approx. 2, approx. 3, approx. 6, approx. 7, approx. 8 or approx. 9 which are reacted with a sulfamide or monoalkyl sulfamides.

- 81 040901

Example Name Analytical data of LCMS-1 Note. 15-6 X-(2-(difluoromethoxy)pyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 441.13 t _R 1.06 Note. 15-7 X-(2,6-dimethoxypyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 434.99 t _R 1.10 Note. 15-8 X-(6-ethoxy-2-methoxypyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 449.15 t _R G17 Note. 15-9 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropyl phenyl)-1-(M-methylsulfamoyl)az etidine3-carboxamide [M+1] ⁺ 469.21 t _R 1.21 Note. 15-10 M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(methylsulfamoyl)-3-(2-isopropylphenyl)azetidine-3carboxamide [M+1] ⁺ 483.11 t _R G25 Note. 15-11 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(Xpropylsulfamoyl)azetidine-3-carboxamide [M+1] ⁺ 496.99 t _R 1.30 Note. 15-12 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(Hisopropylsulfamoyl)azetidine-3-carboxamide [M+1] ⁺ 497.00 t _R 1.29 Note. 15-13 1-(X-cyclopropylsulfamoyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 495.00 t _R 1.26 Note. 15-14 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-(2(sulfamoylamino)ethyl)azetidine-3-carboxamide [M+1] ⁺ 498.29 t _R 0.72 Note. 15-15 X-(2-(difluoromethoxy)-5-fluoropyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 459.13 t _R 1.13 Note. 15-16 3-(2-isopropylphenyl)-X-(2-methoxy-6methylpyridin-3-yl)-1-sulfamoylazetide in-3 carboxamide [M+1] ⁺ 419.05 t _R 1.13 Note. 15-17 X-(2-ethoxy-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetide in-3- [M+1] ⁺ 433.34 t _R 1.21 carboxamide Note. 15-18 X-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 447.14 t _R 1.28

Example 16-1: 1-(N-acetylsulfamoyl)-N-(2-(difluoromethoxy)-6-methylpyrudin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide.

Mixture approx. 15-5 (35 mg, 0.08 mmol) NMM (85 μl, 0.08 mmol) and DMAP (1 mg, 0.008 mmol) in DCM (2 ml) are cooled in ice and acetic anhydride (5 drops) is added. The reaction mixture is stirred for 3 hours and quenched with MeOH. The mixture is evaporated to dryness and purified with prep. HPLC (prep-HPLC-2 conditions) to give the title compound approx. 16-1 as a white solid (18 mg, 47% yield). LCMS-1: t _R =1.17 min, [M+1]+ 497.01; ¹ H NMR (500 MHz, CDCU) δ: 8.60 (s br, 1H), 8.53 (d, J=8.1 Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.31 -7.27 (m, 2H), 7.26 (t, J=72.5 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 5.02-4.84 (m, 2H), 4.76-4.54 (m, 2H), 2.40 (s, 3H), 2.35-2.28 (m, 1H), 2.25 (s, 3H), 1.16 (d, J=6.5 Hz, 6H).

Table 12. Examples 16-2 - 16-5.

Examples 16-2 - 16-5 were synthesized using the procedure described for approx. 16-1, based on approx. 12-4, approx. 12-5, approx. 12-8 or approx. 15-6.

- 82 040901

Example Name Analytical data of LCMS-1 Note. 16-2 1 -(X-acetylsulfamoyl)-X-(2(difluoromethoxy)pyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 483.00 t _RLU Note. 16-3 1-(2-(X-acetylsulfamoyl)acetyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 539.41 t _R 1.12 Note. 16-4 1-(3-(X-acetylsulfamoyl)propanoyl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 553.48 t _R 1.12 Note. 16-5 1-(X-(X-acetylsulfamoyl)-X-methylglycyl)-X(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 568.03 t _R 1.14

Example 17-1: methyl 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxamido)-3-methylbutanoate; Example 17-2: 3-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxamido)-3-methylbutanoic acid.

Method A.

Stage 1. To the hydrochloride solution, approx. 3 (35 mg, 0.085 mmol) and TEA (24 μl, 0.17 mmol, 2 eq.) in DCM (5 ml) methyl 3-isocyanato-3-methylbutanoate (15 mg, 0.085 mmol) was added dropwise. The reaction mixture was stirred at rt. for 1 h (reaction monitored by LCMS) and then concentrated. The residue is purified with prep. HPLC (prep-HPLC-3 conditions) to give approx. 17-1 as a white solid (37.5 mg, 83% yield); LCMS-1: t _R =1.30 min, [M+1]+ 533.44; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.57 (d, J=8.1 Hz, 1H), 7.48-7.40 (m, 2H), 7.39-7.33 (m, 2H), 7.30 (t, J _H- F =72.6 Hz, 1H), 7.28 (d, J=5.3 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 4.93 (s, 1H), 4.72-4.56 (m, 2H), 4.484.29 (m, 2H), 3.67 (s, 3H), 2.69 (s, 2H), 2.42-2.50 (m, 1H), 2.38 (s, 3H), 1.45 (s, 6H), 1.15 (d, J=6.7 Hz, 6H).

Stage 2. Solution approx. 16-1 (33 mg, 0.063 mmol) in MeOH/THF (1:3, 4 ml) was treated with 2n. aq. LiOH solution (1 ml, 1.0 mmol). The reaction mixture was stirred at rt. for 5 h and then concentrated. The residue was purified by prep-HPLC (prep-HPLC-2 conditions) to give approx. 17-2 as a white solid (23 mg, 71% yield). LCMS-1: t _R =1.16 min, [M+1] ⁺ 519.40; 1H NMR (500 MHz, CDCl ₃ ) δ: 8.52 (d, J=8.1 Hz, 1H), 7.44-7.39 (m, 2H), 7.34-7.31 (m, 3H), 7.24 (t, J _H- F= 72.6 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 5.98-5.78 (m, 1H), 4.74-4.50 (m, 2H), 4.50-4.27 (m, 2H), 2.54 (s, 2H ), 2.39 (qt, J=6.1 Hz, 1H), 2.34 (s, 3H), 1.36 (s, 6H), 1.12 (d, J=6.1 Hz, 6H).

Example 17-3: N1-((1H-imidazol-4-yl)methyl)-N4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-1,4- carboxamide.

Method B.

Bis(2,2,2-trifluoroethyl) carbonate (52 µl, 0.34 mmol 2.5 equiv.) and DIPEA (142 µl, 0.82 mmol, 6 equiv.). The resulting mixture was heated at 75° C. for 2 hours and then allowed to cool to rt. Add a solution of approx. 4 (55 mg, 0.14 mmol) and DBU (6 μl, 0.04 mmol, 0.3 eq.) in MeCN (1 ml) and the mixture was heated at 75°C overnight. Then add DCM (20 ml) and the organic solution is washed with water (10 ml), dried over MgSO ₄ , filtered and evaporated under reduced pressure. The crude product is purified by prep-HPLC (prep-HPLC-3 conditions) to give approx. 17-3 as an off-white solid (17.6 mg, 25% yield). LCMS-1: t _R =0.79 min, [M+1] ⁺ 527.35; 1H NMR (400 MHz, CDCl3) δ: 8.46 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.46-7.39 (m, 3H), 7.33-7.30 (m, 1H), 7.27 (t , JhF=72.5 Hz, 1H), 7.11 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.89 (s, 1H), 5.60-6.32 (s br, 1H), 5.51 (t, J =5.0 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.73-3.60 (m, 4H), 3.16-3.10 (m, 1H), 2.52-2.47 (m, 2H), 2.38 (s , 3Н), 2.20-2.14 (m, 2Н), 1.10 (d, J=6.6 Hz, 6H).

Table 13. Examples 17-4 - 17-24.

Examples 17-4 - 17-24 were synthesized using either method A or B described for approx. 17-2 and approx. 17-3, respectively, based on approx. 3 or approx. 4. In the case of method B, bis(2,2,2-trifluoroethyl) carbonate can be replaced by CDI.

- 83 040901

Example Name method Analytical data of LCMS-1 Note. 17-4 (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carbonyl)glycine A [M+1] ⁺ 477.00 Ir 1.05 Note. 17-5 3-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carboxamido)propanoic acid A [M+1] ⁺ 491.17 t _R 1.05 Note. 17-6 methyl (3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)-bvalinate IN [M+1] ⁺ 533.02 t _R 1.29 Note. 17-7 (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2- isopropylphenyl)azetidine-1-carbonyl)-valine IN [M+1] ⁺ 519.12 t _R 1.19 Note. 17-8 methyl (3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)-lalaninate IN [M+1] ⁺ 505.02 t _R 1.18 Note. 17-9 (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2- isopropylphenyl)azetidine-1-carbonyl)-lalanine V [M+1] ⁺ 491.06 t _R 1.Yu

- 84 040901

Note. 17-10 ethyl 1-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1carboxamide o)cyclopropane-1-carboxylate IN [M+1] ⁺ 531.10 t _R 1.21 Note. 17-11 1-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carboxamide o)cyclopropane-1-carboxylic acid acid IN [M+1] ⁺ 503.47 t _R with her Note. 17-12 ethyl 2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)- 2-methylpropanoate IN [M+1] ⁺ 533.15 t _R 1.27 Note. 17-13 2-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)2-methylpropanoic acid V [M+1] ⁺ 505.48 t _R 1.15 Note. 17-14 methyl 1-((3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carboxamido)methyl)cyclopropane-1 carboxylate V [M+1] ⁺ 531.09 t _R 1.23 Note. 17-15 1-((3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carboxamido)methyl)cyclopropane-1 carboxylic acid V [M+1] ⁺ 517.09 t _R 1.13 Note. 17-16 methyl 3-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)- 2,2-dimethylpropanoate V [M+1] ⁺ 533.13 t _R 1.25 Note. 17-17 3-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)2,2-dimethylpropanoic acid V [M+1] ⁺ 519.03 t _R 1.14 Note. 17-18 methyl 4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)2,2-dimethylbutanoate V [M+1] ⁺ 547.24 t _R 1.27 Note. 17-19 4-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxamido)2,2-dimethylbutanoic acid V [M+1] ⁺ 533.06 t _R 1.17 Note. 17-20 X4-(2-(difluoromethoxy)-6-methylpyridin-3yl)-4-(2-isopropylphenyl)piperidine-1,4dicarboxamide A [M+1] ⁺ 447.00 t _R 1.10 Note. 17-21 2-(4-((2-(difluoromethoxy)-6-methylpyridine- 3-yl)carbamoyl)-4-(2isopropylphenyl)piperidine-1 carboxamido)ethyl methacrylate A [M+1] ⁺ 559.27 t _R 1.29 Note. 17-22 X4-(2-(difluoromethoxy)-6-methylpyridine-3ηπ)-Ν 1 -(2-hydroxyethyl)-4-(2isopropylphenyl)piperidine-1,4dicarboxamide A [M+1] ⁺ 491.21 t _R 1.09 Note. 17-23 methyl (3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carbonyl)-Oalaninate IN [M+1] ⁺ 505.01 t _R 1.18 Note. 17-24 (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2- isopropylphenyl)azetidine-1-carbonyl)-Oalanine V [M+1] ⁺ 491.03 t _R 1.10

Example 17-25: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(piperazine-1-carbonyl)azetidine-3-carboxamide.

-85 040901

Hydrochloride solution approx. 3 (30 mg, 0.07 mmol) and TEA (30 μl, 0.22 mmol) in DMF (1 ml) were cooled to 0°C under argon, after which a solution of tert-butyl 4-(carbonochloridoyl)piperazine-1-carboxylate (24.8 mg, 0.09 mmol) in 1 ml of DMF. The reaction mixture was stirred at rt. for 1 h (the reaction is monitored using LCMS) and then quenched with water (0.5 ml). Cleaning with Prep. HPLC (prep-HPLC-3 conditions) gives tert-butyl 4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl) piperazine-1-carboxylate as a white solid (42 mg, 98% yield). LCMS-1: t _R =1.37 min, [M+1]+ 588.02. tert-Butyl 4(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)piperazine-1-carboxylate (40mg) then treated with TFA , as described for approx. 4 to give the title compound of approx. 17-25 as a yellow solid (27 mg, 80%). LCMS-1: t _R =0.76 min, [M+1] ⁺ 488.40.

Example 17-26: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-methylpiperazin-1-carbonyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-methylpiperazine-1 carbonyl)azetidine-3-carboxamide approx. 17-26 are prepared from 4-methyl-1-piperazinecarbonyl chloride according to the procedure described for approx. 17-25. White solid. LCMS-1: t _R =0.77 min, [M+1] ⁺ 502.18.

Example 17-27: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(morpholine-4carbonyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylniridin-3-yl)-3-(2-isopropylphenyl)-1-(morpholine-4-carbonyl)αzetidine-3carboxamide approx. 16-27 are prepared from 4-morpholinecarbonyl chloride according to the procedure described for approx. 16-25. White solid. LCMS-1: t _R =1.19 min, [M+1] ⁺ 489.10.

Example 18-1: Methyl 6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)nicotinate and Example 18-2: 6- (3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)nicotinic acid.

Method C.

Stage 1. Hydrochloride approx. 3 (30 mg, 0.073 mmol), methyl 6-chloropyridine-3-carboxylate (28.7 mg, 0.164 mmol, 2.2 eq.) and Cs ₂ CO ₃ (53 mg, 0.164 mmol, 2.2 eq.) are suspended in DMA and the mixture is stirred at 90° C. for 18 hours (reaction monitored by LCMS). The mixture was cooled to rt, diluted with EtOAc (50 mL) and washed successively with water and brine. The organic phase is dried over MgSO ₄ , filtered and evaporated. The crude product is purified by prepHPLC (prep-HPLC-3 conditions) to give approx. 17-1 as a white solid (18 mg, 50% yield). LCMS-1: t _R =1.36 min, [M+1] ⁺ 511.31; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.83-8.82 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 8.06 (dd, Ji=2.2 Hz, J2=8.8 Hz, 1H), 7.50 -7.45 (m, 2H), 7.43-7.36 (m, 3H), 7.28 (t, Jh-f=72.5 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.37 (d, J=8.8 Hz, 1H), 4.97-4.85 (m, 2H), 4.67-4.51 (m, 2H), 3.89 (s, 3H), 2.59-2.49 (m, 1H), 2.39 (s, 3H), 1.19 (d, J=6.7 Hz, 6H).

Stage 2. Solution approx. 18-1 (18 mg, 0.035 mmol) in MeOH/THF (1:1, 1 ml) was treated with 2N LiOH solution (0.088 ml). The reaction mixture was stirred at rt. for 18 h and the organic solvents are then evaporated. The residue is dissolved in water. The resulting solution is acidified to pH 1 with 1N. aq. HCl solution and then extracted with EtOAc (3x10 ml). The combined extracts are dried over MgSO ₄ , filtered and evaporated to give approx. 18-2 as a colorless oil (14 mg, 80% yield). LCMS-1: t _R =1.21 min, [M+1] ⁺ 497.35; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.86 (d, J=1.6 Hz, 1H), 8.56 (d, J=8.1 Hz, 1H), 8.14 (dd, J1=1.6 Hz, J ₂ =8.9 Hz, 1Н), 7.52-7.38 (m, 4Н), 7.36 (s, 1Н), 7.21 (t, J _h _ _f =72.6 Hz, 1Н), 6.94 (d, J=8.1 Hz, 1Н), 6.45 (d, J=8.9 Hz, 1H), 5.14-4.93 (s br, 2H), 4.85-4.57 (m, 2H), 2.53-2.43 (m, 1H), 2.39 (s, 3H), 1.20 (d, J=6.5 Hz, 6H).

