EA043110B1 - PHENYLPYRROLIDINONE FORMYL PEPTIDE RECEPTOR 2 AGONISTS - Google Patents

Description

Cross-reference to related applications

The application for this patent claims priority under section 35 of the Code of Laws

U.S. §119(e) per U.S. Provisional Application 62/638,556 filed March 5, 2018, the contents of which are incorporated herein in its entirety.

Prerequisites for the creation of the invention

The present invention relates to new pyrrolidinone compounds that are formyl peptide receptor 2 (FPR2) agonists and/or formyl peptide receptor 1 (FPR1) agonists, compositions containing them, and methods of their use, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive disease lung (COPD) and related diseases.

The formyl peptide receptor 2 (FPR2) belongs to a small group of G protein-coupled receptors with seven transmembrane domains that are expressed in many human tissues, including immune cells, and are known to play an important role in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (Journal of Autoimmunity 85, 2017, 64-77). Collectively, these receptors bind a range of structurally diverse agonists, including N-formyl and non-formyl peptides, which act as chemoattractants and activate phagocytes. The endogenous peptide Annexin A1 and its N-terminal fragments are examples of ligands that bind human FPR1 and FPR2. Fatty acids such as the eicosanoid, lipoxin A4, which belongs to the class of small propermissive lipid mediators (SPMs), has also been identified as an FPR2 agonist (Ye RD., et al., Pharmacol. Rev., 2009, 61, 119-61 ).

Endogenous propermissive FPR2 ligands such as lipoxin A4 and annexin A1 have been reported to trigger a wide range of cytoplasmic cascades such as Gi-binding, Ca ²⁺ mobilization, and β-arrestin recruitment. (Int J Mol Sci. 2013 April; 14(4): 7193-7230). FPR2 regulates the innate and adaptive immune systems, including neutrophils, macrophages, T and B cells. In neutrophils, FPR2 ligands modulate movement, cytotoxicity, and lifespan. In macrophages, FPR2 agonism prevents apoptosis and enhances efferocytosis (Chandrasekharan JA, Sharma-Walia N., J. Inflamm. Res., 2015, 8, 181-92). Initiation of inflammation resolution through FPR2 agonism is responsible for enhancing anti-fibrotic wound healing and returning damaged tissue to homeostasis (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63).

Chronic inflammation is part of the pathogenesis pathway of many human diseases, and stimulation of resolution pathways by FPR2 agonists can have both protective and reparative effects. Ischemia-reperfusion injury (I/R) is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Unproductive wound healing associated with cardiomyocyte death and pathological remodeling as a result of ischemia-reperfusion injury leads to scarring, fibrosis, and progressive loss of cardiac function. FPR2 modulation has been proposed to improve myocardial wound healing after injury and reduce adverse myocardial remodeling (Kain V., et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 proclearance agonists in the central nervous system may be useful therapeutic agents for the treatment of various clinical I/R conditions, including cerebral stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and induced I /R spinal cord injury (Liu ZQ., et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

In addition to the beneficial effects of targeting the FPR2 receptor with novel resolution-enhancing agonists for the therapeutic treatment of I/R-induced injury, the benefits of these ligands could also be applied to other diseases. In the cardiovascular system, the FPR2 receptor and its resolution-promoting agonists have been found to be responsible for the stabilization and healing of atherogenic plaques (Petri MH., et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G ., et al., Sci. Trans. Med., 2015, 7(275);275ra20). Also, FPR2 agonists have been shown to be useful in preclinical models of human chronic inflammatory diseases, including: infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic/diabetic diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, kidney fibrosis and organ transplantation (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49- 63, Perrett, M., et al., Trends in Pharm. Sci., 2015, 36, 737-755).

Brief description of the invention

The present invention provides a novel pyrrolidinone and analogues thereof which are useful as FPR2 agonists, including stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof.

The present invention also provides methods and intermediates for preparing the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention.

- 1 043110 or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

The compounds of the invention can be used in therapy.

The compounds of the present invention can be used to treat and/or prevent a variety of diseases or disorders associated with FPR2, such as inflammatory diseases, cardiovascular diseases, chronic respiratory diseases, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, nervous disorders, pain, prion diseases, amyloidosis, and immune disorders. Cardiovascular diseases are selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary disease, iatrogenic cardiac injury and heart failure, including, but not limited to, acute heart failure, ischemic and non-ischemic chronic heart failure, systolic heart failure , diastolic heart failure, heart failure with reduced ejection fraction (HFREF), and heart failure with preserved ejection fraction (HF _P EF).

The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

Other features and advantages of the invention will be apparent from the following detailed description and claims.

Description of the invention

The invention covers compounds of formula (III) that are formyl peptide receptor 2 (FPR2) agonists and/or formyl peptide receptor 1 (FPR1) agonists, compositions containing them and methods for their use, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease ( COPD) and related diseases.

One aspect of the invention is a compound of formula (III)

or a pharmaceutically acceptable salt thereof, wherein

Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , or 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1 R ^1a and 1-2 R ^1b ;

Ar ³ is phenyl substituted with 1-3 R ^3a , or 5-6 membered heteroaryl with 1-3 nitrogen atoms and substituted with 1-3 R ^3a ;

R ^1a is hydrogen or halo;

R ^1b is halo, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

R ^2a is hydrogen, halo, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

R ^3a is cyano, halo, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxyalkyl, C1-4 haloalkyl, (R ¹ R ² N)C1-4 alkyl, R1R2N, C _1-4 alkyl-C(O)(R ² )NC _1-4 alkyl, (C _1-4 alkyl) ₂ (O) P, (C _1-4 alkoxy) ₂ (O) P, (C _1-4 alkoxy) (C _1-4 alkyl) (O) P, C _1-4 alkyl-SO ₂ or C _1-4 alkyl-SO ₂ NH;

R ¹ is hydrogen or C _1-4 alkyl;

R ² is hydrogen or C _1-4 alkyl; or R1R2N taken together are oxazolyl or pyrrolidinyl and are substituted with 0-3 substituents selected from halo, alkyl and oxo;

R ^4a or R ^4b is independently hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxy O1-4alkyl, C1-4haloalkoxy, or C1-4hydroxyalkyl; alternatively, R ^4a and R ^4b together with the carbon atom to which they are both attached form C3-6 cycloalkyl; And

R ^5a or R ^5b independently represents hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 hydroxylalkyl, C _1-4 haloalkoxy, or C _1-4 alkoxyalkyl.

Another aspect of the invention is a compound (III) or a pharmaceutically acceptable salt thereof, wherein

Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; And

Ar ³ is phenyl substituted with 1-3 R ^3a , pyrazolyl substituted with 1-3 R ^3a , pyridinyl substituted with 1-3 R ^3a , or pyrimidinyl substituted with 1-3 R ^3a .

Another aspect of the invention is a compound of formula (IV)

- 2 043110

HN-Ar ¹ k7 V ° ^r2 ?JL

TI

R2 ^; *Y^ (^+(^)1-2 (IV) or a pharmaceutically acceptable salt thereof, where

Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ;

R ^1a is hydrogen or halo;

R ^1b is halo, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy;

R ^2a is hydrogen, halo, C ₁ . ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy;

R ^3a is cyano, halo, C ₁ . ₃ alkyl, C ₁ . ₃ hydroxyalkyl, C ₁ . ₃ alkoxyalkyl, C ₁ . ₃ haloalkyl, R1R2N, (C ₁ . ₃ alkyl) ₂ (O) P, (C ₁ . ₃ alkoxy) ₂ (O) P, (C ₁ . ₃ alkoxy) (C ₁ . ₃ alkyl) (O) P, From ₁ . ₃ alkylSO2 or C ₁ . ₃ alkyl-SO ₂ NH;

R ^4a or R ^4b is independently hydrogen, C1.3alkyl or C1.3hydroxyalkyl; alternatively, R ^4a and R ^4b , together with the carbon atom to which they are both attached, form C3. ₆ cycloalkyl; And

R ^5a or R ^5b is independently hydrogen, C ₁ . ₃ alkyl, C ₁ . ₃ hydroxylalkyl or C ₁ . ₃ alkoxyalkyl.

Another aspect of the invention is a compound of formula (V)

or a pharmaceutically acceptable salt thereof, wherein

R ^1a is hydrogen or F;

R ^1b is halo, C ₁ . ₂ haloalkyl or C ₁ . ₂ alkoxy;

R ^2a is hydrogen, halo, C ₁ . ₃ alkyl, C ₁ . ₃ haloalkyl or C ₃ . ₆ cycloalkyl;

R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ . ₂ alkoxy)(C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH; And

R ^3a is halo.

Another aspect of the invention is a compound of formula (V), or a pharmaceutically acceptable salt thereof, wherein

R ^1a is hydrogen or F;

R ^1b is F, Cl or CF3;

R ^2a is hydrogen, F, Cl, isopropyl, CF ₃ or cyclopropyl;

R ^3a is (CH ₃ )2(O)P, (CH3CHMOJ (CH3CH2O)(CH3)(O)P, CH3SO2 or CH3SO2NH; and

R ^3a is F.

Another aspect of the invention is a compound of formula (VI)

- 3 043110

or a pharmaceutically acceptable salt thereof, wherein

R ^1a is hydrogen or halo;

R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy;

R ^2a is hydrogen, halo, C _1-3 alkyl or C _3-6 cycloalkyl;

R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P, C ₁ _ ₂ alkylSO2 or C _1-2 alkyl-SO ₂ NH.

Another aspect of the invention is a compound of formula (VII)

or a pharmaceutically acceptable salt thereof, wherein

Ar ³ is pyrazolyl substituted with 1-3 R ^3a , pyridinyl substituted with 1-3 R ^3a , or pyrimidinyl substituted with 1-3 R ^3a ;

R ^1a is hydrogen or halo;

R ^1b is halo, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

R ^2a is hydrogen, halo, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

R ^3a is cyano, halo, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxyalkyl, (R ¹ R ² N)C1-4 alkyl, R1R2N-, (C _1-4 alkyl) ₂ (O)P, (C _{1 -4} alkoxy) ₂ (O) P, (C _1-4 alkoxy) (C _1-4 alkyl) (O) P, C ₁ _ ₄ alkylSO 2 or C _1-4 alkyl-SO ₂ NH;

R ¹ is hydrogen or alkyl;

R ² is hydrogen or alkyl; or R ¹ R ² N taken together is oxazolyl or pyrrolidinyl and is substituted with 0-3 substituents selected from halo, alkyl or oxo;

R ^4a or R ^4b is independently hydrogen, C1-4alkyl, C1-4alkoxy, C1-4alkoxyalkyl or C1-4haloalkoxy; R ^4a and R ^4b , together with the carbon atom to which they are both attached, form C3-6 cycloalkyl; And

R ^5a or R ^5b is independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxyalkyl, or C _1-4 haloalkoxy.

Another aspect of the invention is a compound of formula (VIII)

or a pharmaceutically acceptable salt thereof, wherein

- 4 043110

R ^1a is hydrogen or halo;

R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy;

R ^2a is hydrogen, halo, C _1-3 αkyl or C _3-6 cycloalkyl;

R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P, C _1-2 alkylSO2 or C _1-2 alkyl-SO ₂ NH; And

R ^5a or R ^5b is independently hydrogen or C _1-2 alkyl.

Another aspect of the invention is a compound of formula (IX)

or a pharmaceutically acceptable salt thereof, wherein

R ^1a is hydrogen or halo;

R ^1b is halo, C _1-2 haloalkyl or C _1-2 αlkoxy;

R ^2a is hydrogen, halo, C _1-2 haloalkyl, C _1-3 alkyl or C _3-6 cycloalkyl;

i^,R ^{3a R3a}

Qi Cn

Ar ³ represents ^ ^{0-1 or} (

R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 αlkoxy)(C _1-2 αlkyl)(O)P or C _1-2 alkyl-SO ₂ NH;

R ^3a is halo;

R ^4a or R ^4b independently represents hydrogen, C _1-2 alkyl or C _1-2 hydroxyalkyl; or

R ^4a and R ^4b together with the carbon atom to which they are both attached form C _3-6 cycloalkyl; And

R ^5a or R ^5b is independently hydrogen, C _1-2 alkyl or C _1-2 hydroxyalkyl or C _1-2 α alkoxyalkyl.

Another aspect of the invention is a compound of formula (III), (IV), (VII) or (IX), or a pharmaceutically acceptable salt thereof, wherein

R ^4a is hydrogen;

R ^4b is hydrogen;

R ^5a is C _1-2 alkyl, C _1-2 hydroxyalkyl or C _1-2 alkoxyalkyl; And

R ^5b is hydrogen.

Another aspect of the invention is a compound of formula (III), (IV), (VII) or (IX), or a pharmaceutically acceptable salt thereof, wherein

R ^4a is C _1-2 alkyl;

R ^4b is C _1-2 αkyl; or

R ^4a and R ^4b are taken together to form cyclopropyl;

R ^5a is hydrogen; And

R ^5b is hydrogen.

Another aspect of the invention is a compound selected from the group consisting of

- 5 043110

- 6 043110

For a compound of formula (III), (IV), (V), (VI), (VII), (VIII) or (IX), the scope of any occurrence of a variable substituent including Ar ¹ , Ar ² , Ar ³ , R ^1a , R ^1b , R ^2a , R ^3a , R ^4a , R ^4b , R ^5a , R ^5b , R ¹ , R ² may be used independently with the scope of any other variable substituent occurrence. Thus, the invention includes combinations of various aspects.

In one non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a , R ^4b , R ^5a , R ^5b are all hydrogen; Ar ¹ is phenyl, pyridinyl or pyrazinyl, each of which is substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII)

- 7 043110 or (IX) all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ _ ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ αkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ αlkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ αkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ . ₂ alkoxy)(C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C12 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ _ ₆ cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ _ ₂ alkyl) ₂ (O) P, (C ₁ _ ₂ alkoxy) ₂ (O) P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C1 ₂ alkyl-SO ₂ or C1.2 alkyl-SO2NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ β-cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ _ ₂ alkyl) ₂ (O) P, (C ₁ _ ₂ alkoxy) ₂ (O) P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ β-cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ _ ₆ cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ _ ₂ alkyl) ₂ (O) P, (C ₁ _ ₂ alkoxy) ₂ (O) P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C ₃ β-cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ _ ₂ alkyl) ₂ (O) P, (C ₁ _ ₂ alkoxy) ₂ (O) P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)R,

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C _1-2 alkyl-SO ₂ or C _1-2 alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy)(C ₁ _ ₂ alkyl) (O)P, C _1-2 alkyl-SO ₂ or C _1-2 alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ _ ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), all R ^4a , R ^4b , R ^5a , R ^5b are hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In one non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; or R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is phenyl, pyridinyl or pyrazinyl, each of which is substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1_2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkylSO2NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; or R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1_2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkylSO2NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1_2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl,

- 9 043110

_C1 . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _3- bCycloalkyl, C _1-4 alkoxy or C _1-4 haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl) (O)P, C _1-2 alkyl-SO ₂ or C _1-2 alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4αkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _{1 .2} alkyl) ₂ (O)P, (C _{1 .2} αlkoxy) ₂ (O)P, (C _{1 .2} alkoxy)(C _{1 .2} alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or Cl. ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ αkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ . ₂ alkoxy)(C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ αlkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ αlkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy)(C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl,

- 10 043110 alkoxyalkyl, (C _1-2 alkyl) 2 (O) P, (C _1-2 alkoxy) ₂ (O) P, (C _1-2 alkoxy) (C _1-2 alkyl) (O) P, C _1-2 alkyl-SO ₂ or

C _1-2 alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4αalkyl, _{C1-4hydroxyalkyl} , _{C1-4haloalkyl} , _{C3.6cycloalkyl} , _C1-4αlkoxy , or _{C1-4haloalkoxy} ; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ αkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ . ₂ alkoxy)(C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ αlkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment for a compound of formula (III), (IV), (VII) or (IX), R ^4a is methyl, R ^4b is methyl; R ^4a is hydrogen, R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a and R ^5b are all hydrogen; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, C ₁ . ₂ αlkoxy) ₂ (О)Р, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (О)Р, C ₁ . ₂ αlkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In one non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is phenyl, pyridinyl or pyrazinyl, each of which is substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1_2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ αkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy)(C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ _ ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2αlkOkcu; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ αlkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy)(C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2αlkOkcu; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ _ ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2α alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ αlkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ αlkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is phenyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with 14 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _{1 .2} alkyl) ₂ (O)P, (C _{1 .2} αlkoxy) ₂ (O)P, (C _{1 .2} alkoxy)(C _{1 .2} alkyl) (O)P, C1.2alkyl-SO2 or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C ₁ . ₂ haloalkyl or

- 11 043110

C _1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _{3 .6} cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy;

Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl) (O)P, C _1-2 alkyl-SO ₂ or

C _1-2 alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyridinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₄ alkoxy or C ₁ _ ₄ haloalkoxy; Ar ³ is phenyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyrazolyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O)P, (C ₁ . ₂ alkoxy) ₂ (O)P, (C ₁ _ ₂ alkoxy) (C ₁ _ ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C1.2 haloalkyl or C1.2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1. ₄ alkyl, C ₁ . ₄ hydroxyalkyl, C ₁ . ₄ haloalkyl, C _{3 .6} cycloalkyl, C ₁ . ₄ alkoxy or C ₁ . ₄ haloalkoxy; Ar ³ is pyridinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C ₁ . ₂ alkyl) ₂ (O) P, (C ₁ . ₂ alkoxy) ₂ (O) P, (C ₁ . ₂ alkoxy) (C ₁ . ₂ alkyl) (O)P, C ₁ . ₂ alkyl-SO ₂ or C ₁ . ₂ alkyl-SO ₂ NH.

In another non-limiting embodiment, for a compound of formula (III), (IV), (VII) or (IX), R ^4a and R ^4b are all hydrogen; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; Ar ¹ is pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; ^R1a

- 12 043110 is hydrogen or halo; R ^1b is halo, C1-2 haloalkyl or C1-2 alkoxy; Ar ² is phenyl substituted with 1-4 R ^2a ; R ^2a is hydrogen, halo, C1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; Ar ³ is pyrimidinyl substituted with 1-4 R ^3a ; R ^3a is halo, hydroxyalkyl, alkoxyalkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy) (C _1-2 alkyl) (O)P, C _1-2 alkyl-SO ₂ or C _1-2 alkyl-SO ₂ NH.

In one preferred embodiment for a compound of formula (III), (IV) or (VII) or (IX), R ^4a is methyl; R ^4b is methyl; R ^4a is hydrogen; R ^4b is hydroxymethyl; or R ^4a and R ^4b taken together form cyclopropyl; R ^5a is hydrogen, R ^5b is methyl or hydroxymethyl; R ^5a is hydrogen; R ^5b is hydrogen; or R ^4a , R ^4b , R ^5a , R ^5b are all hydrogen; Ar ¹ is phenyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or F; R ^1b is F, Cl or CF3; Ar ² is phenyl substituted with 1-2 R ^2a ; R ^2a is hydrogen, F, Cl, isopropyl, CF3 CF ₃ , cyclopropyl; Ar ³ is phenyl or pyridinyl, each of which is substituted with 1-2 R ^3a ; R ^3a is F, (CH ₃ ) ₂ (O)P, (CH ₃ CH ₂ ) ₂ (O)P, (CH ₃ CH ₂ O)(CH ₃ )(O)P, CH ₃ SO ₂ or CH3SO2NH .

Unless otherwise indicated, these terms are used with the following meanings. Alkyl means a straight or branched alkyl group of 1-6 carbon atoms. Alkenyl means a straight or branched alkyl group of 2-6 carbon atoms with at least one double bond. Alkynyl means a straight or branched alkyl group of 2-6 carbon atoms with at least one triple bond. Cycloalkyl means a monocyclic ring system consisting of 3-7 carbon atoms. Terms with a hydrocarbon group (eg, alkoxy) include straight and branched isomers of the hydrocarbon moiety. Halogen includes fluorine, chlorine, bromine and iodine.

Haloalkyl and haloalkoxy include all halogenated isomers from monohalo to perhalo. Aryl means monocyclic or bicyclic aromatic hydrocarbon groups containing 6-12 carbon atoms, or a bicyclic fused ring system in which one or both rings are aromatic. Bicyclic fused ring systems consist of a phenyl group fused to a four to seven membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. Heteroaryl means a 5-7 membered monocyclic or 8-11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur. If the attachment point of the bond is not specified, the bond may be attached at any suitable location as understood by those skilled in the art. Combinations of substituents and attachment schemes are only those that result in the formation of stable compounds as understood by those of skill in the art. The terms enclosed in parentheses and in multiple parentheses are intended to clearly indicate the ratio of links for specialists in this field of technology. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with an R substituent.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are salts in which the counterions do not significantly affect the physiological activity or toxicity of the compounds and as such act as pharmacological equivalents. These salts can be prepared according to procedures well known in organic chemistry using commercially available reagents. Some anionic salt forms include acetate, acistrat, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. . Some forms of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms, including the structure below with the indicated carbon. The invention includes all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for obtaining and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotating isomers.

The invention is intended to include all isotopes of atoms found in compounds. Isotopes include atoms having the same atomic number but different mass numbers. As a general example, and without limitation, isotopes of hydrogen include deuterium and tritium. Carbon isotopes include ¹³ C and ¹⁴ C. Isotopically labeled compounds of the invention can generally be prepared by standard methods known to those skilled in the art, or by methods analogous to the methods described herein, using the appropriate isotopically labeled reagent instead of the unlabeled reagent. used in other cases. Such connections may be

- 13 043110 many potential applications, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds can advantageously alter biological, pharmacological or pharmacokinetic properties.

biological methods.

N-formyl peptide receptors (FPRs) are a family of chemoattractant receptors that promote leukocyte response during inflammation. FPRs belong to the seven transmembrane G protein-coupled receptor superfamily and are associated with inhibitory G proteins (Gi). Three members of the family (FPR1, FPR2, and FPR3) have been identified in humans and are predominantly found in myeloid cells with a variable distribution, and reportedly in many organs and tissues. Following agonist binding, FPRs activate a variety of physiological pathways such as intracellular signal transduction, Ca ²⁺ mobilization, and transcription. The family interacts with a diverse set of ligands that include proteins, polypeptides, and fatty acid metabolites that activate both pro-inflammatory and resolution-promoting downstream responses. Cyclic adenosine monophosphate (cAMP) FPR2 and FPR1 assays were used to measure the activity of the compounds in this patent.

Cyclic adenosine monophosphate (cAMP) FPR2 and FPR1 assays. A mixture of forskolin (final concentration 5 μM for FPR2 or final concentration 10 μM for FPR1) and IBMX (final concentration 200 μM) were added to 384-well Proxiplates (Perkin-Elmer) pre-loaded with test compounds in DMSO (final concentration 1%), at final concentrations ranging from 0.020 nM to 100 μM. Chinese hamster ovary (CHO) cells overexpressing human FPR1 or FPR2 receptors were cultured in F-12 medium (Ham) supplemented with 10% Qualified FBS, 250 μg/ml Zeocin and 300 μg/ml hygromycin (Life Technologies). Reactions were initiated by adding 2000 human FPR2 cells/well or 4000 human FPR1 cells/well in Dulbecco's PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixtures were incubated for 30 min at room temperature. Intracellular cAMP levels were determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate-conjugated anti-cAMP and cAMP labeled with fluorophore d2 were prepared separately in the supplied lysis buffer. After completion of the reaction, the cells were lysed with an equal volume of d2-cAMP solution and anti-cAMP solution. After incubation for 1 hour at room temperature, time-resolved fluorescence intensity was measured with Envision (Perkin-Elmer) at 400 nm excitation length and dual emission at 590 nm and 665 nm. A calibration curve was built using an external cAMP standard in the concentration range from 1 μM to 0.1 pM by plotting the ratio of fluorescence intensity at an emission wavelength of 665 nm to that at an emission wavelength of 590 nm on cAMP concentrations. The efficacy and activity of the compound in inhibiting cAMP production was then determined by fitting a 4-parameter logistic equation from a plot of cAMP level versus compound concentrations.

The compounds of the examples below were tested in the FPR2 and FPR1 cAMP assay described above and found to have FPR2 and/or FPR1 agonistic activity. In table. 1 below shows the EC ₅₀ values obtained from the FPR2 and FPR1 cAMP assays measured for the compounds of the following examples.

- 14 043110

Table 1

Example hFPR2 cAMP2 EC50 (µM) hFPRl cAMP EC50 (µM) 1 0.00043 0.20 2 0.0042 0.36 3 0.0011 0.22 4 0.00093 1.7 5 0.00068 0.23 6 0.0010 0.19 7 0.0021 0.14 8 0.0020 0.061 9 0.0021 0.031 10 0.0022 0.13 AND 0.0026 0.29 12 0.0025 0.45 13 0.0065 2.5 14 0.0072 0.60 15 0.010 1.5 16 0.012 0.12 17 0.016 4.1 18 0.020 2.1 19 0.022 0.078 20 0.024 >10 21 0.031 0.39 22 0.033 1.5 23 0.0082 0.70 24 0.022 1.4 25 0.00053 0.26 26 0.00055 0.047 27 0.00050 0.11 28 0.0098 0.55 29 0.0070 0.19 thirty 0.00022 0.083 31 0.0040 0.43 32 0.00091 0.25 33 0.0011 0.47 34 0.0041 0.026 35 0.0086 0.052 36 0.0047 0.069 37 0.00140 0.17 38 0.0035 0.042 39 0.00058 0.057 40 0.0046 0.050 41 0.0036 0.50 42 0.0010 0.22 43 0.0033 0.12 44 0.043 0.45 45 0.0030 0.14 46 0.0048 0.093 47 0.0028 0.064 48 0.0037 0.11 49 0.0056 3.4 50 0.014 0.64 51 0.0082 1.3 52 0.010 1.1 53 0.0078 2.7 54 0.0055 0.90

- 15 043110

55 0.022 >10 56 0.0075 7.7 57 0.00095 1.0 58 0.0063 0.61 59 0.0017 0.14 60 0.0037 0.12 61 0.023 0.37 62 0.031 0.72 63 0.00567 4.4 64 0.0088 2.9 65 0.0012 2.6 66 0.0049 0.58 67 0.00248 1.3 68 0.00053 0.15 69 0.022 5.0 70 0.000077 0.020 71 0.0021 1.28 72 0.00061 0.054 73 0.00089 0.17 74 0.0022 0.14 75 0.0034 1.18 76 0.0041 2.1 77 0.0012 0.079 78 0.0012 0.045 79 0.039 >10 80 0.0014 0.086 81 0.00052 0.027 82 0.0025 0.78 83 0.00041 0.00099 84 0.0060 0.28 85 0.00062 0.0051 86 0.00085 0.021 87 0.0016 0.0012 88 0.0053 0.0049 89 0.0044 0.025 90 0.0051 1.4 91 0.0057 0.20 92 0.0083 0.22 93 0.012 0.78 94 0.0018 0.012 95 0.032 0.20 96 0.0029 0.075 97 0.0072 0.11 98 0.0029 0.27 99 0.00079 0.24 100 0.0020 0.092 101 0.00066 0.0011 102 0.0017 0.57 103 0.00057 0.35 104 0.0052 0.049

- 16 043110

105 0.0069 0.071 106 0.0031 0.0035 107 0.011 0.0058 108 0.0014 0.053 109 0.00044 0.39 BY 0.0011 0.64 111 0.030 0.54 112 0.00027 0.39 FROM 0.00039 0.59 114 0.00086 0.27 115 0.0012 0.055 116 0.00121 0.89 117 0.013 0.084 118 0.017 0.32 119 0.014 0.19 120 0.00078 0.16 121 0.00030 0.0050 122 0.00081 0.61 123 0.0015 0.24 124 0.00079 0.76 125 0.00099 0.18 126 0.012 >10 127 0.018 0.92 128 0.0010 0.024 129 0.0024 0.019 130 0.0057 3.0 131 0.0012 0.061 132 0.00048 0.028 133 0.15 >5 134 0.0025 1500 135 0.0029 720

Pharmaceutical compositions and methods of use.

