EA041794B1 - ARYL, HETEROARYL AND HETEROCYCLIC PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS - Google Patents

Description

Field of invention

The invention provides aryl, heteroaryl and heterocyclic drugs for the treatment of medical disorders such as complement-mediated disorders.

State of the art

The complement system is part of the innate immune system that does not adapt to changes during the lifetime of the host, but is recruited and used by the adaptive immune system. For example, it aids or supplements the ability of antibodies and phagocytic cells to eliminate pathogens. This complex regulatory pathway allows for rapid response to pathogenic organisms while protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (increased phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cell lysis (damage to the membranes of foreign cells), and agglutination (aggregation and binding together of pathogens).

The complement system is activated in three ways: classical, alternative and lectin. Complement factor D plays an early and central role in the activation of the alternative pathway of the complement cascade. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of the thioether bond at C3 to form C3(H ₂ O), which binds to factor B to form the C3(H ₂ O)B complex. Complement factor D acts by cleaving factor B in the C3(H ₂ O)Bc complex to form Ba and Bb. The Bb fragment remains bound to C3(H ₂ O) to form an alternative pathway for C3 convertase C3(H ₂ O)Bb. In addition, C3b generated by any of the C3 convertases also associates with factor B to form C3bB, which factor D cleaves to activate the late stage alternative pathway C3 convertase C3bBb. This latter form of the alternative C3 convertase pathway can provide important downstream amplification in all three of the defined complement pathways, ultimately leading to the recruitment and assembly of additional factors in the complement cascade pathway, including cleavage of C5 to C5a and C5b. C5b acts in conjunction with factors C6, C7, C8 and C9 in a membrane attack complex that can destroy pathogenic cells by cell lysis.

Dysfunction or excessive complement activation has been associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative pathway of the complement cascade promotes the production of C3a and C5a, both potent anaphylatoxins that also play a role in a number of inflammatory disorders. Therefore, in some cases it is desirable to reduce the response of the complement pathway, including the alternative complement pathway. Some examples of complement-mediated disorders include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is the leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of an association between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a five-fold increased risk of macular degeneration, and individuals with mutations in other complement factor genes also have an increased risk of AMD. People with factor H mutations also have elevated levels of C-reactive protein, a marker of inflammation. Without adequate factor H function, the alternative pathway of the complement cascade is overactivated, resulting in cell damage.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant hematological disorder characterized by the expansion of hematopoietic stem cells and mature blood progeny cells that are deficient in certain surface proteins. RBCs in PNH are unable to modulate complement activation on their surface, leading to the typical feature of PNH, chronic complement-mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the US for the treatment of PNH. However, many patients treated with eculizumab remain anemic and many patients still require blood transfusions. In addition, treatment with eculizumab requires lifelong intravenous injections.

Additional complement-mediated disorders include those classified as component C3 glomerulopathy (C3G). C3G is a newly defined entity consisting of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) that encompasses the chronic kidney disease population where increased activity of the alternative complement pathway and terminal complement components leads to the formation of glomerular deposits composed exclusively of the C3 component. complement and in the absence of immunoglobulin (Ig).

- 1 041794

Immune complex membrane proliferative glomerulonephritis (IC-MPGN) is a kidney disease that shares many clinical, pathological, genetic and laboratory features with C3G, and therefore can be considered a C3G related disease. In the majority of patients with IC-MPGN, the underlying disease or disorder is most often infections, autoimmune diseases, or monoclonal gammopathy for which renal disease is secondary. Patients with idiopathic IC-MPGN may have low C3 levels and normal C4 levels similar to those seen with C3G, as well as many of the same genetic or acquired factors that are associated with abnormal alternative pathway activity. Although hypotheses currently exist suggesting that most IC-MPGN is due to overactivity of the classical pathway, patients with low C3 and normal C4 are likely to have substantial overactivity of the alternative pathway. IC-MPGN patients with low C3 and normal C4 may benefit from alternative pathway inhibition.