Example 18-3: 6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)picolinic acid.

Method D

To the hydrochloride solution approx. 3 (52 mg, 0.126 mmol) in toluene (2 ml), add ethyl 6-bromopicolinate (43.6 mg, 0.189 mmol, 1.5 equiv.), NaOtBu (36 mg, 0.379 mmol, 3 equiv.), Pd ₂ (dba) ₃ (11.6 mg, 0.013 mmol, 0.1 equiv.) and BINAP (16.2 mg, 0.025 mmol, 0.2 equiv.). The resulting mixture is degassed and heated at 110° C. overnight. The reaction is quenched with 2N. aq. HCl (10 ml) and the mixture was diluted with EtOAc. The phases are separated. The organic phase is dried over MgSO4, filtered and evaporated. The crude product is purified with prep. TLC (eluent: DCM/MeOH: 9/1) to give approx. 18-3 as a yellow solid (10 mg, 17% yield). LCMS-1: t _R =1.22 min, [M+1] ⁺ 497.34; 1H NMR (400 MHz, CDCl ₃ ) δ: 8.57 (d, J=8.0 Hz, 1H), 7.76-7.66 (m, 1H), 7.58 (d, J=7.0 Hz, 1H), 7.47 (s, 2H) , 7.46-7.33 (m, 3H), 7.27 (t, J=70.5 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 5-03- 4.78 (m, 2H), 4.69-4.40 (m, 2H), 2.59-2.47 (m, 1H), 2.39 (s, 3H), 1.20 (d, J=6.4 Hz, 6H).

Table 14. Examples 18-4 - 18-33.

Examples 18-4 - 18-33 synthesized in accordance with method C or method D, described for approx. 18-2 and approx. 18-3, respectively, based on approx. 3 or approx. 7.

- 86 040901

Example Name Method Analytical data of LCMS-1 Note. 18-4 Note. 18-5 Note. 18-6 Note. 18-7 Note. 18-8 Note. 18-9 Note. 18-10 Note. 18-11 Note. 18-12 Note. 18-13 Note. 18-14 Note. 18-15 methyl 2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine5-carboxylate 2-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine5-carboxylic acid methyl 6-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyridazine3-carboxylate 6-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2- isopropylphenyl)azetidin-1-yl)pyridazine3-carboxylic acid methyl 5-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrazine-2carboxylate 5-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2- isopropylphenyl)azetidin-1-yl)pyrazine-2carboxylic acid ethyl 4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine2-carboxylate 4-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine2-carboxylic acid methyl 6-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine4-carboxylate 6-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine4-carboxylic acid ethyl 2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine4-carboxylate 2-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidine4-carboxylic acid WITH WITH S c c c c c c c c c [M+1] ⁺ 512.18 t _R 1.36 [M+1] ⁺ 498.09 t _R 1.24 [M+1] ⁺ 512.38 t _R 1.22 [M+1] ⁺ 498.35 t _R 1.14 [M+1] ⁺ 512.21 t _R 1.29 [M+1] ⁺ 498.48 t _R 1.20 [M+1] ⁺ 526.28 t _R 1.23 [M+1] ⁺ 498.08 t _R 0.95 [M+1] ⁺ 512.37 t _R 1.21 [M+1] ⁺ 498.35 t _R 1.00 [M+1] ⁺ 526.38 t _R 1.38 [M+1] ⁺ 498.34 t _R 1.25

- 87 040901

Note. 18-16 methyl 1-(5-(3-((2-(diφτopmetoksi)-6methylpyridin-3-yl)κarbamoyl)-3-(2isopropylphenyl)azetidin-1 -yl)pyrimidin- 2-yl)cyclopropan-1-carboxylate D [M+1] ⁺ 552.23 t _R 1.31 Note. 18-17 1-(5-(3-((2-(diφτopmetoksi)-6methylpyridin-3-yl)κarbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)pyrimidin2-yl)cyclopropane-1-carboxylic acid D [M+1] ⁺ 538.31 t _R 1.32 Note. 18-18 X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(4-fluoropyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 471.40 t _R 1.34 Note. 18-19 X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(3-fluoropyridin-4-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 471.01 t _R 0.84 Note. 18-20 X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(5-fluoropyrimidin-4-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 472.40 t _R 1.25 Note. 18-21 X-(2-(difluoromethoxy)pyridin-3-yl)-1-(5fluoropyrimidin-4-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ t _R 1 457.98 .19 Note. 18-22 1-(5-cyanopyridin-2-yl)-M-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 478.38 t _R 1.35 Note. 18-23 1-(5-cyanopyridin-2-yl)-X-(2- (difluoromethoxy)pyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 464.30 t _R 1.29 Note. 18-24 1-(5-cyanopyrimidin-2-yl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 479.16 t _R 1.33 Note. 17-25 1-(5-cyanopyrimidin-2-yl)-M-(2- (difluoromethoxy)pyridin-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 465.00 t _R 1.27 Note. 18-26 1-(4-chloro-6-methylpyrimidin-2-yl)-X-(2(difluoromethoxy)-6-methylpyridin-3-yl)-3(2-isopropylphenyl)azetidine-3-carboxamide WITH [M+1] ⁺ 502.00 t _R 1.39 Note. 18-27 ethyl 2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-4carboxylate WITH [M+1] ⁺ 515.46 t _R 1.36 Note. 18-28 2-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-4carboxylic acid WITH [M+1] ⁺ 487.08 t _R 1.21 Note. Note. Note. Note. Note. 18-29 18-30 18-31 18-32 18-33 ethyl 2-(3-((2-(difluoromethoxy)pyridin-3yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-4carboxylate 2-(3-((2-(difluoromethoxy)pyridin-3yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-4carboxylic acid ethyl 2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)oxazole-5carboxylate 2-(3-((2-(difluoromethoxy)-6-methylpyridin3-yl)carbamoyl)-3-(2- isopropylphenyl)azetidin-1-yl)oxazole-5carboxylic acid X-(2-(difluoromethoxy)-6-methylpyridin-3yl)-1-(5-fluoropyrimidin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide WITH WITH WITH WITH WITH [M+1] ⁺ 500.98 t _R 1.29 [M+1] ⁺ 473.21 t _R 1.13 [M+1] ⁺ 515.13 t _R 1.36 [M+1] ⁺ 487.01 t _R 1.20 [M+1] ⁺ 471.99 t _R 1.40

Example 18-34. N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-methylpi- 88 040901 rimidin-4-yl)azetidine-3-carboxamide.

Note. 18-26 (65 mg, 0.129 mmol) is subjected to the hydrogenation conditions described for I-1.A to give N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1 -(2-methylpyrimidin-4yl)azetidine-3-carboxamide Approx. 18-34 as a white solid (53 mg, 83% yield). LCMS-1: tR=0.84 min, [M+1]+ 468.38; 1H NMR (500 MHz, CDCl ,) δ: 8.56 (d, J=8.1 Hz, 1H), 8.16 (d, J=5.9 Hz, 1H), 7.47 (d, J=1.3 Hz, 2H), 7.43- 7.39 (m, 2H), 7.32 (s, 1H), 7.26 (t, J _HF =73.5 Hz 1H), 6.93 (d, J=8.2 Hz, 1H), 6.15 (d, J=5.9 Hz, 1H), 5.00-4.76 (m, 2H), 4.64-4.45 (m, 2H), 2.55 (s, 3H), 2.54-2.48 (m, 1H), 2.39 (s, 3H), 1.19 (d, J=6.7 Hz, 6H).

Example 18-35: methyl 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-1-methyl-1H-imidazol- 5-carboxylate and Example 18-36: 2-(3-((2(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-1-methyl- 1Nimidazole-5-carboxylic acid.

Stage 1. Hydrochloride mixture approx. 3 (100 mg, 0.243 mol), 2-bromo-3methyl-3H-imidazole-4-carboxylic acid methyl ester (56 mg, 0.243 mmol), DIPEA (83 µl, 0.486 mmol), 18-crown6 (1.29 g, 4.86 mmol) and CsF (38 mg, 0.243 mmol) heated to 120°C overnight. The mixture is then evaporated and the residue is purified with prep. HPLC (prep-HPLC-3 conditions) to give methyl 2-(3-((2(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-1 -methyl-1nimidazole-5-carboxylate approx. 18-35 (20 mg, 16%) as a yellow oil. LCMS-1: t _R =1.16 min, [M+1] ⁺ 514.19.

Stage 2. Approx. 18-35 (20 mg, 0.039 mmol) are saponified according to the procedure described for approx. 12-62, obtaining approx. 18-36 (13 mg, 68%) as a white solid. LCMS-1: t _R =0.98 min, [M+1] ⁺ 500.00.

Example 19: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-oxo-4,5dihydrooxazol-2-yl)azetidine-3-carboxamide [ tautomeric form: N-(2-(difluoromethoxy)-6methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-hydroxyoxazol-2-yl)azetidine-3-carboxamide].

For solution approx. 3 (80 mg, 0.21 mmol) in DCM (3 mL) add chloroacetyl isocyanate (19 μL, 0.21 mmol). The reaction mixture was stirred for 1 h at rt. (the course of the reaction is monitored by LCMS). The mixture was poured into water and extracted with DCM (2x15 ml). The combined extracts are dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in THF (4 ml) and DBU (72 μl, 0.48 mmol, 2 eq.) was added. The reaction mixture was stirred at rt. for 1 h, then poured into 1N. aq. HCl and extracted with EtOAc (2x20 ml). The combined extracts are dried over MgSO4, filtered and concentrated. The crude product is then purified with prep. HPLC (prep-HPLC-1 conditions) to give approx. 19 as a colorless oil (72 mg, 65% yield). LCMS-1: t _R =1.11 min, [M+1] ⁺ 459.21; 1H NMR (400 MHz, CDCI3) δ: 8.55 (d, J=8.1 Hz, 1H), 7.57-7.48 (m, 2H), 7.44-7.39 (m, 1H), 7.32 (d, J=7.8 Hz, 1H ), 7.27 (m, 2Н), 6.96 (d, J=8.1 Hz, 1Н), 5.10-4.89 (m, 2Н), 4.86-4.72 (m, 1Н), 4.674.53 (m, 3Н), 2.39 ( s, 3Н), 2.34 (m, 1Н), 1.17 (dd, J1=6.7 Hz, J ₂ =11.7 Hz, 6H).

Example 20: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(1H-tetrazol-5yl)azetidine-3-carboxamide.

For solution approx. 11-6 (32 mg, 0.08 mmol) in DMF (2.5 ml) add ammonium chloride (6.4 mg, 0.12 mmol) and sodium azide (7.8 mg, 0.12 mmol) at rt. The mixture is then heated to 100° C. for 2 hours. The reaction mixture is introduced into the prep. HPLC (prep-HPLC-1 conditions) to give the title compound approx. 20 as a white solid (24 mg, 68% yield).

LCMS-1: t _R =1.12 min, [M+1] ⁺ 444.42; 1H NMR (400 MHz, CDC13) δ: 8.42 (d, J=8.1 Hz, 1H), 7.40-7.27 (m, 4H), 7.21-7.11 (m, 3H), 6.77 (d, J=8.2 Hz, 1H), 4.91-4.65 (m, 2H), 4.58-4.35 (m, 2H), 2.35-2.27 (m, 1H), 2.26 (s, 3H), 1.00 (d, J=6.4 Hz, 6H).

Example 21 N(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-hydroxy-1,2,4-oxadiazol-3-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [tautomeric form: N(2-(difluoromethoxy)-6-methylpyridin3-yl)-3-(2-isopropylphenyl)-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)azetidine-3-carboxamide.

To ethanol solution (1 ml) approx. 11-6 (41 mg, 0.102 mmol) add hydroxylamine hydrochloride (11 mg, 0.158 mmol) and TEA (36 µl, 0.258 mmol). The reaction mixture is heated to 80°C for 2 hours the Mixture is then cooled, concentrated in vacuo, dissolved in EtOAc, washed with water, dried over MgSO ₄ and again concentrated in vacuo. The crude material is redissolved in MeCN (2 ml) and CDI (21 mg, 0.129 mmol) is added. The reaction mixture is heated to 60°C for 2 h, then cooled and concentrated. Cleaning with Prep. HPLC (prep-HPLC-3 conditions) yields the title compound approx. 21 as a white solid (37 mg, 79% yield). LCMS-1: t _R =1.16 min, [M+1] ⁺ 460.04; 1H NMR (400 MHz, DMSO) δ: 12.19 (s, 1H), 8.56 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.53 (d, Jh_f=72.5 Hz, 1H), 7.48 ( d, J=7.7 Hz, 1H), 7.39-7.44 (m, 1H), 7.34-7.38 (m, 1H), 7.277.32 (m, 1H), 7.12 (d, J=8.1 Hz, 1H), 4.64 (d, J=8.0 Hz, 2H), 4.40 (d, J=8.0 Hz, 2H), 2.62-2.54 (m, 1H), 2.38 (s, 3H), 1.11 (d, J=6.7 Hz, 6H) .

Example 22 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((5-hydroxy-1,2,4-oxadiazol-3yl)methyl)-3-(2-isopropylphenyl)azetidine -3-carboxamide [tautomeric form: N-(2-(difluoromethoxy)-6-89 040901 methylpyridin-3 -yl)-3-(2-isopropylphenyl)-1 -((5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)methyl)azetidine3-carboxamide.

The connection header specified in approx. 22 is obtained from approx. 10-48 in accordance with the method described for approx. 21. Yellow solid. LCMS-1: t _R =1.11 min, [M+1]+ 474.34. 1H NMR (500 MHz, CDCl ,) δ: 8.53 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 7.40 (m, 2H), 7.34 (t, J=72.6 Hz, 1H), 7.30-7.34 (m, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.34-4.23 (m, 2H), 3.87-3.70 (m, 2H) , 3.65 (s, 2H), 2.52-2.44 (m, 1H), 2.40 (s, 3H), 1.15 (d, J=6.5 Hz, 6H).

Example 23: 3-(2-cyclopropylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3carboxamide.

3-(2-Cyclopropylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3-carboxamide approx. 23 is prepared from 1-benzhydryl-3-(2-bromophenyl)-M-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide and cyclopropylboronic acid pinacol ester according to the method described for approx. 1. Colorless oil. LCMS-1: t _R =0.71 min, [M+1] ⁺ 374.23. 1H NMR (500 MHz, CDC13) δ: 8.62 (d, J=8.1 Hz, 1H), 8.57 (s, 1H), 7.37 (t, J=72.9 Hz, 1H), 7.31-7.29 (m, 2H), 7.18 (dd, J1=3.5Hz, J2=5.6Hz, 1H), 6.99 (dd, J1=3.5Hz, J2=5.6Hz, 1H), 6.94 (d, J=8.1Hz, 1H), 4.37 (d, J=8.0 Hz, 2H), 4.29 (d, J=8.0 Hz, 2H), 2.40 (s, 3H), 1.46 (m, 1H), 0.89-0.86 (m, 2H), 0.73-0.68 (m, 2H ).

Example 24 3-(2-cyclobutylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3carboxamide.