The compounds of the present invention can be administered to mammals, preferably humans, for the treatment of various conditions and disorders associated with the FPR2 receptor, such as Behçet's disease, Sweet's disease, systemic lupus erythematosus (SLE), Wegener's granulomatosis, viral infection, diabetes, amputations, cancer, bacterial infection, external physical damage, physical disorders including radiation, vasoconstriction, anaphylactic reactions, allergic reactions, rhinitis, shocks (endotoxic, hemorrhagic, traumatic, visceral ischemia and circulatory shock), rheumatoid arthritis, gout, psoriasis, benign prostatic hyperplasia , myocardial ischemia, myocardial infarction, heart failure, brain injury, pulmonary disease, COPD, COAD, COLD, acute lung injury, acute respiratory distress syndrome, chronic bronchitis, pulmonary emphysema, asthma (allergic asthma and non-allergic asthma), cystic fibrosis, fibrosis kidney disease, nephropathy, renal glomerular disease, ulcerative colitis, IBD, Crohn's disease, periodontitis, pain, Alzheimer's disease, AIDS, uveal glaucoma, conjunctivitis, Sjögren's syndrome, rhinitis, atherosclerosis, neuroinflammatory diseases including multiple sclerosis, stroke, sepsis, etc. P.

Unless otherwise indicated, the following terms have the meanings given. The term subject refers to any human or other mammalian species that would potentially benefit from treatment with an FPR2 and/or FPR1 agonist, as understood by those of skill in the art. Some subjects include a person of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, body weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity, arthemia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term patient means a person suitable for therapy, as defined by practitioners in the art. The administration of treatment or treatment encompasses the treatment of a patient or subject as understood by those of skill in the art. Warn or prevention encompasses the preventive treatment (ie, prevention and/or risk reduction) of a subclinical disease state in a patient or subject, aimed at reducing the likelihood of occurrence of a clinical disease state, as understood by practitioners in this field. Patients are selected for preventive therapy based on factors known to increase the risk of a clinical disease state compared to the general population. A therapeutically effective amount means an amount of a compound that is effective, as understood by those of skill in the art.

- 17 043110

Another aspect of the invention is pharmaceutical compositions containing a therapeutically effective amount of a compound of formulas (III)-(IX) in combination with a pharmaceutical carrier.

Another aspect of the invention is pharmaceutical compositions comprising a therapeutically effective amount of a compound of formulas (III)-(IX) in combination with at least one other therapeutic agent and a pharmaceutical carrier.

Pharmaceutical composition means a composition containing a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to media conventional in the art for delivering biologically active agents to animals, in particular mammals, including, for example, an adjuvant, excipient or carrier such as diluents, preservatives, excipients, flow control agents, disintegrants, wetting agents. agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the route of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to a number of factors well known to those skilled in the art. These include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the agent is to be administered; the intended route of administration of the composition; and target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as various solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included for a variety of reasons, such as stabilization of the active agent, as binders, etc., well known to those skilled in the art. A description of suitable pharmaceutically acceptable carriers and factors involved in their selection can be found in various readily available sources such as, for example, Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

In particular, when they are presented as a single dosage unit, there is the possibility of chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and the second therapeutic agent are combined in a single dosage unit, they are formulated in such a way that although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (i.e., reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, not only can contact between the combined active ingredients be minimized, but the release of one of these components in the gastrointestinal tract can also be controlled so that one of these components is not released in the stomach, but is released in the intestine. . One of the active ingredients may also be coated with a material that affects sustained release in the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In addition, the sustained release component can be further coated with an enteric coating so that the release of this component occurs only in the intestine. Another approach may include formulating a combination product in which one component is coated with a sustained release and/or enteric release polymer and the other component is also coated with a polymer such as low viscosity hydroxypropyl methylcellulose (HPMC) or other suitable materials known in the art. , for additional separation of active components. The polymer coating serves to form an additional barrier to interaction with another component.

Another aspect of the invention is a method of treating cardiovascular disease comprising administering to a patient a therapeutically effective amount of a compound of formula (III).

Another aspect of the invention is a method of treating a cardiovascular disease which is selected from the group consisting of angina, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and iatrogenic heart injury.

It should be understood that the treatment or prevention of heart failure may also include the treatment or prevention of a cardiovascular event. Treatment or prevention, as referred to herein, may refer to the treatment or prevention of certain adverse symptoms or conditions associated with or resulting from a cardiovascular event. For example, treatment or prevention may include reducing or preventing negative changes in shortening fraction, heart mass, lung mass, myocyte cross-sectional area, cardiac fibrosis induced by pressure overload, stress-induced cellular aging and/or cardiac hypertrophy properties, or any combination thereof, associated with or resulting from a cardiovascular event. Treatment may be given in preparation for

- 18 043110 cardiovascular event or in response to it to mitigate negative effects. Prevention may include a proactive or prophylactic type of treatment to prevent a cardiovascular event or reduce the onset of adverse effects of a cardiovascular event.

In one embodiment, the present invention provides the use of compounds of formulas (III)-(IX) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of heart failure, e.g., heart failure due to hypertension, coronary heart disease, non-ischemic heart disease, exposure cardiotoxic compound, myocarditis, Kawasaki disease, type I and II diabetes, thyroid disease, viral infection, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, systolic dysfunction left ventricular dysfunction, left ventricular diastolic dysfunction, coronary artery bypass grafting, pacemaker surgery, fasting, eating disorders, muscular dystrophies, and a genetic defect. Preferably, the heart failure to be treated is diastolic heart failure, heart failure with reduced ejection fraction (HF _R EF), heart failure with preserved ejection fraction (HF _P EF), acute heart failure and chronic heart failure of an ischemic and non-ischemic nature.

In one embodiment, the present invention provides the use of compounds of formulas (III)-(IX) for the treatment of systolic and/or diastolic dysfunction, wherein the compound is administered in a therapeutically effective amount to increase the ability of cardiac muscle cells to contract and relax, thereby increasing filling and emptying. right and left ventricles, preferably the left ventricle.

In another embodiment, the present invention provides the use of compounds of formulas (III)-(IX) for the treatment of heart failure, wherein the compound is administered in a therapeutically effective amount to increase left ventricular ejection fraction.

In yet another embodiment, the present invention provides the use of compounds of formulas (III)-(IX) for the treatment of heart failure, wherein the compound is administered in a therapeutically effective amount to reduce fibrosis in cardiac tissue.

Another aspect of the invention is a method for treating a heart disease, wherein the treatment is carried out after a myocardial infarction.

Another aspect of the invention is a method of treating dermatological disorders including, but not limited to, rosacea, fulminant rosacea, sunburn, psoriasis, menopause-associated hot flashes, hot flashes associated with hot flashes and redness, hot flushes associated with erythema, flushing resulting from orchiectomyatopic dermatitis , treatment of redness and itching from insect bites, photoaging, seborrheic dermatitis, acne, allergic dermatitis, telangiectasia (dilation of pre-existing small blood vessels) of the face, angioectasia, rhinophyma (nasal hypertrophy with follicular dilatation), skin rashes similar to acne (may oozing or crusting), burning or tingling sensation, skin erythema, skin hyperactivity with cutaneous vasodilation, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hemorrhoids, erythema multiforme minor, erythema multiforme major, nodosum erythema, eye puffiness, urticaria, pruritus, rash hemorrhagic, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex chronicus, perioral dermatitis, pseudofolliculitis of the beard area, granuloma annulare, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema, skin wound healing, hypertrophic scarring, keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging, photodamage, melasma , post-inflammatory hyperpigmentation, other pigmentation disorders and alopecia (scarring and non-scarring forms). The following compounds are expected to have therapeutic effects in many different types of skin diseases, but have been shown by demonstrating activity in accelerated wound healing.

Another aspect of the invention is a method of treating a heart condition comprising administering to a patient a therapeutically effective amount of a compound of formula (III) in combination with other therapeutic agents.

The compounds of the present invention may be administered by any suitable means, for example, orally as tablets, capsules (each including sustained release or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, dried spray dispersion), syrups and emulsions; sublingually; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular, or intrathoracic injection, or by infusion techniques (eg, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal septum, for example by inhalation spray; topically, for example in the form of a cream or ointment; or rectally, for example in the form of suppositories. They can be administered separately, but are usually administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The dosage regimen of the compounds of the present invention will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, as well as the mode and route of its administration; type, age, sex, health, medical indication and body weight of the recipient; the nature and severity of symptoms; type of concomitant treatment; frequency of treatment; route of administration, renal and hepatic function of the patient, and the desired effect.

As a general guide, the daily oral dose of each active ingredient, when used to achieve the indicated effects, will be in the range of about 0.01-5000 mg per day, preferably about 0.1-1000 mg per day and most preferably about 0.01- 250 mg per day. When administered intravenously, the most preferred doses will be in the range of about 0.01-10 mg/kg/min during infusion at a constant rate. The compounds of the present invention may be administered as a single daily dose or the total daily dose may be administered in divided doses two, three or four times a day.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight based on the total weight of the composition. A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a #1 gelatin capsule. A typical injectable preparation is prepared by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 ml of saline to obtain an injection.

The compounds of the present invention may be used in combination with other suitable therapeutic agents useful in the treatment of the aforementioned diseases or disorders, including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathy agents, anti-neuropathic agents, anti-nephropathic agents , antiischemic agents, antihypertensive agents, antiobesity agents, antihyperlipidemic agents, antihypertriglyceridemic agents, antihypercholesterolemic agents, antirestenotic agents, antipancreatic agents, hypolipidemic agents, anorectic agents, memory enhancing agents, antidementia agents, cognition promoting agents, appetite suppressing agents, agents for treatment of heart failure, agents for the treatment of peripheral arterial diseases, agents for the treatment of malignant tumors and anti-inflammatory agents.

The compounds of the present invention can be used with at least one of the following anti-heart failure agents selected from loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin-neprilysin receptor inhibitors (ARNI), beta-blockers , mineralocorticoid receptor antagonists, nitroxide donors, RXFP1 agonists, APJ agonists, and cardiotonic agents. These agents include, but are not limited to, furosemide, bumetanide, torsemide, sacubitrial-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losar tan, olmesartan, telmisartan and valsartan.

The compounds of the present invention may be used in combination with at least one of the following therapeutic agents in the treatment of atherosclerosis: antihyperlipidemic agents, agents that increase plasma HDL levels, antihypercholesterolemic agents, inhibitors of cholesterol biosynthesis (such as inhibitors of HMG-CoA reductase), an agonist LXR, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (eg, anion exchange resins or quaternary amines (eg, cholestyramine or colestipol)), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrizol , vitamin B6, vitamin B ₁₂ , antioxidant vitamins, β-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the present invention may be used in combination with at least one of the following therapeutic agents in the treatment of a cholesterol biosynthesis inhibitor, in particular an HMG-CoA reductase inhibitor. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

- 20 043110

The compounds of the invention may be used in combination with at least one of the following antidiabetic agents, depending on the desired targeted therapy. Studies show that the modulation of diabetes and hyperlipidemia can be further improved by adding a second agent to the therapeutic regimen. Examples of antidiabetic agents include, but are not limited to, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as pioglitazone, pioglitazone, troglitazone, and rosiglita zones ) and related insulin sensitizers such as selective and non-selective PPARa, PPARe and PPARy activators; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-SO ₄ ); antiglucocorticoids; TNFa inhibitors; dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin, saxagliptin), GLP-1 agonists or analogs (such as exenatide), α-glucosidase inhibitors (such as acarbose, miglitol and voglibose), pramlintide (a synthetic analog of the human amylin hormone), others insulin secretagogues (such as repaglinide, gliquidone and nateglinide), insulin, and the therapeutic agents described above for the treatment of atherosclerosis.

The compounds of the present invention may be used in combination with at least one of the following anti-obesity agents selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, fentyramine, β3 adrenoceptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used to treat obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotropin releasing factor, galanin, and gamma-aminobutyric acid. (GABA).

The compounds of the present invention can also be used as standard or reference compounds, for example as a quality standard or control, in tests or assays involving FPR2. Such compounds can be provided in a commercial kit, for example, for use in pharmaceutical research related to FPR2 activity. For example, a compound of the present invention can be used as a reference in an assay to compare its known activity with a compound of unknown activity. This should assure the experimenter that the assay was performed correctly and provide a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing new assays or protocols, the compounds of the present invention can be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays involving FPR2.

The present invention also includes the finished product. As used herein, the term "finished product" includes, but is not limited to, kits and packages. The finished product according to the present invention contains: (a) the first container; (b) a pharmaceutical composition located inside the first container, the composition containing the first therapeutic agent, which is a compound of the present invention or its pharmaceutically acceptable salt form; and (c) a package leaflet stating that the pharmaceutical composition can be used to treat dyslipidemias and their consequences. In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination (as previously defined) with a second therapeutic agent for the treatment of dyslipidemias and their consequences. The product may further comprise: (d) a second container, wherein the components (a) and (b) are located inside the second container, and the component (c) is located inside or outside the second container. Location inside the first and second containers means that the corresponding container holds the item within its boundaries. The first container is a container used to store the pharmaceutical composition. This container can be used for manufacturing, storage, transportation and/or individual/wholesale.

The first container is intended to contain a bottle, jar, vial, flask, syringe, tube (for example, for a cream preparation) or any other container used to manufacture, contain, store or distribute a pharmaceutical product. The second container is used to house the first container and optionally the package insert. Examples of the second container include, but are not limited to, boxes (eg, cardboard or plastic), boxes, cartons, pouches (eg, paper or plastic bags), sachets, and bags. The package insert may be physically attached to the outside of the first container using tape, adhesive, staples, or other attachment method, or it may be inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When placed on the outside of the second container, it is preferred that the package insert be physically attached using tape, adhesive, staples, or other method of attachment. Alternatively, it may be adjacent to or touching the outside of the second container without being physically attached.

- 21 043110

The package insert is a label, tag, marker, etc., which provides information related to the pharmaceutical composition located inside the first container. The information provided is usually determined by the regulatory agency that controls the area where the finished product will be sold (for example, the US Food and Drug Administration). Preferably, the package insert specifically indicates the indications for which the pharmaceutical composition is approved. The package insert may be made of any material on which a person can read the information contained in or on it. Preferably, the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information is formed (eg, printed or applied).

Chemical methods

Abbreviations used herein are defined as follows: 1x means single, 2x means two times, 3x means three times, °C means degrees Celsius, aq means water, col means column, eq means equivalent or equivalents, g means gram or grams, mg means milligram or milligrams, l means liter or liters, ml means milliliter or milliliters, μl means microliter or microliters, N means normal, M means molar, nM means nanomolar, mole means mole or mole, mmol means millimole or millimoles, min means minute or minutes , h means hour or hours, rt means room temperature, RT means retention time, ON means overnight, atm means atmospheres, psi means pounds per square inch, conc. means concentrate, aq means aqueous, sat or sat'd means saturated, MW means molecular weight, mw or pwave means microwave, mp means melting point, Wt means mass, MS or Mass Spec means mass spectrometry, ESI means mass spectroscopy with electrospray ionization, HR means high resolution, HRMS means high resolution mass spectrometry, LCMS means liquid chromatography mass spectrometry, HPLC means high pressure liquid chromatography, RP HPLC means reverse phase HPLC, TLC or tlc means thin layer chromatography, NMR means spectroscopy nuclear magnetic resonance, nOe means nuclear Overhauser spectroscopy, 1H means proton, δ means delta, s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, br means wide, Hz means hertz, α, β, R, S, E, and Z are stereochemical designations familiar to those skilled in the art.

ace acetic ASON acetic acid Acn (or MeCN) acetonitrile BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BISPIN bis(pinacolato)dibor bn benzyl Vos mpem-butyl carbonyl BOC2O di-tert-butyl dicarbonate Bu butyl dba as in (P02(bba)s) dibenzylideneacetone DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine

- 22 043110

DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene Et ethyl EtOH ethanol EtOAc ethyl acetate HATU 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate z-Bu isobutyl z-Pr isopropyl LAH lithium aluminum hydride Me methyl MeOH methanol NBS N-bromosuccinimide NMM A-methylmorpholine NMP N-methylpyrrolidone Pet petroleum Ph phenyl Pr propyl rt room temperature EBU tert-butyl TBDMS-C1 Ebutyldimethylchlorosilane TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Ts tozil Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The disclosed compounds may be prepared by a variety of methods known in the art, including those indicated in the following Schemes and in the specific embodiments section. The numbering of structures and the numbering of variables shown in the synthesis schemes are different from the numbering of structures or variables in the claims or the rest of the description, and should not be confused with it. The variables in the schemes are only intended to illustrate how to prepare some of the compounds of this invention.

The disclosure is not limited to the above illustrative examples, and these examples are to be considered in all respects as illustrative and non-limiting, and therefore it is intended that all changes that fall within the spirit and range of equivalence of the claims are to be included within its scope.

When planning any synthetic route in this area, consideration must be given to the choice of the protecting group used to protect the reactive functional groups present in the compounds described in this invention. An authoritative source that describes many alternatives for the trained practitioner is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007)).

Compounds having the general formula (III) wherein A, B, C, R ^x , R ^y and R ^z are defined above as Ar ¹ , Ar ² and Ar ³ , (R ^2a )1.4, (R ^3a )1.4 and (R ^1a )1.2, (R ^1b )1.2, respectively, can be obtained by one or more synthetic schemes.

- 23 043110

The 1-arylpyrrolidinone compounds of the present invention wherein the A, B and C rings are substituted phenyl rings can be prepared using the general method shown in Scheme 1 starting with the suitably protected 3-aminopyrrolidin-2-one 1a where PG is a protecting group such as Boc or Cbz. 1a can be obtained by methods known to those skilled in the art. Copper or Pd catalyzed coupling of 1a with a substituted iodobenzene or bromobenzene 1b or other suitable haloaryl or heteroaryl compound in a suitable solvent such as butanol or dioxane or toluene in the presence of a base such as potassium carbonate or cesium carbonate and a suitable ligand such as as N,N'dimethylethylenediamine or xanthophos (xanthphos), can provide 1-phenylpyrrolidinones 1c. Additional routes for this conversion include other variants of copper-catalyzed Ullmann, Goldberg, and Buchwald amidation, or Pd-catalyzed Buchwald amidation, depending on the nature of the B ring, using methods known to those skilled in the art for these types of combinations (see, for example, Yin & Buchwald Organic Lett. 2000, 2, 1101; KlaPers et al. Jacs, 2001, 123, 7727; Klapars et al. Jacs, 2002, 124, 7421; Yin & Buchwald Jacs. 2002, 124, 6043; Kiyomor, Madoux & Buchwal D. , Tet. Lett., 1999, 40, 2657). Subsequent palladium-catalyzed coupling of 1c with an appropriately substituted phenylboronic acid 1d or a similar boronate or trifluoroborate reagent can provide the biaryl compound 1e. Removal of the Boc or Cbz protecting group from 1e followed by condensation of the resulting free amine with a suitably substituted phenyl isocyanate 1g or phenyl carbamate 1h can provide ureas 1f. Suitable isocyanates or 4-nitrophenyl carbamates are either commercially available or can be easily obtained from the corresponding aniline using methods known to the person skilled in the art. Alternatively, ureas 1f can be prepared by treating the deprotected 3-aminopyrrolidinone intermediate with 4-nitrophenyl chloroformate to form a carbamate, followed by condensation with an appropriately substituted aniline 1j. The person skilled in the art will also appreciate that additional compounds of the present invention in which the A, B or C rings are heteroaryl rings such as pyridine, pyrimidine, thiazole, etc. can also be prepared using the methods described in Scheme 1, by replacing 1b with a suitable heteroaryl iodide or bromide, 1d with heteroarylboronic acid or boronate, and 1e with heteroarylamine, isocyanate or p-nitrophenyl carbamate. Racemic compounds were separated using chiral HPLC or SFC to obtain individual enantiomers.

Scheme 1

Alternatively, as described in Scheme 2, the compounds of this invention can be prepared from intermediate 1c by first deprotecting the amine and forming a urea bond

- 24 043110 with ring A, using the conditions described above to convert 1e to 1f to give compounds 2a.

Compound 2a can then be coupled with an appropriate boronic acid or boronate under Pd catalysis conditions as shown in Scheme 1 to convert 1c to 1e. Racemic compounds can be resolved using chiral HPLC or SFC to give single enantiomers.

Scheme 2

In addition, as shown in Scheme 3, compounds of the present invention can be prepared from intermediate 2a by conversion to boronate 3a using iridium/Pd C-H borylation according to the methods of Suzuki and Miyaura, followed by coupling of the resulting pinacolatobor compounds with aryl or heteroaryl halides using palladium or copper catalyzed processes to give compounds 1f. Racemic compounds can be resolved using chiral HPLC or SFC to give single enantiomers.

Scheme 3

Alternatively, as described in Scheme 4, the compounds of this invention can be prepared by bromination of the amine 4a to give intermediate 4b. Subsequent coupling of the amide with 2,4-dibromobutyryl chloride under basic conditions such as potassium phosphate in acetonitrile, followed by aqueous ammonia-mediated ring closure, can provide lactam 1c. Intermediate 1c can be converted to final products using the reactions shown in Schemes 1-3. Racemic compounds can be separated by chiral HPLC or SFC to give single enantiomers.

Scheme 4

As described in Scheme 5, compounds of this invention with substituted lactams can be prepared from intermediate 5a. Copper or Pd catalyzed coupling of 5a with substituted iodobenzene or bromobenzene 1b or other suitable haloaryl or haloheteroaryl compound in a suitable solvent such as butanol, dioxane or toluene in the presence of a base such as potassium carbonate or cesium carbonate and a suitable ligand such as N,N'dimethylethylenediamine or Xanthphos can provide 1-phenylpyrrolidinones 5b. Additional routes for this conversion include other variants of copper-catalyzed Ullmann and Buchwald amidation, or Pd-catalyzed Buchwald amidation, depending on the nature of ring B, using methods known to those skilled in the art for these types of combinations. Subsequent preparation of lithium lactam enolate and treatment with an azide such as trisyl azide can give intermediate 5c (see, for example, J. Org. Chem. 2003, 68, 7219-7233). Reduction of the azide to an amine followed by protection of the amine can give intermediate 5d. The chemistry described in the previous schemes can be used to convert this intermediate to the compounds claimed in this patent. Racemic compounds can be separated by chiral HPLC or SFC to give single enantiomers.

Scheme 5 ___ ____ N ₃ ____ _X NHPG

Cui, K ₂ CO _{3 R} X Ί _r _T U _r _E G

IR^ ^- Ligand ^|\|^<) Azidation 1) Reduction ^{Κ 0} Pd £ (dba) ₃ , ^ΚΧ - ώ ^KX - ^{A 2,3 a And a}

5а Ligand , Cs ₂ CO ₃ ψ γ

Br Br Br

5b 5c 5d

Compounds of the present invention can also be synthesized using the route shown in Scheme 6. Palladium-catalyzed borylation of intermediate 1c gives intermediate 6a. Palladium-mediated coupling of suitably substituted aryl halides such as 6b can provide biaryllactam 1e. The chemistry described in the previous schemes can be used to convert this intermediate to the compounds claimed in this patent. Racemic compounds can be resolved using chiral HPLC or SFC to give single enantiomers.

Scheme 6

Other features of the invention will become apparent in the course of the following description of illustrative embodiments, which are presented to illustrate the invention and are not intended to limit it.

In the illustrative examples, the following methods were used, unless otherwise noted. Purification of intermediates and final products was carried out using normal or reversed phase chromatography. Normal phase chromatography was performed using prepackaged SiO ₂ cartridges eluting with either hexanes and ethyl acetate gradients or DCM and MeOH unless otherwise noted. Preparative reverse phase HPLC was performed using C18 columns with UV detection at 220 nm or preparative LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or gradients of Solvent A (95% water, 5% ACN, 0.1% TFA) and Solvent B (5% water, 95% ACN, 0.1% TFA), or gradients of Solvent A (95% water, 2% ACN, 0.1% HCOOH) and Solvent B (98% ACN, 2% water, 0.1% HCOOH) or gradients of Solvent A (95% water, 5% ACN, 10 mM NH ₄ OAc) and Solvent B (98% ACN, 2% water, 10 mM NH ₄ OAc), or gradients of Solvent A (98% water, 2% ACN, 0.1% NH4OH) and Solvent B (98% ACN, 2% water, 0.1% NH4OH).

LC/MS methods used to characterize compounds by example. Reversed phase analytical HPLC/MS was performed on a Waters Acquity system connected to a MICROMASS® ZQ mass spectrometer.

Method A: linear gradient 0-100% B over 3 min, 0.75 min retention time at 100% B;

UV imaging at 220 nm;

column: Waters VEN C18 2.1x50 mm;

flow rate: 1.0 ml/min;

Solvent A: 0.1% TFA, 95% water, 5% Acn;

Solvent B: 0.1% TFA, 5% water, 95% Acn.

Method B: Linear gradient 0-100% B over 3 min, 0.75 min retention time at 100% B;

UV imaging at 220 nm;

column: Waters VEN C18 2.1x50 mm;

flow rate: 1.0 ml/min;

Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn;

Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn.

Analytical HPLC: methods used to characterize compounds by example.

Method C: Ascentis Express C18, 2.1 x 50 mm, particles 2.7 µm; Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.1% TFA; temperature: 50°C; gradient: 0-100% B over 3 minutes, then 1 minute hold at 100% B; flow rate: 1.1 ml/min.

- 26 043110

Method D: Ascentis Express C18, 2.1x50 mm, particles 2.7 µm; Solvent A: 95% water, 5% Acn with mM ammonium acetate; Solvent B: 95% Acn, 5% water with 10 mM ammonium acetate; temperature:

50°C; gradient: 0-100% B over 3 minutes, then 1 minute hold at 100% B; flow rate:

1.1 ml/min.

Method E: Column-Kinetex C18, 75x3 mm, particles 2.6 µm; Solvent A: 98% water, 2% Acn with 10 mM ammonium acetate; Solvent B: 98% Acn, 2% water with 10 mM ammonium acetate; temperature: 25°C; gradient: 20-100% B over 4 min, then 0.6 min hold at 100% B; flow rate: 1.0 ml/min; then gradient: 100-20% B over 0.4 min; flow rate: 1.5 ml/min, UV 220 nm.