Other disorders that are associated with the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia or hemodialysis, optic neuromyelitis (NMO), myasthenia gravis (MG), fatty liver, non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis of the liver, liver failure, dermatomyositis and amyotrophic lateral sclerosis. Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and significant role in the alternative complement pathway and its potential role in signal amplification in the classical and lectin complement pathways. Factor D inhibition effectively interrupts the pathway and attenuates the formation of the membrane attack complex.

Although initial attempts have been made to develop factor D inhibitors, there are currently no clinically approved small molecule factor D inhibitors. Examples of factor D inhibitor compounds are described in the following inventions. U.S. Patent 6,553,340 to Biocryst Pharmaceuticals entitled Compounds useful in the complement, coagulate and kallikrein pathways and method for their preparation describes fused bicyclic ring compounds that are potential factor D inhibitors. Development of the factor D inhibitor BCX1470 was terminated due to lack of specificity. and short half-life of the compound.

PCT Patent Publication WO2012/093101 owned by Novartis entitled Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration describes some factor D inhibitors. Additional factor D inhibitors are described by Novartis in PCT patent publications WO2013/164802, WO2013/ 192345, Wo2014/002051, Wo2014/002052, Wo2014/002053, Wo2014/002054, Wo2014/002057, Wo2014/002058, Wo2014/002059, Wo2014/005150, Wo2014/143638, Wo2015/2015/143638, WO20 WO2015/066241.

An article published by Novartis titled Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors (Vulpetti et al., J. Med. Chem. 10.1021/acs.jmedchem.6b01684) describes the virtual mapping of active sites for regions that contribute a lot to binding energy using factor D crystal structure and NMR-based screening (structure-based drug design (SBDD) and fragment-based screening (FBD)). Another Novartis article titled Small-molecule factor D inhibitors targeting the alternative complement pathway (Maibaum et al., Nat. Chem. Bio. 2016;12;1105) discloses small molecule inhibitors developed using a structural approach combined with screening based on fragments.

Patent publication PCT WO2017/098328 from Lifesci Pharmaceuticals entitled Therapeutic Inhibitory Compounds describes various factor D inhibitors with variations in the heterocyclic ring of the central heterocyclic ring. PCT Patent Publication WO2018/015818 is also entitled Therapeutic Inhibitory Compounds and describes factor D inhibitors without a cyclic core.

PCT Patent Publication WO 2004/045518 Bristol-Myers Squibb entitled Open chain prolyl urea-related modulators of androgen receptor function describes open chain propylurea and thiourea related compounds for the treatment of androgen receptor related conditions such as age-related diseases. such as sarcopenia.

PCT patent publication WO 1999/048492 owned by Japan Tobacco Inc. entitled Amide derivatives and nociceptin antagonists describes compounds with a proline-like core and aromatic substituents linked to the proline core via amide linkages useful in the treatment of pain.

Ferring B.V. and Yamanouchi Pharmaceutical Co. ltd. PCT patent publication WO 1993/020099 titled CCK and/or gastrin receptor ligands describes compounds with a proline-like core and heterocyclic substituents linked to the proline core via amide linkages for the treatment of, for example, gastric disorders or pain. Patent publication PCT WO1995/029697 by Alexion Pharmaceuticals entitled Methods and compositions for the treatment of glomerulitis and other inflammatory diseases describes antibodies directed to the C5 complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathological activation of the complement system. The anti-C5 antibody eculizumab (Soliris®) from Alexion Pharmaceutical is currently the only specific complement antibody on the market and is the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).