Step 1. To a solution of 1-benzhydryl-3-(2-bromophenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide (200 mg, 0.09 mmol) in THF (2 ml) , degassed with argon, add (dppp)NiCl ₂ (5.6 mg, 0.01 mmol). Then 0.5M cyclobutylzinc bromide in THF (2.7 ml, 1.38 mmol) was added dropwise at room temperature. The mixture is heated to 80°C and stirred overnight. The mixture is then quenched with water and NaHCO ₃ added. The aqueous solution is extracted with EtOAc (2x60 ml). The organic extracts are dried over MgSO ₄ , filtered and evaporated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give 1-benzhydryl-3-(2-cyclobutylphenyl)-N-(2(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3-carboxamide as a colorless oil (115 mg, 60% yield. LCMS-2: tR=1.09 min, [M+1] ⁺ 554.36.

Step 2 3-(2-cyclobutylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3carboxamide approx. 24 is prepared from 1-benzhydryl-3-(2-cyclobutylphenyl)-N-(2-(difluoromethoxy)-6methylpyridin-3-yl)azetidine-3-carboxamide according to the hydrogenation conditions described for approx. 1. Beige solid (10 mg, 73% yield). LCMS-1: t _R =0.74 min, [M+1] ⁺ 388.31.

Example 25: 3-(2-cyclopentylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3carboxamide.

-Benzhydryl-3-(2-(cyclopent-1-en-1-yl)phenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide approx. 25 is prepared from 1-benzhydryl-3-(2-bromophenyl)-N-(2-(difluoromethoxy)6-methylpyridin-3-yl)azetidine-3-carboxamide and cyclopenten-1-ylboronic acid according to the method described for approx. 1, Colorless oil. LCMS-1: t _R =0.78 min, [M+1] ⁺ 402.37.

Example 26: 3-(2-(cyclopent-1-en-1-yl)phenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine3-carboxamide.

1-Benzhydryl-3-(2-(cyclopent-1-en-1-yl)phenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine3-carboxamide (50 mg, 0.09 mmol) obtained in accordance with the synthesis route described for approx. 1 was dissolved in 1,2-dichloroethane (2 ml). 1-Chloroethyl chloroformate (14 µl, 0.133 mmol) is added and the reaction mixture is stirred in a microwave oven (175 W) at 80°C for 8 h (formation of intermediate 1-chloroethyl 3-(2-(cyclopent-1-en- 1-yl)phenyl)-3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)azetidine-1-carboxylate was monitored by LCMS). Then MeOH (1 ml) is added. The reaction mixture is stirred at 45°C for 30 min and then concentrated. The residue is purified with prep. HPLC (prep-HPLC-1 conditions) to give approx. 26 as a pale yellow oil (36 mg, 100% yield). LCMS-1: t _R =0.76 min, [M+1] ⁺ 400.35.

Example 27: 3-(2-cyclohexylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3carboxamide.

3-(2-Cyclohexylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3-carboxamide approx. 27 is prepared from 1-benzhydryl-3-(2-bromophenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3yl)azetidine-3-carboxamide and cyclohexen-1-ylboronic acid according to the method described for . 1. Colorless oil. LCMS-1: t _R =0.82 min, [M+1] ⁺ 416.27. 1H NMR (400 MHz, CDC13) δ: 8.59 (d, J=8.1 Hz, 1H), 8.14 (s, 1H), 7.34 (t, J=72.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.33-7.29 (m, 1H), 7.17 (m, 1H), 6.93 (d, J=8.1 Hz, 1H), 4.32 (br s, 4H), 2.40 (s, 3H), 2.07-1.98 (m, 1H ), 1.78-1.71 (m, 2Н), 1.65-1.61 (m, 2Н), 1.47-1.38 (m, 2Н), 1.25-1.29 (m, 4Н).

Example 28: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-(tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-(tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3carboxamide approx. 28 can be obtained from 1-benzhydryl-3-(2-bromophenyl)-M-(2-(difluoromethoxy)-6-90 040901 methylpyridin-3-yl)azetidine-3-carboxamide and 3,6-dihydro- 2H-pyran-4boronic acid according to the method described for approx. 1. LCMS-1: t _R =0.62 min, [M+1]

418.22.

Example 29 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-propylphenyl)azetidine-3-carboxamide.

18[-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-propylphenyl)azetidine-3-carboxamide approx. 29 is obtained by hydrogenation of approx. 23 according to the method described for approx. 1. LCMS-1: t _R = 0.72 min, [M+1] ⁺ 376.10.

Example 30: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-sulfamoyl-3-(2-(tetrahydro-2H-pyran4-yl)phenyl)azetidine-3-carboxamide.

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-sulfamoyl-3-(2-(tetrahydro-2H-pyran-4yl)phenyl)azetidine-3-carboxamide approx. 30 is obtained from approx. 28 according to the method described for approx. 15-5. LCMS-1: t _R =l.00 min, [M+1] ⁺ 497.13.

Table 15. Examples 31-1 - 31-7.

Examples 31-1 - 31-7 were synthesized using the procedure described for approx. 12-61 and approx. 12-62, based on approx. 23, approx. 24, approx. 25, approx. 27, approx. 28 or approx. -29.

Example Name Analytical data of LCMS-1 Note. 31-1 4-(3-(2-cyclopropylphenyl)-3-((2- (difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 502.04 t _R 1.16 Note. 31-2 4-(3-(2-cyclobutylphenyl)-3-((2- (difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 516.00 t _R 1.23 Note. 31-3 4-(3-(2-cyclopentylphenyl)-3-((2- (difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 530.03 t _R 1.28 Note. 31-4 4-(3-(2-(cyclopent-1-en-1-yl)phenyl)-3-((2(difluoromethoxy)-b-methylpyridine-Zyl)carbamoyl)azetidin-1-yl)-2,2- dimethyl-4oxobutanoic acid [M+1] ⁺ 528.00 t _R 1.25 Note. 31-5 4-(3-(2-cyclohexylphenyl)-3-((2(difluoromethoxy)-6-methylpyridine-Zyl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 544.39 t _R 1.32 Note. 31-6 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-(tetrahydro-2H-pyran-4yl)phenyl)azetidin-1-yl)-2,2-dimethyl -4oxobutanoic acid [M+1] ⁺ 546.12 tR 1.06 Note. 31-7 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-propylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 504.13 t _R 1.21

Example 32: 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-(tetrahydro-2H-pyran4-yl)phenyl)azetidin-1-yl)oxazole -4-carboxylic acid.

2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-(tetrahydro-2H-pyran-4yl)phenyl)azetidin-1-yl)oxazol-4- carboxylic acid Approx. 32 is obtained from approx. 28, following the procedure described for approx. 18-28 (beige solid). LCMS-1: t _R =l.06 min, [M+1] ⁺ 528.98.

Example 33 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-6-methylphenyl)azetidine3-carboxamide.

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-6-methylphenyl)azetidine-3carboxamide approx. 33 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine 1-1.C and intermediate 1-7 following the procedure described for approx. 1 (colorless oil). LCMS-1: t _R =0.73 min, [M+1] ⁺ 390.35.

Example 34 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-5-methylphenyl)azetidine3-carboxamide.

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-5-methylphenyl)azetidine-3-carboxamide approx. 34 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine 1-1.C and intermediate 1-8 following the procedure described for approx. 1 (colorless oil). LCMS-1: t _R =0.77 min, [M+1] ⁺ 390.02; 'H NMR (500 MHz, CDC1 ₃ ) δ: 8.60 (d, J=8.1 Hz, 1H), 8.12 (s, 1H), 7.33 (t, J=72.8 Hz, 1H), 7.28 (d, J=8.0 Hz,

-91 040901

1Н), 7.22 (d, J=8.1 Hz, 1Н), 6.96 (s, 1Н), 6.93 (d, J=8.1 Hz, 1Н), 4.34 (m, 4Н), 2.45-2.33 (m, 7Н), 1.13 (d, J=6.6

Hz, 6H).

Example 35: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-4-methylphenyl)azetidine3-carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-4-methylphenyl)azetidine-3-carboxamide approx. 35 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine 1-1.C and intermediate I-9 following the procedure described for approx. 1 (colorless oil). LCMS-1: tR=0.77 min, [M+1]+ 389.97.

Example 36: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-fluoro-6-isopropylphenyl)azetidine-3carboxamide.

X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-fluoro-6-isopropylphenyl)azetidine-3-carboxamide approx. 36 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine 1-1.C and intermediate I-10 following the procedure described for approx. 1 (white solid). LCMS-1: t _R =0.71 min, [M+1] ⁺ 394.14.

Example 37: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(5-fluoro-2-isopropylphenyl)azetidine-3carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(5-fluoro-2-isopropylphenyl)azetidine-3-carboxamide approx. 37 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine 1-1.C and intermediate I-11 following the procedure described for approx. 1. LCMS-1: t _R =0.73 min, [M+1]+394.32.

Example 38: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-5-methoxyphenyl)azetidine-3carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropyl-5-methoxyphenyl)azetidine-3-carboxamide approx. 38 is prepared from 2-(difluoromethoxy)-6-methylpyridin-3-amine T-1.C and intermediate I-12 following the procedure described for approx. 1. LCMS-1: t _R =0.74 min, [M+1]+406.35.

Table 16. Examples 39-1 - 39-6.

Examples 39-1 - 39-6 were synthesized using the procedure described for approx. 12-61 and approx. 12-62, based on approx. 33, approx. 34, approx. 35, approx. 36, approx. 37 or approx. 38.

Example Name Analytical data of LCMS-1 Note. 39-1 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropyl-6methylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 518.05 t _R 1.26 Note. 39-2 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropyl-5methylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 518.06 t _R 1.26 Note. 39-3 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropyl-4methylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 518.23 t _R 1.23 Note. 39-4 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-fluoro-6isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 522.18 t _R 1.20 Note. 39-5 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(5-fluoro-2isopropylphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 522.00 t _R 1.20 Note. 39-6 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropyl-5methoxyphenyl)azetidin-1-yl)-2,2-dimethyl-4oxobutanoic acid [M+1] ⁺ 534.01 t _R 1.21

Example 40: 2-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)ethoxy)-2-methylpropanoic acid .

2-(2-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)ethoxy)-2-methylpropanoic acid approx. 40 is obtained from approx. 3 and methyl 2-methyl-2-2(2oxoethoxy)propanoate (obtaining disclosed in WO 2017177004), in accordance with the reductive amination reaction, as described for approx. 11-17. The methyl ester functional group is then hydrolyzed under basic conditions using 2N. LiOH. LCMS-1: t _R =0.84 min, [M+1] ⁺ 516.12.

Example 41 4-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)methyl)cyclohexane-1 -carboxylic acid.

4-((3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-cyclohexane-1-carboxylic acid approx. 41 is obtained from approx. 3 and commercially available 4-formylcyclohexanecarboxylic acid ethyl ester according to the reductive amination reaction as described for approx. 11-17. The ethyl ester functional group is then hydrolyzed under basic conditions using 2N hydrochloric acid. LiOH. LCMS-1: tR=0.82 min, [M+1]+ 516.30.

Examples 42-48 were synthesized using the procedure described for approx. 12-142.

Example Name Analytical data of LCMS-1 Note. 42 H-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)-N-propylglycine [M+1] ⁺ 533.33 t _R 0.99 Note. 43 N-cyclopropyl-N-(2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)glycine [M+1] ⁺ 531.31 t _R 1.15 Note. 44 3-((2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)amino)propanoic acid [M+1] ⁺ 505.31 t _R 0.80 Note. 45 3-((2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)amino)-2,2- dimethylpropanoic acid [M+1] ⁺ 533.07 t _R 0.88 Note. 46 1 -(((2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)amino)methyl)cyclopropane -1-carboxylic acid [M+1] ⁺ 530.96 t _R 0.83 Note. 47 3-((2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)amino)-3-methylbutanoic acid [M+1] ⁺ 533.33 t _R 0.89 Note. 48 1 -(2-(3-((2-(difluoromethoxy)-6-methylpyride in-3 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)piperidine-4-carboxylic acid [M+1] ⁺ 545.32 t _R 0.80

Example 49: (R)-2-amino-5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-5 -oxopentanoic acid.

(R)-2-amino-5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-5-oxopentanoic acid approx. 49 (51 mg, beige solid) is obtained from approx. 3 and commercially available Boc-D-Glu-OtBu following the procedure described for approx. 12-63 - 12114. LCMS-1: t _R =0.89 min, [M+1] ⁺ 487.08.

Examples 50 - 52.

Examples 50-52 were synthesized using the procedure described for approx. 12-62, based on approx. 3.

Example Name Analytical data of LCMS-1 Note. 50 (18.48)-4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carbonyl)cyclohexane-1-carboxylic acid [M+1] ⁺ 530.11 t _R 1.22 Note. 51 Note. 52 (18,3K)-3-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1 carbonyl)cyclohexane-1-carboxylic acid 4-(2-( 3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)cyclohexane-1-carboxylic acid [M+1] ⁺ 529.97 t _R 1.19 [M+1] ⁺ 543.97 t _R 1.20

Example 5 3: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3,3-dimethyl-4-(methylsulfonamido)-4oxobutyl)-3-(2-isopropylphenyl)azetidine-3 -carboxamide.

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3,3-dimethyl-4-(methylsulfonamido)-4-oxobutyl)3-(2-isopropylphenyl)azetidine-3-carboxamide prim . 53 is obtained by reaction approx. 11-31 (20 mg, 0.038 mmol) with DCC (10 mg, 0.049 mmol) and methanesulfonamide (14 mg, 0.15 mmol) in DCM (5 mL), in the presence of DMAP (6.5 mg, 0.053 mmol). White solid (10 mg, 45% yield). LCMS-1: t _R =0.84 min,

- 93 040901

[M+1]+ 567.08.

Table 17. Examples 54-58.

Examples 54-58 receive in accordance with the procedure described for approx. 12-142 using bromoacetyl bromide, aminocarboxylic acid ester and approx. 3. Alternatively, this type of derivative can be obtained from [(tert-butoxycarbonyl)amino]acetic acid and approx. 3 followed by Boc deprotection and nucleophilic substitution on methyl bromoacetate. The fully finished side chain can also be assembled before being combined with approx. 3. For example, N-ethyl-N-(2-methoxy-2oxoethyl)glycine is prepared from commercially available N-(tert-butoxycarbonyl)-N-ethylglycine which is reacted with benzyl bromide followed by nucleophilic substitution on methyl bromoacetate and hydrogenation: 1H NMR (400 MHz, CDCl ₃ ) δ: 9.43-9.02 (s br, 1H), 3.79 (s, 3H), 3.67 (s, 2H), 3.51 (s, 2H), 2.95 (q, J=7.2 Hz, 2H ), 1.19 (t, J=7.2 Hz, 3Н)._________________________________________________

Example Name Analytical data of LCMS-1 Note. 54 methyl H-(2-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-H-(2methoxyethyl)glycinate [M+1] ⁺ 563.43 t _R 1.14 Note. 55 (Н-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)-Н-(2-methoxyethyl) glycine [M+1] ⁺ 549.37 t _R 0.97 Note. 56 methyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)glycinate [M+1] ⁺ 505.34 Ir 0.82 Note. 57 (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)glycine [M+1] ⁺ 491.33 tR 0.89 Note. 58 H-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)-X-ethylglycine [M+1] ⁺ 519.38 Ir 0.94

Example 59: 3-(2-isopropylphenyl)-N-(6-methyl-2-propoxypyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide.