SFC and methods for determining chiral purity

Method I: Chiralpak AD-H, 250x4.6mm, 5.0µm particles; %CO ₂ : 60%, % co-solvent: 40% {0.2% DEA IN IPA:Acn (1:1)}, total flow rate: 4.0 g/min, backpressure: 100 bar, temperature: 25°C , UV: 218 nm.

Method II: Chiralpak OD-H, 250x4.6 mm, particles 5.0 µm; %CO ₂ : 60%, % co-solvent: 40% {0.2% DEA IN IPA:Acn (1:1)}, total flow: 4.0 g/min, backpressure: 104 bar, temperature: 24.9 °C, UV: 287 nm.

Method III: Chiralpak OJ-H, 250x4.6mm, 5.0µm particles; %CO ₂ : 60%, % co-solvent: 30% (0.3% DEA in methanol), total flow rate: 4.0 g/min, back pressure: 101 bar, temperature: 23.6°C, UV: 272 nm .

Method IV: Chiralpak AS-H, 250x4.6 mm, 5.0 µm particles; %CO ₂ : 60%, % co-solvent: 40% (0.3% DEA in methanol), total flow: 4.0 g/min, back pressure: 102 bar, temperature: 25.4°C, UV: 272 nm .

Method V: Chiralcel OJ-H, 250x4.6mm, 5.0µm particles; %CO ₂ : 60%, % co-solvent: 40% (0.2% DEA in methanol), total flow rate: 4.0 g/min, back pressure: 102 bar, temperature: 24.6°C, UV: 272 nm .

Method VI: Luxcellulose-2, 250x4.6 mm, particles 5.0 µm; %CO ₂ : 60%, % co-solvent: 35% (0.2% DEA in methanol), total flow: 3.0 g/min, back pressure: 101 bar, temperature: 23.6°C, UV: 260 nm .

Method VII: Chiralcel AS-H, 250x4.6 mm, 5.0 µm particles; %CO ₂ : 60%, % co-solvent: 40% (0.2% DEA in methanol), total flow: 4.0 g/min, back pressure: 101 bar, temperature: 24.4°C, UV: 270 nm .

Method VIII: Chiralpak IC, 250x4.6mm, 5.0µm particles; %CO2: 60%, % co-solvent: 40% (0.2% DEA in methanol), total flow rate: 4.0 g/min, back pressure: 101 bar, temperature: 24.4°C, UV: 270 nm.

Method IX: Column: chiralpak IF (250x4.6 mm), 5 microns, mobile phase: 0.2% DEA in ethanol, flow rate: 1.0 ml/min.

Method X: Column: LUX AMYLOSE 2 (250x4.6 mm), 5 microns, mobile phase: 0.2% DEA in n-hexane:ethanol: 5:95, flow rate: 1.0 ml/min.

Method XI: Column: CHIRALCEL OD-H (250x4.6 mm), 5 microns, mobile phase: 0.2% DEA in n-hexane:ethanol: 70:30, flow rate: 1.0 ml/min.

Method XII: Column: CHIRAL PAK ID (250x4.6 mm), 5 microns, mobile phase: 0.1% DEA in methanol, flow rate: 1.0 ml/min.

NMR was used to characterize compounds by example. 1 H NMR spectra were obtained using Bruker or JEOL® Fourier transform spectrometers operating at the following frequencies: 1 H NMR: 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). ¹³ C NMR: 100 MHz (Bruker or JEOL®). Spectra data are presented in the following format: chemical shift (multiplicity, interaction constants and number of hydrogen atoms). Chemical shifts are reported in ppm downfield relative to internal standard, tetramethylsilane (δ units, tetramethylsilane = 0 ppm) and/or relative to solvent peaks that appear in 1H NMR spectra at 2.49 ppm for CD2HSOCD3, 3 .30 ppm for CD2HOD, 1.94 for CD3CN, and 7.24 ppm for CHCl3, and which in the ¹³ C NMR spectra appear at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD and 77.0 ppm for CDCl3. All ¹³ C NMR spectra were with separated protons.

Intermediate 1: 3-aminopyrrolidin-2-one

To a stirred solution of hexamethyldisilazane (11 ml, 523 mmol) in CH3CN (100 ml) at room temperature was added a solution of DL-2,4-diaminobutyric acid dihydrochloride (10 g, 52 mmol) in Acn (100 ml). The resulting reaction mixture was refluxed for 40 hours. The crude reaction mixture was then poured into ice-cold MeOH (400 ml), stirred at room temperature for 30 minutes and evaporated under reduced pressure. Received solid

- 27 043110 the substance was dissolved in CH ₂ Cl ₂ (700 ml) and the insoluble residue was removed by vacuum filtration.

The filtrate was then concentrated under reduced pressure to give 3-aminopyrrolidin-2-one (4.1 g, 41 mmol, 78% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.59 (br. s., 2H), 3.23-3.10 (m, 1H), 3.09-3.03 (m, 2H), 2.23-2.22 (m, 1H), 1.70-1.57 (m, 1H).

Intermediate 2: tert-butyl (2-oxopyrrolidin-3-yl) carbamate

NHBoc

N^°H

To a stirred solution of 3-aminopyrrolidin-2-one (4.0 g, 40 mmol) in methanol-triethylamine (130 ml, 9:1) under argon at room temperature was added Boc anhydride (9.6 ml, 41 mmol) . The reaction mixture was stirred at room temperature overnight followed by heating under reflux for two hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Ether (50 mL) was added to the crude residue and the solid was filtered on a Buchner funnel to give Intermediate 2 (4.0 g, 20 mmol, 50% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.69 (br. s., 1H), 6.99 (d, J=8.0 Hz, 1H), 4.06-3.96 (m, 1H), 3.19-3.10 (m, 2H), 2.29-2.19 (m, 1H), 1.89-1.76 (m, 1H), 1.35 (s, 9H).

Intermediate 3: tert-butyl (1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidin-3yl)carbamate

To a stirred solution of intermediate 2 (1.0 g, 5.0 mmol) in 1,4-dioxane (10 mL) was added 1,4-dibromo-2,3-difluorobenzene (1.6 g, 6.0 mmol) and Cs ₂ CO ₃ (3.3 g, 10 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with Xantphos (0.29 g, 0.50 mmol) and Pd ₂ (dba) ₃ (0.23 g, 0.25 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 120° C. for 16 hours. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether-EtOAc) to give intermediate 3 (1.1 g, 2.8 mmol, 47% yield) as a brown solid. MS (ESI) m/z: 391.2 (M+H)+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61-7.59 (m, 1H), 7.35-7.28 (m, 2H), 4.39-4.28 (m, 1H), 3.82-3.64 (m, 2H), 2.42 -2.31 (m, 1H), 2.10-1.97 (m, 1H), 1.40 (s, 9H).

Intermediate 4: tert-Butyl (1-(2,3-difluoro-2'-(methylsulfonamido)-[1,1'-biphenyl]-4yl)-2-oxopyrrolidin-3-yl)carbamate

(2-(methylsulfonamido)-phenyl)boronic acid (0 .45 g, 2.1 mmol) and potassium phosphate, tribasic (0.74 g, 4.2 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with PdCl ₂ (dppf)-CH ₂ Cl ₂ (0.17 g, 0.21 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 80° C. for 16 hours. The reaction mixture was cooled and filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether-EtOAc) to give intermediate 4 (0.44 g, 0.91 mmol, 43% yield) as a brown solid. MS (ESI) m/z: 482.2 [M+H] ⁺ ;

1Н NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 7.53-7.44 (m, 2H), 7.38-7.29 (m, 4H), 7.24-7.17 (m, 1H), 4.36-4.31 ( m, 1H), 3.86-3.69 (m, 2H), 2.90 (s, 3H), 2.41-2.37 (m, 1H), 2.10-2.02 (m, 1H), 1.41 (s, 9H).

- 28 043110

Intermediate 5: N-(4'-(3-amino-2-oxopyrrolidin-1-yl)-2',3'-difluoro-[1,1'-biphenyl]2-yl)methanesulfonamide hydrochloride

To an ice-cold solution of intermediate 4 (440 mg, 0.91 mmol) in 1,4-dioxane (1 ml) was added 4N HCl in 1,4-dioxane (4.6 ml, 1 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The tarry solid was triturated with diethyl ether (20 mL x 2) and dried to give intermediate 5 (350 mg, 0.84 mmol, 92% yield) as a brown solid. MS (ESI) m/z: 418.2 [M+H]+;

1Н NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.71 (br. s., 3H), 7.55-7.47 (m, 2H), 7.45-7.24 (m, 4H), 4.33-4.25 ( m, 1H), 3.97-3.85 (m, 2H), 2.89 (s, 3H), 2.64-2.54 (m, 1H), 2.30-2.17 (m, 1H).

Intermediate 6: tert-butyl (R)-(2-oxopyrrolidin-3-yl)carbamate

NHBoc n

1-Propanophosphonic acid anhydride (50% in EtOAc, 210 ml, 340 mmol) was added to a solution of Boc-D-2,4-diaminobutyric acid (50 g, 230 mmol) and TEA (96 ml, 690 mmol) in DCM (1500 ml) at 0°C. The reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (MeOH/DCM). The product was recrystallized from EtOAc/petroleum ether to give intermediate 6 (32 g, 70 mmol, 70% yield) as a white solid. MS (ESI) m/z: 201.2 (M+H) ⁺ .

1Н NMR (400 MHz, DMSO-d6) δ = 7.69 (s, 1H), 6.99 (br. d., J=9.0 Hz, 1H), 4.01 (q, J=9.0 Hz, 1H), 3.173.09 ( m, 2H), 2.28-2.19 (m, 1H), 1.90-1.75 (m, 1H), 1.39 (s, 9H).

Intermediate 7: tert-butyl (R)-(1-(2,3-difluoro-4-bromophenyl)-2-oxopyrrolidin-3yl)carbamate

Reaction mixture of intermediate 6 (20 g, 100 mmol), 2,3-difluoro-1,4-dibromobenzene (14 g, 110 mmol), tribasic potassium phosphate (32 g, 150 mmol) and copper iodide (7.6 g 40 mmol) in 1,4dioxane (250 ml) was purged with nitrogen for 5 min. N,N'-dimethylethylenediamine (5.5 ml, 50 mmol) was added and the reaction mixture was heated in a pressure tube at 65° C. for 12 hours. The reaction mixture was diluted with EtOAc, filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography (35% EtOAc in petroleum ether) and recrystallized (EtOAc/petroleum ether) to give Intermediate 7 (18 g, 39 mmol, 39% yield) as a white solid. MS (ESI) m/z: 439.0 (M+H) ⁺ .

1Н NMR (400 MHz, CDCl3) δ = 7.54 (ddd, J=8.5, 6.3, 2.3 Hz, 1H), 7.09 (ddd, J=8.5, 6.3, 2.3 Hz, 1H), 5.16 (br. s., 1H ), 4.41-4.30 (m, 1H), 3.87 (m, 1H), 3.79-3.69 (m, 1H), 2.85-2.73 (m, 1H), 2.17-2.05 (m, 1H), 1.48 (m, 9H ).

Intermediate 8: (2-bromophenyl)dimethylphosphine oxide

In a pressure test tube, a reaction mixture of 1-bromo-2-iodobenzene (2.3 ml, 18 mmol), tribasic potassium phosphate (5.6 g, 27 mmol) and Xantphos (0.61 g, 1.1 mmol) in DMF (40 ml) was degassed with argon for 3 min. Dimethylphosphine oxide (1.7 g, 21 mmol) and PdOAc2 (0.20 g, 0.88 mmol) were added. The mixture was degassed with argon, sealed, and heated for 16 h at 110°C.

The reaction mixture was cooled to room temperature, filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography (CHCl ₃ /MeOH) to give intermediate 8 (2.1 g, 9.0 mmol, 51% yield). MS (ESI) m/z:

- 29 043110

233.0 (M+H) ⁺ .

1Н NMR (300 MHz, DMSO-d ₆ ) δ = 7.97 (ddd, J=11.9, 7.8, 2.0 Hz, 1H), 7.76 (ddd, J=7.8, 3.9, 1.2 Hz, 1H),

7.65-7.44 (m, 2H), 1.83 (d, J=13.5 Hz, 6H).

Intermediate 9: tert-Butyl (R)-(1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]4-yl)-2-oxopyrrolidin-3-yl)carbamate

Reaction mixture of intermediate 7 (15 g, 38 mmol), intermediate 8 (11 g, 46 mmol), bispin (24 g, 96 mmol) and K ₃ PO ₄ (24 g, 115 mmol) in 1,4-dioxane (250 ml) was purged with argon for 5 min. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (3.1 g, 3.8 mmol) was added and the mixture was again purged with argon and then stirred in a pressure tube at 105° C. for 24 h. The reaction mixture was diluted EtOAc, filtered through celite and concentrated under reduced pressure. The crude product was purified by column chromatography (5% MeOH in CHCl ₃ ) to give intermediate 9 (9.0 g, 19 mmol, 51% yield). MS (ESI) m/z: 465.4 (M+H)+.

1Н NMR (400 MHz, DMSO-d6) δ = 7.92 (ddd, J=12.8, 7.6, 1.3 Hz, 1H), 7.70-7.49 (m, 2H), 7.41-7.23 (m, 4H), 4.54-4.23 ( m, 1H), 3.87-3.70 (m, 2H), 2.44-2.37 (m, 1H), 2.21-2.00 (m, 1H), 1.51 (br. d., J=13.1 Hz, 6H),

1.42(s, 9H).

Intermediate 10: (K)-3-amino-1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]-4yl)pyrrolidin-2-one hydrochloride nh ₂ -hci o <>

HCl (4 M in 1,4-dioxane, 200 ml, 800 mmol) was added to a stirred solution of intermediate 9 (34 g, 73 mmol) in 1,4-dioxane (500 ml) at room temperature. The reaction mixture was stirred for 3 h and concentrated under reduced pressure to give intermediate 10 (28 g, 70 mmol, 95% yield), which was used in the next synthetic step without further purification. MS (ESI) m/z: 365.2 (M+H) ⁺ .

1Н NMR (400 MHz, DMSO-d6) δ = 8.62 (br. s., 3H), 7.95-7.81 (m, 1H), 7.68-7.57 (m, 2H), 7.39-7.32 (m, 2H), 7.31 -7.24 (m, 1H), 4.33-4.19 (m, 1H), 3.94-3.84 (m, 2H), 2.61-2.53 (m, 1H), 2.25-2.15 (m, 1H), 1.53 (d, J= 13.1 Hz, 6H).

Intermediate 11: phenyl (4-chloro-2-fluorophenyl) carbamate

Q _o ° \ /=\

HN—< D—CI

F

Phenylchloroformate (20 ml, 160 mmol) was slowly added to a solution of 4-chloro-2-fluoroaniline (19 ml, 170 mmol) and pyridine (35 ml, 430 mmol) in DCM (250 ml) at 0°C. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with water.

The mixture was extracted with DCM (3 x 200 ml). The combined organic layers were washed with 0.5N HCl and 10% sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The solid was stirred in petroleum ether (100 ml) for 15 min, filtered and dried to give intermediate 11 (36 g, 40 mmol, 78% yield).

1Н NMR (300 MHz, Chloroform-d) δ = 10.22-9.99 (m, 1H), 7.73 (br. t, J=8.7 Hz, 1H), 7.52 (dd, J=10.7, 2.1 Hz, 1H), 7.47 -7.38 (m, 2H), 7.34-7.18 (m, 4H).

Intermediate 12: phenyl (2-fluoro-4-(trifluoromethyl)phenyl)carbamate

- 30 043110

Phenyl chloroformate (4.5 ml, 36 mmol) was added slowly to a solution of 2-fluoro-4(trifluoromethyl)aniline (8.0 g, 45 mmol) and pyridine (9.0 ml, 110 mmol) in DCM (80 ml) at 0°C. The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water and the mixture was extracted with DCM (3 x 200 ml). The combined organic layers were washed with 0.5N HCl and 10% sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The solid was stirred with petroleum ether (100 ml) for 15 min, filtered and dried to give intermediate 11 (9.0 g, 30 mmol, 67% yield). MS (ESI) m/z: 317.2 (M+NH4)+.

1H NMR (300 MHz, Chloroform-d) δ = 10.43 (s, 1H), 8.04 (br. t., J=8.1 Hz, 1H), 7.75 (br. d., J=10.9 Hz, 1H), 7.60 (br. d., J=8.6 Hz, 1H), 7.52-7.38 (m, 2H), 7.36-7.21 (m, 3H).

Intermediate 13: (R)-1-(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)-3-(2fluoro-4-(trifluoromethyl)phenyl)urea

HCl (4 M in dioxane, 32 ml, 130 mmol) was added dropwise to a solution of intermediate 7 (10 g, 26 mmol) in DCE (300 ml) at 0°C. The reaction mixture was stirred for 2 hours at room temperature and concentrated under reduced pressure. The crude intermediate was dissolved in 1,4-dioxane (300 ml) and cooled to 0°C. DIEA (22 ml, 130 mmol) was added dropwise over 10 min, intermediate 12 (6.9 g, 23 mmol) was added and the mixture was stirred for 12 h at room temperature. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (2% MeOH:DCM) to give intermediate 13 (12 g, 24 mmol, 95% yield). MS (ESI) m/z: 496.0 (M+H)+.

Intermediate 14: (R)-1-(1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-2-oxopyrrolidine- 3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

A solution of intermediate 13 (12 g, 24 mmol) and bispin (18 g, 73 mmol) in 1,4-dioxane (120 ml) was degassed with argon for 5 min. PdCl ₂ (dppf)-CH2Cl2 (4.0 g, 4.8 mmol) was added and the reaction mixture was slowly heated to 110° C. and stirred for 16 h. The mixture was filtered through celite and the layer was washed with EtOAc. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give intermediate 14 (13 g, 24 mmol, 99% yield). MS (ESI) m/z: 544.2 (M+H) ⁺ .

Intermediate 15: (3-bromopyridin-2-yl)dimethylphosphine oxide

To a stirred solution of 3-bromo-2-iodopyridine (5.0 g, 18 mmol) in DMF (5 ml) was added dimethylphosphine oxide (1.7 g, 21 mmol) and K ₃ PO ₄ (4.1 g, 19 mmol ). The reaction mixture was purged with nitrogen for 5 min and loaded with Xantphos (1.0 g, 1.8 mmol) and Pd(OAc) ₂ (0.20 g, 0.88 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 100° C. for 9 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (5% MeOH-CHCl ₃ ) to give intermediate 15 (2.7 g, 12 mmol, 66% yield) as a brown liquid. MS (ESI) m/z: 234.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.72 (d, J=4.8 Hz, 1H), 8.23-8.20 (m, 1H), 7.53-7.49 (m, 1H), 1.66 (d, J= 13.6 Hz, 6H).

- 31 043110

Intermediate 16: (2-bromo-6-fluorophenyl)dimethylphosphine oxide

To a stirred solution of 1-bromo-3-fluoro-2-iodobenzene (2.0 g, 6.7 mmol) in 1,4-dioxane (15 mL) was added dimethylphosphine oxide (0.62 g, 8.0 mmol) and K3PO4 (1.6 g, 7.3 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with Xantphos (0.39 g, 0.67 mmol) and Pd ₂ (dba) ₃ (0.30 g, 0.33 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 100° C. for 9 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (0-100% EtOAc-hexane, then 3% MeOH-CHCl ₃ ) to give Intermediate 16 (0.33 g, 1.3 mmol, 20% yield) as a yellow solid. MS (ESI) m/z: 250.9 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.63 (d, J=8.0 Hz, 1H), 7.52 (td, J=8.0, 6.0 Hz, 1H), 7.43-7.28 (m, 1H), 1.87 (d, J=16.6 Hz, 3H), 1.86 (d, J=16.6 Hz, 3H).

Intermediate 17: diethylphosphine oxide

ABOUT

II

Diethylphosphonate (30 g, 220 mmol) was added to a stirred solution of 2 M ethylmagnesium bromide (330 ml, 650 mmol) in THF at room temperature and the mixture was stirred for an additional 2 h. A cold solution of K2CO3 (90 g, 650 mmol) in water (120 ml) and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and azeotropically distilled with toluene (20 ml x 3). The crude product was diluted with DCM (100 ml), filtered through a cotton pad and concentrated under reduced pressure to give intermediate 17 (12 g, 110 mmol, 52% yield) as a yellowish liquid. MS (ESI) m/z: 107.2 [M+H] ⁺ .

Intermediate 18: (2-bromophenyl)diethylphosphine oxide

To a stirred solution of 1-bromo-2-iodobenzene (10 g, 35.3 mmol) in DMF (50 ml) was added diethylphosphine oxide (4.5 g, 42 mmol) and K3PO4 (15 g, 71 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with Xantphos (1.0 g, 1.8 mmol) and palladium(II) acetate (0.40 g, 1.8 mmol). The reaction mixture was again purged with nitrogen for 3 min, heated to 100° C. and stirred for 16 h. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH-EtOAc) to give intermediate 18 (3.2 g, 12 mmol, 35% yield) as a yellowish liquid. MS (ESI) m/z: 263.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.05-7.94 (m, 1H), 7.79-7.68 (m, 2H), 7.64-7.48 (m, 1H), 2.26-2.03 (m, 4H), 0.93 (td, J=17.4, 7.7 Hz, 6H).

Intermediate 19: dimethyl (2-bromophenyl)phosphonate

To a stirred solution of 2-bromophenyl trifluoromethanesulfonate (2.0 g, 6.6 mmol) in toluene (100 ml) was added dimethylphosphonate (1.1 g, 9.8 mmol) and DIEA (1.7 ml, 9.8 mmol) . The reaction mixture was purged with nitrogen for 5 min and loaded with 1,3-bis(diphenylphosphino)propane (0.14 g, 0.33 mmol) and palladium(II) acetate (0.04 g, 0.17 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 110° C. for 16 hours. The reaction mixture was cooled and filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (5-10% MeOH in chloroform) to give intermediate 19 (1.2 g, 3.6 mmol, 55% yield) as a colorless liquid. MS (ESI) m/z: 267.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ = 8.02-8.00 (m, 1H) 7.70-7.69 (m, 1H) 7.43-7.41 (m, 2H) 3.83-3.73 (m, 6H).

Intermediate 20: Ethyl (2-bromophenyl)(methyl)phosphinate

Diethylmethylphosphonite (0.58 g, 4.2 mmol) and K ₃ PO ₄ (2.3 g , 11 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with Xantphos (0.21 g, 0.35 mmol) and palladium(II) acetate (0.040 g, 0.18 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 110° C. for 16 hours. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether-EtOAc) to give intermediate 20 (0.35 g, 1.3 mmol, 38% yield) as a brown liquid.

- 32 043110

MS (ESI) m/z: 263.1 [M+H]+.

1Н NMR (400 MHz, CDCl3) δ = 8.18-8.13 (m, 1H) 7.67-7.65 (m, 1H) 7.64-7.38 (m, 2H) 4.07-4.03 (m, 1H)

3.85-3.80 (m, 1H) 1.86 (d, J=15.0 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H).

Intermediate 21: 4-bromo-3-cyclopropyl-2-fluoroaniline

To an ice-cold solution of 3-cyclopropyl-2-fluoroaniline (0.85 g, 5.6 mmol) in DMF (11 mL) under argon atmosphere was added NBS (1.0 g, 5.6 mmol) at room temperature. The reaction mixture was gradually warmed to room temperature over 3 h and quenched with aqueous Na2S2O3 (10 mL). The biphasic mixture was extracted with EtOAc (30 ml x 2). The combined organic layer was washed with brine (15 ml x 2), dried over Na2SO4, concentrated under reduced pressure and purified by flash column chromatography (25% EtOAc-petroleum ether) to give intermediate 21 (1.2 g, 5.0 mmol, 89% yield as an orange liquid.

1H NMR (400 MHz, CDCl ₃ ) δ = 7.11 (d, J=8.5 Hz, 1H), 6.51 (t, J=8.8 Hz, 1H), 3.67 (br s, 2H), 1.80 (tt, J=8.6 , 5.7 Hz, 1H), 1.07–0.82 (m, 4H).

Intermediate 22: tert-Butyl (1-(4-bromo-3-cyclopropyl-2-fluorophenyl)-2oxopyrrolidin-3-yl)carbamate

K ₃ PO ₄ (1.0 g, 4.8 mmol) was added to a stirred solution of intermediate 21 (1.1 g, 4.8 mmol) in Acn (10 ml) at 0° C. under nitrogen atmosphere. The resulting mixture was treated with 2,4dibromobutanoyl chloride (0.60 mL, 4.5 mmol) and stirred for 2 h. Then K2CO3 (2.0 g, 14 mmol) was added and the mixture was stirred for 16 h. The solid was filtered through a pad celite, and the pad was washed with Acn (15 ml x 2). The filtrate was partially evaporated, ammonia (aqueous solution, 10 ml, 460 mmol) was added and the mixture was stirred at 40°C for 16 h. The mixture was extracted with EtOAc (20 ml x 3) and washed with brine (20 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated to give crude 3-amino-1-(4-bromo-3-cyclopropyl-2-fluorophenyl)pyrrolidin2-one (1.0 g, 3.2 mmol, 67% yield ), which was used in the next step without further purification.

TEA (0.98 ml, 7 0 mmol) and (Voc) ₂ O (0.90 ml, 3.9 mmol). The reaction mixture was stirred at room temperature for 6 hours. Then the reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 ml) and was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by flash chromatography (20% EtOAc-petroleum ether) to give intermediate 22 (1.0 g, 2.4 mmol, yield 69%). as a yellowish resinous solid. MS (ESI) m/z: 413.1 [M+H]+.

¹ H NMR (400 MHz, CDCl3) δ = 7.38 (dd, J=8.5, 1.5 Hz, 1H), 7.14-7.09 (m, 1H), 5.18 (br. s., 1H), 4.374.33 (m, 1H), 3.86-3.74 (m, 1H), 3.69-3.62 (m, 1H), 2.79-2.75 (m, 1H), 2.15-2.01 (m, 1H), 1.80 (tt, J=8.6, 5.7 Hz, 1H), 1.48 (s, 9H), 1.14–1.01 (m, 2H), 0.91–0.84 (m, 2H).

Intermediate 23: tert-Butyl (1-(2-cyclopropyl-2'-(dimethylphosphoryl)-3-fluoro-[1,1'biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a solution of intermediate 22 (0.50 g, 1.2 mmol) in 1,4-dioxane (10 ml) at room temperature was added (2-bromophenyl)dimethylphosphine oxide (0.42 g, 1.8 mmol), 4 ,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.92 g, 3.6 mmol) and K ₂ CO ₃ (0.42 g, 3.0 mmol). The reaction mixture was purged with nitrogen for 5 min and then loaded with PdCl ₂ (dppf).DCM (0.090 g, 0.12 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 100° C. for 16 h. The reaction mixture was cooled and filtered through a pad of celite and the filtrate was concentrated under reduced

- 33 043110 pressure. The crude intermediate was purified by flash chromatography (MeOH-CHCl ₃ ) to give intermediate 23 (0.30 g, 0.62 mmol, 51% yield) as an orange solid. MS (ESI) m/z: 487.1 [M+H]+.