February 2015 Achillion Pharmaceuticals filed for PCT Patent No. PCT/US2015/017523 and US Patent Application No. 14/631,090 entitled Alkyne Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017538 and US Patent Application No. 14/631,233 entitled Amide Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017554 and US Patent Application No. 14/631,312 entitled Amino Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017583 and US Patent Application No. 14/631,440 entitled Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017593 and US Patent Application No. 14/631,625 entitled Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017597 and US Patent Application No. 14/631,683 entitled Ether Compounds for Treatment of Complement Mediated Disorders; PCT patent application no. PCT/US2015/017600 and US Patent Application No. 14/631,785 entitled Phosphonate Compounds for Treatment of Complement Mediated Disorders; and patent application PCT No. PCT/US2015/017609 and US Patent Application No. 14/631,828 entitled Compounds for Treatment of Complement Mediated Disorders and US Patent Application No. 14/630,959 entitled Factor D Inhibitors Useful for Treating Infectious Disorders.

Additional complement factor D inhibitors are described in US Pat. Nos. 9,828,396; 9,695,205; 9,598,446; 9,732,103; 9,796,741; 9,732,104; 9,663,543; 9,758,537 and 9,643,986; international publications No. WO 2015/130784; WO 2015/130795; WO 2015/130806; WO 2015/130830; WO 2015/130838; WO2015/130842; WO 2015/130845 and WO 2015/130854; and US Patent Publications No. US 2017-0298084; US 2016-0362398; US 2017-0189410; US 2017-0298085; US 2018-0030075; US 2016

0362399; US 2018-0022766; US 2016-0362433; US 2017-0260219; US 2016-0362432; US 2018-0022767; US 2016-0361329 and US 2017-0226142; all owned by Achillion Pharmaceuticals, Inc.

Given the wide range of medical disorders caused by negative immune or inflammatory responses, new compounds are needed for treatment.

The essence of the invention

In one aspect of the invention, there is provided a compound of formula

or a pharmaceutically acceptable salt thereof;

where A is

B represents

R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from halo and C ₁ -C ₆ alkyl;

C5 selected from:

L represents

L3 is -C(O)-;

R ⁵ is hydrogen or C ₁ -C ₆ alkyl;

R ⁶ is selected from halogen, -CHO, -C(O)NH ₂ , -C ₂ -C ₆ -alkanoyl, -C(O)NH(CH ₃ ), -C(O)OR ⁹ and C1-C6

- 3 041794 alkyl;

R ⁸ and R ⁸ are hydrogen;

R ⁹ is selected from hydrogen and C1-C6 alkyl;

X ¹¹ is N or CR ¹¹ ;

X ¹² is CR ¹² ;

X ¹³ is N or CR ¹³ ;

X ¹⁴ is CR ¹⁴ ;

where one of R ¹² and R ¹³ is R ³² and the other is R ³¹ ;

and where in the absence of R ¹³ , R ¹² represents R ³² ;

R ³¹ is independently selected from hydrogen, halogen, -COOH, C ₁ -C ₆ -alkoxy and -C(O)OR ⁹ ,

R ³² is selected from 5-7 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S and 8-10 membered bicyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (mono- and di-C ₁ -C ₆ alkylamino)C ₀ -C ₂ -alkyl, -C ₀ -C ₆ -alkyl-(4-6-membered heterocycle containing at least one heteroatom selected from N, O or S) and C ₁ -C ₆ -haloalkoxy; or

R ³² is selected from ^{N and} ' and

R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C 2 -C 6 alkynyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₄ alkyl (mono- and di-C ₁ -C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) and C ₁ -C ₆ -haloalkyl.

In some embodiments, B is selected from:

In some embodiments, B is selected from:

^R25

^R26

In some embodiments, R ³² is selected from

^R27

F

In some embodiments, R ³² is

In some embodiments, R ³² is

In some embodiments, R ³² is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted with 1 or 2 substituents selected from halogen, hydroxyl, amino, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, (mono - and di-C ₁ -C ₆ alkylamino) C ₀ -C ₂ -alkyl, -C ₀ -C ₆ -alkyl-(4-6-membered heterocycle containing at least one heteroatom selected from N, O or S) and C ₁ -C ₆ haloalkoxy. In some embodiments, the optional substituents are selected from halogen, hydroxyl, and C ₁ -C ₆ alkyl. In some embodiments, C5 is:

In some embodiments, C5 is

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In some embodiments, R ¹⁴ is hydrogen.