1) 3-(2-Isopropylphenyl)-N-(6-methyl-2-propoxypyridin-3-yl)azetidine-3-carboxamide is obtained from commercially available 6-methyl-2-propoxypyridin-3-amine I-1.D (73 mg) and I-6 (70 mg) using the POC13 method described for approx. 4 (36 mg, yellow oil). LCMS-1: tR=1.29 min, [M+1] ⁺ 447.33. 6Methyl-2-propoxypyridine-3-amine I-1.D was synthesized using the procedure described for T-1.A starting from commercially available 2-fluoro-6-methyl-3-nitropyridine and n-propanol. 1H NMR (400 MHz, CDC13) δ: 6.87 (d, J=7.5 Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 4.34 (s, 2H), 2.38 (s, 3H), 1.84 ( d, J=7.2 Hz, 2H), 1.06 (s, 3H).

2) 3-(2-Isopropylphenyl)-N-(6-methyl-2-propoxypyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide approx. 59 is prepared from 3-(2-isopropylphenyl)-N-(6-methyl-2-propoxypyridin-3-yl)azetidine-3-carboxamide according to the method described for approx. 15-5. LCMS-1: tR=1.29 min, [M+1] ⁺ 447.33.

Intermediate T-19: 5-chloro-3-(difluoromethoxy)pyridine-2-amine.

3-(Difluoromethoxy)pyridine-2-amine (500 mg, 2.97 mmol) was dissolved in DMF (8 ml). Nchlorosuccinimide (485 mg, 3.56 mmol) was added and the mixture was stirred at 80° C. for 2 h (reaction monitored by LCMS). Water is added and the compound is extracted with EtOAc. The organic phase is dried over MgSO ₄ , filtered and evaporated. The residue is purified by prep-HPLC-2. HPLC fractions were extracted with DCM (3x50 ml) and the collected organic layers were dried over MgSO ₄ , filtered and evaporated to give the title compound T-19 as a brown solid (424 mg, 73% yield). 1H NMR (400 MHz, DMSO d ₆ ) δ: 7.85 (s, 1H), 7.45 (s, 1H), 7.17 (t, J=73.4 Hz, 1H), 6.34 (s br, 2H).

Intermediate T-20: 1-(tert-butoxycarbonyl)-3-(2-cyclopentylphenyl)azetidine-3carboxylic acid.

1-Boc-3-(2-cyclopentylphenyl)azetidine-3-carboxylic acid T-20 is obtained by analogy with T-6, starting from 1-benzhydryl-3-(2-bromophenyl)azetidine-3-carbonitrile and cyclopentene-1 -ylboronic acid. 1H NMR (400 MHz, DMSO d ₆ ) δ: 13.15-12.90 (s br, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.30-7.24 (m, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.20-7.14 (m, 1H), 4.42 (d, J=7.9 Hz, 2H), 4.21 (d, J=7.9 Hz, 2H), 2.63-2.53 (m, 1H), 1.98-1.89 (m, 2Н), 1.83-1.74 (m, 2Н), 1.65-1.59 (m, 2Н), 1.52-1.45 (m, 2Н), 1.39 (s, 9Н).

Intermediate T-21: 3-(3-bromopyridin-2-yl)-1-(tert-butoxycarbonyl)azetidine-3carboxylic acid.

3-(3-Bromopyridin-2-yl)-1-Boc-azetidine-3-carboxylic acid T-21 is obtained by analogy with the procedure described for T-6, starting from ethyl 1-Boc-3-cyanoazetidine and 3- bromine-2-fluoropyridine. 1H NMR

- 94 040901 (400 MHz, DMSO d ₆ ) δ: 8.45 (dd, J1=1.4 Hz, J2=4.7 Hz, 1H), 7.91 (dd, J1=1.4 Hz, J2=7.9 Hz, 1H), 7.14 (dd ,

J1=4.7 Hz, J2=7.9 Hz, 1H), 4.31-4.16 (m, 4H), 1.37 (s, 9H).

Intermediate I-22: 1-(tert-butoxycarbonyl)-3-(6-fluoro-3-isopropylpyridin-2yl)azetidine-3-carboxylic acid.

1-Boc-3-(6-fluoro-3-isopropylpyridin-2-yl)azetidine-3-carboxylic acid I-22 is obtained by analogy with I-6, starting from ethyl 1-Boc-azetidine-3-carboxylate and 3 -bromo-2,6-difluoropyridine. 1H NMR (400 MHz, DMSO d6) δ: 8.02 (t, J=8.3 Hz, 1H), 7.15 (dd, Ji=2.5 Hz, J2=8.8 Hz, 1H), 4.42-4.27 (m, 4H), 2.48 -2.42 (m, 1H), 1.39 (s, 9H), 1.14 (d, J=6.6 Hz, 6H).

Intermediate I-23: 3-(3-bromopyridin-2-yl)-1-(tert-butoxycarbonyl)azetidine-3carboxylic acid.

3-(3-Bromopyridin-2-yl)-1-Boc-azetidine-3-carboxylic acid I-23 is obtained by analogy with the procedure described for I-6, starting from ethyl 1-Boc-3-cyanoazetidine and 3- chloro-4-cyanopyridine. 1H NMR (400 MHz, DMSO d ₆ ) δ: 8.42 (s, 1H), 8.38 (d, J=4.9 Hz, 1H), 7.33 (d, J=4.9 Hz, 1H), 4.44-4.19 (m, 4H ), 1.37 (s, 9Н).

Intermediate I-24: 1-benzyl-4-(2-bromopyridin-3-yl)piperidine-4-carboxylic acid.

1-Benzyl-4-(2-bromopyridin-3-yl)piperidine-4-carboxylic acid I-24 was prepared according to the procedure described for Intermediate I-4. LCMS-2: t _R =0.55 min, [M+1]+ 374.99 and 377.06.

Intermediate I-25: 1-(tert-butoxycarbonyl)-4-(4-chloropyridin-3-yl)piperidine-4carboxylic acid.

1-Boc-4-(4-chloropyridin-3-yl)piperidine-4-carboxylic acid I-25 is prepared according to the procedure described in WO 2009051715 starting from tert-butyl bis(2-chloroethyl)carbamate and 2- (4chloropyridin-3-yl)acetonitrile (Synthesis 1992, 6, 528-30).

Intermediate I-26: 1-(tert-butoxycarbonyl)-3-(3-chloropyrazin-2-yl)azetidine-3carboxylic acid.

1-Boc-3-(3-chloropyrazin-2-yl)azetidine-3-carboxylic acid I-26 is prepared by analogy with the procedure described for I-6, starting from ethyl 1-Boc-3-cyanoazetidine and 2.3 -dichloropyrazine. ¹ H NMR (400 MHz, DMSO d ₆ ) δ: 8.70 (d, J=2.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 4.49 (d, J=8.6 Hz, 2H), 4.41 -4.25 (m, 2H), 1.37 (s, 9H).

Intermediate I-27: 4-(5-bromopyrimidin-4-yl)-1-(tert-butoxycarbonyl)piperidine4-carboxylic acid.

4-(5-Bromopyrimidin-4-yl)-1-Boc-piperidine-4-carboxylic acid I-27 is prepared by analogy with the procedure described in WO 2009051715 starting from tert-butyl bis(2-chloroethyl)carbamate and 2 -(5chloropyrimidin-4-yl)acetonitrile.

Intermediate I-28: 4-(4-bromopyrimidin-5-yl)-1-(tert-butoxycarbonyl)piperidine4-carboxylic acid.

4-(4-Bromopyrimidin-5-yl)-1-Boc-piperidine-4-carboxylic acid I-28 is obtained by analogy with the procedure described in WO 2009051715, starting from tert-butyl bis(2-chloroethyl)carbamate and 2 -(4bromopyrimidin-5-yl)acetonitrile. 2-(4-Bromopyrimidin-5-yl)acetonitrile is synthesized by the reaction of nucleophilic substitution of sodium cyanide on 4-bromo-5-(bromomethyl)pyrimidine.

Example 60: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)azetidine-3carboxamide.

N-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)azetidine-3-carboxamide approx. 60 is prepared from T-1.C and I-21 under POCl ₃ /Pyr/DMF conditions followed by Suzuki coupling with isopropenylboronic acid pinacol ester, hydrogenation and finally Boc deprotection with TFA. LCMS-1: t _R =0.67 min, [M+1] ⁺ 377.27.

Example 61 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(3-isopropylpyridin-2yl)azetidin-1-yl)-4-oxobutanoic acid.

4-(3-((2-(Difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(3-isopropylpyridin-2-yl)azetidin1-yl)-4-oxobutanoic acid approx. 61 is obtained from approx. 60 according to the method described for approx. 12-62. LCMS-1: t _R =1.02 min, [M+1] ⁺ 477.34.

Example 62: N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)-1sulfamoylazetidine-3-carboxamide.

N-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)-1-sulfamoylazetidine-3-carboxamide approx. 62 is obtained from approx. 60 according to the method described for approx. 15-5. LCMS-1: t _R =1.08 min, [M+1] ⁺ 456.28.

Example 63: N1 -cyclopropyl-Ni-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)azetidine-1,3-dicarboxamide

N1 -Cyclopropyl-N3-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2yl)azetidine-1,3-dicarboxamide approx. 63 is obtained from approx. 60 according to the method described for approx. 17-2. LCMS-1: t _R =1.09 min, [M+1] ⁺ 460.36.

- 95 040901

Table 18. Examples 64 and 65.

Examples 64 and 65 are obtained from approx. 60 and 4-chloro-5-fluoro-2-methylpyrimidine or 2-chloro-3-fluoro-6picoline according to method C described for approx. 18-2.

Example Name Analytical data of LCMS-1 Note. 64 M-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5fluoro-2-methylpyrimidin-4-yl)-3-(3isopropylpyridin-2-yl)azetide in-3-carboxamide [M+1] ⁺ 487.33 t _R 1.00 Note. 65 Т4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3fluoro-6-methylpyridin-2-yl)-3-(3isopropylpyridin-2-yl)azetide in-3-carboxamide [M+1] ⁺ 486.32 t _R 1.42

Example 66 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4-yl)azetidine-3carboxamide.

N-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4-yl)azetidine-3carboxamide approx. 66 is prepared from 1-1.C and 1-24 under POCl ₃ /Pyr/DMF conditions followed by Suzuki coupling with isopropenylboronic acid pinacol ester, hydrogenation and finally Boc deprotection with TFA. LCMS-1: t _R =0.50 min, [M+1] ⁺ 377.28.

Example 67 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4-yl)-1-sulfamoylazetidine-3-carboxamide.

X-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4-yl)-1-sulfamoylazetidine-3-carboxamide approx. 67 is obtained from approx. 66 according to the method described for approx. 15-5. LCMS-1: t _R =0.73 min, [M+1] ⁺ 456.27.

Example 68 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyrazin-2-yl)azetidine-3carboxamide.

X-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyrazin-2-yl)azetidine-3-carboxamide approx. 68 is prepared from 1-1.C and 1-26 under POCl ₃ /Pyr/DMF conditions followed by Suzuki coupling with isopropenylboronic acid pinacol ester, hydrogenation and finally Boc deprotection with TFA. LCMS-1: t _R =0.60 min, [M+1] ⁺ 378.29.

Example 69 X-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyrazin-2-yl)-1-sulfamoyl-azetidine-3-carboxamide.

X-(2-(Difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyrazin-2-yl)-1-sulfamoyl azetidine3-carboxamide approx. 69 is obtained from approx. 68 according to the method described for approx. 15-5. LCMS-1: t _R = 1.00 min, [M+1] ⁺ 457.27.

Table 19. Examples 70-77.

Examples 70-77 are prepared from commercially available or synthesized 3-alkoxypyridine-2amines and intermediates 1-6,1-20 or 1-21 using the POCl ₃ procedure described for approx. 4. If 1-21 is used, a Suzuki/hydrogenation sequence is performed to introduce the iPr moiety after the amide coupling.

Example Name Analytical data of LCMS-1 Note. 70 X-(5-chloro-3-methoxypyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 361.23 t _R 0.63 Note. 71 X-(5-bromo-3-methoxypyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 404.25 and 406.23 t _R 0.65 Note. 72 N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 396.25 t _R 0.68 Note. 73 X-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 440.21 and 442.21 t _R 0.69 Note. 74 X-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 376.29 t _R 0.64 Note. 75 X-(3,5-dimethoxypyridin-2-yl)-3-(2isopropylphenyl)azetidine-3-carboxamide [M+1] ⁺ 356.27 t _R 0.64 Note. 76 X-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2cyclopentylphenyl)azetidine-3-carboxamide [M+1] ⁺ 422.27 t _R 0.76 Note. 77 X-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(3isopropylpyridin-2-yl)azetidine-3-carboxamide [M+1] ⁺ 397.23 t _R 0.62

Table 20. Examples 78-1 - 78-3.

Examples 78-1 to 78-3 were synthesized by reductive amination as described for PR-96040901 approx. 11-17, based on approx. 72 or approx. 73. Functional groups such as an acid or alcohol group may be protected with an appropriate protecting group. For example, esters are saponified with 2n. LiOH after the reductive amination step.

Example Name Analytical data of LCMS-1 Note. 78-1 methyl 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoate [M+1] ⁺ 524.32 tR 0.82 Note. 78-2 4-(3-((5-Chloro-3-(difluoromethoxy)pyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoic acid [M+1] ⁺ 510.30 t _R 0.76 Note. 78-3 4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoic acid [M+1] ⁺ 554.28 and 556.28 ΐκ 0.78

Table 21. Examples 79-1 - 79-7.

Examples 79-1 - 79-7 are synthesized using an amide combination of approx. 70, approx. 71, approx. 72, approx. 73 or approx. 74 and an acyl chloride or carboxylic acid in the presence of EDC/HOBt or TSP and an organic base (eg DIPEA, pyridine). Functional groups such as an acid or alcohol group may be protected with an appropriate protecting group. For example, esters are saponified with 2n. LiOH after the reductive amination step.

Example Name Analytical data of LCMS-1 Note. 79-1 methyl 4-(3-((5-bromo-3-(difluoromethoxy)pyridin2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin1-yl)-2,2-dimethyl-4-oxobutanoate [M+1] ⁺ 582.28 and 584.28 t _R 1.24 Note. 79-2 4-(3-((5-bromo-3-(difluoromethoxy)pyridine-2- [M+1] ⁺ 568.24 yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoic acid and 570.24 t _R 1.14 Note. 79-3 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 524.28 t _R 1.12 Note. 79-4 4-(3-((5-Chloro-3-methoxypyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 488.30 tR 1.06 Note. 79-5 4-(3-((5-bromo-3-methoxypyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 532.26 and 534.26 t _R 1.08 Note. 79-6 4-(3-((3-(d ifluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoic acid [M+1] ⁺ 504.30 tR 1.06 Note. 79-7 1-(2-(3-((3-(difluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)cyclobutane-1-carboxylic acid [M+1] ⁺ 516.40 t _R 1.08

Table 22. Examples 80-1 and 80-2.

Examples 80-1 and 80-2 were synthesized using the procedure described for approx. 13-1 - 13-27, based on approx. 74._________________________________________________________________________________

Example Name Analytical data of LCMS-1 Note. 80-1 benzyl 3-((3-((3-(difluoromethoxy)-5-methylpyridin2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoate [M+1] ⁺ 602.36 tR 1.30 Note. 80-2 3-((3-((3-(difluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoic acid [M+1] ⁺ 512.27 t _R 1.05

Table 23. Examples 81-1 - 81-5.