1Н NMR (400 MHz, CDCl ₃ ) δ = 8.25-8.10 (m, 1H), 7.62-7.48 (m, 2H), 7.33-7.21 (m, 2H), 7.07-6.95 (m, 1H), 5.26-5.10 (m, 1H), 4.48-4.27 (m, 1H), 3.93-3.79 (m, 1H), 3.79-3.67 (m, 1H), 2.88-2.74 (m, 1H), 2.20-2.01 (m, 1H) , 1.54-1.37 (m, 16H), 1.04-0.85 (m, 2H), 0.73-0.68 (m, 2H).

Intermediate 24: 3-Amino-1-(2-cyclopropyl-2'-(dimethylphosphoryl)-3-fluoro-[1,1'biphenyl]-4-yl)pyrrolidin-2-one hydrochloride

To an ice-cold solution of intermediate 23 (0.33 g, 0.68 mmol) in 1,4-dioxane (1 ml) under argon atmosphere was added 4 M HCl in 1,4-dioxane (3.0 ml, 12 mmol) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a gummy solid. The crude product was triturated with petroleum ether (10 ml x 2) and dried to give intermediate 24 (0.26 mg, 0.67 mmol, 99% yield) as a brown, gummy solid. MS (ESI) m/z: 387.1 [M+H]+.

Intermediate 25: tert-Butyl (1-(4-bromo-3-fluoro-2-(trifluoromethyl)phenyl)-2oxopyrrolidin-3-yl)carbamate

K ₃ PO ₄ (0.58 d, 2.7 mmol). The resulting mixture was treated with 2,4-dibromobutanoyl chloride (0.29 ml, 2.2 mmol) and stirred for 2 h. Then K ₂ CO ₃ (1.1 g, 8.1 mmol) was added and the reaction mixture was stirred for 16 h. The mixture was filtered through a pad of celite and the pad was washed with Acn (15 ml x 2). The filtrate was partially evaporated and ammonia (aqueous) (10 ml, 462 mmol) was added. The mixture was stirred at 40°C for 16 h, and then was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and evaporated to give crude 3-amino-1-(4-bromo-2-fluoro-3-(trifluoromethyl)phenyl)pyrrolidin2-one (0.88 g, 2.6 mmol, 95% yield, which was used in the next step without further purification.

TEA (3.7 ml, 26 mmol) and (Voc) ₂ O (3.4 ml, 15 mmol). The reaction mixture was stirred at room temperature for 6 h and then quenched with saturated aqueous NH ₄ Cl (20 ml) and was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography (30% EtOAc-petroleum ether) to give intermediate 25 (4.8 g, 11 mmol, 82% yield ). as a yellowish resinous solid. MS (ESI) m/z: 442.8 [M+H]+.

'H NMR (300 MHz, CDCI3) δ = 7.82 (t, J=7.8 Hz, 1H), 7.02 (br. d., J=8.7 Hz, 1H), 5.23-5.05 (m, 1H), 4.43-4.23 (m, 1H), 3.80-3.53 (m, 2H), 2.89-2.68 (m, 1H), 2.21-2.03 (m, 1H), 1.47 (s, 9H).

Intermediate 26: tert-Butyl (1-(2'-(dimethylphosphoryl)-2-fluoro-3-(trifluoromethyl)[1,1'-biphenyl]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

NHBoc ^p ₃ ckh

Y J

ABOUT

II / and

To a solution of intermediate 25 (0.60 g, 1.4 mmol) in 1,4-dioxane (10 ml) at room temperature was added (2-bromophenyl)dimethylphosphine oxide (0.41 mg, 1.8 mmol), 4 ,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.52 g, 2.0 mmol) and K2CO3 (0 .56 mg, 4.1 mmol). reactionary

- 34 043110 the mixture was purged with nitrogen for 5 min and then loaded with PdCl2(dppf).DCM (56 mg, 0.070 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 100° C. for 16 hours. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/petroleum ether) to give intermediate 26 (0.30 g, 0.58 mmol, 43% yield) as an orange solid. MS (ESI) m/z: 515.1

Intermediate 27: 3-amino-1-(2'-(dimethylphosphoryl)-2-fluoro-3-(trifluoromethyl)-[1,1'biphenyl]-4-yl)pyrrolidin-2-one hydrochloride nh ₂ .hci

F ₃ C^k

Tj

II and

To an ice-cold solution of intermediate 26 (0.30 g, 0.58 mmol) in 1,4-dioxane (5 ml) under argon at room temperature was added 4 M HCl in 1,4-dioxane (5 ml) and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The solid was triturated with petroleum ether (10 mL x 2) and dried to give Intermediate 27 (0.20 g, 0.48 mmol, 83% yield) as a brown tarry solid. MS (ESI) m/z: 415.1 [M+H]+.

Intermediate 28: (S)-1-(4-bromo-2,3-difluorophenyl)-5-(hydroxymethyl)pyrrolidin-2one

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol) in 1,4-dioxane (15 mL) was added 1,4-dibromo-2,3 -difluorobenzene (2.4 g, 8.7 mmol), K ₃ PO ₄ (3.7 g, 17 mmol) and N,N'-dimethylethylenediamine (0.15 g, 1.7 mmol). The reaction mixture was purged with nitrogen for 5 min and then loaded with copper(I) iodide (0.17 g, 0.87 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 95° C. for 12 h. The reaction mixture was cooled, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (3% MeOH-CHCl ₃ ) to give intermediate 28 (0.80 g, 2.6 mmol, 30% yield) as a yellowish solid. MS (ESI) m/z: 305.9 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ = 7.59 (ddd, J=8.8, 7.0, 2.3 Hz, 1H), 7.24 (ddd, J=9.0, 7.0, 2.0 Hz, 1H), 4.80 (t, J =5.0 Hz, 1H), 4.20-4.04 (m, 1H), 3.37 (dd, J=5.0, 4.0 Hz, 2H), 2.56-2.45 (m, 1H), 2.43-2.35 (m, 1H), 2.25- 2.18 (m, 1H), 2.07-1.95 (m, 1H).

Intermediate 29: (S)-1-(4-bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one

To a stirred solution of intermediate 28 (0.80 g, 2.6 mmol) in DCM (10 mL) under argon at room temperature was added TEA (0.55 mL, 3.9 mmol) and tert-butyldimethylsilyl chloride (0.43 g, 2.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 ml) and extracted with DCM (20 ml x 2). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure. The crude product was purified by column chromatography (15% EtOAc-petroleum ether) to give intermediate 29 (0.85 g, 2.0 mmol, 77% yield) as a white solid. MS (ESI) m/z: 420.2 [M+H] ⁺ .

1Н NMR (400 MHz, CDCl ₃ ) δ = 7.35 (m, 1H), 7.15 - 7.05 (m, 1H), 4.24-4.17 (m, 1H), 3.62-3.49 (m, 2H), 2.69-2.63 (m , 1H), 2.54-2.50 (m, 1H), 2.41-2.26 (m, 1H), 2.14-2.03 (m, 1H), 0.84 (s, 9H), -0.02 (s, 3H), -0.05 (s , 3H).

- 35 043110

Intermediate 30: (3R,5S)-3-azido-1-(4-bromo-2,3-difluorophenyl-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one ^N 3 tbso _x / v

Br

To a stirred solution of intermediate 29 (1.0 g, 2.4 mmol) in THF (20 mL) at 78°C was added lithium diisopropylamide (1.8 mL, 3.6 mmol) and stirring was continued for 30 min. The mixture was then cannulated with a solution of 2,4,6-triisopropylbenzenesulfonyl azide (1.0 g, 3.3 mmol) in THF (5 ml) and the mixture was stirred for 4 h. The reaction mixture was then quenched with saturated aqueous NaHCO ₃ (2 ml) and gradually warmed to room temperature. The reaction mixture was diluted with EtOAc (40 ml), washed with H2O (10 ml x 2) and brine (20 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography (15% EtOAc-petroleum ether, 40 g column) to give Intermediate 30 (0.85 g, 1.8 mmol, 77% yield) as an orange solid. MS (ESI) m/z: 461.1 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.65 (ddd, J=9.0, 7.0, 2.0 Hz, 1H), 7.36-7.28 (m, 1H), 4.72-4.64 (m, 1H), 4.33- 4.24 (m, 1H), 3.63-3.52 (m, 2H), 2.48-2.28 (m, 1H), 2.14 (dt, J=13.3, 8.7 Hz, 1H), 0.91-0.66 (m, 9H), -0.06 (s, 3H), -0.08 (s, 3H).

Intermediate 31: tert-butyl ((3R,5S)-1-(4-bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxopyrrolidin-3-yl)carbamate

NHBoc

_TBSO4 /V

Br

To a stirred solution of intermediate 30 (0.85 g, 1.8 mmol) in THF (8 ml) was added triphenylphosphine (0.73 g, 2.8 mmol) and H ₂ O (0.8 ml). The reaction mixture was stirred at room temperature for 3 hours and heated at 65° C. for 6 hours. The solvent was evaporated under reduced pressure and used in the next step without further purification. To a stirred solution of crude (5S)-3-amino-1-(4-bromo-2,3-difluorophenyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one in DCM (5 ml) Boc anhydride (0.84 ml, 3.6 mmol) and TEA (0.75 ml, 5.4 mmol) were added under argon at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated aqueous NH ₄ Cl (15 ml) and extracted with CHCl ₃ (20 ml x 2). The combined organic layers were washed with brine (15 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure. The crude product was purified by column chromatography (15% EtOAc-petroleum ether) to give intermediate 31 (0.80 g, 1.5 mmol, 83% yield) as a white solid. MS (ESI) m/z: 535.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ = 7.41-7.32 (m, 1H), 7.15-7.01 (m, 1H), 5.02-5.22 (m, 1H), 4.73-4.61 (m, 1H), 4.52-4.43 ( m, 1H), 4.21-4.10 (m, 1H), 3.61-3.52 (m, 1H), 2.63-2.51 (m, 1H), 2.35-2.31 (m, 1H), 1.43 (s, 9H), 0.84 ( s, 9H), -0.06 (s, 3H), -0.08 (s, 3H).

Intermediate 32: tert-butyl ((3R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl ]-4-yl)-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of intermediate 31 (0.80 g, 1.49 mmol) in 1,4-dioxane (10 mL) was added (2-bromophenyl)dimethylphosphine oxide (0.52 g, 2.2 mmol), bis(pinacolato ) diboron (1.1 g 4.5 mmol) and K ₂ CO ₃ (0.42 mg, 3.0 mmol). The reaction mixture was purged with argon for 5 min and the PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.13 mg, 0.15 mmol) was loaded. The reaction mixture was again purged with nitrogen for 3 minutes and heated at 100° C. for 12 hours. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH/CHCl ₃ ) to give intermediate 32 (0.40 g, 0.66 mmol, 44% yield) as a brown solid. MS (ESI) m/z: 609.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ = 8.01-7.97 (m, 1H), 7.85-7.81 (m, 1H), 7.80-7.64 (m, 2H), 7.59-7.27

- 36 043110 (m, 3H), 4.66-4.56 (m, 1H), 4.42-4.33 (m, 1H), 3.76-3.55 (m, 2H), 2.46-2.28 (m, 2H), 1.54-1.39 (m , 15H), 0.84 (s, 9H), 0.06 (s, 3H), -0.08 (s, 3H).

Intermediate 33: (3R,5S)-3-amino-1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'biphenyl]-4-yl)-5-(hydroxymethyl)pyrrolidine- 2-one hydrochloride

To an ice-cold solution of intermediate 32 (0.40 g, 0.66 mmol) in 1,4-dioxane (1 mL) under argon at room temperature was added 4 M HCl in 1,4-dioxane (2.5 mL, 10 mmol) and stirred at room temperature for two hours. The solvent was evaporated under reduced pressure and the tarry solid was further triturated with EtOAc (10 mL x 2) and dried to give Intermediate 33 (0.22 g, 0.56 mmol, 85% yield) as a brown solid. MS (ESI) m/z: 395.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ = 7.97-7.88 (m, 1H), 7.82-7.72 (m, 1H), 7.69-7.47 (m, 2H), 7.43-7.25 (m, 2H), 4.35 -4.29 (m, 2H), 4.11-3.86 (m, 4H), 3.55-3.34 (m, 2H), 2.48-2.27 (m, 2H), 1.52 (brd, J=13.1 Hz, 6H).

Intermediate 34: 1-(4-Bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one

To a solution of racemic 5-methylpyrrolidin-2-one (1.0 g, 10 mmol) in 1,4-dioxane (10 ml) at room temperature was added 1,4-dibromo-2,3-difluorobenzene (3.3 g, 12 ml), K ₃ PO ₄ (4.3 g, 20 mmol) and N,N'-dimethylethylenediamine (0.18 g, 2.0 mmol). The reaction mixture was purged with nitrogen for 5 min and then loaded with copper(I) iodide (0.19 g, 1.0 mmol). The reaction mixture was again purged with nitrogen for 3 minutes and heated at 80° C. for 6 hours. The reaction mixture was cooled, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether-EtOAc) to give intermediate 34 (0.90 g, 3.1 mmol, 31% yield) as a brown liquid. MS (ESI) m/z: 291.0 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl3) δ = 7.38-7.01 (m, 1H), 6.99-6.96 (m, 1H), 4.24-4.20 (m, 1H), 2.62-2.51 (m, 2H), 2.50-2.38 (m, 1H), 1.81-1.76 (m, 1H), 1.17 (d, J=6.4 Hz, 3H).

Intermediate 35: 3-azido-1-(4-bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one

To a stirred solution of intermediate 34 (0.20 g, 0.69 mmol) in THF (3 ml) at -78°C was added lithium diisopropylamide (0.69 ml, 1.4 mmol) and stirring was continued for 40 minutes. The mixture was then cannulated with a solution of 2,4,6-triisopropylbenzenesulfonyl azide (0.26 g, 0.83 mmol) in THF (2 ml) and the mixture was stirred for 4 h. The mixture was then quenched with saturated aqueous NH ₄ Cl (10 ml) , gradually warmed to room temperature and extracted with EtOAc (20 ml x 2). The combined organic layers were washed with brine (15 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography (12% EtOAcpetroleum ether) to give Intermediate 35 (0.10 g, 0.21 mmol, 31% yield) as an orange solid. MS (ESI) m/z: 331.1 [M+H] ⁺ .

Ή NMR (400 MHz, CDCl3) δ = 7.40-7.36 (m, 1H), 7.04-6.98 (m, 1H), 4.36-4.31 (m, 1H), 4.26-4.21 (m, 1H), 2.32-2.26 ( m, 1H), 2.14-2.043 (m, 1H), 1.16 (d, J=6.4 Hz, 3H).

Intermediate 36: tert-Butyl (1-(4-bromo-2,3-difluorophenyl)-5-methyl-2oxopyrrolidin-3-yl)carbamate

To a stirred solution of 3-azido-1-(4-bromo-2,3-difluorophenyl)-5-methylpyrrolidin-2-one (1.5

- 37 043110 g, 4.5 mmol) in THF (21 ml) were added triphenylphosphine (2.4 g, 9.1 mmol) and water (3 ml). The reaction mixture was stirred at room temperature for 30 min and heated to 65°C for 6 h.

The solvent was evaporated under reduced pressure and the crude product was used in the next step without further purification.

TEA (0.82 ml, 5.9 mmol) and Boc anhydride (1.4 ml, 5.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated aqueous NH ₄ Cl (25 ml) and extracted with CHCl ₃ (30 ml x 2). The combined organic layers were washed with brine (25 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (50% EtOAc-petroleum ether) to give Intermediate 36 (1.3 g, 3.2 mmol, 82% yield) as a brown solid. MS (ESI) m/z: 405.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDClj) δ = 7.39-7.26 (m, 1H), 7.0-6.99 (m, 1H), 5.29-5.07 (m, 1H), 4.58-4.31 (m, 1H), 4.30-4.13 (m, 1H), 2.51-2.04 (m, 1H), 1.81-1.76 (m, 1H), 1.45 (s, 9H), 1.30-1.15 (m, 3H). (mixture of diastereomers)

Intermediate 37: tert-Butyl (1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]-4yl)-5-methyl-2-oxopyrrolidin-3-yl)carbamate

To a stirred solution of intermediate 36 (1.0 g, 2.5 mmol) in 1,4-dioxane (15 mL) was added (2-bromophenyl)dimethylphosphine oxide (0.58 g, 2.5 mmol), bis(pinacolato )diboron (1.9 g, 7.4 mmol) and K ₂ CO ₃ (1.0 g, 7.4 mmol). The reaction mixture was purged with nitrogen for 5 min and loaded with PdCl ₂ (dppf).CH ₂ Cl ₂ adduct (0.20 g, 0.25 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 110° C. for 15 h. The mixture was cooled, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (MeOH/CDCl ₃ ) to give intermediate 37 (0.70 g, 1.5 mmol, 59% yield) as a brown solid. MS (ESI) m/z: 479.2 [M+H]+.

1Н NMR (400 MHz, CDCl ₃ ) δ = 7.78-7.73 (m, 1H), 7.62-7.51 (m, 3H), 7.37-7.28 (m, 1H), 7.23-7.18 (m, 1H), 5.31-5.11 (m, 1H), 4.59-4.24 (m, 2H), 2.58-2.32 (m, 1H), 1.77-1.74 (m, 3H), 1.65-1.49 (m, 13H), 1.30-1.23 (m, 3H) . (Mixture of diastereomers).

Intermediate 38: 3-amino-1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]-4-yl)5-methylpyrrolidin-2-one hydrochloride

To an ice-cold solution of intermediate 37 (0.70 g, 1.5 mmol) in 1,4-dioxane (5 ml) under argon was added 4 M HCl (7.3 ml, 29 mmol) in 1,4-dioxane and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give intermediate 38 (0.50 g, 1.2 mmol, 82% yield) as a brown liquid. MS (ESI) m/z: 379.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.78-7.73 (m, 1H), 7.62-7.51 (m, 3H), 7.37-7.28 (m, 1H), 7.23-7.18 (m, 1H), 5.38- 4.98 (m, 3H), 4.59-4.42 (m, 2H), 2.58-2.29 (m, 1H), 1.71-1.63 (m, 3H), 1.55-1.49 (m, 4H), 1.30-1.23 (m, 3H ).

Example 1: (R)-N-(4'-(3-(3-(4-Chlorophenyl)ureido)-2-oxopyrrolidin-1-yl)-2',3'-difluoro-[1,1'biphenyl ]-2-yl)methanesulfonamide

- 38 043110

To a stirred solution of intermediate 5 (50 mg, 0.12 mmol) in DCE (2 mL) under nitrogen at room temperature were added successively DIPEA (0.084 mL, 0.48 mmol) and 1-chloro-4-isocyanatobenzene (22.0 mg , 0.144 mmol). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with ice water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude compound was purified by reverse phase chromatography followed by chiral HPLC as in Example 1 (16 mg, 0.028 mmol, 24%). RT = 1.732 min, 94.2% (method C); MS (ESI) m/z: 535.1 [M+H]+;

1H NMR (400 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.87 (s, 1H), 7.96 (s, 1H), 7.58-7.29 (m, 10H), 4.64-4.48 (m, 1H) , 3.96-3.82 (m, 1H), 3.81-3.66 (m, 1H), 2.74 (s, 3H), 2.59-2.55 (m, 1H), 2.20-2.07 (m, 1H).

Example 25: (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]-4yl)- 2-oxopyrrolidin-3-yl)urea

DIEA (61 ml, 350 mmol) was added slowly to a solution of intermediate 10 (28 g, 70 mmol) in DCE (560 ml) at 0°C. After stirring for 2 min, intermediate 11 (17 g, 63 mmol) was added and the reaction mixture was slowly heated to 50° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (5% MeOH in DCM). The product was purified by preparative HPLC, washed with water and dried to give the compound of Example 25 (29 g, 54 mmol, 78% yield) as a white solid.

Example 57: (R)-1-(1-(2'-(dimethylphosphoryl)-2,3-difluoro-[ 1,1'-biphenyl]-4-yl)-2-oxopyrrolidin-3yl)-3-( 2-fluoro-4-(trifluoromethyl)phenyl)urea

DIEA (5.5 ml, 6.2 mmol) was added slowly to a solution of intermediate 10 (2.5 g, 6.2 mmol) in DCE (70 ml) at 0°C. After stirring for 2 min, intermediate 12 (1.7 g, 5.6 mmol) was added and the reaction mixture was slowly heated to 50° C. and stirred for 8 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (6.5% MeOH in DCM). The product was purified by preparative HPLC, washed with water and dried to give the compound of Example 57 (2.2 g, 3.9 mmol, 62% yield) as a white solid.

Example 73: (R)-1-(1-(4-(2-(dimethylphosphoryl)pyridin-3-yl)-2,3-difluorophenyl)-2-oxopyrrolidin3-yl)-3-(2-fluoro-4 -(trifluoromethyl)phenyl)urea

To a solution of intermediate 14 (13 g, 24 mmol) and intermediate 15 (5.6 g, 24 mmol) in 1,4-dioxane (260 ml) and water (26 ml) was added potassium phosphate (10 g, 48 mmol ) and PdCl ₂ (dppf)CH ₂ Cl ₂ (2.0 g, 2.4 mmol). The reaction mixture was stirred for 30 min, the temperature was slowly raised to 110° C. and stirred for 12 h. The mixture was filtered through celite and the pad was washed with EtOAc. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography (2% MeOH in DCM) to give the compound of Example 73 (9.1 g, 16 mmol, 66% yield).

Example 89: (R)-1-(1-(2-Cyclopropyl-2'-(dimethylphosphoryl)-3-fluoro-[1,1'-biphenyl]-4-yl)-2oxopyrrolidin-3-yl)-3 -(2-fluoro-4-(trifluoromethyl)phenyl)urea

- 39 043110

To an ice-cold suspension of intermediate 24 (0.13 g, 0.34 mmol) in DMF (2 ml) under argon at room temperature was added DIEA (0.18 ml, 1.0 mmol) and intermediate 12 (0. 12 g, 0.41 mmol). The resulting solution was then heated at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography followed by chiral HPLC to give the compound of Example 89 (0.07 g, 0.12 mmol, 33% yield). .

Example 91: (R)-1 -(4-Chloro-2-fluorophenyl)-3-( 1 -(2'-(dimethylphosphoryl)-2-fluoro-3 -(trifluoromethyl)-[ 1,1'biphenyl]- 4-yl)-2-oxopyrrolidin-3-yl)urea

To an ice-cold suspension of intermediate 27 (0.080 g, 0.18 mmol) in DCE (2 ml) under argon at room temperature was added DIEA (0.06 ml, 0.36 mmol) and intermediate 11 (0.060 g, 0 .21 mmol). The resulting solution was then heated at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography followed by chiral HPLC to give the compound of Example 91 (0.060 g, 0.11 mmol, 60% yield) as a white solid.

Example 109 1-(4-chloro-2-fluorophenyl)-3-(1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'-biphenyl]-4-yl)5-methyl -2-oxopyrrolidin-3-yl)urea

To an ice-cold suspension of intermediate 38 (0.20 g, 0.48 mmol) in DCE (10 ml) under argon at room temperature was added DIEA (0.34 ml, 1.9 mmol) and intermediate 11 (73 mg , 0.25 mmol). The resulting solution was then heated at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography followed by chiral HPLC to give the compound of Example 109 (0.02 g, 0.04 mmol, 8.3 yield %) as a white solid.

Example 112: 1-(4-Chloro-2-fluorophenyl)-3-((3R,5S)-1-(2'-(dimethylphosphoryl)-2,3-difluoro-[1,1'biphenyl]-4) -yl)-5-(hydroxymethyl)-2-oxopyrrolidin-3-yl)urea

To an ice-cold suspension of intermediate 22 (0.11 g, 0.28 mmol) in DMF (2 mL)

- 40 043110 DIEA (0.15 ml, 0.84 mmol) and intermediate 11 (0.11 g, 0.42 mmol) were added under argon at room temperature. The resulting solution was then heated at 50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography followed by chiral HPLC to give the compound of Example 112 (0.05 g, 0.08 mmol, 29% yield) .

Connections according to the following examples in the table. 1 was obtained using the same procedure as shown above in examples 1, 25, 57, 73, 89, 91, 109 and 112.

Etc. Structure LCMS (M+H) + HPLC method, RT (min) and purity Ή NMR 2 HN-Z~V HNg{ ^{0 F} L G OH Y'F 490.1 Method D, RT = 1.75 min, 99.3% ΉNMR (400MHz, DMSO-de) δ = 8.64 (d, 7=2.2Hz, 1H), 8.16 (t, 7=8.8Hz, 1H), 7.63 (d, 7=7.6Hz, 1H), 7.54 - 7.32 ( m, 4H), 7.31 - 7.08 (m, 4H), 5.16 (t, 7=5.5 Hz, 1H), 4.63 - 4.48 (m, 1H), 4.35 (d, 7=5.4 Hz, 2H), 3.97 - 3.85 (m, 1H), 3.84 3.74 (m, 1H), 2.65 - 2.56 (m, 1H), 2.16 2.03 (m, 1H). 3 HN-Z Cl cl ⁰ LI OH pT iq 472.1 Method D, RT = 1.89 min, 98.9% Ή NMR (400 MHz, DMSO-de) δ = 8.86 (s, 1H), 7.63 (d, 7=7.6 Hz, 1H), 7.54 7.34 (m, 5H), 7.34 - 7.14 (m, 4H), 6.72 (d , 7=7.3Hz, 1H), 5.16 (t, 7=5.4Hz, 1H), 4.55 (dt, 7=10.1, 8.1Hz, 1H), 4.35 (d, 7=5.4Hz, 2H), 3.95 - 3.83 (m, 1H), 3.83 3.72 (m, 1H), 2.60 - 2.54 (m, 1H), 2.19 2.06 (m, 1H). 4 0% « °4 ^Z ° / ° mf O 588.2 (M+Nill Method D, RT = 1.66 min, 95.2% Ή NMR (400 MHz, DMSO-de) <5 = 9.18 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.60 7.45 (m, 2H), 7.45 - 7.31 (m, 4H), 7.26 7.20 (m, 1H), 7.03 - 6.97 (m, 1H), 4.604.52 (m, 1H), 3.98 - 3.82 (m, 2H), 3.79 3.73 (m, 1H), 2.87 (s, 3H), 2.18 - 2.06 (m, 1H). 5 Хъ, °% O 553.1 Method C, RT = 1.79 min, 96.8% Ή NMR (400MHz, DMSO-de) <5 = 9.18 (s, 1H), 8.65 (d, 7=2.2Hz, 1H), 8.16 (t, 7=8.9Hz, 1H), 7.56 - 7.29 (m, 6H ), 7.29 7.13 (m, 3H), 4.64 - 4.48 (m, 1H), 3.96 3.87 (m, 1H), 3.78-3.74 (m, 1H), 2.74 (s, 3H), 2.62 - 2.56 (m, 1H ), 2.13 - 2.01 (m,lH). 6 hn—/ W HN-Z V# V ^F laA'° ^F N ⁰ I j ^F I ^H o 1 T ⁰ 569.1 Method C, RT = 1.86 min, 97.2% Ή NMR (400 MHz, DMSO-de) <5 = 9.16 (s, 1H), 7.96 (s, 1H), 7.70 - 7.56 (m, 4H), 7.55 - 7.45 (m, 2H), 7.44 - 7.30 (m, 3H), 7.28 - 7.20 (m, 1H), 6.86 (d, 7=7.6 Hz, 1H), 4.60-4.54 (m, 1H), 3.96 - 3.86 (m, 1H), 3.77-3.75 (m, 1H) , 2.74 (s, 3H), 2.61 - 2.54 (m, 1H), 2.21 - 2.06 (m, 1H).