In some embodiments, R ¹⁴ is methyl.

In some embodiments, R ¹¹ is hydrogen.

In some embodiments, R ³¹ is hydrogen.

In another aspect of the invention, there is provided a compound selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a compound of the formula

Vg

or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a compound of the formula

or a pharmaceutically acceptable salt thereof.

According to another aspect of the invention, a pharmaceutical composition for the treatment of a disorder mediated by complement factor D is provided, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, there is provided a method of treating a complement factor D mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is a human.

In some embodiments, the disorder is selected from acute respiratory distress syndrome, age-related macular degeneration (AMD), arthritis, asthma, Alzheimer's disease dementia, amyotrophic lateral sclerosis, antibody-mediated transplant rejection, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid syndrome, atypical or typical hemolytic uremic syndrome, cardiovascular disease, cold agglutination syndrome, chronic obstructive pulmonary disease (COPD), cirrhosis, Crohn's disease, C3 glomerulopathy, C3 glomerulonephritis, diabetic retinopathy, hard sediment disease, dermatomyositis, dermatitis, acquired epidermolysis bullosa, fatty liver, focal segmental glomerulosclerosis, geographic retinal atrophy, glomerulonephritis, graft versus host disease, Guillain-Barré syndrome, hemolytic anemia, suppurative hidradenitis, IgA nephropathy, ischemic-r overperfusion injury, liver failure, inflammation of the liver, lupus nephritis, membranoproliferative glomerulonephritis, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myelitis opticomyelitis, nonalcoholic steatohepatitis (NASH), ophthalmic disease, pancreatitis, paroxysmal nocturnal hemoglobinuria, pemphigoid, pemphigus vulgaris, reduction of preeclampsia, reduction of preeclampsia glomerular filtration rate, renovascular disorder, respiratory disease, retinal degeneration, retinal detachment, rheumatoid arthritis, scleroderma, Shiga toxin-associated sepsis, E. coli hemolytic uremic syndrome, spinal cord injury, sickle cell disease, traumatic brain injury, and ulcerative colitis. In some embodiments, the disorder is age-related macular degeneration (AMD).

In some embodiments, the disorder is retinal degeneration, ophthalmic disease, multiple sclerosis, arthritis, COPD, cardiovascular disease, atypical or typical hemolytic uremic syndrome, or respiratory disease, or rheumatoid arthritis.

In some embodiments, the disorder is IgA nephropathy.

In some embodiments, the disorder is paroxysmal nocturnal hemoglobinuria (PNH).

In some embodiments, the disorder is geographic retinal atrophy.

In some embodiments, the disorder is lupus nephritis.

In some embodiments, the disorder is sickle cell anemia.

In some embodiments, the disorder is myasthenia gravis.

In some embodiments, the disorder is C3 glomerulopathy.

In some embodiments, the disorder is C3 glomerulonephritis or hard sediment disease.

In some embodiments, the disorder is a decrease in glomerular filtration rate.

In some embodiments, the disorder is a renovascular disorder. In some embodiments, the disorder is myelitis optica.

In yet another aspect, the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of a disorder mediated by complement factor D in a subject.

In some embodiments, the subject is a human.

Brief description of the figures

In FIG. 1 shows a six-step process for the synthesis of the intermediate tert-butyl(1R,3S,5R)-3((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2 -carboxylate.

In FIG. Figure 2 shows a two-step process for the synthesis of the intermediate 2-bromo-3-fluoro-5-methylpyridine 1-oxide (compound 3 in Figure 2).

In FIG. 3 shows a three-step process for the synthesis of the tert-butyl 2-(3-acetyl-7methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate intermediate.

In FIG. 4 shows a seven-step process for the synthesis of the intermediate 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid.

In FIG. 5 shows a two-step process for the synthesis of the tert-butyl 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate intermediate.