Examples 81-1 - 81-5 are synthesized in accordance with the procedure described for approx. 15-5, based on approx. 70, approx. 71, approx. 72, approx. 73, approx. 75, approx. 76 or approx. 77.

-97040901

Example Name Analytical data of LCMS-1 Note. 81-1 X-(5-chloro-3-methoxypyridin-2-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 439.27 t _R 0.99 Note. 81-2 N-(5-bromo-3-methoxypyridin-2-yl)-3-(2- [M+1] ⁺ 483.10 isopropylphenyl)-1-sulfamoylazetidine-3carboxamide and 485.10 t _R 1.00 Note. 81-3 N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2isopropylφenyl)-l-sylφamoylazetidine-3carboxamide [M+1] ⁺ 475.22 t _R 1.06 Note. 81-4 N-(5-bromo-3-(difluoromethoxy)pyride in-2-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 521.20 t _R 1.2 Note. 81-5 N-(3,5-dimethoxypyridin-2-yl)-3-(2isopropylphenyl)-1-sulfamoylazetidine-3carboxamide [M+1] ⁺ 435.31 t _R 0.90 Note. 81-6 N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2cyclopentylφenyl)-l-sylφamoylazetidine-3carboxamide [M+1] ⁺ 501.23 t _R 1.15 Note. 81-7 N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(3isopropylpyridin-2-yl)-l-sylφamoylazetidine-3carboxamide [M+1] ⁺ 476.14 t _R 0.98

Table 24. Examples 82-1 and 82-2.

Examples 82-1 and 82-2 are synthesized from isocyanatocyclopropane and approx. 72 or approx. 73 using method A described for approx. 17-2.

Example Name method Analytical data of LCMS-1 Note. 82-1 X3-(5-chloro-3-(difluoromethoxy)pyridine-2H4)-N 1 -cyclopropyl-3 -(2isopropylphenyl)azetidine-1,3dicarboxamide A [M+1] ⁺ 479.29 t _R 1.09 Note. 82-2 N3-(5-bromo-3-(difluoromethoxy)pyridin-2yl)-X 1 -cyclopropyl-3 -(2isopropylphenyl)azetidine-1,3dicarboxamide A [M+1] ⁺ 523.24 and 525.24 t _R 1.10

Table 25. Examples 83-1 - 83-3.

Examples 83-1 - 83-3 were synthesized from prim 74 using the procedure described for prim 14-1.

Example Name Analytical data of LCMS-1 Note. 83-1 2-methoxy-2-oxoethyl 3-((3-(difluoromethoxy)-5methylpyridin-2-yl)carbamoyl)-3-(2isopropylphenyl)azetidine-1-carboxylate [M+1] ⁺ 492.30 t _R 1.13 Note. 83-2 2-((3-((3-(difluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)acetic acid [M+1] ⁺ 478.30 t _R 1.04 Note. 83-3 1 -((3-((3-(difluoromethoxy)-5-methylpyridin-2yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)cyclopropane-1-carboxylic acid [M+1] ⁺ 518.32 t _R 1.09

Example 84: N-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2-isopropylphenyl)-1-(4-oxo-4,5dihydrooxazol-2-yl)azetidine-3-carboxamide.

X-(3-(Difluoromethoxy)-5-methylpyridin-2-yl)-3-(2-isopropylphenyl)-1-(4-oxo-4,5-dihydrooxazol2-yl)azetidine-3-carboxamide approx. 84 synthesized from approx. 74 using the procedure described for approx. 19. LCMS-1: t _R =0.97 min, [M+1] ⁺ 459.31.

Reference Example 85: X-(2-methoxypyridin-3-yl)-3-phenylazetidine-3-carboxamide.

1) A solution of intermediate 1-2 (678 mg, 1.61 mmol) in THF (30 ml) and MeOH (60 ml) is degassed with argon. Palladium hydroxide (210 mg) is then added and the reaction mixture is hydrogenated at atmospheric pressure for 2 hours. The mixture is filtered through a pad of celite. The packing is washed with

-98040901 cue THF/MeOH (1:1) and the organic solution was concentrated in vacuo to give 3-phenylazetidine3-carboxylic acid (271 mg, 95%). The latter (271 mg, 1.53 mmol) was dissolved in THF/water (60/10 ml) and DIPEA (1.05 ml) was added followed by Boc ₂ O (334 mg, 1.53 mmol). After 2 hours, the volatiles are evaporated and the remaining aqueous solution is extracted with DCM (20 ml, then 3x10 ml). The organic extracts are combined and evaporated. The residue was purified by prep-HPLC (prep-HPLC-1 conditions) to give 1-(tert-butoxycarbonyl)-3-phenylazetidine-3-carboxylic acid as a white solid (340 mg, 80% yield). 1H NMR (400 MHz, CDCl ₃ ) δ: 7.43-7.37 (m, 2H), 7.36-7.30 (m, 3H), 4.63 (d, J=8.7 Hz, 2H), 4.34 (d, J=8.7 Hz, 2H).

2) 1-Boc-3-phenylazetidine-3-carboxylic acid is coupled with commercially available 2-methoxypyridine-3-amine under POCl ₃ /Pyr/DMF conditions followed by Boc deprotection with TFA to give the title compound approx. 85 as a white solid. LCMS-1: t _R =0.49 min, [M+1]+ 284.18.

Reference Example 86: 1-(N-(2-methoxyethyl)sulfamoyl)-N-(2-methoxypyridin-3-yl)-3-phenylazetidine-3-carboxamide.

1-(N-(2-Methoxyethyl)sulfamoyl)-N-(2-methoxypyridin-3-yl)-3-phenylazetidine-3-carboxamide approx. 86 is obtained from approx. 85 by analogy with approx. 15-1. LCMS-1: 0.97 min, [M+1] ⁺ 421.30. 1H NMR (400 MHz, CDCl ₃ ) δ: 8.59 (d, J=7.8 Hz, 1H), 7.85 (d, J=4.8 Hz, 1H), 7.61 (s, 1H), 7.55-7.47 (m, 2H) , 7.47-7.40 (m, 1H), 7.35 (d, J=7.7 Hz, 2H), 6.90 (dd, J1=5.1 Hz, J2=7.7 Hz, 1H), 4.67 (t, J=5.8 Hz, 1H) , 4.63 (d, J=7.6 Hz, 2H), 4.37 (d, J=7.6 Hz, 2H), 3.85 (s, 3H), 3.53 (t, J=4.9 Hz, 2H), 3.40-3.31 (m, 5H).

Biological analyzes

Beta Arrestin Recruitment Assay to Determine IC ₅₀ Values for Human LPAR1

Tango™ EDG2-bla U2OS cells were obtained from Invitrogen. These cells contain the human LPA1 receptor cDNA linked to the TEV protease site and the transcription factor Gal4-VP16 inserted into such a Tango™ GPCR-bla U2OS parental cell line. This parental cell line stably expresses the beta-arrestin/TEV protease fusion protein and the beta-lactamase (bla) reporter gene under the control of the UAS response element. Upon binding of LPA (an agonist), the LPA1 receptor is activated, resulting in arrestin protease recruitment and proteolytic release of the transcription factor. The transcription factor then regulates transcription of the beta-lactamase reporter construct, as measured by the addition of live cell substrate.

10,000 Tango™ EDG2-bla U2OS cells are plated in a 384-well black clear bottom plate in 30 µl of Freestyle 293 Expression Medium (Invitrogen) and incubated for 20 h at 37°C, 5% CO2. To perform antagonism assays, add 5 µl per well of test compound (DMSO dilution series/Freestyle 293 Expression Medium/0.1% BSA without fatty acids (Sigma)) or buffer control, and incubate for 30 min at 37°C C, 5% _CO2 . Add 5 µl per well LPA 18:1 (final concentration 500 nM) (solution in Freestyle 293 Expression Medium/0.1% BSA without fatty acids (Sigma)) and the plate is incubated for 16 h at 37°C, 5% CO ₂ . Cells are then loaded in the dark with LiveBLAzer-FRET™ B/G Substrate (Invitrogen) for 2 h and fluorescence emission at 460 nm and 530 nm is measured using a SynergyMx plate reader (BioTek). After subtracting the background from both channels, calculate the ratio of the emission values at 460/530 nm for each well, then build a graph and fit it to a 4-parameter logistic function to obtain IC ₅₀ values. The IC ₅₀ is the concentration of the antagonist that inhibits 50% of the maximal response.

The antagonistic activity values (IC50 values) of the exemplary compounds were measured; mentioned values of antagonistic activity are presented in table. 26.

- 99 040901

Table 26. _IC50

Example IC ₅₀ LPARi [nM] Example IC ₅₀ LPARi [nM] Example IC ₅₀ LPARi [nM] 1 421 12-36 21 14-6 143 2 320 12-37 22 14-7 79 3 10 12-38 25 14-8 14 4 8 12-39 481 14-9 42 4-1 19 12-40 60 14-10 4 5 594 12-41 69 14-11 127 6 84 12-42 71 14-12 5 6-1 605 12-43 106 14-13 29 7 413 12-44 79 14-14 thirty 8 338 12-45 61 15-1 5 9 163 12-46 556 15-2 7 10 7 12-47 59 15-3 AND 11-1 6 12-48 9 15-4 15 11-2 5 12-49 thirty 15-5 1.3 11-3 32 12-50 9 15-6 10 11-4 5 12-51 360 15-7 4 11-5 29 12-52 9 15-8 4 11-6 AND 12-53 17 15-9 10 11-7 13 12-54 10 15-10 10 11-8 55 12-55 3 15-11 6 11-9 14 12-56 7 15-12 25 11-10 12 12-57 17 15-13 AND 11-11 5 12-58 10 15-14 2 11-12 22 12-59 10 15-15 10 11-13 16 12-60 58 15-16 50 11-14 14 12-61 276 15-17 31 11-15 22 12-62 65 15-18 7 11-16 4 12-63 10 16-1 69

- 100040901

11-17 48 12-64 19 16-2 158 11-18 8 12-65 3 16-3 83 11-19 14 12-66 12 16-4 120 11-20 6 12-67 75 16-5 47 11-21 60 12-68 33 17-1 18 11-22 108 12-69 230 17-2 12 11-23 775 12-70 60 17-3 8 11-24 280 12-71 10 17-4 34 11-25 20 12-72 4 17-5 41 11-26 400 12-73 7 17-6 9 11-27 38 12-74 97 17-7 26 11-28 12 12-75 50 17-8 4 11-29 AND 12-76 7 17-9 48 11-30 98 12-77 31 17-10 13 11-31 7 12-78 27 17-11 46 11-32 805 12-79 15 17-12 AND 11-33 8 12-80 18 17-13 25 11-34 79 12-81 34 17-14 7 11-35 43 12-82 6 17-15 16 11-36 9 12-83 24 17-16 9 11-37 6 12-84 51 17-17 12 11-38 270 12-85 140 17-18 6 11-39 10 12-86 27 17-19 7 11-40 270 12-87 41 17-20 AND 11-41 67 12-88 5 17-21 5 11-42 43 12-89 2 17-22 9 11-43 310 12-90 14 17-23 5 11-44 5 12-91 5 17-24 86 11-45 64 12-92 110 17-25 270 11-46 17 12-93 7 17-26 240 11-47 41 12-94 51 17-27 210 11-48 304 12-95 14 18-1 16 11-49 547 12-96 34 18-2 6 11-50 47 12-97 13 18-3 7 11-51 41 12-98 26 18-4 31 11-52 79 12-99 16 18-5 AND 11-53 115 12-100 23 18-6 10 11-54 95 12-101 83 18-7 12 11-55 142 12-102 12 18-8 10 11-56 64 12-103 19 18-9 AND 11-57 12 12-104 41 18-10 120 11-58 68 12-105 54 18-11 34 11-59 38 12-106 59 18-12 AND 11-60 47 12-107 150 18-13 17 11-61 39 12-108 28 18-14 560 11-62 48 12-109 20 18-15 47

- 101 040901

11-63 92 12-110 66 18-16 2 11-64 63 12-111 18 18-17 8 11-65 315 12-112 39 18-18 1 11-66 14 12-113 53 18-19 2 11-67 326 12-114 2675 18-20 2 11-68 23 12-115 7 18-21 10 11-69 15 12-116 63 18-22 1 11-70 69 12-117 7 18-23 4 11-71 7 12-118 thirty 18-24 2 11-72 52 12-119 35 18-25 5 11-73 46 12-120 AND 18-26 48 11-74 28 12-121 310 18-27 10 11-75 29 12-122 15 18-28 6 11-76 18 12-123 41 18-29 71 11-77 4.6 12-124 56 18-30 41 11-78 191 12-125 35 18-31 20 11-79 19 12-126 46 18-32 34 11-80 297 12-127 43 18-33 3 11-81 88 12-128 10 18-34 3 11-82 193 12-129 58 18-35 thirty 11-83 20 12-130 48 18-36 16 11-84 45 12-131 640 19 4 11-85 191 12-132 35 20 37 11-86 10 12-133 140 21 12 11-87 26 12-134 6 22 21 11-88 6 12-135 8 23 664 11-89 73 12-136 9 24 31 11-90 45 12-137 225 25 8.6 11-91 46 12-138 43 26 235 11-92 44 12-139 165 27 13 11-93 65 12-140 122 28 23 11-94 64 12-141 204 29 420 11-95 15 12-142 18 thirty 33 12-1 15 13-1 7 31-1 19 12-2 10 13-2 7 31-2 6 12-3 16 13-3 14 31-3 5 12-4 20 13-4 10 31-4 89 12-5 14 13-5 4 31-5 14 12-6 13 13-6 26 31-6 185 12-7 13 13-7 17 31-7 8 12-8 10 13-8 7 32 447 12-9 27 13-9 37 33 33 12-10 155 13-10 20 34 142 12-11 7 13-11 366 35 75 12-12 7 13-12 4 36 8 12-13 17 13-13 1755 37 112

- 102 040901

12-14 7 13-14 12-15 36 13-15 12-16 9 13-16 12-17 25 13-17 12-18 25 13-18 12-19 17 13-19 12-20 2 13-20 12-21 5.6 13-21 12-22 7 13-22 12-23 21 13-23 12-24 19 13-24 12-25 15 13-25 12-26 7 13-26 12-27 4 13-27 12-28 222 13-28 12-29 32 13-29 12-30 25 13-30 12-31 337 14-1 12-32 1715 14-2 12-33 10 14-3 12-34 33 14-4 12-35 41 14-5 54 69 71 55 44 72 56 8 73 57 54 74 58 48 75 59 270 76 60 333 77 61 70 78-1 62 3 78-2 63 8 78-3 64 15 79-1 65 37 79-2 66 1660 79-3 67 82 79-4 68 7620 79-5 69 27 79-6 70 866 79-7 Ref. example 85 >10,000 Ref. example 86

10 38 287 280 39-1 51 16 39-2 15 7.0 39-3 40 72 39-4 5 55 39-5 10 18 39-6 56 14 40 29 270 41 96 100 42 7 750 43 14 400 44 155 25 45 63 28 46 100 110 47 95 10 48 103 49 49 44 12 50 68 4.3 51 80 6 52 51 16 53 17 9 564 80-1 55 15 80-2 110 10 81-1 15 486 81-2 13 4380 81-3 2 19 81-4 2 1030 81-5 63 457 81-6 22 17 81-7 5 13 82-1 3 65 82-2 3 AND 83-1 74 17 83-2 88 123 83-3 76 104 84 310 200 61 >10,000

Evaluation of effectiveness in vivo

The in vivo efficacy of the compounds of formulas (I), (II) and (III) can be determined using a mouse model of LPA-induced vascular perspiration. Female Balb/c mice are treated with either vehicle or test compound (po) at least 1 h prior to administration of the Evans blue albumin marker (50 mg/kg, iv, 0.9% NaCl) and subsequent stimulation with LPA ( 5 mcg, i.c.). After 30 min, mice are sacrificed by CO2 inhalation. Skin disks from injection sites are removed, digested in formamide (500 μl, 37° C., 24 h) and Evans blue content is quantified by colorimetric analysis. The results are expressed as the amount of Evans blue vascularized into tissues per skin disc (µg/disc).