- 41 043110

7 ΗΝ-ΛΛ ΗΝ—Ζ \=/ ^{C 0 f/} ~^ Ν ⁰ Vx,F LX ,ογτ °' χχ 538.2 Method D, RT = 1.75 min, 95.9% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 8.65 (s, 1Η), 8.23 - 8.05 (m, 2H), 7.91 - 7.68 (m, 2H), 7.5 l(d, 7=7.3 Hz, 1H), 7.46 7.35 (m, 2H), 7.35 - 7.25 (m, 1H), 7.207.18 (m, 2H), 4.63 - 4.48(m, 1H), 3.943.87 (m, 1H), 3.83 - 3.69 (m, 1H), 3.05 (s, 3H), 2.63–2.54 (m, 1H), 2.10–2.05 (m, 1H). 8 ΗΝ4 ^Ν Ό-° πA 467.2 Method D, RT = 1.85 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.88 (s, 1H), 8.05 (d, 7=8.1 Hz, 1H), 7.96 7.85 (m, 1H), 7.79 - 7.63 (m, 2H), 7.59 7.49 ( m, 1H), 7.49 - 7.37 (m, 3H), 7.30 (d, 7=8.8 Hz, 2H), 6.75 (d, 7=7.6 Hz, 1H), 4.63 - 4.51 (m, 1H), 3.98 - 3.87 (m, 1H), 3.87 - 3.73 (m, 1H), 2.58 (br. s., 1H), 2.18-2.11 (m, 1H). 9 ««-НЪ d ^of L^o 485.1 Method D, RT = 1.91 min, 96.8% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (s, 1H), 8.15 (t, 7=8.9 Hz, 1H), 8.04 (d, 7=7.9 Hz, 1H), 7.94 - 7.83 (m, 1H) , 7.78 7.60 (m, 2H), 7.57 - 7.49 (m, 1H), 7.48 7.34 (m, 2H), 7.20 (d, 7=7.6Hz, 2H), 4.64 - 4.52 (m, 1H), 3.98 - 3.88 (m, 1H), 3.86 - 3.76 (m, 1H), 2.65 - 2.55 (m, 1H), 2.182.00 (m, 1H). 10 ΗΝ-ΛΛ ΗΝ—Ζ V=/ ^C / f O Ν ⁰ U^ ^F LX /° il ^F °' xx 520.1 Method D, RT = 1.69 min, 99.1% Ή NMR (400 MHz, DMSO-de) δ = 8.88 (s, 1H), 8.15 (dd, 7=7.7, 1.3 Hz, 1H), 7.89 - 7.71 (m, 2H), 7.52 (dd, 7=7.3, 1.5 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.36 - 7.22 (m, 3H), 6.74 (d, 7=7.6 Hz, 1H), 4.62 - 4.49 (m, 1H), 3.97 - 3.85 (m, 1H), 3.84 - 3.73 (m, 1H), 3.06 (s, 3H), 2.60 - 2.54 (m, 1H), 2.19-2.O7 (m, 1H). eleven HN-dV/ HN-^ XZX ^F / ( 0 ^h N ⁰ 554.2 Method D, RT = 1.81 min, 97.1% Ή NMR (400MHz, DMSO-de) <5 = 9.18 (s, 1H), 8.15 (dd, 7=7.8, 1.5Hz, 1H), 7.90 - 7.72 (m, 2H), 7.70 - 7.55 (m, 4H) , 7.52 (dd, 7=7.5, 1.3 Hz, 1H), 7.42 (t, 7=7.6 Hz, 1H), 7.36 - 7.25 (m, 1H), 6.86 (d, 7=7.3 Hz, 1H), 4.65 - 4.50 (m, 1H), 4.00 - 3.86 (m, 1H), 3.81-3.77 (m, 1H), 3.06 (s, 3H), 2.62 -2.54 (m, 1H), 2.16-2.11 (m, 1H). 12 HN —Z \ „ HN-^ VjZ ^C / ( 0 N ⁰ XX/NH ₂ 485.2 Method D, RT = 1.50 min, 96.9% Ή NMR (400MHz, DMSO-de) δ = 8.94 (s, 1H), 7.62 (s, 1H), 7.49 - 7.34 (m, 7H), 7.31 - 7.23 (m, 2H), 6.81 (d, 7=7.3 Hz, 1H), 4.61 -4.50(m, 1H), 4.16 (q, 7=6.8 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.79 - 3.74 (m, 1H), 3.60 - 3.20 (m, 2H), 2.61 - 2.54 (m, 1H), 2.17-2.07 (m, 1H), 1.35 (d, 7=6.6 Hz, ZN).

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13 HN-/Z \\ _r . HN-/ )=/ ^C lh o F ^{7 0} JJ ^F J* ^H 0 Г if '% o 554.1 Method D, RT = 1.67 min, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 9.40 (s, 1H), 9.15 (s, 1H), 8.77 (d, 7=7.1 Hz, 1H), 8.17 (d, 7=2.2 Hz, 1H ), 7.98 (dd, 7=10.3, 2.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.41 - 7.27 (m, 3H), 7.20 (t, 7=7.1 Hz, 1H), 4.68 - 4.55 ( m, 1H), 3.95–3.81 (m, 2H), 2.86 (s, 3H), 2.60–2.55 (m, 1H), 2.28–2.14 (m, lH). 14 ΗΝ-ΖΛ/ hn-^ l/V / ( o ^h N ⁰ 0 1 ^H 0 Г if '% ⁰ 533.2 Method C, RT = 2.07 min, 99.2% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 9.19 (s, 1H), 8.96 (br. s., 1H), 7.75 (d, 7=8.8 Hz, 2H), 7.65 - 7.56 (m, 4H), 7.45 (d, 7=8.8 Hz, 2H), 7.41 - 7.27 (m, 4H), 6.81 (d, 7=7.6 Hz, 1H), 4.58 - 4.49 (m, 1H), 3.89-3.79(m, 2H) , 2.73 (s, 3H), 2.51–2.50 (m,lH), 2.10–2.01 (m, 1H). 15 /=N HN-Z \ HN-^ ^C ' GU ⁰ N^O IJ ^F 1 H ₀ \Ύ ⁰ 537.2 Method D, RT = 1.54 min, 99.7% Ή NMR (400MHz, DMSO-de) <5 = 9.71 (s, 1H), 9.13 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 7.55 (d, 7=7.6 Hz, 1H ), 7.51 7.45 (m, 2H), 7.41 - 7.31 (m, 3H), 7.24 7.17 (m, lH), 4.58 - 4.49 (m, 1H), 3.893.79 (m, 2H), 2.88 (s, 3H ), 2.51-2.50 (m,lH), 2.20-2.10 (m, 1H). 16 ΗΝ-ΖΛ HN—/ \__/ ^Cl / C 0 N ⁰ and 1^ ^F F^Z II 460.1 Method D, RT = 2.00 min, 92.1% Ή NMR (400 MHz, DMSO-de) δ = 8.88 (s, 1H), 7.62 - 7.50 (m, 2H), 7.50 - 7.42 (m, 3H), 7.42 - 7.33 (m, 3H), 7.33 - 7.22 (m , 2H), 6.75 (d, 7=7.3 Hz, 1H), 4.65 4.49 (m, 1H), 3.97 - 3.84 (m, 1H), 3.84 3.70 (m, 1H), 2.61 - 2.53 (m, 1H), 2.21 2.04 (m, 1H). 17 HN-Γ\^, JM L-L ^C1 / 1 o N ⁰ F^A IJ ^F IH ₀ Λ ^Ν Ι ⁰ 536.1 Method D, RT = 1.66 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 9.43 (s, 1H), 9.15 (br. s., 1H), 8.23 (d, 7=2.7 Hz, 1H), 8.05 (d, 7=7.8 Hz, 1H ),7.8O (dd, 7=8.8, 2.7 Hz, 1H), 7.57 (d, 7=8.8 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.40 - 7.27 (m, 3H), 7.20(t , 7=7.1 Hz, 1H), 4.63 - 4.54 (m, 1H), 3.95-3.81 (m, 2H), 2.86 (s, 3H), 2.60 -2.55 (m, 1H), 2.21 -2.11 (m, 1H ). 18 HN^V/ J4 N-%V / v ^{0 F} N ⁰ F^xL I j ^F 1 ^H O 1 If '% ⁰ 571.2 Method D, RT = 1.68 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 10.13 (s, 1H), 9.12 (br. s., 1H), 9.05 (s, 1H), 8.73 (s, 1H), 7.89 (d, 7=7.6 Hz ,1H), 7.52 - 7.46 (m, 2H), 7.41 - 7.31 (m, 3H), 7.25 - 7.16 (m, 1H), 4.66 - 4.60 (m, 1H), 3.953.81 (m, 2H), 2.60 - 2.55 (m, 1H), 2.88 (s, 3H), 2.24 -2.13 (m, 1H). 19 ΗΝ-ΖΛ-η HN-^ V ⁰ ri ⁰ IJ f^ Z^F 1 and 461.1 Method D, RT = 1.73 min, 96.8% Ή NMR (400MHz, DMSO-de) δ = 8.88 (s, 1H), 8.38 (d, 7=4.6Hz, 1H), 8.16 (t, 7=7.9Hz, 1H), 7.56 (t, 7=6.2Hz , 1H), 7.53 - 7.35 (m, 4H), 7.30 (d, 7=9.0 Hz, 2H), 6.74 (d, 7=7.3 Hz, 1H), 4.64 - 4.49 (m, 1H), 3.96 - 3.85 ( m, 1H), 3.84 - 3.73 (m, 1H), 2.61 - 2.54 (m, 1H), 2.21 - 2.01 (m, 1H).

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20 ^ην --ΖΑ/ / ( o ⁿ Ν ⁰ O η ο \ ιΓ '% ⁰ 534.2 Method D, RT = 1.63 min, 98.8% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 9.43 (s, 1Η), 8.95 (s, 1H), 8.71 (d, 7=2.2 Hz, 1H), 8.19 (dd,7=8.7, 1.8 Hz, 1H ), 7.88 7.71 (m, 3H), 7.52 (d, 7=8.8 Hz, 2H), 7.47 - 7.28 (m, 4H), 6.99 (d, 7=7.3 Hz, 1H), 4.64 - 4.54 (m, 1H ), 3.99 - 3.78 (m, 2H), 2.74 (s, 3H), 2.50-2.46 (m, 1H) 2.15-2.02 (m, 1H). 21 ΗΝ-ΖΛ _Γι ΗΝ-Ζ V;/ ^Cl Γ~( ο F ~~ ST |^ ^F Μ 478.1 Method D, RT = 2.05 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (d, 7=2.2 Hz, 1H), 8.16 (t, 7=8.9 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.50 - 7.32 (m, 5H), 7.27 - 7.14 (m, 2H), 4.64 - 4.50 (m, 1H), 3.98 - 3.85 (m, 1H), 3.84 - 3.75 (m, 1H), 2.64 - 2.55 (m, 1H), 2.17 - 2.01(m, 1H). 22 / ( 0 n^ ⁰ TT.NH ₂ 485.2 Method D, RT = 1.55 min, 100% Ή NMR (400MHz, DMSO-de) δ = 8.97 (s, 1H), 7.61 (s, 1H), 7.53 - 7.33 (m, 7H), 7.33 - 7.22 (m, 2H), 6.84 (d, 7=7.3 Hz, 1H), 4.55 (m, 1H), 4.14 (q, 7=6.8 Hz, 1H), 3.91-3.84 (m, 1H), 3.78 - 3.73 (m, 1H), 2.64 - 2.55 (m, 1H) , 2.12 (m, 1H), 1.34 (d, 7=6.6 Hz, ZN). 23 F. hnT ^N C^ ^ci cl ⁰ Fvjv T j ^F I h _o GT /x o 554.2 Method D, RT = 1.46 min, 94.8% Ή NMR (400 MHz, DMSO-de) δ = 8.83 (br. s., 1H), 8.63 (br. s., 1H), 8.16 (t,7= 8.9 Hz, 1H), 8.08 (br. s., 1H), 7.47 - 7.32 (m, 2H), 7.32 - 7.10 (m, 4H), 6.65 (br. s., 1H), 4.64 - 4.48 (m, 1H), 3.92 - 3.82 (m, 1H), 3.75 (t,7= 8.7 Hz, 1H), 2.95 (br. s., 3H), 2.63 -2.54 (m, 1H), 2.21 - 1.96 (m, 1H). 24 ^ ^ω \ ° Λ O 0^2 j o 521.1 Method D, RT = 1.62 min, 99.7% 1H NMR (400 MHz, DMSO-de) δ 9.47 (s, 1H), 8.25 (d, 7=2.7 Hz, 1H), 8.15 (d, 7=7.6 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.88 7.72 (m, 3H), 7.65 (d, 7=9.3 Hz, 1H), 7.55 - 7.46 (m, 1H), 7.43 (t, 7=7.2 Hz, 1H), 7.31 (t, 7=7.0 Hz, 1H), 4.67 - 4.56 (m, 1H), 3.97 - 3.87 (m, 1H), 3.85 - 3.77 (m, 1H), 3.06 (s, 3H), 2.63 - 2.55 (m, 1H), 2.20 -2.10 ( m, 1H). 25 °4 O 0*^2 at O 536.2 Method D, RT = 1.476 min, 98.6% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (br. s., 1H), 8.16 (t,7= 9.0 Hz, 1H), 7.97 - 7.84 (m, 1H), 7.69 - 7.57 (m, 2H ), 7.43 (dd,7= 11.0.2.5 Hz, 1H), 7.40 -7.32 (m, 2H), 7.32 - 7.23 (m, 1H), 7.23 - 7.12 (m, 2H), 4.56 (dt,7= 9.9 , 8.1 Hz, 1H), 3.95 3.85 (m, 1H), 3.78 (br. t., 7= 8.8 Hz, 1H), 2.63 - 2.54 (m, 1H), 2.14 - 1.99 (m, 1H), 1.52 ( br.d.,7= 13.1 Hz, 6H).

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26 F. HN-Z 'V / ^Cl cl ° A 1 ⁿ o \ II ⁰ 557.2 Method D, RT = 1.89 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 8.95 (br.s., 1H), 8.63 (d, J = 22 Hz, 1H), 8.17 (t, J = 8.9 Hz, 1H), 7.52 - 7.24 (m , 7H), 7.23 - 7.13 (m, 2H), 7.12 (s, 1H), 4.63 4.47 (m, 1H), 3.82 (td, J= 9.5, 6.5 Hz, 1H), 3.71-3.59 (m, 1H) , 2.86 (s, 3H), 2.63 - 2.56 (m, 1H), 2.17 - 2.04 (m, 1H), 2.01 - 1.95 (m, 1H), 1.04 - 0.83 (m, 2H), 0.80 - 0.58 (m, 2H). 27 F ΗνΎ% HN-^ ^Cl / V '° IN ⁰ if) U °' ^x 559.2 Method D, RT = 1.868 min, 99.6% Ή NMR (400MHz, DMSO-d ₆ ) <5 = 9.01 (s, 1H), 8.62 (d, J= 2.0 Hz, 1H), 8.17 (t, J= 8.9 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.48 - 7.32 (m, 6H), 7.32 - 7.26 (m, 1H), 7.25 - 7.12 (m, 2H), 4.60 - 4.50 (m, 1H), 3.82-3.71 (m, 1H) , 3.56 (t, J= 9.3 Hz, 1H), 3.06 - 3.02 (m, 1H) 2.81 (s, 3H), 2.65 - 2.56 (m, 1H), 2.12 - 2.02 (m, 1H), 1.31 - 1.13 ( m, 6H). 28 E HN - HN~Z \L Y ^Cl d ° < N \ 464.1 Method D, RT = 1.732 min, 98.6% Ή NMR (400MHz, DMSO-de) δ = 8.62 (d, J=22Hz, 1H), 8.15 (t, 7= 8.9Hz, 1H), 7.84 (d, J= 2.4Hz, 1H), 7.80 - 7.68 (m, 1H), 7.49 - 7.28 (m, 2H), 7.24 - 7.06 (m, 2H), 6.73 - 6.61 (m, 1H), 4.63 - 4.46 (m, 1H), 3.94 (s, 3H), 3.91 -3.78 (m, 1H), 3.78 - 3.67 (m, 1H), 2.64 - 2.53 (m, 1H), 2.16 -2.01 (m, 1H). 29 Οί® about 1 °' \ j O 572.2 Method C, RT = 1.887 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.93 ( s, 1H), 8.41 (t, J= 8.4 Hz, 1H), 8.15 (dd, J= 7.9, 1.3 Hz, 1H), 7.90 - 7.72 (m, 2H), 7.66 (dd,7= 11.5, 1.7 Hz, 1H), 7.51 (dd, J= 7.5, 1.3 Hz, 2H), 7.46 - 7.37 (m, 1H), 7.37 - 7.21 (m, 2H), 4.65 - 4.51 (m, 1H), 4.00 -3.87 (m, 1H), 3.81 (ί,7=8.8Γ ₄ , 1H), 3.06 (s, 3H), 2.65 - 2.56 (m, 1H), 2.20-2.02 ( m, 1H). thirty o A z® \ / Г p ?Q< Χχ/Χ J ^{w w} \ 580.1 Method C, RT = 1.632 min, 98.7% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (s, 1H), 8.14 (t, 7= 8.8 Hz, 1H), 8.01 7.87 (m, 1H), 7.72 - 7.57 (m, 2H), 7.48 7.36 ( m, 2H), 7.29 (m, 2H), 7.23 - 7.16 (m, 1H), 7.10 (d, J= 7.6 Hz, 1H), 4.70 4.58 (m, 1H), 4.39 - 4.27 (m, 1H), 3.51 3.43 (m, 1H), 3.39 - 3.35 (m, 1H), 3.24 (s, 3H), 2.46 - 2.44 (m, 1H), 2.34 - 2.26 (m, 1H), 1.61-1.40 (m, 6H)

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31 E HN— HN-/ ^CFs rL ⁰ N^O % 524.2 Method D, RT = 1.719 min, 99.2% Ή NMR (400 MHz, DMSO-de) δ = 8.93 (d, 7= 2.4 Hz, 1H), 8.41 (t, 7= 8.2 Hz, 1H), 7.72 - 7.58 (m, 2H), 7.55 - 7.31 (m, 5H), 7.30 - 7.17 (m, 2H), 5.16 (t,7= 5.5 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.35 (d, 7= 5.6 Hz, 2H), 3.97 - 3.84 (m , 1H), 3.80 (t, 7 = 8.7 Hz, 1H), 2.61 (dd, 7= 19.4, 6.7 Hz, 1H), 2.15 -2.03 (m, 1H). 32 F HN—/'i hnA( ^Cl d ⁰ M n o G ii d kd ⁰ 535.2 Method C, RT = 1.550 min, 100% Ή NMR (400 MHz, DMSO-de) <5 = 9.11 (br. s., 1H), 8.63 (d, 7=2.4 Hz, 1H), 8.16 (t, 7= 8.9 Hz, 1H), 7.56 (t, 7= 8.2 Hz, 1H), 7.50 - 7.28 (m, 7H), 7.24 - 7.12 (m, 2H), 4.60 - 4.50 (m, 1H), 3.92 - 3.82 (m, 1H), 3.74 (t,7= 8.4 Hz, 1H), 2.86 (s, 3H), 2.60 (dd, 7= 12.0, 8.1 Hz, 1H), 2.14 -2.03 (m, 1H). 33 F HN—idX ^HN d Vj/ ^CF3 T ) ^F I ^H 0 Ad kd 0 587.2 Method C, RT = 1.726 min, 98.1% Ή NMR (400 MHz, DMSO-de) <5 = 9.12 (br. s., 1H), 8.93 (d, 7= 2.9 Hz, 1H), 8.41 (t, 7= 8.3 Hz, 1H), 7.66 (d, 7= 11.7 Hz, 1H), 7.56 - 7.43 (m, 3H), 7.43 - 7.27 (m, 4H), 7.23 (t, 7 =7.1 Hz, 1H), 4.66 - 4.54 (m, 1H), 4.00 - 3.86 (m, 1H), 3.78 (t,7= 9.2 Hz, 1H), 2.91 (s, 3H), 2.66 - 2.57 (m, 1H), 2.16 -2.04 (m, 1H). 34 F. HN-dd HN-Z \ud~~ ^C H ^{0 F} xJs. T j VV H ^H Ω 1 II d d> ⁰ 565.2 Method C, RT = 1.606 min, 96.7% Ή NMR (400MHz, DMSO-de) δ = 8.78 (s, 1H), 8.63 (d, 7= 2.7 Hz, 1H), 8.16 (t, 7= 8.9 Hz, 1H), 7.53 - 7.46 (m, 1H) , 7.46 - 7.36 (m, 2H), 7.34 - 7.15 (m, 5H), 7.11 (dd, 7= 8.4, 1.6 Hz, 1H), 4.60 - 4.49 (m, 1H), 3.94 - 3.80 (m, 1H) , 3.74 - 3.72 (m, 1H), 3.66 (s, 3H), 2.90 (s, 3H), 2.63 2.54 (m, 1H), 2.12 - 2.01 (m, 1H). 35 / 3¾ a O 502.1 Method D, RT = 1.634 min, 93.3% Ή NMR (400 MHz, DMSO-de) δ = 8.63 (d, 7= 2.2 Hz, 1H), 8.21 -8.10 (m, 1H), 7.59 (d, 7= 7.1 Hz, 1H), 7.50 - 7.35 (m, 2H), 7.33 (t, 7= 8.1 Hz, 1H), 7.28 - 7.12 (m, 4H), 7.06 (dd, 7= 8.1, 1.7 Hz, 1H), 5.06 (t, 7= 5.5 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.33 -4.29 (m, 2H), 3.94 - 3.81 (m, 1H), 3.75 (t,7= 8.8 Hz, 1H), 3.55 (s, 3H), 2.59 (dd, 7= 12.2.7.3 Hz, 1H), 2.14 - 1.98 (m, 1H).

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36 \ -π O ° oL '° y O 565.1 Method D, RT = 1.669 min, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 8.68 (s, 1H), 8.37 (s, 1H), 8.16 (t, J= 8.9 Hz, 1H), 7.56 - Ί3Ί (m, 3H), 7.35 - 7.15 (m, 5H), 7.15-7.05 (m, 1H), 4.59 - 4.49 (m, 1H), 3.87 (s, 3H), 3.79 (dd, J= 9.7, 6.5 Hz, 1H), 3.69 (t, J = 8.6 Hz, 1H), 2.88 (s, 3H), 2.59 (dd, J= 11.7.7.3 Hz, 1H), 2.13 - 1.96 (m, 1H). 37 qAl About ΖΙ about 1 %', 0^1 - at o 593.2 Method C, RT = 1.902min, 97.5% Ή NMR (400MHz, DMSO-de) δ = 8.97 (br. s., 1H), 8.49 - 8.30 (m, 2H), 7.65 (d, J= 11.7 Hz, 1H), 7.55 (d, 7= 2.0 Hz , 1H), 7.52 (d, J= 9.0 Hz, 1H), 7.48 - 7.22 (m, 7H), 4.59 - 4.52 (m, 1H), 3.83 - 3.77 (m, 1H), 3.57 - 3.55 (m, 1H ), 3.06 - 3.02 (m, 1H), 2.87 (s, 3H), 2.66 - 2.58 (m, 1H), 2.14 - 2.01 (m, 1H), 1.31 - 1.13 (m, 6H). 38 /°J-z ABOUT at o 496.2 Method C, RT = 1.863 min, 92.2% Ή NMR (400 MHz, DMSO-de) δ = 8.67 (s, 1H), 8.38 (s, 1H), 8.17 (m, 1H), 7.59 (d, J= 7.3 Hz, 1H), 7.49 - 7.30 (m, 4H), 7.30-7.11 (m, 4H), 4.61 -4.50(m, 1H), 4.43 (s, 2H), 3.91 (s, 1H), 3.81 - 3.76 (m, 1H), 3.59 - 3.56 (m, 1H), 3.04–3.01 (m, 1H), 2.64–2.55 (m, 1H), 2.14–2.03 (m, 1H), 1.31–1.13 (m, 6H). 39 E HN — HN-^ V_#~ ^CF3 HO / ( ^{0 F} xJ\ T j ^F Ύ> Qp 602.1 Method C, RT = 1.731 min, 92.6% Ή NMR (400 MHz, DMSO-de) δ = 8.92 (br. s., 1H), 8.41 (t, J= 8.4 Hz, 1H), 8.15 (d, J= Ί3 Hz, 1H), 7.91 - 7.76 (m , 2H), 7.66 (br. d., J= 12.0 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.43 - 7.29 (m, 2H), 7.25 (br. d., 7= 6.8 Hz, 1H ), 5.13 (br. d., J= 1.7 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.27 - 4.13 (m, 1H), 3.54 - 3.42 (m, 2H), 3.06 (s, 3H) , 2.57 - 2.24 (m, 1H), 2.35 - 2.31 (m, 1H). 40 E HN-Zp^, HN-Z ^Cl cl ° 1 4^0 Cr °\ kJ '° 544.2 Method D, RT = 1.851 min, 100% Ή NMR (400MHz, DMSO-de) δ = 8.63 (d, 7= 2.0Hz, 1H), 8.17 (t, 7= 8.9Hz, 1H), 8.12 (dd, 7= 7.9, 1.1Hz, 1H), 7.82 7.75 (m, 1H), 7.73 - 7.64 (m, 1H), 7.54 7.36 (m, 3H), 7.34 - 7.25 (m, 2H), 7.23 7.09 (m, 2H), 4.57 - 4.52 (m, 1H), 3.84 3.74 (m, 1H), 3.59 (t,7= 9.0 Hz, 1H), 3.06 - 3.02 (m, 1H), 2.82 (s, 3H), 2.65 2.56 (m, 1H), 2.13 -2.00 (m, 1H), 1.31 1.06 (m, 6H).