In FIG. 6 shows a six-step process for the synthesis of the hydrochloric acid (S)-3-fluoro-4-methylpent-3en-2-amine salt intermediate.

In FIG. 7 shows a six-step process for the synthesis of hydrochloric acid intermediate (R)-1-((R)-2,2dichlorocyclopropyl)ethane-1-amine salt.

In FIG. Figure 8 shows an extended eight-step synthesis of compound 208 shown in Scheme

- 6 041794 me 153.

In FIG. 9 shows an eight-step process for the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2(oxetan-3-yl)pyrimidin-5-yl)-1 H-indazol- 1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide.

In FIG. 10 shows a four-step process for the synthesis of (1R,3S,5R)-N-(6-bromo-3-methylpyridin2-yl)-5-methyl-2-(2-(7-methyl-5-(2-methylpyrimidin-5- yl)-3-(oxetan-3-yl)-III-indazol-1-yl)acetyl)-2azabicyclo[3.1.0]hexane-3-carboxamide.

In FIG. 11 shows a three-step process for the synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl )-N-((S)-3-fluoro-4-methylpent-3-en-2-yl)5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide.

In FIG. 12 shows a seven-step process for the synthesis of compound 100.

In FIG. Figure 13 shows a three-step synthesis of compound 50, which is an alternative to the synthesis shown in Scheme 45.

In FIG. 14 shows an extended six-step synthesis of compound 107 shown in Scheme 80.

In FIG. 15A shows an eight-step process for the synthesis of intermediate 2-(3-acetyl-7-methyl-5(2-(3-((trimethylsilyl)oxy)oxetan-3-yl)pyrimidin-5-yl)-1H-indazol-1- yl) acetic acid.

In FIG. 15B shows the final two steps in the synthesis of (1R,3S,5R)-2-(2-(3-αcetyl-5-(2-(3hydroxyoxetan-3-yl)pyrimidin-5-yl)-7-methyl-1H-indazole -1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide from the intermediate shown in FIG. 18A.

In FIG. 16 shows an eight-step process for the synthesis of (1R,3S,5R)-2-(2-(3-αcetul-5-(2-(3fluoroxetan-3-yl)pyrimidin-5-yl)-7-methyl-1H-indazol- 1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide.

In FIG. 17 schematically shows various potential attachment points for R ³⁰¹ functionality on an A-ring, B-ring, C-ring, or heteroaryl-containing R ³² group. X ⁹ used in FIG. 17 is selected from -CH ₂ -, -O-, -NH- and -N-alkyl-.

In FIG. 18A, 18B, 18C, 18D, 18E, 18F, 18G, 18H, 18I, 18J, 18K, 18L, 18M, 18N, 18O, 18P, 18Q, 18R, 18S, 18T, 18U, and 18V are examples of compounds that illustrate the formula I, formula II or formula III.

In FIG. 19 shows formula I, formula II and formula III.

Detailed description

The present invention includes a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, wherein at least one of R ¹² or R ¹³ in group A is an aryl, heteroaryl or heterocyclic substituent which is R ³² . In one embodiment, a compound or salt or composition thereof as described herein is used to treat a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or abnormality of a cell that adversely affects the cell's ability to participate in or respond to normal complement activity, including the alternative complement pathway, or an undesired complement-mediated response to medical treatment, such as surgery or other medical procedure, or administration of a pharmaceutical or biopharmaceutical drug, blood transfusion, or other administration of allogeneic tissue, or liquids.