For example, connection approx. 12-21, after oral administration to mice at a dosage of 100 mg/kg, compared with a group of animals treated with only the vehicle, is able to effectively reduce LPA-induced fluid leakage through the vessels. The reduction in vascular leakage compared to the vehicle group was >60%.

- 103 -

Claims (16)

CLAIM 1. Compound of formula (I) ^R1 Formula (I), where W is N and Z is CH; or Z is N and W is CH; R ¹ means hydrogen or fluorine; R ² means hydrogen, halogen, methyl, ethyl, methoxy or ethoxy; R ³ is C _1-3 alkoxy or C _1-3 fluoroalkoxy; Ar ¹ is phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, where said Ar ¹ group is substituted by R ⁴ and R ⁵ , where R ⁴ means n-propyl, isopropyl, C _3-6 cycloalkyl, optionally containing a ring oxygen atom, or cyclopent-1-en-1-yl; And R ⁵ is one substituent independently selected from hydrogen, fluorine, methyl or methoxy; m and n are independently an integer 1 or 2; and the -LR ⁶ group is hydrogen; - C ₁ . ₄ alkyl; - C ₀ _ ₆ αkylene-C ₃ _ ₆ cycloαalkyl; where C ₃ _ ₆ cycloalkyl is independently unsubstituted or monosubstituted with halogen; - DREAM; - L1-CO-RC ¹¹ where RC ¹¹ independently represents hydroxy; -O-benzyl; -O-C1_6alkyl; C1-fluoroalkyl; or -NR ⁿ¹¹ R ⁿ¹² ; where independently RN ¹¹ means hydrogen or C1_ ₄ alkyl, and RN ¹² means hydrogen, C1.4 alkyl, -SO2-C1.6 alkyl or -OR ^O11 where R ^O11 independently represents hydrogen, C1. ₆ alkyl, or benzyl; And - L ¹ - independently represents - C ₁ _ ₆ alkylene-, -CO-C ₁ _ ₆ alkylene-, -SO ₂ -C ₁ _ ₆ alkylene-, -CO-O-C ₁ _ ₆ alkylene-, -CO-NH-C ₁ _ ₆ alkylene- or -SO ₂ -NH-C ₁ _ ₆ alkylene-; - C ₁ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene- or -SO ₂ -C ₁ . ₆ alkylene-; where in the above groups specified C ₁ . ₆ alkylene is independently monosubstituted with hydroxy, C ₁ . ₃ αlkoxy, -O-CO-C ₁ . ₄ alkyl or -NR ^N13 R ^N14 ; where independently R ^N13 is hydrogen or C1-4αkyl and R ^N14 is hydrogen, C1. ₄ alkyl or -CO-OC ₁ . ₄ alkyl; - C ₂ . ₆ alkylene-, -CO-C ₂ . ₆ alkylene- or -SO ₂ -C ₂ . ₆ alkylene-; where in the above groups specified C ₂ . ₆ alkylene is independently disubstituted, where the substituents are independently selected from hydroxy and NR ⁿ¹⁵ r ⁿ¹⁶ ; where independently R ^N15 is hydrogen or C1_4 alkyl and R ^N16 is hydrogen, C1_ ₄ alkyl or —CO-OC ₁ . ₄ alkyl; _-C0 . ₄ alkylene-C ₃ _ ₈ cycloalkylene-C ₀ _ ₄ alkylene-, -CO-C ₀ . ₄ alkylene-C ₃ _8Cycloalkylene-C ₀ _ ₄ alkylene-, -SO ₂ C ₀ . ₄ alkylene-C ₃ _ ₈ cycloalkylene-C ₀ _ ₄ alkylene-, -CO-NH-C ₀ _ ₄ alkylene-C ₃ _ ₈ cycloalkylene-C ₀ _ ₄ alkylene- or -CO-O-C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-; _-C0 . ₄ αkylene-Su ¹ -C0_4alkylene-, -CO-C0.4alkylene-Su ¹ -C0_ ₄ alkylene-, -CO-OC ₀ . ₄ alkylene-Su ¹ -C0_4 alkylene-, -CO-NH-C0_4 alkylene-Su ¹ -C0_ ₄ alkylene-, -SO ₂ -C ₀ . ₄ alkylene-Cu ¹ -C0_4 alkylene- or -SO2-NH-C0_4 alkylene-Cu ¹ C0. ₄ alkylene-; where Cy ¹ independently represents C ₃ _ ₆ heterocycloalkyl containing one ring oxygen atom or one ring nitrogen atom, where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted with C ₁ _ ₄ alkyl or -CO-OC ₁ . ₄ alkyl; - C ₂ . ₄ alkylene-O-C ₂ . ₄ alkylene-O-C ₁ - ₄ alkylene- or -CO-C1. ₄ alkylene-O-C ₂ . ₄ alkylene-O-C 1 - ₄ alkylene-; - C ₂ . ₄ alkylene-X ¹¹ -C1.4 alkylene-, -CO-O-C2.4 alkylene-X ¹¹ -C1. ₄ alkylene-, -CO-NH-C ₂ . ₄ alkylene-X ¹¹ C1_4 alkylene- or -SO2-NH-C2_4 alkylene-X ¹¹ -C1_ ₄ alkylene-; where X ¹¹ independently represents an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted by C ₁ _ ₄ alkyl, C ₃ _ ₆ cycloalkyl or —CO-OC ₁ . ₄ alkyl; - CO-C ₁ _ ₄ alkylene-X ¹² -C1_4 alkylene-, -SO2-C1_4 alkylene-X ¹² -C1_ ₄ alkylene- or -CO-C ₁ _ ₄ alkylene- - 104 040901 X ¹² -C ₀ . ₄ alkylene-C ₃ . _b cycloalkylene-C ₀ . ₄ alkylene-; where X ¹² is independently an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C _1-4 alkyl, C ₃ . _b cycloalkyl, -CO-OC _1-4 alkyl or C _1-3 αlkoxy-C _2-4 alkyl; -C ₂ . ₄ alkylene-X ¹³ -C1.4 alkylene-; where X ¹³ represents -NH-CO- and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy; - C _1-4 alkylene-X ¹⁴ -C _1-4 alkylene-; where X ¹⁴ represents-CO-NH-; - CO-C _2-b alkenylene- or -SO ₂ -C _2-b alkenylene-; or - CO-C _2-b fluoroalkylene-; - L ² -hydroxy; where -L ² - represents - CO-C _1-b alkylene- or -SO ₂ -C _1-b alkylene-; where in the above groups, the specified C _1-b αkylene is independently unsubstituted or monosubstituted by hydroxy, C ₁ -fluoroalkyl or -NR ⁿ²¹ R ⁿ²² , where independently R ^N21 means hydrogen or C1-4 alkyl, and R ^N22 means hydrogen, C 1-4 αalkyl or -CO -OC _1-4 alkyl; - C _2-b alkylene-, -CO-O-C _2-b α-alkylene-, -CO-NH-C _2-b alkylene- or -SO ₂ -NH-C _2-b alkylene-, where in the above groups the indicated C _2-b alkylene is independently unsubstituted or monosubstituted with hydroxy, C ₁ fluoroalkyl, or -NR ⁿ²³ R ⁿ²⁴ , where independently R ^N23 is hydrogen or C1-4 alkyl and R ^N24 is hydrogen, C1-4αkyl, or -CO-OC _1-4 alkyl; - C _0-4 alkylene-C _3-b cycloalkylene-C _0-4 alkylene-, -CO-C _0-4 alkylene-C _3-b cycloalkylene-C _0-4 alkylene- or -SO ₂ -C _0-4 alkylene-C _3-b cycloalkylene-C _0-4 alkylene-; - C _0-4 αkylene-Su ² -C0-4 alkylene-, -CO-C0-4 alkylene-Su ² -C0-4 alkylene- or -SO ₂ -C _0-4 alkylene-Su ² -C0-4 alkylene-; where Cy ² is independently a C3-bheterocycloalkylene group containing one ring oxygen atom or one ring nitrogen atom; where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted by C ₁ . ₄ alkyl or -CO-OC ₁ _ 4 alkyl; - C ₂ . ₄ alkylene-(O-C ₂ . ₄ alkylene)p- or -CO-C ₁ . ₄ alkylene-(O-C ₂ . ₄ alkylene)p-; where p is independently the integer 1 or 2; - C ₂ . ₄ alkylene-X ²¹ -C2.4 alkylene-; where X ²¹ represents a nitrogen atom which is unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . _b cycloalkyl or -CO-OC ₁ . ₄ αkyl; - CO-C ₁ . ₄ alkylene-X ²² -C2.4 alkylene-, -CO-C1.4 alkylene-X ²² -C1. ₄ alkylene-C ₃ . _b cycloalkylene- or -SO ₂ C ₁ . ₄ alkylene-X ²² -C2.4 alkylene-; where X ²² represents a nitrogen atom that is independently unsubstituted or monosubstituted by C1. ₄ alkyl, C ₃ . _b cycloalkyl or -CO-OC ₁ . ₄ αkyl; - C ₂ . ₄ alkylene-X ²³ -C1.4alkylene-; where X ²³ represents -NH-CO- and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy; - C ₁ . ₄ alkylene-X ²⁴ -C2.4 alkylene-; where X ²⁴ represents -CO-NH- and where the specified C2. ₄ alkylene is independently unsubstituted or monosubstituted by hydroxy; or 3,4-dioxocyclobut-1-en-1,2-diyl; - L ³ -O-RO ³¹ where RO ³¹ means -C ₁ . ₄ αlkyl, -CO-C ₁ . ₄ alkyl or -CO-C ₂ . ₄ alkenyl; And - L ³ - independently represents - C ₂ . _b alkylene-, -CO-C ₁ . _b alkylene- or -SO ₂ -C ₁ . _b alkylene-, -CO-O-C ₂ . _b αkylene-, -CO-NH-C ₂ . _b alkylenyl -SO ₂ -NH-C ₂ . _b alkylene-; - L ⁴ -NR ⁿ¹ R ⁿ² where independently R ^N1 means hydrogen or C1.4alkyl; and R ^N2 is hydrogen; C1. ₄ alkyl; _C1 . ₃ fluoroalkyl; _C3 . _b cycloalkyl; _C1 . ₃ alkoxy-C ₂ . ₄ alkylene; -CO-C ₁ . ₄ alkyl; -SO ₂ -C ₁ . ₄ alkyl; or -SO ₂ -C ₁ fluoroalkyl; And - L ⁴ - independently represents - C ₂ . _b alkylene-, -CO-C ₁ . _b alkylene-, -SO ₂ -C ₁ . _b alkylene-, -CO-O-C ₂ . _b αkylene-, -CO-NH-C ₂ . _b alkylene- or -SO ₂ -NH-C ₂ . _b alkylene-; or _-C0 . ₄ alkylene-Su ⁴ -C0.4 alkylene-, -CO-C0.4 alkylene-Su ⁴ -C0. ₄ alkylene- or -SO ₂ -C ₀ . ₄ alkylene-Su ⁴ -C0.4alkylene-; where Cy ⁴ is independently C3. _b heterocycloalkylene group containing one ring oxygen atom; - L ⁵ -NR ⁿ³ R ⁿ⁴ , where R ⁿ³ means hydrogen, C1.4alkyl or C1.3αlkoxy-C2.4αkylene; and R ^N4 means -COO-C1. ₄ alkyl; -CO-NR ^N51 R ^N52 , where R ^N51 and R ^N52 are independently selected from hydrogen and C ₁ . ₄ alkyl; or -SO ₂ NR ^N53 R ^N54 , where independently R ^N53 is hydrogen or C1.4 alkyl and R ^N54 is hydrogen, C1-4 alkyl or -CO-C ₁ . ₄ alkyl; and -L ⁵ - independently represents - C ₂ . _b alkylene-, -CO-C ₁ . _b alkylene- or -SO ₂ -C ₁ . _b alkylene-, -CO-O-C ₂ . _b αkylene-, -CO-NH-C ₂ . _b alkylenyl -SO ₂ -NH-C ₂ . _b alkylene-; - L ⁶ -N(R ⁿ⁶¹ )-OR ⁰⁶¹ , where R ⁿ⁶¹ means hydrogen, -CO-C1.4alkyl or -CO-O-C1.4αkyl; and RO ⁶¹ is independently hydrogen, C1. _b alkyl or benzyl; and -L6- independently represents - C ₂ . _b alkylene-, -CO-C ₁ . _b alkylene-, -SO ₂ -C ₁ . _b alkylene-, -CO-O-C ₂ . _b αkylene-, -CO-NH-C ₂ . _b alkylene- or -SO ₂ -NH-C ₂ . _b alkylene-; - L ⁷ -NR ^N5 R ⁿ⁶ , where R ^N5 means hydrogen or C1.4alkyl; R ^N 6 means hydrogen, C1. ₄ alkyl, -CO-C ₁ . ₄ alkyl, C ₁ . ₃ fluoroalkyl or C ₃ . _b cycloalkyl; And - 105 040901 -L ⁷ - independently represents -CO- or -SO ₂ -; -L ⁸ -SO2-R ^S81 where R ^S81 is independently -C1-6 alkyl; C ₁ -fluoroalkyl; hydroxy; -NR ^N81 R ^N82 where independently R ^N81 is hydrogen or C1-4 alkyl and R ^N82 is hydrogen, C1-4 alkyl, -COC _1-6 alkyl; And - L ⁸ - independently represents - C _1-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 αkylene-; - L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said NO ¹ is independently unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from C1-4alkyl; halogen; cyano; hydroxy; hydroxymethyl; -C0-2alkylene-Cy ⁹¹ -COOR ^O91 where RO ⁹¹ is hydrogen or C1-4alkyl and where Cy ⁹¹ is a C3-6cycloalkylene group; or -C0-2alkylene-COOR ^O92 where RO ⁹² is hydrogen or C1-4alkyl; And - L ⁹ - independently represents - C _0-6 alkylene-, -CO-C _0-6 alkylene-, -SO ₂ -C _0-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 αkylene-; - L ¹⁰ -C _4-6 heterocyclyl, where C _4-6 heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, said C _4-6 heterocyclyl is independently unsubstituted or mono-, di-, or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom; and/or two methyl substituents attached to a ring carbon atom in the alpha position to a ring nitrogen atom or a ring oxygen atom; and/or two oxo substituents on the ring sulfur atom; and/or C _1-4 alkyl, C _1-3 alkoxy-C _2-4 alkyl, C _2-3 fluoroalkyl, or —CO—C _1-4 alkyl attached to a free valency ring nitrogen atom; And - L ¹⁰ - independently represents - C _0-6 alkylene-, -CO-C _0-6 alkylene-, -SO ₂ -C _0-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-; - L ¹¹ -cyano; where -L ¹¹ - represents -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene or -C _0-6 alkylene-; - L ¹² -NO2; where -L ¹² - represents -C2-6alkylene-; - L ¹³ -C1-4 alkyl; where -L ¹³ - represents -CO-, -CO-O- or -SO2-; or a pharmaceutically acceptable salt thereof. 2. Connection according to claim 1, where W is N, Z is CH; and R ² means hydrogen, methyl, methoxy or ethoxy; or Z is N, W is CH; and R ² means chlorine, bromine, methyl or methoxy; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, where R ³ represents methoxy or difluoromethoxy; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, where the fragment is where R ¹ means hydrogen or fluorine; R ² means hydrogen, chlorine, methyl, ethyl, methoxy or ethoxy; and R ³ means C _1-3 αlkoxy or C _1-3 fluoroalkoxy; or - 106 040901 where R ¹ means hydrogen; R ² means halogen, methyl or methoxy; and R ³ means ^^alkoxy or Ci-sfluoroalkoxy; or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, where the fragment is a ring independently selected from the following groups A) or B): or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of paragraphs.1-5, where Ar ¹ represents phenyl; where the specified phenyl group is substituted by R ⁴ and R ⁵ where R ⁴ is n-propyl, isopropyl or monocyclic C _3-6 cycloalkyl; And R ⁵ is hydrogen, fluoro or methyl; or a pharmaceutically acceptable salt thereof. 7. The compound according to any one of claims 1-5, where the fragment is a ring independently selected from the following groups A) or B): - 107 040901 N N OR or a pharmaceutically acceptable salt thereof. 8. Connection according to any one of paragraphs.1-7, where m and n are both 1; or a pharmaceutically acceptable salt thereof. 