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41 ABOUT 9 . o /° 506.1 Method D, RT = 1.825 min, 97.2% Ή NMR (400 MHz, DMSO-d ₆ ) <5 = 9.15 (s, 1H), 7.78 - 7.50 (m, 5H), 7.50 - 7.43 (m, 1H), 7.43 - 7.31 (m, 2H), 7.30 - 7.16 (m, 2H), 6.85 (d, J= 7.3 Hz, 1H), 5.16 (t, J= 5.4 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.35 (d, J= 5.4 Hz, 2H) , 3.99 - 3.83 (m, 1H), 3.83 - 3.72 (m, 1H), 2.64 - 2.53 (m, 1H), 2.20 -2.05 (m, 1H). 42 F HN - {(A - hn-^ ^with HO / ( ^{0 χ Λ} _Ν ^ο F\J\ T ) ^F d>° u' 568.1 Method C, RT = 1.598 min, 98.9% Ή NMR (400 MHz, DMSO-de) <5 = 8.61 (br. s., 1H), 8.22 - 8.07 (m, 2H), 7.88 7.73 (m, 2H), 7.58 - 7.49 (m, 1H), 7.45 7.25 (m, 3H), 7.23 - 7.15 (m, 1H), 7.09 (d, J = 7.1 Hz, 1H), 4.76-4.64 (m, 1H), 4.24-4.13 (m, 1H), 3.99 - 3.87 (m , 1H), 3.49–3.45 (m, 2H), 3.05 (s, 3H), 2.57–2.55 (m, 1H), 2.26–2.21 (m, 1H). 43 F. hn~g \ ^HN % ^CF 3 A h o g g 591.2 Method C, RT = 2.008 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.08 8.82 (m, 2H), 8.42 (t, J= 8.3 Hz, 1H), 7.71 - 7.61 (m, 1H), 7.52 (d, J= 8.3 Hz, 1H ), 7.48 - 7.36 (m, 2H), 7.36 - 7.20 (m, 5H), 7.12 (s, 1H), 4.65 -4.52 (m, 1H), 3.83 (td, J= 92, 6.1 Hz, 1H), 3.66 (t, J= 9.2 Hz, 1H), 2.86 (s, 3H), 2.67 - 2.58 (m, 1H), 2.19-2.03 (m, 1H), 2.00 - 1.90 (m, 1H), 1.04 - 0.83 ( m, 2H), 0.79 - 0.62 (m, 2H). 44 HN—ALHN—VZ ^C H ^{0 F} F^J\ Xj ^f ^t ril ⁿ ^ ^N _r 1 0 545.2 Method C, RT = 1.776 min, 100% ^X H NMR (400 MHz, DMSO-de) δ = 8.63 (s, 1H), 8.33 (d, 7= 7.8 Hz, 1H), 8.15 (t, J= 8.9 Hz, 1H), 7.51 (s, 1H), 7.49 - 7.30 (m, 6H), 7.25 - 7.15 (m, 2H), 4.98 (m, 1H), 4.61 -4.51 (m, 1H), 3.89 (td, J= 9.5, 6.6 Hz, 1H), 3.77 ( t, J= 8.7 Hz, 1H), 2.58 (dd, J= 13.6, 5.7 Hz, 1H), 2.16 2.01 (m, 1H), 1.85 (s, 3H), 1.38 (d, J= 7.1 Hz, ZN) . 45 O With I/ G o X 542.2 Method C, RT = 1.778 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.63 (s, 1H), 8.17 (t, J= 8.9 Hz, 1H), 7.98 (dd, J= 12.8, 7.7 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.59 - 7.47 (m, 2H), 7.45 - 7.26 (m, 4H), 7.25 - 7.13 (m, 2H), 4.60 - 4.49 (m, 1H), 3.80 (f7=6.1Hz, 1H), 3.61 -3.52 (m, 1H), 3.07 - 2.99 (m, 1H), 2.59 - 2.55 (m, 1H), 2.28 - 1.99 (m, 1H), 1.33 (d, J= 13.4Hz, 6H), 1.23 - 1.10 (m, 6H). 46 577.2 Method C, RT = 1.716 min, 100% ^X H NMR (400 MHz, DMSO-de) δ = 8.64 (d, J= 2.4 Hz, 1H), 8.16 (t, 7= 8.9 Hz, 1H), 7.93 (dd, 7= 12.3,8.2 Hz, 1H), 7.61 (t, 7= 7.5Hz, 1H), 7.54 (t, 7= 7.5Hz, 1H), 7.42 (dd,7= 11.2,2.4Hz, 1H), 7.39 - 7.32 (m, 1H), 7.32 - 7.24 (m, 2H), 7.24 - 7.06 (m, 3H), 4.63 - 4.50 (m, 1H), 3.83 (td, 7= 9.6, 6.7 Hz, 1H), 3.67 (t, 7= 8.8 Hz, 1H), 2.65 - 2.56 (m, 1H), 2.16 - 2.05

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O at G r dh \__ (br, 1Н), 2.00 - 1.90 (br, 1Н), 1.34 (d, J= 13.2 Hz, ZN), 1.33 (d,J= 13.2 Hz, ZN), 0.98 - 0.84 (br, 2Н), 0.82 - 0.65 (m, 2H). 47 F. HN—Z'k HN—Z 'G/ ^C ri ⁰ : 560.2 Method C, RT = 1.760 min, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 8.80 (br. s., 1H), 8.62 (s, 1H), 8.25 - 8.05 (m, 2H), 7.68 - 7.51 (m, 2H), 7.51 - 7.35 (m, 2H), 7.31 - 7.10(m, 3H), 6.93 - 6.91 (m, 1H), 4.59 - 4.50 (m, 1H), 3.77 (d, J= 6.4 Hz, 1H), 3.56 (d, J = 8.3 Hz, 1H), 3.10 (s, 3H), 3.04 - 2.98 (m, 1H), 2.65 - 2.62 (m, 1H), 2.18 - 1.96 (m, 1H), 1.39 - 1.15 (m, 6H). 48 E hnA // ^Cl cl ⁰ A ^<N ^° *0 HO \ II /% 558.2 Method C, RT = 1.861 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 10.5 (br. s., 1H), 8.64 (d, J= 2.1 Hz, 1H), 8.31 - 8.04 (m, 2H), 7.71 (dd, J= 7.6, 1.7 Hz, 1H), 7.47 - 7.35 (m, 2H), 7.35 - 7.27 (m, 1H), 7.26 - 7.14 (m, 3H), 7.10 (br. s., 1H), 4.64 -4.50 (m, 1H ), 3.81 (td,J= 9.6, 6.5 Hz, 1H), 3.65 (t, J= 9.0 Hz, 1H), 3.20 (s, 3H), 2.66 - 2.57 (m, 1H), 2.15 2.02 (m, 1H ), 2.01 - 1.88 (m, 1H), 1.03 0.83 (m, 2H), 0.78 - 0.55 (m, 2H). 49 /% ABOUT About f O 519.1 Method C, RT = 1.469 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.45 (s, 1H), 8.25 (d, J= 2.7 Hz, 1H), 8.00 7.87 (m, 2H), 7.82 (dd, J= 9.0, 2.7 Hz, 1H ), 7.71 - 7.54(m, 3H), 7.44 - 7.31 (m, 2H), 7.31 - 7.22 (m, 1H), 4.66 - 4.56 (m, 1H), 4.01 - 3.85 (m, 1H), 3.84 - 3.76 (m, 1H), 2.59-2.86 (m, 1H), 2.21 - 2.11 (m, 1H), 1.52 (d,J= 13.2 Hz, 6H). 50 'v o 503.2 Method D, RT = 1.498 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (d, J =1.1 Hz, 1H), 8.20 - 8.08 (m, 1H), 7.62 (s, 1H), 7.53 - 7.28 (m, 6H), 7.25 7.16 (m, 2H), 4.62 - 4.49 (m, 1H), 4.17 (q, J= 6.6 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.82 - 3.72 (m, 1H), 3.34 (br. s ., 2H), 2.65 - 2.55 (m, 1H), 2.13 - 2.02 (m, 1H), 1.35 (d, 7= 6.6 Hz, ZN). 51 o1a dx o l O 9 Oh oh 568.2 Method C, RT = 1.709 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.99 (s, 1H), 7.99 - 7.86 (m, 1H), 7.73 - 7.57 (m, 2H), 7.57 - 7.44 (m, 2H), 7.42 - 7.32 (m , 2H), 7.32 - 7.14 (m, 3H), 6.81 (d, J= 7.3 Hz, 1H), 4.61 - 4.49 (m, 1H), 3.94 3.84 (m, 1H), 3.83-3.71 (m, 1H) , 2.61 2.53 (m, 1H), 2.18 - 2.05 (m, 1H), 1.52 (d,J = 13.2 Hz, 6H).

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52 ω .у η ι \ 1 ρ α ζ .ί \__ ° \__ υ ^ζ 4^Ο 538.1 Method D, RT = 1.774 min, 100% Ή NMR (400MHz, DMSO-de) δ = 8.61 (d, J= 2.2 Hz, 1H), 8.23 - 8.04 (m, 2H), 7.87 -7.63 (m, 2H), 7.49 (dd,7=7.5, 1.1 Hz, 1H), 7.42 (dd, J= 11.1, 2.3 Hz, 1H), 7.35 (d, 7= 9.0 Hz, 2H), 7.24 - 7.11 (m, 2H), 4.63 - 4.50 (m, 1H), 3.83 - 3.75 (m, 1H), 3.75 - 3.67 (m, 1H), 3.05 (s, 3H), 2.63-2.55 (m, 1H), 2.19-2.08 (m, 1H). 53 Ε ΗΝ-^ν,, ΗΝ—/ ^Cl d ° FAo FxJ\^ ^F mu 1* 536.1 Method C, RT = 1.594 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.65 8.57 (m, 1H), 8.19 - 8.12 (m, 1H), 7.96 7.86 (m, 1H), 7.69 - 7.56 (m, 2H), 7.46 7.37 (m, 4H), 7.24 - 7.17 (m, 2H), 4.64 4.53 (m, 1H), 3.84 - 3.67 (m, 2H), 2.66 2.57 (m, 1H), 2.19 - 2.06 (m, 1H), 1.52 (d, 7= 13.2Hz, 6H). 54 o / °' \ f ο _χ 516.2 Method C, RT = 1.485 min, 98.5% Ή NMR (400MHz, DMSO-de) δ = 8.49 (s, 1H), 8.14 (dd, 7= 7.8, 1.5 Hz, 1H), 7.91 -7.71 (m, 2H), 7.51 (dd,7=7.8, 1.5 Hz, 1H), 7.41 (t, 7= 7.8 Hz, 1H), 7.38 7.22 (m, 3H), 6.92 - 6.74 (m, 2H), 6.56 (d, 7= 7.3 Hz, 1H), 4.56 - 4.50 ( m, 1H), 3.99 - 3.83 (m, 1H), 3.83 - 3.75 (m, 1H), 3.71 (s, 3H), 3.06 (s, 3H), 2.61 - 2.54 (m, 1H), 2.20 -2.01 ( m, 1H). 55 LA_TS /> ⁴ \ / L O / o A o 571.2 Method C, RT = 1.589 min, 100% Ή NMR (400MHz, DMSO-de) δ = 9.86 (s, 1H), 9.13 (d, 7= 6.8 Hz, 1H), 8.49 (s, 1H), 8.22 (dd,7= 10.4, 1.8 Hz, 1H) , 8.00 - 7.84 (m, 1H), 7.72 - 7.56 (m, 2H), 7.46 - 7.30 (m, 2H), 7.27 (t, J = 7.8 Hz, 1H), 4.74 - 4.61 (m, 1H), 4.00 - 3.87 (m, 1H), 3.86 - 3.78 (m, 1H), 2.66 - 2.56 (m, 1H), 2.30-2.17 (m, 1H), 1.52 (d,7= 13.2 Hz, 6H). 56 '\/° O 0^2 A ABOUT 537.2 Method C, RT = 1.475 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.44 (s, 1H), 8.68 (d, 7=6.8 Hz, 1H), 8.19 (s, 1H), 8.05 (dd, 7= 10.0, 2.2 Hz, 1H) , 7.98 - 7.88 (m, 1H), 7.67 - 7.40 (m, 2H), 7.47 7.31 (m, 2H), 7.29 - 7.21 (m, 1H), 4.70 4.62 (m, 1H), 3.98 - 3.84 (m, 1H), 3.84 3.74 (m, 1H), 2.63 - 2.55 (m, 1H), 2.27 2.13 (m, 1H), 1.52 (d,7= 13.2 Hz, 6H). 57 E ΗΝ—Τλ HN-V ^CF 3 A ⁰ i 570.2 Method C, RT = 1.728 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.93 (d, 7= 2.0 Hz, 1H), 8.41 (t, 7= 8.6 Hz, 1H), 7.98 - 7.85 (m, 1H), 7.72 - 7.55 (m, 3H), 7.51 (d, 7= 8.3 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.30 - 7.22 (m, 1H), 4.65 - 4.54 (m, 1H), 3.96 - 3.85 (m, 1H) , 3.79-3.45 (m, 1H), 2.65 - 2.57 (m, 1H), 2.16 - 2.02 (m, 1H), 1.52 (d,7= 13.2 Hz, 6H).

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58 E ΗΝ-ΖΆ hn-Z ^c ri ⁰ 537.2 Method C, RT = 1.671 min, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 8.75 (br.s., 1H), 8.19 (d, 7= 8.1 Hz, 1H), 8.14 (t, J= 8.9 Hz, 1H), 7.78 - 7.67 ( m, 2H), 7.46 - 7.23 (m, 5H), 7.23 - 7.16 (m, 1H), 4.61 - 4.50 (m, 1H), 4.27 (br. s., 1H), 3.96 - 3.85 (m, 1H) , 3.82 - 3.75 (m, 1H), 2.93 - 2.89 (m, 3H), 2.62 - 2.54 (m, 1H), 2.15 - 2.04 (m, 1H). 59 Al-O 7? Oh J A ABOUT 537.2 Method C, RT = 1.672 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.76 (br. s., 1H), 8.26 - 8.06 (m, 2H), 7.81 7.64 (m, 2H), 7.51 - 7.29 (m, 5H), 7.20 (ddd , 7= 9.0, 2.4, 1.3 Hz, 1H), 4.56 (dd, 7 = 17.9, 8.3 Hz, 1H), 4.28 (br. s., 1H), 3.92 - 3.90 (m, 1H), 3.79 (t, 7= 8.3 Hz, 1H), 2.93 - 2.89 (m, 3H), 2.64 - 2.53 (m, 1H), 2.16-2.01 (m, 1H). 60 b A V° o v° 576.3 Method C, RT = 2.041 min, 100% 41 NMR (400 MHz, DMSO-de) δ = 8.91 (d, 7= 2.9 Hz, 1H), 8.43 (t, 7= 8.6 Hz, 1H), 7.98 (dd, 7= 12.7, 7.8 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.60 - 7.47 (m, 3H), 7.37 (dd, 7= 7.0, 3.5 Hz, 1H), 7.35 - 7.23 (m, 3H), 4.63 -4.51 (m, 1H), 3.86 -3.74 (m, 1H), 3.58 (t, 7= 8.7 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.66 - 2.56 (m, 1H), 2.17 - 2.02 (m, 1H), 1.34 (d ,7= 13.2 Hz, 6H), 1.18 (d, 7= 6.8 Hz, ZN), 1.20 (d, 7= 6.8 Hz, ZN). 61 €^~С^rch ~°l ° _O X Qj o 543.2 Method C, RT = 1.774 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 9.44 (s, 1Η), 8.67 (d, 7= 5.9 Hz, 1H), 8.19 (d, 7= 2.2 Hz, 1H), 8.04 (dd, 7= 10.1, 2.2 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.68 - 7.59 (m, 1H), 7.59 - 7.48 (m, 2H), 7.37 (dd,7 = 6.4, 4.2 Hz, 1H), 7.31 (d ,7= 1.0 Hz, 2H), 4.60-4.55 (m, 1H), 3.83 - 3.75 (m, 1H), 3.64 - 3.59 (m, 1H), 3.13 - 3.05 (m, 1H), 2.63 - 2.54 (m , 1H), 2.29 - 2.20 (m, 1H), 1.34 (d,7= 13.2 Hz, 6H), 1.19 (d, 7 = 6.8 Hz, ZN), 1.20 (d, 7= 6.8 Hz, ZN). 62 O ^ O“ ^z 01 / V o' f za o 524.2 Method C, RT = 1.607 min, 99.6% Ή NMR (400MHz, DMSO-de) δ = 9.74 (br. s., 1H), 8.90 (d,7= 1.5Hz, 1H), 8.41 (d,7= 1.2Hz, 1H), 7.98 -7.89 (m , 1H), 7.67 - 7.43 (m, 3H), 7.41 - 7.20 (m, 3H), 7.13 (d,7= 1.7 Hz, 1H), 4.64-4.54 (m, 1H), 3.83 (td,7= 9.5 , 6.7 Hz, 1H), 3.73 3.65 (m, 1H), 2.65 - 2.56 (m, 1H), 2.24 2.13 (m, 1H), 2.03 - 1.93 (m, 1H), 1.34 (d,7= 13.2 Hz, 6H), 1.02 - 0.82 (m, 2H), 0.80 - 0.65 (m, 2H).

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63 O G ,9 >- 520.2 Method C, RT = 1.517 min, 100% 41 NMR (400 MHz, DMSO-de) δ = 9.83 (br. s., 1H), 8.90 (s, 1H), 8.41 (d, J= 1.5 Hz, 1H), 7.99 - 7.85 (m, 1H), 7.73 - 7.53 (m, 3H), 7.51 - 7.30 (m, 2H), 7.30 - 7.20 (m, 1H), 4.67 - 4.55 (m, 1H), 3.95 - 3.87 (m, 1H), 3.80-3.77 (m, 1H), 2.64 - 2.56 (m, 1H), 2.28 - 2.00 (m, 1H), 1.52 (d, J= 13.2 Hz, 6H). 64 QA-l About l O 0^2 R O 553.3 Method C, RT = 1.742 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.79 (s, 1H), 8.59 (s, 1H), 8.08 (dd, J= 8.8, 2.2 Hz, 2H), 7.96 -7.86 (m, 1H), 7.79 ( d, J= 8.8 Hz, 1H), 7.72 - 7.55 (m, 2H), 7.45 - 7.31 (m, 2H), 7.31 - 7.23 (m, 1H), 4.70 - 4.59 (m, 1H), 3.98 - 3.84 ( m, 1H), 3.84 - 3.74 (m, 1H), 2.65 - 2.55 (m, 1H), 2.28 -2.08 (m, 1H), 1.53 (d, J= 13.2 Hz, 6H). 65 OAr. >0 o / O O*^ R o Ξ th 514.3 Method C, RT = 1.496 min, 97.9% 41 NMR (400 MHz, DMSO-de) δ = 8.48 (s, 1H), 7.98 - 7.88 (m, 1H), 7.72 - 7.52 (m, 2H), 7.43 - 7.19 (m, 5H), 6.88 - 6.77 (m , 2H), 6.55 (d, J =7.3 Hz, 1H), 4.58 4.49 (m, 1H), 3.93 - 3.83 (m, 1H), 3.773.74 (m, 1H), 3.71 (s, 3H), 2.60 - 2.54 (m, 1H), 2.23 - 1.99 (m, 1H), 1.52 (d, J= 13.2 Hz, 6H). 66 E HN - \ „r. HN—ZV // ^SRz cl ⁰ T j ^F γο ₄ AXA GT NH 571.2 Method C, RT = 1.815 min, 96.2% Ή NMR (400 MHz, DMSO-de) δ = 8.41 (t, 7=8.2 Hz, 1H), 8.18 (br. s., 1H), 7.80 - 7.69 (m, 2H), 7.67 (d, J= 10.0 Hz , 1H), 7.52 (d, J= 8.6 Hz, 1H), 7.46 - 7.29 (m, 4H), 7.29 - 7.06 (m, 1H), 4.65 - 4.53 (m, 1H), 3.98 - 3.86 (m, 1H ), 3.80 (t, J= 8.9 Hz, 1H), 2.93 - 2.89 (m, 3H), 2.64 - 2.55 (m, 1H), 2.16-2.04 (m, 1H). 67 fj o 565.2 Method C, RT = 1.804 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.45 (s, 1H), 8.69 (d, J= 6.4 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J= 10.3 Hz, 1H), 7.89 (dd, J= 11.5,7.3 Hz, 1H), 7.64 (quin, J= 7.8 Hz, 2H), 7.48 - 7.26 (m, 2H), 7.17 (t, J= 7.9 Hz, 1H), 4.70 - 4.59 ( m, 1H), 3.96 3.85 (m, 1H), 3.85 - 3.74 (m, 1H), 2.63 2.54 (m, 1H), 2.29 - 2.11 (m, 1H), 1.80 1.60 (m, 4H), 0.93 - 0.88 (m, 6H). 68 ρ-ϊ 598.2 Method C, RT = 2.038 min, 100% Ή NMR (400 MHz, DMSO-de) <5 = 8.91 (br. s., 1H), 8.41 (t, J= 8.6 Hz, 1H), 7.97 - 7.83 (m, 1H), 7.75 - 7.56 (m, 3H ), 7.51 (d, J= 8.8 Hz, 1H), 7.42 - 7.23 (m, 3H), 7.22 - 7.11 (m, 1H), 4.63 - 4.51 (m, 1H), 3.96 - 3.87 (m, 1H), 3.81-3.76 (m, 1H), 2.64 - 2.56 (m, 1H), 2.17 - 2.02 (m, 1H), 1.80 - 1.60 (m, 4H), 0.93 - 0.88 (m, 6H).

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69 F ΗΝ-Ζ \_U~ ^0SR s cL ° Τ J A 586.2 Method C, RT = 1.903 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.70 (s, 1H), 8.22 (t, J= 9.2 Hz, 1H), 7.92 (dd, J= 12.5, 7.8 Hz, 1H), 7.73 - 7.55 (m, 2H), 7.49 - 7.30 (m, 3H), 7.30 - 7.23 (m, 1H), 7.23 - 7.09 (m, 2H), 4.63 - 4.52 (m, 1H), 4.00 - 3.84 (m, 1H), 3.80- 3.75 (m, 1H), 2.64 -2.56 (m, 1H), 2.18 - 2.01 (m, 1H), 1.52 (d,J= 13.2 Hz, 6H). 70 Ε ^ην Α νΛ~ ^Cl cl ° SPo 554.2 Method C, RT = 1.663 min, 99.2% 41 NMR (400 MHz, DMSO-de) δ = 8.63 (d, 7= 5.4 Hz, 1H), 8.16 (t, 7= 8.9 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.52 - 7.36 (m, 2H), 7.35 - 7.24 (m, 1H), 7.24 - 7.08 (m, 4H), 4.61 - 4.50 (m, 1H), 3.94 - 3.82 (m, 1H), 3.79 - 3.67 (m, 1H), 2.59 ( dd, 7 = 12.7, 7.6 Hz, 1H), 2.13 -2.01 (m, 1H), 1.86 - 1.59 (m, 6H) 71 oh oh 532.3 Method D, RT = 1.383 min, 98.9% 41 NMR (400 MHz, DMSO-de) δ = 8.24 (s, 1H), 7.92 (dd, 7= 12.2, 8.1 Hz, 1H), 7.84 (t, 7= 9.3 Hz, 1H), 7.74 - 7.55 (m, 2H), 7.37 (d,7= 6.8Hz, 2H), 7.30 - 7.22 (m, 1H), 6.97 (d, J=7.1Hz, 1H), 6.87 (dd, 7= 12.2, 2.6Hz, 1H), 6.72 (dd, 7= 8.9, 1.8 Hz, 1H), 4.61 - 4.48 (m, 1H), 3.95 3.84 (m, 1H), 3.82 - 3.59 (m, 1H), 3.74 (s, 3H), 2.62 - 2.55 (m, 1H), 2.15-2.02 (m, 1H), 1.52 (d,7= 13.2 Hz, 6H). 72 E HN—^X ^r- HN—ZV // ^CF 3 cl ⁰ 588.2 Method C, RT = 1.794 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.95 (dd, 7= 8.2, 2.5 Hz, 1H), 8.41 (t, 7= 8.2 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.53 - 7.43 ( m, 2H), 7.38 - 7.28 (m, 2H), 7.23 - 7.16 (m, 2H), 4.62 - 4.54 (m, 1H), 3.94 - 3.83 (m, 1H), 3.81 - 3.70 (m, 1H), 2.64 - 2.53 (m, 1H), 2.16-2.02 (m, 1H), 1.76 - 1.64 (m, 6H). 73 aarCH _ζ ^η AH Hz o J 0 ^ 2 X q 588.2 (M+N Hl Method D, RT = 1.647 min, 100% 41 NMR (400 MHz, DMSO-de) δ = 8.94 (d, 7= 2.9 Hz, 1H), 8.84 (d, 7= 4.2 Hz, 1H), 8.42 (t, 7= 8.3 Hz, 1H), 7.87-7.86 (m, 1H), 7.73 - 7.62 (m, 2H), 7.52 (d, 7= 8.6 Hz, 1H), 7.43 - 7.25 (m, 3H), 4.65 4.52 (m, 1H), 3.98 - 3.86 (m, 1H), 3.82 3.70 (m, 1H), 2.64 - 2.56 (m, 1H), 2.16 2.04 (m, 1H), 1.62 (d,7= 13.2 Hz, 6H).

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74 E HN—/L HN—/ 'dz ^C ri ⁰ t j Td d- ^N 554.2 (M+N well Method D, RT = 1.498 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.84 (brd, 7= 4.2 Hz, 1H), 8.64 (s, 1H), 8.15 (t, 7= 8.9 Hz, 1H), 7.86 (dd, 7= 3.5, 7.5 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.42 (dd, J = 2.4, 11.0 Hz, 1H), 7.37 (brd,7= 8.1 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.20 (br d, J = 7.6 Hz, 2H), 4.62 - 4.50 (m, 1H), 3.95 3.84 (m, 1H), 3.82-3.71 (m, 1H), 2.64 2.56 (m, 1H), 2.13 - 2.00 (m, 1H), 1.62 (d, 7= 13.4 Hz, 6H). 75 --4 o 0 Ζ^Λ _ O' \_ X/yXXJ 564.2 Method C, RT = 1.723 min, 99.9% Ή NMR (400 MHz, DMSO-de) δ = 8.62 (d, 7= 2.4 Hz, 1H), 8.16 (t, 7= 8.9 Hz, 1H), 7.87 (ddd, 7= 11.6.7.5, 1.7 Hz, 1H) , 7.70 - 7.53 (m, 2H), 7.43 (dd, 7 = 11.0, 2.4 Hz, 1H), 7.36 (ddd, 7= 7.5, 3.6, 1.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.23 7.16 (m, 2H), 4.64 - 4.50 (m, 1H), 3.84 - 3.74 (m, 1H), 3.73 - 3.63 (m, 1H), 2.66 2.57 (m, 1H), 2.19 - 2.01 (m, 1H), 1.71 (m, 4H), 0.93 - 0.88 (m, 6H). 76 b ^? r° ο , V 570.2 Method C, RT = 1.867 min, 98.9% Ή NMR (400 MHz, DMSO-de) δ = 8.91 (d, 7= 2.9 Hz, 1H), 8.41 (m, 1H), 7.91 (ddd, 7= 13.0, 7.6, 1.2 Hz, 1H), 7.73 7.56 (m , 3H), 7.52 (d, 7= 9.5 Hz, 1H), 7.46 -7.38 (m, 3H), 7.35 (d,7=7.1 Hz, 1H), 4.68 - 4.55 (m, 1H), 3.85 - 3.76 ( m, 1H), 3.74 - 3.66 (m, 1H), 2.67 - 2.59 (m, 1H), 2.21-2.10 (m, 1H), 1.49 (d, 7 = 13.5 Hz, 6H). 77 b ^w o 586.2 Method C, RT = 1.781 min, 99.8% Ή NMR (400 MHz, DMSO-de) δ = 8.95 (t, 7= 3.2 Hz, 1H), 8.42 (t, 7= 8.2 Hz, 1H), 8.01 - 7.90 (m, 1H), 7.70 - 7.58 (m, 3H), 7.55 - 7.47 (m, 2H), 7.39 - 7.21 (m, 3H), 4.63 - 4.53 (m, 1H), 3.97 - 3.85 (m, 1H), 3.82 - 3.70 (m, 1H), 2.64 - 2.55 (m, 1H), 2.17 -2.03 (m, 1H), 1.48 (d,7 = 12.8 Hz, VN), 1.46 (d, 7= 12.8 Hz, VN). 78 F. HN—(dd HN—/ dd~ ^C x ° Cl^d\ X ] ci^d Cd 568.1 Method C, RT = 1.691 min, 99.8% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (dd, 7= 6.1, 2.4 Hz, 1H), 8.17 (t, 7= 8.9 Hz, 1H), 7.98 - 7.88 (m, 1H), 7.70 - 7.57 ( m, 2H), 7.54 - 7.39 (m, 3H), 7.29 (td, 7 = 3.5, 7.1 Hz, 1H), 7.24 - 7.13 (m, 2H), 4.63 - 4.49 (m, 1H), 3.87 - 3.76 ( m, 1H), 3.73 - 3.64 (m, 1H), 2.66 - 2.57 (m, 1H), 2.16 - 2.01 (m, 1H), 1.52 - 1.44 (m, 6H).

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79 F HN-T M ⁰ NN T ^F F 500.1 Method C, RT = 1.763 min, 100% Ή NMR (400 MHz, DMSO-d ₆ ) δ = 8.73 (s, 1H), 8.63 (d, J= 2.2 Hz, 1H), 8.33 (s, 1H), 8.15 (t, J= 8.8 Hz, 1H), 7.90 (s, 1H), 7.70 (t, J= 7.2 Hz, 1H), 7.48 - 7.33 (m, 2H), 7.29 - 7.11 (m, 2H), 4.55 (dd, J = 18.1,8.6 Hz, 1H) , 3.92–3.84 (m, 1H), 3.81–3.72 (m, 1H), 2.61 (m, 1H), 2.12–2.00 (m, 1H). 80 F HN— HN^ZV // ^CF 3 d ⁰ Cl^iC T ] Cl%< CT 602.1 Method C, RT = 1.821 min, 99.5% Ή NMR (400 MHz, DMSO-de) δ = 8.94 (dd, J= 5.9, 2.9 Hz, 1H), 8.42 (m, 1H), 7.99 - 7.89 (m, 1H), 7.72 - 7.55 (m, 3H), 7.54.7.44 ( _m , 3H), 7.35 (dd, J= 7.1, 2.9 Hz, 1H), 7.32 - 7.24 (m, 1H), 4.65 - 4.53 (m, 1H), 3.87 - 3.78 (m, 1H), 3.74 - 3.67 (m, 1H), 2.63 (dt, J= 6.4, 5.1 Hz, 1H), 2.17 - 2.03 (m, 1H), 1.50 - 1.45 (m, 6H). 81 Ο-η CyJX>-ZC ' \ / i z Λ o J About O%2 a O 552.2 Method D, RT = 2.358 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (br. s., 1H), 8.15 (t, J= 8.8 Hz, 1H), 7.94 (dd, J= 12.5, 1.5 Hz, 1H), 7.69 -7.58 (m, 2H), 7.55 - 7.48 (m, 1H), 7.42 (dd, J= 11.3,2.3 Hz, 1H), 7.32 (d, 7=7.8 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.22 - 7.16 (m, 2H), 4.56 (s, 1H), 3.96 - 3.83 (m, 1H), 3.83 - 3.70 (m, 1H), 2.61 - 2.57 (m, 1H), 2.13-2.01 (m, 1H ), 1.48 (d, J= 12.8 Hz, VV), 1.46 (d,J= 12.8 Hz, VV). 82 F hnT^ ¹ Η0 _χ Cl ° ^χΛ ν% Ϊ j F^yj^f M 508.1 Method C, RT = 1.834 min, 100% Ή NMR (400MHz, DMSO-de) δ = 8.63 (d,J = 1.0Hz, 1H), 8.15 (t, J= 8.8Hz, 1H), 7.63 - 7.50 (m, 2H), 7.50 - 7.29 (m, 5H), 7.24-7.15 (m, 1H), 7.11 (d,J=7.3 Hz, 1H), 5.10 (t, J= 4.9 Hz, 1H), 4.81 4.62 (m, 1H), 4.29-4.12 (m, 1H), 3.49 3.47 (m, 2H), 2.55 -2.52 (m, 1H), 2.31 2.21 (m, 1H). 83 About t ' \ /o J about a O 586.2 Method C, RT = 2.031 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.66 (d, J= 2.5 Hz, 1H), 8.15 (t, J= 8.8 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.75 (t, J= 7.8 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.43 (dd, J = 11.3,2.3 Hz, 1H), 7.31-7.13 (m, 4H), 4.62 - 4.50 (m, 1H), 3.97 - 3.94 (m, 1H), 3.81 - 3.73 (m, 1H), 2.63 - 2.55 (m, 1H), 2.17-2.05 (m, 1H), 1.54 (d,J= 13.6 Hz, ZN), 1.52 (d, 7 = 13.6 Hz, ZN).

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84 dd >0 o J O 0^2 at O 555.2 (M+N H4G Method C, RT = 1.369 min, 92.6% Ή NMR (400MHz, DMSO-de) δ = 9.47 (s, 1H), 8.97 (d, J= 5.6 Hz, 1H), 8.66 (d, J= 2.4 Hz, 1H), 8.15 (t, J= 8.9 Hz , 1H), 7.48 - 7.34 (m, 3H), 7.25 - 7.17 (m, 2H), 4.62 - 4.54 (m, 1H), 3.96 - 3.85 (m, 1H), 3.78 (t, J= 8.6 Hz, 1H ), 2.63 - 2.54 (m, 1H), 2.15 -2.04 (m, 1H), 1.69 (d, J= 13.7 Hz, 6H). 85 o 9 G R DG LL. ^sh o 570.2 Method C, RT = 1.722 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.68 8.58 (m, 1H), 8.15 (t, J= 8.8 Hz, 1H), 7.76 - 7.65 (m, 1H), 7.52 - 7.35 (m, 3H), 7.25 - 7.15 (m, 3H), 7.13 - 7.06 (m, 1H), 4.59 - 4.48 (m, 1H), 3.91 - 3.81 (m, 1H), 3.78 - 3.67 (m, 1H), 2.55 - 2.52 (m, 1H), 2.13 - 2.01 (m, 1H), 1.73 - 1.61 (m, 6H). 86 o s G r St i- ^sh o 604.1 Method C, RT = 1.834 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.98 8.91 (m, 1H), 8.45 - 8.38 (m, 1H), 7.76 7.62 (m, 2H), 7.52 (br. d., J= 9.3 Hz, 1H) , 7.48 - 7.40 (m, 2H), 7.36 - 7.30 (m, 1H), 7.24-7.18 (m, 1H), 7.11 (d,7=6.6 Hz, 1H), 4.62 - 4.52 (m, 1H), 3.92 - 3.83 (m, 1H), 3.78 - 3.70 (m, 1H), 2.64 - 2.56 (m, 1H), 2.14-2.06 (m, 1H), 1.72 - 1.64 (m, 6H). 87 oAa L o J O 0^2 and O 602.2 Method C, RT = 1.795 min, 100% Ή NMR (400MHz, DMSO-de) δ = 8.65 (dd, J= 1.7, 8.8Hz, 1H), 8.15 (t,7=8.9Hz, 1H), 7.88 (dd,7= 7.3, 12.7Hz, 1H) , 7.70 - 7.53 (m, 3H), 7.43 (dd, 7= 2.4, 11.0 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.24 7.10 (m, 2H), 4.61 - 4.52 (m, 1H), 3.96 3.85 (m, 1H), 3.81 - 3.71 (m, 1H), 2.61 2.54 (m, 1H), 2.17 - 2.03 (m, 1H), 1.64 1.48 (m, 6H). 88 F ΗΝ-^Λ ΗΝ—Ζ Vd~ ^CF3 Η ⁰ f^U\ L1 F3C0V 6* 636.2 Method C, RT = 1.919 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.94 (dd, 7= 2.9, 8.6 Hz, 1H), 8.41 (m, 1H), 7.92 - 7.82 (m, 1H), 7.71 - 7.54 (m, 4H), 7.51 (d, 7= 8.8 Hz, 1H), 7.39 - 7.31 (m, 3H), 4.63 - 4.53 (m, 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.73 (m, 1H), 2.63 - 2.57 (m, 1H), 2.18 -2.06 (m, 1H), 1.61 - 1.50 (m, 6H).

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89 F ΗΝ-^Λ HN-Z ^CF 3 a ⁰ TJ 592.2 Method C, RT = 1.872 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.96 8.89 (m, 1H), 8.41 (t, J= 8.3 Hz, 1H), 8.03 - 7.93 (m, 1H), 7.71 - 7.49 (m, 4H), 7.39 - 7.26 (m, 3H), 7.14 - 7.07 (m, 1H), 4.58 - 4.49 (m, 1H), 3.87 - 3.78 (m, 1H), 3.74 - 3.67 (m, 1H), 2.63 - 2.54 (m, 1H), 2.13 - 2.02 (m, 1H), 1.60 - 1.50 (m, 1H), 1.45 (d,7= 13.4 Hz, ZN), 1.42 (d,7= 13.4 Hz, ZN), 0.79 - 0.72 (m , 1H), 0.71 0.61 (m, 3H). 90 F. GH ° ^{Χ Λ} _Ν ^Ο ^F \/\ TJ ^F I 9' / and ^Ρχ 614.2 Method C, RT = 1.768 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 8.94 (d, J= 2.0 Hz, 1H), 8.40 (t, J = 8.3 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.72 - 7.58 (m, 3H), 7.51 (m, 1H), 7.40 (m, 1H), 7.34 7.18 (m, 3H), 4.71 - 4.58 (m, 1H), 4.33 (m, 1H), 3.48 (dd, J= 10.5, 3.9 Hz, 1H), 3.40 - 3.36 (m, 1H), 3.24 (s, 3H), 2.49 - 2.44 (m, 1H), 2.37 - 2.23 (m, 1H), 1.62 - 1.36 (m, 6H). 91 F ΗΝ-ΖΛ HN-Z Λ // ^Cl d ⁰ F ₃ C^k Ά 586.2 Method C, RT = 1.778 min, 99.8% Ή NMR (400 MHz, DMSO-de) δ = 8.71 8.59 (m, 1H), 8.22 - 8.12 (m, 1H), 7.93 7.90 (m, 1H), 7.83 - 7.75 (m, 1H), 7.70 7.58 (m, 2H), 7.48 - 7.33 (m, 3H), 7.24 7.14 (m, 2H), 4.62 (d, J= 1.2 Hz, 1H), 3.96 - 3.84 (m, 1H), 3.81 - 3.71 (m, 1H), 2.65 - 2.58 (m, 1H), 2.10 - 2.04 (m, 1H), 1.67 - 1.33 (m, 6H). 92 F HN-Z\, HN-Z ^CF 3 H ⁰ F ₃ Cy#% % 620.2 Method C, RT = 1.911 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.00 8.89 (m, 1H), 8.47 - 8.37 (m, 1H), 7.95 7.86 (m, 1H), 7.83 - 7.74 (m, 1H), 7.71 7.60 (m, 3H), 7.55 - 7.48 (m, 1H), 7.45 7.36 (m, 2H), 7.35 - 7.32 (m, 1H), 4.75 4.43 (m, 1H), 3.96 - 3.84 (m, 1H), 3.81 3.71 (m , 1H), 2.66 - 2.58 (m, 1H), 2.102.04 (m, 1H), 1.60 - 1.48 (m, 6H). 93 po J Ο J q 589.2 (M+N well Method C, RT = 1.532 min, 94.1% Ή NMR (400MHz, DMSO-de) δ = 9.47 (s, 1H), 9.03 - 8.85 (m, 2H), 8.42 (t, J= 8.2 Hz, 1H), 7.67 (br. d., J= 11.5 Hz , 1H), 7.53 (s, 1H), 7.48 - 7.30 (m, 3H), 4.60 (td, J= 10.2, 8.0 Hz, 1H), 4.01 3.87 (m, 1H), 3.79 (br. t., J = 8.8 Hz, 1H), 2.65 - 2.55 (m, 1H), 2.18 - 2.04 (m, 1H), 1.69 (d,7= 13.7 Hz, 6H). 94 0¾. d ° J T At 620.2 Method C, RT = 1.932 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.95 (d, 7= 3.2 Hz, 1H), 8.41 (t, 7= 8.4 Hz, 1H), 7.90 - 7.80 (m, 1H), 7.76 (t, 7= 7.9Hz, 1H), 7.67 (dd,7= 1.8, 11.6Hz, 1H), 7.63 - 7.55 (m, 2H), 7.52 (d, 7= 9.0Hz, 1H), 7.34 (d,7= 7.1Hz, 1H), 7.29 - 7.19 (m, 2H), 4.64 - 4.55 (m, 1H), 3.96 - 3.87 (m, 1H), 3.83 - 3.74 (m, 1H), 2.99 - 2.87 (m, 1H), 2.64 - 2.56 (m, 1H), 2.16 - 2.06

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(w, 1H), 1.60-1.48 (w, 6H). 95 F HN— HN-Z L ZZ ^Cl d ° L ) hf ₂ cV 0' 568.2 Method C, RT = 1.608 min, 99% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (br. s., 1H), 8.16 (t, J= 8.8 Hz, 1H), 7.98 - 7.87 (m, 1H), 7.74 - 7.57 (m, 3H) , 7.43 (dd,7= 11.2,2.4 Hz, 1H), 7.32 - 7.10 (m, 4H), 6.59 (t, J= 52.4 Hz, 1H), 4.60 - 4.50 (m, 1H), 3.95 - 3.85 (m , 1H), 3.81 - 3.71 (m, 1H), 2.62 - 2.55 (m, 1H), 2.17 - 2.03 (m, 1H), 1.50 (d, J= 13.2 Hz, ZN), 1.44 (d, J= 13.2 Hz, 3H). 96 1 *G° o V z // \ _/=\ 532.2 Method C, RT = 1.813 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (d, J= 1.5 Hz, 1H), 8.16 (m, 1H), 8.04 7.92 (m, 1H), 7.69 - 7.54 (m, 2H), 7.43 (dd , J= 11.1,2.3 Hz, 1H), 7.36 - 7.26 (m, 2H), 7.24 - 7.13 (m, 3H), 4.59 - 4.45 (m, 1H), 3.89 - 3.78 (m, 1H), 3.69 - 3.55 (m, 1H), 2.62 -2.54 (m, 1H), 2.12 (m, 3H), 2.10 - 1.99 (m, 1H), 1.45 (br. d., J= 13.4 Hz, ZN), 1.36 (br. d., 7=13.4 Hz, ZN). 97 1 q 585.2 Method C, RT = 1.809 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.95 (d, 7= 2.7 Hz, 1H), 8.42 (t, 7= 8.4 Hz, 1H), 8.02 - 7.84 (m, 1H), 7.81 - 7.74 (m, 1H), 7.70 - 7.62 (m, 2H), 7.57 (d, 7= 7.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.46 (dd, J = 6.8, 1.7 Hz, 1H), 7.42 (dd ,7= 7.2, 1.7 Hz, 1H), 7.40 - 7.32 (m, 1H), 4.68 - 4.56 (m, 1H), 4.45 (s, 2H), 4.00 - 3.88 (m, 1H), 3.85 - 3.77 (m , 1H), 2.66 - 2.56 (m, 1H), 2.18 -2.05 (m, 1H). 98 F HN-— ^hn ~z Ά/ ^CFa rL ⁰ Cl-Zx 4 586.2 Method C, RT = 1.764 min, 99.9% Ή NMR (400 MHz, DMSO-de) δ = 8.93 (br. s., 1H), 8.42 (m, 1H), 7.94 - 7.90 (m, 1H), 7.71 - 7.57 (m, 3H), 7.56 - 7.49 ( m, 1H), 7.49 - 7.41 (m, 1H), 7.41 - 7.26 (m, 3H), 4.67 - 4.53 (m, 1H), 3.88 - 3.79 (m, 1H), 3.76 - 3.66 (m, 1H), 2.67 - 2.56 (m, 1H), 2.20 -2.05 (m, 1H), 1.57 - 1.48 (m, 6H). 99 F hn-ZA-^, HN-Z° rL° ci-Ζχ Y D σ' 552.2 Method C, RT = 1.595 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (br.s., 1H), 8.17 (t, 7= 8.9 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.71 - 7.57 (m, 2H) , 7.50 - 7.30 (m, 4H), 7.25 - 7.09 (m, 2H), 4.65 - 4.49 (m, 1H), 3.82 (dt, J= 9.4, 6.4 Hz, 1H), 3.74 - 3.61 (m, 1H) , 2.66 - 2.56 (m, 1H), 2.15 - 2.03 (m, 1H), 1.57 - 1.48 (m, 6H). 100 F HN—Z'i HN—Z 1 // ^CF 3 cl ⁰ kA Y 5 ^F 1¾) m 599.2 Method C, RT = 1.857 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.93 (d, J= 2.7 Hz, 1H), 8.85 (dd,7=4.6, 1.2 Hz, 1H), 8.42 (m, 1H), 7.86 - 8.82 (m, 1H), 7.70 - 7.60 (m, 2H), 7.55 - 7.47 (m, 1H), 7.42 - 7.29 (m, 2H), 7.24 - 7.16 (m, 1H), 4.64 - 4.52 (m, 1H), 3.96 - 3.87 (m, 1H), 3.81 - 3.73 (m, 1H), 2.65 - 2.58 (m, 1H), 2.16 - 1.81 (m, 5H), 1.02 - 0.85 (m, 6H).

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101 Ε HN— ΗΝ-Z \uZ~ ^C ri ° F-χΖχ X) ^F A>° U'( 583.1 (M+N id ⁴ Method C, RT = 1.746 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.69 8.56 (m, 1H), 8.15 (t, J= 8.9 Hz, 1H), 8.04 - 7.91 (m, 1H), 7.76 - 7.59 (m, 2H), 7.49 - 7.32 (m, 3H), 7.29 - 7.10 (m, 3H), 4.62 - 4.51 (m, 1H), 3.97-3.61 (m, 4H), 2.57 - 2.52 (m, 1H), 2.14 - 2.01 (m, 1H), 1.44 (d,7= 14.4 Hz, ZN), 1.12 (t, 7= 7.1 Hz, ZN). 102 F ΗΝ-Ζ^λ,,^ \_HN-^ L/~ ^CF 3 / i '° N ⁰ FxJ\ Y ί 'v 598.2 Method C, RT = 1.965 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.96 (d, 7= 2.7 Hz, 1H), 8.46 (t, 7 = 8.3 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.72 - 7.57 (m, 3H), 7.53 (d, 7= 8.8 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.30 - 7.22 (m, 2H), 4.65 (d, 7= 9.0 Hz, 1H), 3.88 (br. d ., 7= 9.3 Hz, 1H), 3.45 (br. d., 7=9.3 Hz, 1H), 1.53 (d, 7 = 13.2 Hz, 6H), 1.22 (s, 3H), 1.06 (s, 3H) . 103 F HN-Zl. , Z HN-^ V_Z~ ^C / i '° N ⁰ F^k T 1 581.2 (M+N id ⁴ Method C, RT = 1.965 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.68 (d,7= 1.5 Hz, 1H), 8.22 (t,7= 9.0 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.70 - 7.56 (m, 2H), 7.45 (dd,7= 11.2,2.4 Hz, 1H), 7.41 - 7.29 (m, 2H), 7.29 - 7.17 (m, 2H), 7.12 (d, 7= 9.0 Hz, 1H), 4.62 (d , 7= 9.0 Hz, 1H), 3.86 (br. d., 7= 9.3 Hz, 1H), 3.45 (br. d., 7= 9.3 Hz, 1H), 1.54 (d, 7= 13.2 Hz, 6H) , 1.21 (s, 3H), 1.05 (s, 3H). 104 F. HN—Z'x HN—/ Z^^ ^CF 3 ri ° FxJx ^F d° u\° 600.2 Method C, RT = 1.871 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.98 8.86 (m, 1H), 8.41 (t,7= 8.68 Hz, 1H), 8.02 - 7.92 (m, 1H), 7.77 - 7.60 (m, 3H), 7.56 - 7.48 (m, 1H), 7.46 - 7.30 (m, 3H), 7.28 - 7.18 (m, 1H), 4.65 - 4.51 (m, 1H), 3.98 - 3.81 (m, 2H), 3.81 - 3.73 (m, 1H), 3.73 - 3.61 (m, 1H), 2.65 - 2.54 (m, 1H), 2.17-2.02 (m, 1H), 1.44 (d, 7= 14.67 Hz, ZN), 1.12 (t, 7= 7.1 Hz , ZN). 105 b To z/? G* 600.2 Method C, RT = 1.871 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.02 8.90 (m, 1Η), 8.41 (t, 7= 8.3 Hz, 1H), 8.05 - 7.92 (m, 1H), 7.76 - 7.60 (m, 3H), 7.51 (dd,7=8.7, 1.1Hz, 1H), 7.46 - 7.31 (m, 3H), 7.28 - 7.15 (m, 1H), 4.65 - 4.53 (m, 1H), 3.97 - 3.74 (m, 3H), 3.74 - 3.60 (m, 1H), 2.65 - 2.56 (m, 1H), 2.18 - 2.02 (m, 1H), 1.45 (d,7= 14.43 Hz, ZN), 1.12 (t, 7= 7.1 Hz, ZN). 106 580.1 Method C, RT = 1.763 min, 94.7% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (d, 7= 2.5 Hz, 1 Η) 8.15 (t, 7= 8.9 Hz, 1 H), 7.96 - 7.88 (br, 1 H), 7.67 - 7.64 ( br, 2 H), 7.51 (d, 7= 8.6 Hz, 1 H), 7.37 - 7.47 (br, 2 H), 7.27 (d, 7 = 8.8 Hz, 1 H), 7.167.23 (br, 2 H ), 4.47 - 4.64 (w, 1 H), 3.90 4.01 (w, 1H), 3.82 - 3.90 (w, 1 H), 2.54 2.62 (w, 1 H), 2.01 - 2.15 (w, 1 H), 1.53

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F. HN—fA—ci rl % σ ^% (d,J = 13.2 Hz, 6 N). 107 F HN—<A HN% Λ A ^CI n ° HF ₂ cA% % 568.1 Method C, RT = 1.662 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.74 (d, J= 1.71 Hz, 1 Η), 8.11 (t, 7= 8.93 Hz, 1 Η), 7.89 - 8.01 (m, 1 Η), 7.57 - 7.71 (m, 3 Η), 7.40 - 7.40 (m, 1 Η), 7.34 - 7.48 (m, 1 Η), 7.32 (d,7= 8.31 Hz, 1 Η), 7.25 7.14 (m, 2 Η), 7.04 (t,7= 52.4 Hz, 1H) 4.41 - 4.55 (m, 1 Η), 3.89 - 4.01 (m, 1 Η), 3.64 - 3.71 (m, 1 Η), 2.56 - 2.52 (m, 1 Η), 2.18 - 2.31 (m, 1 Η), 1.30 - 1.63 (m, 6 Η). 108 E HN—(AX HN—/ V// ^CF 3 d ⁰ 4 kJ °~ 602.1 Method C, RT = 1.892 min, 100% 41 NMR (400 MHz, DMSO-de) δ = 8.93 (d, 7= 2.5 Hz, 1 Η), 8.41 (t, 7= 8.4 Hz, 1 Η), 8.0 - 7.87 (m, 1 Η), 7.77 - 7.71 (m, 1 Η), 7.69 - 7.59 (m, 2 Η), 7.55 - 7.49 (m, 1 Η), 7.48 - 7.42 (m, 1 Η), 7.41 - 7.27 (m, 2 Η), 7.23 - 7.13 (m, 1 Η), 4.65 - 4.54 (m, 1 Η), 3.97 - 3.86 (m, 1 Η), 3.82 - 3.71 (m, 1 Η), 3.51 (s, ZN), 3.49 (s, ZN), 2.65–2.56 (m, 1 Η), 2.18–2.02 (m, 1 Η). 109 °A o o^i X about 550.2 Method C, RT = 1.650 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.63 (d, 7= 2.0 Hz, 1 Η), 8.14 (t, 7= 8.9 Hz, 1 Η), 7.99 - 7.84 (m, 1 Η), 7.72 - 7.55 (m, 2 Η), 7.37 - 7.50 (m, 2 Η), 7.35 - 7.25 (m, 2 Η), 7.23-7.17 (m, 1 Η), 7.14 (d,7= 7.1 Hz, 1 Η), 4.70 - 4.58 (m, 1 Η), 4.36 - 4.23 (m, 1 Η), 2.36 - 2.25 (m, 2 Η), 1.46 (d,7 = 12.4 Hz, 6H), 1.19 (d, 7= 6.4 Hz , 3 H). BY F HN-<A \_HN-^ A/ ^CF 3 / V '° N ⁰ fA\ X j ^F Xv 599.2 Method C, RT = 1.851 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.96 (d, 7= 3.18 Hz, 1 Η), 8.84 (m, 1 Η), 8.46 (t, 7= 8.2 Hz, 1 Η), 7.87 (m, 1H ), 7.63 7.72 (m, 2 H), 7.52 (d, 7= 9.5 Hz, 1 H), 7.19 - 7.39 (m, 3 H), 4.65 (d, 7= 9.1 Hz, 1 H), 3.88 (d , 7= 9.2 Hz, 1 H), 3.45 (d, J = 9.2 Hz, 1 H), 1.63 (d,7= 13.2 Hz, 6H), 1.23 (s, ZN), 1.07 (s, ZN). 111 F HN—<A_^ HO / ( ⁰ ' N^ ⁰ F\J\ X) ^f Ή °. / u ^Ρχ 566.2 Method C, RT = 1.404 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.63 (s, 1H), 8.17 (t,7= 8.8 Hz, 1H), 8.00 7.88 (m, 1H), 7.70 - 7.58 (m, 2H), 7.49 7.36 ( m, 2H), 7.33 - 7.13 (m, 4H), 4.93 (t, 7= 5.0 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.25 -4.12(m, 1H), 3.44 (br. t. , 7= 4.0 Hz, 2H), 2.67 - 2.61 (m, 1H), 1.98 - 1.85 (m, 1H), 1.64 - 1.42 (m, 6H).