9. The compound according to any one of paragraphs.1-8, where the group-LR ⁶ represents hydrogen; - L ¹ -CO-R ^C11 where R ^C11 independently represents hydroxy; -O-benzyl; -O-Cl.6 alkyl; Ci-fluoroalkyl; or -NR ⁿ¹¹ R ⁿ¹² ; where independently RN ¹¹ means hydrogen or C1-4alkyl and RN ¹² means hydrogen, C1-4alkyl, -SO2-C1-6-alkyl or -OR ⁰¹¹ where R ⁰¹¹ independently represents hydrogen, C1-6alkyl, or benzyl; And - L ¹ - independently represents - C _1-6 alkylene-, -C0-C _1-6 alkylene-, -SO2-C _1-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene - or -SO2-NH-C _1-6 alkylene-; - C _1-6 alkylene-, -CO-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups, the specified C _1-6 alkylene is independently monosubstituted with hydroxy, C _1-3 alkoxy, -0-C0-C _1-4 alkyl or -NR ⁿ¹³ R ⁿ¹⁴ ; where independently RN ¹³ means hydrogen or C1-4alkyl and RN ¹⁴ means hydrogen, C1-4alkyl or -C0-0-C _1-4 alkyl; - C _2-6 alkylene-, -CO-C _2-6 alkylene- or -SO ₂ -C _2-6 alkylene-; where in the above groups the specified C _2-6 alkylene is independently disubstituted, where the substituents are independently selected from hydroxy and -NR ⁿ¹⁵ R ⁿ¹⁶ ; where independently RN ¹⁵ means hydrogen or C1-4alkyl and RN ¹⁶ means hydrogen, C1-4alkyl or -C0-0-C _1-4 alkyl; - C _o-4 alkylene-C _3-8 cycloalkylene-C _o-4 alkylene-, -CO-C _o-4 alkylene-C _3-8 cycloalkylene-C _o-4 alkylene-, -S0 ₂ Co _-4 alkylene- C _3-8 cycloalkylene-Co _-4 alkylene-, -CO-NH-C _0-4 alkylene-C _3-8 cycloalkylene-C _0-4 alkylene- or -CO-O-C _0-4 alkylene-C _{3- 8} cycloalkylene-C _0-4 alkylene-; - C _o-4 alkylene-Su ¹ -Co-4 alkylene-, -CO-Co-4 alkylene-Su ¹ -Co-4 alkylene-, -CO-0-C _o-4 alkylene-Su ¹ -Co-4 alkylene-, - CO-NH-C0-4alkylene-Su ¹ -Co-4alkylene-, -SO ₂ -C _0-4 alkylene-Su ¹ -Co-4alkylene- or -SO2-NH-C0-4alkylene-Su 1Co-4alkylene-; where Cy ¹ is independently C3-6 heterocycloalkyl containing one ring oxygen atom or one ring nitrogen atom, where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted with C _1-4 alkyl or -C0-0-C _1-4 alkyl; - CO-C _1-4 alkylene-X ¹² -C1-4 alkylene-, -SO2-C1-4 alkylene-X ¹² -C1-4 alkylene- or -CO-C _1-4 alkylene-X ¹² Co-4 alkylene-C3-8 cycloalkylene -Co-4alkylene-; where X ¹² independently represents an oxygen or nitrogen atom that is independently unsubstituted or monosubstituted with C 1-4 alkyl, C _3-6 cycloalkyl, —C 0-0-C _1-4 alkyl, or C _1-3 alkoxy-C _2-4 alkyl; - C _2-4 alkylene-X ¹³ -C 1-4 alkylene-; where X ¹³ represents -NH-CO- and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy; - CO-C _2-6 alkenylene- or -SO ₂ -C _2-6 alkenylene-; or - CO-C _2-6 fluoroalkylene-; - L ² -hydroxy; where -L ² - represents - C0-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-; where in the above groups said C _1-6 alkylene is independently unsubstituted or monosubstituted with hydroxy, C 1 -fluoroalkyl or -NR ⁿ²¹ R ⁿ²² , where independently RN ²¹ is hydrogen or C 1-4 alkyl and RN ²² is hydrogen, C 1-4 alkyl or -C 0-0 -C _1-4 alkyl; - C _2-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _2-6 alkylene- or -SO ₂ -NH-C _2-6 alkylene-, where in the above- - 108 040901 in these groups, said C _2-6 alkylene is independently unsubstituted or monosubstituted with hydroxy, C ₁ fluoroalkyl or -NR ⁿ²³ R ⁿ²⁴ , where independently R ^N23 is hydrogen or C1-4 alkyl and R ^N24 is hydrogen, C 1-4 alkyl or -CO- O-C _1-4 alkyl; -Co _-4 alkylene-C _3-6 cycloalkylene-C _o-4 alkylene-, -CO-Co _-4 alkylene-C _3-6 cycloalkylene-C _0-4 alkylene- or -SO ₂ -Co _-4 alkylene-C _3-6 cycloalkylene-Co _-4 alkylene-; - C _0-4 alkylene-Cu2-C _0-4 alkylene-, -CO-C _0-4 alkylene-Cu2-C _0-4 alkylene- or -SO ₂ -C _0-4 alkylene-Cu ² -C0-4 alkylene -; where Cy ² is independently a C3-6 heterocycloalkylene group containing one ring oxygen atom or one ring nitrogen atom; where the specified ring nitrogen, if it has a free valency, is independently unsubstituted or monosubstituted With _1-4 alkyl or CO-OS _1-4 alkyl; - CO-C _1-4 alkylene-X ²² -C 2-4 alkylene-, -CO-C 1-4 alkylene-X ²² -C 1-4 alkylene-C _3-6 cycloalkylene- or -SO ₂ -C _1-4 alkylene-X ²² -C 2-4 alkylene-; where X ²² represents a nitrogen atom that is independently unsubstituted or monosubstituted with C 1-4 alkyl, C _3-6 cycloalkyl or —CO—O—C _1-4 alkyl; or - C _2-4 alkylene-X ²³ -C 1-4 alkylene-; where X ²³ represents -NH-CO- and where the specified C2-4alkylene is independently unsubstituted or monosubstituted by hydroxy; - L ⁴ -NR ^N1 R ^N2 where independently R ^N1 means hydrogen or C1-4 alkyl; and RN ² means hydrogen; C1-4alkyl; C _1-3 fluoroalkyl; C _3-6 cycloalkyl; C _1-3 alkoxy-C _2-4 alkylene; -CO-C _1-4 alkyl; -SO ₂ -C _1-4 alkyl; or -SO ₂ -C ₁ fluoroalkyl; And - L ⁴ - independently represents - C _2-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _2-6 alkylene- or -SO ₂ -NH-C _2- 6alkylene-; or - C _0-4 alkylene-Cu ⁴ -C0-4 alkylene-, -CO-C0-4 alkylene-Cu ⁴ -C0-4 alkylene- or -SO ₂ -C _0-4 alkylene-Cu ⁴ -C0-4 alkylene-; where Su ⁴ is independently a C3-6 heterocycloalkylene group containing one ring oxygen atom; - L ⁵ -NR ^N3 R ^N4 where RN ³ means hydrogen, C1-4alkyl or C1-3alkoxy-C2-4alkylene; and R ^N4 is -CO-O-C1-4 alkyl; -CO-NR ^N51 R ^N52 where RN ⁵¹ and RN ⁵² are independently selected from hydrogen and C1-4 alkyl; or -SO2-NR ^N53 R ^N54 where independently RN ⁵³ is hydrogen or C1-4 alkyl and R ^N54 is hydrogen, C _1-4 alkyl or -CO-C _1-4 alkyl; and -L ⁵ - independently represents - C _2-6 alkylene-, -CO-C _1-6 alkylene- or -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _2-6 alkylenyl-SO ₂ -NH-C _2-6 alkylene-; - L ⁶ -N(R ^N61 )-OR ⁰⁶¹ , where RN ⁶¹ means hydrogen, -CO-C1-4 alkyl or -CO-O-C1-4 alkyl; and RO ⁶¹ is independently hydrogen, C1-6alkyl or benzyl; and -L ⁶ - independently represents - C _2-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _2-6 alkylene- or -SO ₂ -NH-C _2-6 alkylene-; - L ⁷ -NR ^N5 R ^N6 where RN ⁵ means hydrogen or C1-4alkyl; RN ⁶ is hydrogen, C1-4 alkyl, -CO-C _1-4 alkyl, C _1-3 fluoroalkyl or C _3-6 cycloalkyl; And - L ⁷ - independently represents - CO- or -SO ₂ -; - L ⁸ -SO2-R ^S81 where RS ⁸¹ is independently -C1-6 alkyl; C ₁ -fluoroalkyl; hydroxy; -NR ^N81 R ^N82 where independently RN ⁸¹ is hydrogen or C1-4 alkyl and RN ⁸² is hydrogen, C1-4 alkyl, -CO-C _1-6 alkyl; And - L ⁸ - independently represents - C _1-6 alkylene-, -CO-C _1-6 alkylene-, -SO ₂ -C _1-6 alkylene-, -CO-O-C _2-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-; - L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, wherein said NO ¹ is independently unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from C1-4 alkyl; halogen; cyano; hydroxy; hydroxymethyl; -C0-2alkyleneSu ⁹¹ -COOR ^O91 where RO ⁹¹ is hydrogen or C1-4alkyl and where Cy ⁹¹ is a C3-6cycloalkylene group; or -C0-2alkylene-COOR ^O92 where RO ⁹² is hydrogen or C1-4alkyl; And - L ⁹ - independently represents - C _0-6 alkylene-, -CO-C _0-6 alkylene-, -SO ₂ -C _0-6 alkylene-, -CO-O-C _1-6 alkylene-, -CO-NH-C _1-6 alkylene- or -SO ₂ -NH-C _1-6 alkylene-; - L ¹⁰ -C _4-6 heterocyclyl, where C _4-6 heterocyclyl independently contains one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen; where in the above groups, said C _4-6 heterocyclyl is independently unsubstituted or mono-, di-, or tri-substituted, where the substituents are independently selected from one or two oxo substituents, each of which is attached to the ring carbon atom in the alpha position to the ring nitrogen atom; and/or - 109 040901 two methyl substituents attached to the ring carbon atom in the alpha position to the ring nitrogen atom or the ring oxygen atom; and/or two oxo substituents on the ring sulfur atom; and/or _C1 . ₄ alkyl, C ₁ . ₃ alkoxy-C ₂ . ₄ alkyl, C ₂ . ₃ fluoroalkyl or -CO-C ₁ . ₄ αlkulα attached to a ring nitrogen atom having a free valency; And - L ¹⁰ - independently represents - C ₀ .6alkylene- or -CO-C ₀ . ₆ alkylene-; - L ¹¹ -cyano; where -L ¹¹ - represents -CO-C ₁ . ₆ alkulen-, -SO ₂ -C ₁ . ₆ alkylene or -C ₀ . ₆ alkylene-; or - L ¹³ -C ₁ . ₄ alkyl; where -L ¹³ - represents -CO-, -CO-O or -SO2; or a pharmaceutically acceptable salt thereof. 10. The compound according to any one of claims 1 to 8, where the -LR ⁶ group is - L ¹ -COOH; Where - L ¹ - represents - C ₁ . ₆ alkylene-, -CO-C ₁ . ₆ alkylene-, -SO ₂ -C ₁ . ₆ alkylene-, -CO-O-C ₁ . ₆ αkylene-, -CO-NH-C ₁ . ₆ alkylene- or -SO ₂ -NH-Cl. ₆ alkulen-; - CO-Cl. ₆ alkylene-; where specified C ₁ . ₆ alkylene is monosubstituted with hydroxy; _-C0 . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-, -CO-C ₀ . ₄ αkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-, -SO ₂ -C ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene- or -CO-OC ₀ . ₄ alkylene-C ₃ . ₈ cycloalkylene-C ₀ . ₄ alkylene-; - CO-C ₀ . ₄ alkylene-Su ¹ -C0.4αkilen-; where Cy ¹ is independently C3. ₆ heterocycloalkyl containing one ring oxygen atom; - CO-C ₁ . ₄ alkylene-X ¹² -C1.4αalkylene-; where X ¹² is independently a nitrogen atom that is unsubstituted or monosubstituted by C1. ₄ alkyl; - CO-C ₂ . ₆ alkenylene- or -SO ₂ -C ₂ . ₆ alkenylene-; or - CO-C ₂ . ₆ fluoroalkylene-; - L ² -hydroxy; where -L ² - represents - C ₂ . ₆ alkylene-, where C ₂ . ₆ alkylene is unsubstituted or monosubstituted by hydroxy; or - CO-C ₁ . ₄ alkylene-X ²² -C2.4αalkylene-; where X ²² is a nitrogen atom that is independently unsubstituted or monosubstituted by C1. ₄ alkyl or C ₃ . ₆ cycloalkyl; - L ⁷ -NR ^N5 R ⁿ⁶ where RN ⁵ means hydrogen; RN ⁶ means hydrogen or C ₃ _ ₆ cycloalkyl; And - L ⁷ - independently represents - CO- or -SO ₂ -; - L9-HET ¹ where NO ¹ is a 5- or 6-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl; where the specified NO ¹ is independently unsubstituted or mono - or disubstituted, where the substituents are independently selected from C1.4αkyl; halogen; cyano; hydroxy; hydroxymethyl; -C0.2αkilen-Cy ⁹¹ -COOR ^O91 where R ^O91 is hydrogen or C1. ₄ alkyl and where Cy ⁹¹ represents a C3.6 cycloalkylene group; or -C0.2alkylene-COOR ^O92 where R ^O92 is hydrogen or C1. ₄ αlkyl; And - L ⁹ - independently represents _-C0 . ₆ alkylene-, -CO-C ₀ . ₆ αkylene-; or a pharmaceutically acceptable salt thereof. 11. The compound according to any one of claims 1-8, where the -LR ⁶ group is - L ¹ -COOH; And - L ¹ - represents - CH2-CH2-, -CH2-CH2-CH2-, -CH2-C(CH3)2-CH2-, *-CH2-CH2-C(CH3)2-, *-CH2-CH2-CH2-C(CH3 )2-, *-CO-CH2-CH2-, *-CO-CH(CH3)-CH2-, *-CO-CH2-C(OH)(CH3)-, *-CO-CH2-CH2-CH2- , *-CO-CH2-C(CH3)2-, *-CO-C(CH3)2-CH2-, *-SO2-CH2-, *-SO2-CH2-CH2-, *-SO2-CH2-CH2 -CH2-, *-SO2-CH2-C(CH3)2-, *-CO-O-CH2-, *-CO-O-CH(CH3)-, *-CO-O-CH2-C(CH3) 2-, *-CO-NH-C(CH3)2-CH2-, *-CO-NH-CH2-C(CH3)2-, *-CO-NH-CH ₂ -CH ₂ -C(CH ₃ ) ₂ -, *-SO ₂ -NH-CH ₂ -; *-Cn ₂ -Cn ₂ -CH ₂ -cyclopropane-1,1-diyl-, *-CO-cyclopropane1,2-diyl-, *-CO-CH ₂ -cyclopropane-1,1-diyl-, *-CO -CH ₂ -cyclobutane-1,1-diyl-, *-SO ₂ -cyclopropane-1,1diyl-CH ₂ -, *-CO-O-cyclopropane-1,1 -diyl-, *-CO-O-CH ₂ -cyclopropane-1,1-diyl-; *-CO-CH2-(tetrahydro-2H-pyran-4,4-diyl)-; * -CO-CH ₂ -N(n-butyl)-CH ₂ -; *-SO2-CH=CH-, *-CO-C(CH2)-CH2-; or *-CO-CF2-CH2-; - L ² -hydroxy; where -L ² - represents * -CH ₂ -CH(OH)-CH ₂ -; or * -CO-CH ₂ -NH-CH ₂ -CH ₂ -, * -CO-CH ₂ -NH-CH (CH ₃ ) -CH ₂ -, * -CO-CH ₂ -NH-CH ₂ -CH ( _CH3 )-; - L ⁷ -NH2; Where - L ⁷ - represents - SO2-; - L ⁹ -HET1, where -L ⁹ -HET1 represents - 110 040901 -L ⁷ -NH-cyclopropyl; Where -L ⁷ - represents -CO-; where, in the above groups, asterisks indicate a bond that is attached to the rest of the molecule; or a pharmaceutically acceptable salt thereof. 12. The compound of claim 1, wherein said compound is N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)pyrrolidine-3-carboxamide; 1-(2-aminoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-hydroxyethyl)-3-(2-isopropylphenyl)azetidine-3carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxypropyl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 1-cyano-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 1-(3-(1H-tetrazol-5-yl)propyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxy-3-methylbutyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 1-(2-aminopropyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)propanoic acid; 1-(2-cyanoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2,3-dihydroxypropyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2,3-dihydroxypropyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(oxetan-3-yl)azetidine-3-carboxamide; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)butanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)- 2,2-dimethylbutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)- 3,3-dimethylbutanoic acid; 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)-1H-pyrrole-2-carboxylic acid; 5-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)methyl)furan-2-carboxylic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(4-hydroxy-4-methylpentyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethylpentanoic acid; - 111 040901 1-(3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)propyl)cyclopropane-1-carboxylic acid; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(methylsulfonamido)ethyl)azetidine-3-carboxamide; (S)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-hydroxy-3-(2-hydroxyacetamido)propyl)-3(2-isopropylphenyl)azetidine-3-carboxamide ; 1-(cyanomethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 1-(2-(1H-tetrazol-5-yl)ethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 1-(4-cyanobutanoyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine3-carboxamide; 1-acetyl-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(3-sulfamoylpropanoyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(N-methylsulfamoyl)acetyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-((methylsulfonyl)glycyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(N-methyl-N-sulfamoylglycyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(5,5,5-trifluoro-4oxopentanoyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)-1-(5,5,5-trifluoro-4oxopentanoyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxyoxetan-3-yl)acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxyisoxazole-5-carbonyl)-3-(2isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-oxo-2,3-dihydroisoxazole-5-carbonyl)-3-(2isopropylphenyl)azetidine-3-carboxamide; 1-(2-(1H-tetrazol-1-yl)acetyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-4-carboxamide; 1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2isopropylphenyl)azetidine-3- carboxamide; 1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-4- carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1H-pyrazol-5-yl)acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1 -(2-(3-oxo-2,3-dihydro-1 H-pyrazol-5-yl)acetyl)-4(2- isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1 H-pyrazol-4-yl)acetyl)-3-(2isopropylphenyl)azetidine-3-carboxamide ; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetyl)-3(2-isopropylphenyl) )azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-hydroxy-1 