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112 Ε ΗΝ—< ⁼ \ ^ΗΝ 4 ^c but _h /4 ° ΕχΧ T ) ^F ^| q, u ^Pχ 566.2 Method C, RT = 1.425 min, 100% Ή NMR (400 MHz, DMSO-de) <5 = 8.61 (s, 1H), 8.14 (t, J= 8.9 Hz, 1H), 7.98 7.87 (m, 1H), 7.71 - 7.56 (m, 2H), 7.46 7.36 (m, 2H), 7.36 - 7.24 (m, 2H), 7.22 7.15 (m, 1H), 7.09 (d, 7= 7.6 Hz, 1H), 5.15 - 5.05 (m, 1H), 4.76 - 4.63 (m, 1H), 4.24-4.11 (m, 1H), 3.47 (br. d., 7=3.9 Hz, 2H), 2.53 (br. s., 1H), 2.29 - 2.20 (m, 1H), 1.60-1.41 ( m, 6H). 113 F HN—((X. , Ά > ^N % ^C / V '° N ⁰ F-^ik TI % 565.2 Method C, RT = 1.719 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.84 (d, 7= 4.9 Hz, 1 H), 8.68 (d, 7= 2.5 Hz, 1 H), 8.22 (t, J=8.9 Hz, 1 H), 7.87 (ddd, 7 = 7.8, 4.4, 1.5Hz, 1H), 7.67 (ddd, 7= 7.8, 4.9, 2.5Hz, 1H), 7.44 (dd,7= 11.3, 2.5Hz, 1H), 7.26 - 7.38 (m, 2 H), 7.21 (ddd, 7 = 8.9, 2.5, 1.1 Hz, 1 H), 7.00 - 7.16 (m, 1 H), 4.62 (d, 7=9.1 Hz, 1H), 3.86 ( d,7 = 9.1Hz, 1H), 3.44 (d, 7= 9.1Hz, 1H), 1.63 (d, 7= 13.7Hz, 6H), 1.19 - 1.28 (m, 3H), 1.05 (s, 3H ). 114 E hn-^A HN-^ ^CF 3 HO / ( ⁰ T j ^F q, u ^Ρχ 600.2 Method D, RT = 1.577 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 9.06 8.51 (br. s., 1H), 8.45 - 8.36 (m, 1 H), 8.00 - 7.87 (m, 1 H), 7.71 - 7.57 (m, 3 H ), 7.51 (dd, 7=9.17, 1.10 Hz, 1 H), 7.44 7.11 (m, 4 H), 4.78-4.61 (m, 1 H), 4.26 4.21 (m, 1 H), 3.50-3.40 (m , 3 H), 2.61 2.53 (m, 1 H), 2.33 - 2.22 (m, 1 H), 1.44 - 1.55 (m, 6H). 115 E HN—(TX HN^ Vj/ ^CF 3 ⁰ N ⁰ F^Jx π 584.2 Method D, RT = 1.805 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.97 8.85 (m, 1 H), 8.46 - 8.34 (m, 1 H), 7.99 7.89 (m, 1 H), 7.70 - 7.57 (m, 3 H), 7.52 (br. d., 7= 8.6 Hz, 1 H), 7.46 - 7.17 (m, 4 H), 4.71 - 4.57 (m, 1 H), 4.34 - 4.15 (m, 1 H), 2.37 - 2.30 (m , 1 H), 1.75 - 1.62 (m, 1H), 1.59 - 1.39 (m, 6 H), 1.19 (d, 7 = 6.4 Hz, 3 H). 116 E HN—(TX HN^ Vj/ ^CF 3 *7 t '° N ⁰ FxJx. T j 'σ ⁴ ” 584.2 Method D, RT = 1.802 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.92 (d, 7= 2.7 Hz, 1 Η), 8.40 (t, 7= 8.3 Hz, 1 Η), 7.97 - 7.89 (m, 1 Η), 7.71 - 7.58 (m, 3 Η), 7.51 (d,7= 8.8 Hz, 1 Η), 7.40 (m, 1 Η), 7.36 - 7.25 (m, 3 Η), 4.66 (td, 7= 9.2, 7.3 Hz, 1 Η), 4.35 - 4.24 (m, 1 Η), 2.38 2.24 (m, 2 Η), 1.63-1.41 (m, 6 Η), 1.20 (d, 7= 6.4 Hz, 3 Η). 117 558.2 Method C, RT = 1.711 min, 99.4% Ή NMR (400 MHz, DMSO-de) δ = 8.65 (br.s., 1H), 8.18 (t, 7= 8.9 Hz, 1 H), 7.96 (m, 1 H), 7.69 - 7.53 (m, 2 H ), 7.43 (dd, 7= 12.5, 2.5 Hz, 1 H), 7.37 - 7.26 (m, 2 H), 7.25 - 7.10 (m, 3 H), 4.57 (dt, 7 = 10.3, 8.1 Hz, 1 H ), 3.95 - 3.65 (m, 2 H), 2.66 - 2.55 (m, 1 H), 2.14 - 2.03 (m, 1H), 1.80 - 1.69 (m, 1 H), 1.51 - 1.30 (m, 6 H) ,

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F. HN—((X HN—Z ^Cl cl ⁰ A JLJ ^F 1 0.98 - 0.83 (br, 2 N), 0.67 - 0.43 (br, 2 N). 118 F HN—ΑΆ— hnA A' ⁰¹ A SAo to 1 F Jx^OMe Г ii 491 Method C, RT = 1.921 min, 99.3% Ή NMR (400 MHz, DMSO-de) δ = 8.63 (d, 7=2.1 Hz, 1 Η), 8.29 (dd, 7= 5.0, 2.1 Hz, 1 Η), 8.15 (t,7= 8.8 Hz, 1 Η ), 7.78 (dd, 7= 7.3, 2.1 Hz, 1 Η), 7.47 - 7.36 (m, 2 Η), 7.35 - 7.28 (m, 1 Η), 7.25 - 7.05 (m, 3 Η), 4.62 - 4.48 (m, 1 Η), 3.95 - 3.84 (m, 1 Η), 3.89 (s, ZN), 3.83 - 3.71 (m, 1 Η), 2.63 - 2.52 (m, 1 Η), 2.14 - 2.03 (m, 1H). 119 About a. _a fy=° g p L z II \___ ^T Lz XZ^O 545.1 Method C, RT = 1.737 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.64 (d, 7= 2.0 Hz, 1H), 8.19-8.05 (m, 1H), 7.63 - 7.52 (m, 2H), 7.50 - 7.35 (m, 4H), 7.27-7.13 (m, 3H), 4.55 (td,7= 10.5, 8.0 Hz, 1H), 4.30 (t, 7= 7.9 Hz, 2H), 3.96 - 3.81 (m, 3H), 3.81-3.72 (m, 1H), 2.61 - 2.54 (m, 1H), 2.13 - 2.02 (m, 1H). 120 \ "° I ⁴ __. U Η Η ί 585.0 Method E, RT = 2.500 min, 99.9% Ή NMR (400MHz, DMSO-de) δ = 8.93 (d, 7= 2.7 Hz, 1H), 8.85 (d, 7= 4.7 Hz, 1H), 8.40 (t, 7= 8.2 Hz, 1H), 7.90 (m , 1H), 7.72 - 7.63 (m, 2H), 7.51 (m, 1H), 7.37 - 7.28 (m, 3H), 4.67 (m, 1H), 4.30 (m, 1H), 2.46 - 2.23 (m, 2H ), 1.62 (d, 7= 13.2 Hz, 6H), 1.19 (d, 7= 5.2 Hz, ZN). 121 oVj, /A O J ABOUT 551.2 Method C, RT = 1.596 min, 90.1% Ή NMR (400 MHz, DMSO-de) δ = 8.85 (d, 7= 4.9 Hz, 1H), 8.69 - 8.60 (m, 1H), 8.20 - 8.09 (m, 1H), 7.91 (dd, 7= 6.7, 4.9 Hz, 1H), 7.68 (m, 1H), 7.43 (dd,7= 11.0, 2.5 Hz, 1H), Ί3Ί - 13Q (m, 1H), 7.29 7.18 (m, 3H), 4.69 - 4.50 (m, 1H ), 4.34 4.10 (m, 1H), 2.86 - 2.76 (m, 1H), 1.65 1.62 (m, 1H), 1.63 (d,7= 13.4 Hz, VN), 1.62 (d,7= 13.4 Hz, VN) , 1.12 (d, 7= 6.1 Hz, ZN). 122 0%% /A O J ABOUT A 551.2 Method C, RT = 1.592 min, 92.5% Ή NMR (400 MHz, DMSO-de) δ = 8.85 (d, 7= 4.2 Hz, 1 Η), 8.65 (s, 1 Η), 8.15 (t, 7= 8.9 Hz, 1 Η), 7.90 (m, 1 Η), 7.68 (m, 1 Η), 7.42 (dd,7= 11.1,2.3 Hz, 1 Η), 7.36 - 7.31 (m, 2 Η), 7.22 - 7.14 (m, 2 Η), 4.70 - 4.59 ( m, 1 Η), 4.34 - 4.26 (m, 1 Η), 2.37 - 2.27 (m, 2 Η), 1.62 (d, 7= 13.5 Hz, 6 Η), 1.12 (d, J = 6.1 Hz, ZN) .

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123 F ΗΝ-Ζλ. HN-Z Y // ^CF 3 ΗΟ _χ Cl ° ^x 'SAo f.1 Y j ^F jm 618.2 (M+N NdG Method C, RT = 1.502 min, 100% Ή NMR (400MHz, DMSO-de) <5 = 8.91 (d, J= 2.7 Hz, 1H), 8.85 (d, J= 4.6 Hz, 1H), 8.41 (t, J= 8.6 Hz, 1H), 7.89 ( dd, J = 7.5, 4.0 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.51 (br. d.,7=8.6 Hz, 1H), 7.34 (t, J= 6.4 Hz, 2H), 7.25 ( d, J= 7.3 Hz, 1H), 5.12 (t, J= 4.9 Hz, 1H), 4.77 - 4.66 (m, 1H), 4.19 (br. d., J= 8.3 Hz, 1H), 3.49 3.43 (m , 2H), 2.62 - 2.53 (m, 1H), 2.33 2.22 (m, 1H), 1.63 (d, J= 13.4 Hz, ZN), 1.62 (d,7= 13.4 Hz, ZN). 124 F HN-cT HO--y HN-^ l^ ^CF 3 IC '° N ° Y ) ^F [ 4 / μ ^Ρχ 600.2 Method C, RT = 1.577 min, 100% Ή NMR (400 MHz, DMSO-de) <5 = 9.19 (br. s., 1H), 8.45 (t, J= 8.4 Hz, 1H), 7.96 - 7.86 (m, 1H), 7.70 - 7.58 (m, 3H ), 7.52 (d, J= 8.4 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.31 -7.22(m, 2H), 4.87 (t, J= 8.1 Hz, 1H), 4.18-4.07 (m, 1H), 3.71 (br. d., J = 8.8 Hz, 1H), 3.64 - 3.58 (m, 1H), 3.4 - 3.2 (m, 2H), 2.85 - 2.72 (m, 1H), 1.52 (br. d ., J= 13.2 Hz, 6H). 125 X -Π -η O X .o Z” ⁴ z o J A O 583.2 (M+N NdG Method D, RT = 1.442 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.70 8.63 (m, 1H), 8.13 (t, 7= 8.6 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.71 - 7.58 (m, 2H), 7.45 - 7.35 (m, 3H), 7.29 - 7.17 (m, 3H), 4.37 (dd,7= 10.0, 8.3 Hz, 1H), 3.88 3.81 (m, 1H), 3.76 - 3.66 (m, 1H), 3.61 ( dd, 7= 11.0, 6.6 Hz, 2H), 2.66 - 2.56 (m, 1H), 1.53 (br. d., 7= 13.2 Hz, 6H). 126 X -π -η O X ,О II z o J and O 583.2 (M+N NdG Method D, RT = 1.482 min, 94.5% Ή NMR (400 MHz, DMSO-de) δ = 8.90 (s, 1H), 8.19 (t,7= 8.9 Hz, 1H), 7.98 7.86 (m, 1H), 7.69 - 7.59 (m, 2H), 7.43 (dd ,7= 11.2,2.4 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.30 - 7.24 (m, 1H), 7.23 - 7.18 (m, 1H), 7.12 (d, 7= 7.8 Hz, 1H), 4.85 (t,7= 8.1 Hz, 1H), 4.17 - 4.07 (m, 1H), 3.71 (br. d., 7 = 9.5 Hz, 1H), 3.60 (br. dd., 7 = 9.5, 3.2 Hz, 2H), 2.76 - 2.70 (m, 1H), 1.52 (br. d., 7= 13.2 Hz, 6H). 127 X -π -η O X -o I/* z o J A ABOUT 583.2 (M+N NdG Method D, RT = 1.490 min, 96.5% Ή NMR (400 MHz, DMSO-de) <5 = 8.91 (s, 1H), 8.20 (t,7= 9.1 Hz, 1H), 7.98 7.86 (m, 1H), 7.71 - 7.61 (m, 2H), 7.43 ( dd,7= 11.0.2.5 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.30 - 7.24 (m, 1H), 7.21 - 7.16 (m, 1H), 7.13 (d, 7= 8.0 Hz, 1H) , 4.86 (t, 7 = 8.2 Hz, 1H), 4.16 - 4.08 (m, 1H), 3.72 (br. d., 7 = 9.3 Hz, 1H), 3.60 (br. dd., 7 = 9.3, 3.2 Hz , 2H), 2.76 - 2.71 (m, 1H), 1.53 (br. d., 7= 13.2 Hz, 6H).

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128 E HN— ^ΗΝ ^ Aj/ ^CF 3 ,J i '° N ^{0 F} Xv Y-N 585.0 Method E, RT = 2.517 min, 99.7% Ή NMR (400 MHz, DMSO-de) δ = 8.93 (br. s., 1H), 8.84 (d, J= 3.9 Hz, 1H), 8.41 (t, J= 8.1 Hz, 1H), 7.93 - 7.88 (m , 1H), 7.74-7.61 (m, 2H), 7.51 (br. d.,7=8.3 Hz, 1H), 7.44 - 7.21 (m, 3H), 4.70 - 4.52 (m, 1H), 4.22 (br. d., J= 9.5 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.57 - 2.52 (m, 1H), 1.63 (d, 7 = 13.4 Hz, ZN), 1.61 (d, J= 13.4 Hz, ZN), 1.13 (d, J= 6.4 Hz, ZN). 129 E HN—(Γλ HN,JC '° N ⁰ Tj ^F ΊΓ 4 kJ '° 552.1 Method D, RT = 1.831 min, 100% Ή NMR (400 MHz, DMSO-de) <5 = 8.718.55 (m, 1H), 8.21 - 8.09 (m, 2H), 7.91 7.73 (m, 2H), 7.61 - 7.50 (m, 1H), 7.42 (dd , 7= 11.2.2.0 Hz, 1H), 7.37 - 7.24 (m, 2H), 7.24 - 7.11 (m, 2H), 4.70 - 4.52 (m, 1H), 4.39 -4.13 (m, 1H), 3.06 (s , 3H), 2.38 -2.23 (m, 2H), 1.12 (d, 7= 6.1 Hz, ZN). 130 n- HN-Z / v ⁰ N ° F^Z\ T ) 'U 548.2 Method C, RT = 1.578 min, 99.6% Ή NMR (400 MHz, DMSO-de) δ = 9.73 9.50 (m, 1H), 8.95 (d,7 = 1.2 Hz, 1H), 8.44 (d, 7= 1.5 Hz, 1H), 7.97 - 7.85 (m, 1H ), 7.71 - 7.56(m, 2H), 7.43 - 7.31 (m, 3H), 7.30 - 7.21 (m, 1H), 4.67 (d, 7= 9.0 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.47 (br. d., 7= 9.5 Hz, 1H), 1.53 (d,7 = 13.2 Hz, 6H), 1.23 (s, 3H), 1.07 (s, 3H). 131 E HN—YX „ oy ^ην Ά VZ~ ^CF 3 ZN / ( ⁰ ' ⁴ N^° F^J^ X] yy uX 669.4 Method D, RT = 1.764 min, 100% 1H NMR (400 MHz, DMSO-de) δ = 8.93 (d, 7= 2.0 Hz, 1H), 8.40 (t, 7= 8.6 Hz, 1H), 7.94 (dd, 7= 12.6, 7.5 Hz, 1H), 7.73 - 7.57 (m, 3H), 7.50 (br. d., 7= 8.6 Hz, 1H), 7.41 - 7.17 (m, 4H), 4.78 - 4.66 (m, 1H), 4.47 - 4.28 (m, 1H) , 3.32 - 3.20 (m, 2H), 3.29 - 3.07 (m, 2H), 2.56 - 2.48 (m, 2H), 2.46-2.17 (m, 6H), 1.51 (br. d.,7= 13.2 Hz, 6H ). 132 οΧχζ °< ° O^i O 579.2 (M+N well Method D, RT = 1.736 min, 100% Ή NMR (400 MHz, DMSO-de) δ = 8.61 8.54 (m, 1H), 8.14 (t,7= 8.8 Hz, 1H), 7.96 - 7.88 (m, 1H), 7.68 - 7.59 (m, 2H), 7.44 (dd, 7= 11.1,2.6 Hz, 1H), 7.41 7.35 (m, 2H), 7.30 - 7.24 (m, 1H), 7.22 7.18 (m, 1H), 7.09 - 7.01 (m, 1H), 4.78 4.67 (m, 1H), 4.16 - 4.05 (m, 1H), 3.62 3.53 (m, 1H), 1.52 (br. d., 7= 13.2 Hz, 6H), 0.90-0.71 (m, 4H). 133 o ω — z ^ _Γ ° o ^X <° 1 0 Ο/' ^^X 524.1 Method E, RT = 1.518 min, 98.9% 1H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 7.92 (m, 1H), 7.52 - 7.72 (m, 2H), 7.33 - 7.41 (m, 2H), 7.21 - 7.29 (m, 1H), 7.04 (m, 2H), 6.73 (d, J= 7.5 Hz, 1H), 4.53 (m, 1H), 3.83 - 3.95 (m, 1H), 3.71 - 3.81 (m, 1H), 2.60 - 2.54 (m, 1H), 2.04-2.19 (m, 1H), 1.52 (br. d., J=13.2 Hz, 6H).

- 64 043110

Those skilled in the art will appreciate that the present invention is not limited to the above illustrative examples and that the present invention may be embodied in other specific forms without departing from its essential features. Therefore, it is desirable that these examples be considered in all respects as illustrative and not restrictive, with the scope of the invention defined by the appended claims and not by the above examples, and therefore all changes within the meaning and degree of equivalence of the claims should be included in its scope.

Claims (20)

1. Compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , or 6-membered heteroaryl with 1-3 nitrogen atoms and substituted with 1 R ^1a and 1-2 R ^1b ; Ar ³ is phenyl substituted with 1-3 R ^3a , or 5-6 membered heteroaryl with 1-3 nitrogen atoms and substituted with 1-3 R ^3a ; R ^1a is hydrogen or halo; R ^1b is halo, C ₁ _ ₄ haloalkyl, C ₁ _ ₄ alkoxy or C ₁ _ ₄ haloalkoxy; R ^2a is hydrogen, halo, C ₁ _ ₄ alkyl, C ₁ _ ₄ hydroxyalkyl, C ₁ _ ₄ haloalkyl, C ₃ _ ₆ cycloalkyl, C ₁ _ ₄ alkoxy, or C ₁ _ ₄ haloalkoxy; R ^3a is cyano, halo, C1_4 alkyl, C1_4 hydroxyalkyl, C1_4 alkoxy-C1_4 alkyl, C1_4 haloalkyl, (R ¹ R ² N)C1_ ₄ alkyl, R1R2N, C ₁ _ ₄ alkyl-C(O)(R ² )NC ₁ _ ₄ - alkyl, (C ₁ _ ₄ alkyl) ₂ (O) P, (C ₁ _ ₄ alkoxy) ₂ (O) P, (C ₁ _ ₄ alkoxy) (C ₁ _ ₄ alkyl) (O) P, C ₁ _ ₄ alkyl-SO ₂ or C ₁ _ ₄ alkyl-SO ₂ NH; R ¹ is hydrogen or C ₁ _ ₄ alkyl; R ² is hydrogen or C ₁ _ ₄ alkyl; or R1R2N taken together are oxazolyl or pyrrolidinyl and are substituted with 0-3 substituents selected from halo, C ₁ _ ₄ alkyl and oxo; R ^4a or R ^4b is independently hydrogen, C1_4 alkyl, C1_4 alkoxy, C1_4 alkoxy, C1_4 alkyl, C1_4 haloalkoxy, or C1_4 hydroxyalkyl; alternatively, R ^4a and R ^4b together with the carbon atom to which they are both attached form C3_ ₆ cycloalkyl; And R ^5a or R ^5b is independently hydrogen, C ₁ _ ₄ alkyl, C ₁ _ ₄ alkoxy, C ₁ _ ₄ hydroxyalkyl, C ₁ _ ₄ haloalkoxy, or C ₁ _ ₄ alkoxy C ₁ _ ₄ alkyl. 2. The compound according to claim 1 or its pharmaceutically acceptable salt, where Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; And Ar ³ is phenyl substituted with 1-3 R ^3a , pyrazolyl substituted with 1-3 R ^3a , pyridinyl substituted with 1-3 R ^3a , or pyrimidinyl substituted with 1-3 R ^3a . 3. The compound according to claim 1 or 2, having the formula (IV) - 65 043110 or a pharmaceutically acceptable salt thereof, wherein Ar ¹ is phenyl substituted with 1-2 R ^1a and 1-2 R ^1b , pyridinyl substituted with 1 R ^1a and 1-2 R ^1b , or pyrazinyl substituted with 1 R ^1a and 1-2 R ^1b ; R ^1a is hydrogen or halo; R ^1b is halo, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; R ^2a is hydrogen, halo, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; R ^3a is cyano, halo, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy-C _1-4 alkyl, C _1-3 haloalkyl, R1R2N, (C _1-3 alkyl) ₂ (O )P, (C _1-3 alkoxy) ₂ (O)P, (C _1-3 alkoxy) (C _1-3 alkyl) (O) P, C _1-3 alkylSO2 or C _1-3 alkyl-SO ₂ NH ; R ^4a or R ^4b is independently hydrogen, C1-3alkyl or C1-3hydroxyalkyl; alternatively, R ^4a and R ^4b , together with the carbon atom to which they are both attached, form C3-6 cycloalkyl; And R ^5a or R ^5b independently represents hydrogen, C _1-3 alkyl, C _1-3 hydroxylalkyl or C _1-3 alkoxyalkyl. 4. Compound according to claim 3 having the formula (V) or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen or F; R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy; R ^2a is hydrogen, halo, C _1-3 alkyl, C _1-3 haloalkyl or C _3-6 cycloalkyl; R ^3a is halo, C _1-3 hydroxyalkyl, C _1-3 alkoxy-C _1-3 alkyl, (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P, C _1-2 alkyl-SO ₂ or C _1-2 alkyl-SO ₂ NH; And R ^3a is halo. 5. The compound according to claim 4 or its pharmaceutically acceptable salt, where R ^1a is hydrogen or F; R ^1b is F, Cl or CF ₃ , R ^2a is hydrogen, F, Cl, isopropyl, CF ₃ or cyclopropyl; R ^3a is (CH ₃ ) ₂ (O)P, (CH ₃ CH ₂ ) ₂ (O)P, (CH ₃ CH ₂ O)(CH ₃ )(O)P, CH3SO2 or CH3SO2NH; And R ^3a is F. 6. Compound according to claim 3 having formula (VI) - 66 043110 or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen or halo; R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy; R ^2a is hydrogen, halo, C _1-3 alkyl or C _3-6 cycloalkyl; R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P, C _1-2 alkylSO2 or C _1-2 alkyl-SO ₂ NH. 7. The compound according to claim 3 or its pharmaceutically acceptable salt, where R ^4a is hydrogen; R ^4b is hydrogen; R ^5a is C _1-2 alkyl, C _1-2 hydroxyalkyl or C _1-2 alkoxy-C _1-2 alkyl; And R ^5b is hydrogen. 8. The compound according to claim 3 or its pharmaceutically acceptable salt, where R ^4a represents C _1-2 alkyl; R ^4b is C _1-2 alkyl; R ^5a is hydrogen; And R ^5b is hydrogen. 9. The compound according to claim 1 or 2, having the formula (VII) or a pharmaceutically acceptable salt thereof, wherein Ar ³ is pyrazolyl substituted with 1-3 R ^3a , pyridinyl substituted with 1-3 R ^3a , or pyrimidinyl substituted with 1-3 R ^3a ; R ^1a is hydrogen or halo; R ^1b is halo, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; R ^2a is hydrogen, halo, C _1-4 alkyl, C _1-4 hydroxyalkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; R ^3a is cyano, halo, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy-C1-4 alkyl, (R ¹ R ² N)C1-4 alkyl, R1 R2 N-, (C _1-4 alkyl) ₂ (O)P , (C _1-4 alkoxy) ₂ (O)P, (C _1-4 alkoxy)(C _1-4 alkyl)(O)P, C _1-4 alkylSO2 or C _1-4 alkyl-SO ₂ NH; R ¹ is hydrogen or C _1-4 alkyl; R ² is hydrogen or C _1-4 alkyl; or R1R2N taken together are oxazolyl or pyrrolidinyl and are substituted with 0-3 substituents selected from halo, C _1-4 alkyl or oxo; R ^4a or R ^4b is independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxyalkyl, or C _1-4 haloalkoxy; R ^4a and R ^4b , together with the carbon atom to which they are both attached, form C _3-6 cycloalkyl; And R ^5a or R ^5b is independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxyalkyl, or C _1-4 haloalkoxy. 10. Compound according to claim 9 having formula (VIII) - 67 043110 or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen or halo; R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy; R ^2a is hydrogen, halo, C _1-3 alkyl or C _3-6 cycloalkyl; R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P, C _1-2 alkylSO2 or C _1-2 alkyl-SO ₂ NH; And R ^5a or R ^5b is independently hydrogen or C _1-2 alkyl. 11. Compound according to claim 1 having formula (IX) or a pharmaceutically acceptable salt thereof, wherein R ^1a is hydrogen or halo; R ^1b is halo, C _1-2 haloalkyl or C _1-2 alkoxy; R ^2a is hydrogen, halo, C _1-2 haloalkyl, C _1-3 alkyl or C _3-6 cycloalkyl; or Ar ³ represents R ^3a is (C _1-2 alkyl) ₂ (O)P, (C _1-2 alkoxy)(C _1-2 alkyl)(O)P or C _1-2 alkyl-SO ₂ NH; R ^3a is halo; R ^4a or R ^4b is independently hydrogen, C1-2alkyl or C1-2hydroxyalkyl; or R ^4a and R ^4b together with the carbon atom to which they are both attached form C3-6 cycloalkyl; And R ^5a or R ^5b independently represents hydrogen, C _1-2 alkyl or C _1-2 hydroxyalkyl or C _1-2 alkoxy-C _1-2 alkyl. 12. A compound selected from the group consisting of - 68 043110 - 69 043110 - 70 043110 or a pharmaceutically acceptable salt thereof. 13. A compound that is, or a pharmaceutically acceptable salt thereof. 14. A compound that is - 71 043110 or a pharmaceutically acceptable salt thereof. 15. A compound that is, or a pharmaceutically acceptable salt thereof. 16. A compound that is or a pharmaceutically acceptable salt thereof. 17. A compound that is or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition containing a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier, diluent or excipient. 19. A method of treating heart failure, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 17 to a patient in need thereof. 20. The method of claim 19, wherein the heart failure is selected from the group consisting of congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF _R EF), heart failure with preserved ejection fraction (HF _P EF), acute heart failure, chronic heart failure of ischemic and non-ischemic nature.