H-pyrazol-4-yl)acetyl)-4-(2isopropylphenyl)piperidine-4-carboxamide ; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetyl)-4(2-isopropylphenyl )piperidine-4-carboxamide; 1-alanyl)-I-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)-1-((2-methoxyethyl)glycyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2-hydroxyethyl)glycyl)-4-(2-isopropylphenyl)piperidine-4-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((2-hydroxyethyl)glycyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-((2-methoxyethyl)glycyl)azetidine-3-carboxamide; (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((R)-(2-hydroxypropyl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide; - 112 040901 (S)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((S)-(2-hydroxypropyl)glycyl)-3-(2isopropylphenyl)azetidine-3-carboxamide ; (R)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((R)-(1-hydroxypropan-2-yl)glycyl)-3-(2isopropylphenyl)azetidine-3- carboxamide; (S)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-((R)-(1-hydroxypropan-2-yl)glycyl)-3-(2isopropylphenyl)azetidine-3- carboxamide; 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-3oxopropanoic acid; 3-(4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1-yl)3-oxopropanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-4oxobutanoic acid; 4-(4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1-yl)4-oxobutanoic acid; (S)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-methyl-4-oxobutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 1 - (2- (3 - ((2- (difluoromethoxy) -6-methylpyridin-3 -yl) carbamoyl) -3- (2-isopropylphenyl) azetidin-1 yl) -2-oxoethyl) cyclopropane-1-carboxylic acid ; 1 - (2- (3 - ((2- (difluoromethoxy) -6-methylpyridin-3 -yl) carbamoyl) -3- (2-isopropylphenyl) azetidin-1 yl) -2-oxoethyl) cyclobutane-1-carboxylic acid ; (R)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-3-methyl-4-oxobutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3,3-dimethyl-4-oxobutanoic acid; 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)but-3-enoic acid; (1 S,2R)-2-(3-((2-(difluoromethoxy)-6-methylpyridin-3 -yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1-carboxylic acid ; (1R,2S)-2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)cyclopropane-1-carboxylic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-5oxopentanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)3,3-difluoro-4-oxobutanoic acid; (S)-4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-hydroxy-2-methyl-4 -oxobutanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(5,5,5-trifluoro-4hydroxypentanoyl)azetidine-3-carboxamide; 4-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)tetrahydro-2H-pyran- 4-carboxylic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(sulfamoylglycyl)azetidine-3-carboxamide; 1-(N-acetyl-N-hydroxyglycyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)acetic acid; 2-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)sulfonyl)acetic acid; 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)propanoic acid; 3-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidin-1yl)sulfonyl)propanoic acid; 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)-2,2-dimethylpropanoic acid; 2-(1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)sulfonyl)cyclopropyl)acetic acid; 4-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)butanoic acid; (E)-3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)acrylic acid; - 113 040901 N-(2-(difluoromethoxy)-6-methyl-pyridin-3-yl)-1-((3-(hydroxyamino)-3-oxopropyl)sulfonyl)-3(2-isopropylphenyl)azetidine-3-carboxamide; 2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1 carbonyl)oxy)acetic acid; 2-((4-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-4-(2-isopropylphenyl)piperidine-1carbonyl)oxy)acetic acid; (R)-2-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)propanoic acid; 1-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carbonyl)oxy)cyclopropane-1-carboxylic acid; 3-((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1 carbonyl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1 carbonyl)oxy)methyl)cyclopropane-1-carboxylic acid; ((3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)sulfonyl)glycine; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(2-(difluoromethoxy)pyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(2,6-dimethoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-ethoxy-2-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(N-methylsulfamoyl)azetidine-3-carboxamide; 1-(N-cyclopropylsulfamoyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-(sulfamoylamino)ethyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-5-fluoropyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxamido)-3-methylbutanoic acid; N1-((1H-imidazol-4-yl)methyl)-N4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2isopropylphenyl)piperidine-1,4-carboxamide; 3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxamido)-2,2-dimethylpropanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1 carboxamido)-2,2-dimethylbutanoic acid; N4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-4-(2-isopropylphenyl)piperidine-1,4dicarboxamide; N4-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-N1-(2-hydroxyethyl)-4-(2isopropylphenyl)piperidine-1,4-dicarboxamide; 6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)nicotinic acid; 6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)picolinic acid; 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)pyrimidine-5-carboxylic acid; 6-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)pyridazine-3-carboxylic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)pyrazine-2-carboxylic acid; 1-(5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)pyrimidin-2-yl)cyclopropan-1-carboxylic acid ; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(4-fluoropyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-fluoropyridin-4-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-fluoropyrimidin-4-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)pyridin-3-yl)-1-(5-fluoropyrimidin-4-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 1-(5-cyanopyridin-2-yl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azeti- 114 040901 din-3-carboxamide; 1-(5-cyanopyridin-2-yl)-M-(2-(difluoromethoxy)pyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 1-(5-cyanopyrimidin-2-yl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; 1-(5-cyanopyrimidin-2-yl)-N-(2-(difluoromethoxy)pyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3carboxamide; 2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)oxazole-4-carboxylic acid; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-fluoropyrimidin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(2-methylpyrimidin-4yl)azetidine-3-carboxamide; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-oxo-4,5-dihydrooxazol2-yl)azetidine-3-carboxamide; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(4-hydroxyoxazol-2yl)azetidine-3-carboxamide; Na(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-hydroxy-1,2,4-oxadiazol-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; No(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-(5-oxo-4,5-dihydro-1,2,4oxadiazol-3-yl)azetidine- 3-carboxamide; 3-(2-cyclopentylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3-carboxamide; 3-(2-cyclohexylphenyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)azetidine-3-carboxamide; 4-(3-(2-cyclobutylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 4-(3-(2-cyclopentylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-(2-cyclohexylphenyl)-3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-propylphenyl)azetidin-1-yl)-2,2dimethyl-4-oxobutanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-fluoro-6-isopropylphenyl)azetidine-3-carboxamide; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropyl-5-methylphenyl)azetidin-1-yl)-2,2-dimethyl-4- oxobutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-fluoro-6-isopropylphenyl)azetidin1-yl)-2,2-dimethyl-4-oxobutanoic acid ; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(5-fluoro-2-isopropylphenyl)azetidin1-yl)-2,2-dimethyl-4-oxobutanoic acid ; N-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)-N-propylglycine; methyl N-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2-oxoethyl)-N-( 2-methoxyethyl)glycinate; N-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)-N-(2- methoxyethyl)glycine; methyl (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin1-yl)-2-oxoethyl)glycinate; (2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2-oxoethyl)glycine; N-(2-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1 yl)-2-oxoethyl)-N-ethylglycine; 3-(2-isopropylphenyl)-N-(6-methyl-2-p-ropoxypyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)azetidine-3-carboxamide; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(3-isopropylpyridin-2-yl)azetidin1-yl)-4-oxobutanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)-1-sulfamoylazetidine3-carboxamide; N1-cyclopropyl-N3-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-2-yl)azetidine-1,3-dicarboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(5-fluoro-2-methylnirimidin-4-yl)-3-(3-isopropylpyridin2-yl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-fluoro-6-methylpyridin-2-yl)-3-(3-isopropylpyridin-2-yl)azetidine-3-carboxamide ; - 115 040901 N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(3-isopropylpyridin-4-yl)azetidine-3-carboxamide; N-(2-(difluoromethoxu)-6-methylnurudin-3-yl)-3-(3-uzonronylnurudin-4-yl)-1-sulfamoylazetudine3-carboxamide; N-(2-(difluoromethoxy)-6-methylnurudin-3-yl)-3-(3-isopropylpyrazin-2-yl)azetidine-3-carboxamide; N-(2-(difluoromethoxy)-6-methylnurudin-3-yl)-3-(3-isopropylpyrazin-2-yl)-1-sulfamoylazetidine3-carboxamide; N-(5-chloro-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(5-bromo-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(3,5-dimethoxypyridin-2-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2-cyclopentylphenyl)azetidine-3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(3-isopropylpyridin-2-yl)azetidine-3-carboxamide; methyl 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethylbutanoate; 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethylbutanoic acid; 4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethylbutanoic acid; methyl 4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2,2-dimethyl-4-oxobutanoate; 4-(3-((5-bromo-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 4-(3-((5-chloro-3-(difluoromethoxy)pyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 4-(3-((5-chloro-3-methoxypyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2dimethyl-4-oxobutanoic acid; 4-(3-((5-bromo-3-methoxypyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)-2,2dimethyl-4-oxobutanoic acid; 4-(3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; 1-(2-(3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)-2-oxoethyl)cyclobutane-1-carboxylic acid; benzyl 3-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoate; 3-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1yl)sulfonyl)propanoic acid; N-(5-chloro-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(5-bromo-3-methoxypyridin-2-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3carboxamide; N-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3carboxamide; N-(3,5-dimethoxypyridin-2-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(2-cyclopentylphenyl)-1-sulfamoylazetidine-3carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-3-(3-isopropylpyridin-2-yl)-1-sulfamoylazetidine3-carboxamide; N-(5-chloro-3-(difluoromethoxy)pyridin-2-yl)-M1-cyclopropyl-3-(2-isopropylphenyl)azetidine-1,3dicarboxamide; N-(5-bromo-3-(difluoromethoxy)pyridin-2-yl)-M1-cyclopropyl-3-(2-isopropylphenyl)azetidine-1,3dicarboxamide; 2-methoxy-2-oxoethyl 3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1-carboxylate; 2-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)acetic acid; 1-((3-((3-(difluoromethoxy)-5-methylpyridin-2-yl)carbamoyl)-3-(2-isopropylphenyl)azetidine-1carbonyl)oxy)cyclopropane-1-carboxylic acid; or N-(3-(difluoromethoxy)-5-methylpyridin-2-yl)-3-(2-isopropylphenyl)-1-(4-oxo-4,5-dihydrooxazol2-yl)azetidine-3-carboxamide; or a pharmaceutically acceptable salt thereof. - 116 040901 13. A compound according to claim 1, wherein said compound is: 4-(3-((2-(difluoromethoxy)-6methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)- 2,2-dimethylbutanoic acid; or 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)2,2-dimethyl-4-oxobutanoic acid; or a pharmaceutically acceptable salt thereof. 14. Pharmaceutical composition acting as an antagonist of the LPARj receptor; said composition contains a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 15. The use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as a drug which is an LPARj receptor antagonist. 16. The use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the prevention or treatment of fibrosis, dermatological disorders, pain, malignant, benign proliferative diseases, respiratory diseases, nervous system disorders, cardiovascular diseases, inflammatory disorders , obesity or insulin resistance. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 117 -