In certain aspects of the invention, the compound provided herein contains one or more of the following.

a) ring A of the formula:

- 7 041794

b) ring A of the formula:

c) ring A of the formula:

d) ring B of the formula:

e) ring C selected from:

f) ring C of the formula:

g) ring C selected from a proline spirocycle (such as that described in the article published by Litter et al. titled Development of a Manufacturing Process for an HCV Protease Inhibitor Candidate Molecule (Organic Process Research & Development 2015, 19, 270-283) ;

h) R ³² selected from a cyclic sulfonimidamide (such as that described in the article published by Pemberton et al. titled Synthesis and Functionalization of Cyclic Sulfonimidamides: A Novel Chiral Heterocyclic Carboxylic Acid Biostere (ACS Med. Chem Letters 2012, 3, 574 -578);

i) a compound of the invention with at least one R ²⁰¹ substituent selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl-, and hydroxyalkyl; -alkyl-O-alkyl, including -CH2OCH3, alkyl-S-alkyl, -alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic moiety-Oaliphatic moiety, -aliphatic moiety-S-aliphatic moiety, -aliphatic moiety-N(aliphatic moiety)-aliphatic moiety, -aliphatic moiety-NHaliphatic moiety, -aliphatic moiety-O-heterocycle, -aliphatic moiety-S

- 8 041794 heterocycle, -aliphatic fragment-K(aliphatic fragment)-heterocycle, -aliphatic fragment-KH-heterocycle, -alkyl-NHC(O)haloalkyl, -alkyl-NR ⁹ C(O)haloalkyl, -αlkyl-C( O)NH haloalkyl, -alkyl-C(O)NR ⁹ -haloalkyl, -alkyl-NHC(O) haloalkyl, -alkyl-NH ⁹ C(O)aliphatic fragment, -alkyl-C(O)NH-aliphatic fragment, - alkyl-NH ⁹ C(O)aliphatic moiety, -alkyl-NHC(O)aliphatic moiety, -substituted alkyl-N(R ⁹ )- substituted alkyl, alkylheteroaryl, heteroaryl, heterocycle, alkyl-heterocycle, -alkyl-O-haloalkyl , -K(aliphatic fragment)2; and where each R ²⁰¹ may be optionally substituted as defined in the terminology section below, and where each R ²⁰¹ may be optionally substituted with R ³⁰¹ which may be directly linked to R ²⁰¹ or may be linked to R ²⁰¹ via amino, hydroxyl, thio, carboxyl, phosphate, phosphonate or sulfonate bond optionally and appropriately;

j) a compound with at least one R ²⁰¹ substituent on ring A;

k) a compound with at least one R ²⁰¹ substituent on ring B;

1) a compound with at least one R ²⁰¹ substituent on ring C;

m) certain stable acylated embodiments and acyl prodrugs of the present invention which include an R ³⁰ substituent, as further described below.

These compounds can be used to treat medical conditions in a patient in need thereof, usually a human. The active compound may act as an inhibitor of the factor D complement cascade. In one embodiment, a method of treating such a disorder is provided, which comprises administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, as described in more detail below.

In some embodiments, compounds are provided that have minimal effect on a BSEP (bile salt exporting pump) (e.g., with an IC ₅₀ greater than about 20, 30, 40, 50, 60, 75, or 100 μM or greater) or with a therapeutic a BSEP index relative to complement factor D inhibition (eg, IC ₅₀ - BSEP inhibition/IC ₅₀ - complement inhibitor D inhibition) of at least 50, 100, 200, 300, 400, 500, 750, or 1000 or more. BSEP inhibition correlates with cholestatic drug-induced liver injury. Some compounds of the present invention with low BSEP inhibition have at least one R ²⁰¹ . In some embodiments, the compounds of the present invention exhibit minimal hydrolysis of the amide bond between the C-ring and the B-ring in vivo, for example by incorporating a proline that has a cis substituent to the proline-carbonyl bond towards the B-ring. In some embodiments, the cis substituent is at the Q3 position or at the Q2 position, or is a group that connects Q3 and Q2.

It has also been found that the insertion of a B-ring substituent ortho to the amide (e.g. 2-(L1)-3-methyl-6-substituted pyridine or 2-(L1)-3-cyclopropyl-6-substituted pyridine) can reduce the possibility of formation of reactive metabolites. In one aspect of the invention, an acylated R ³⁰¹ variant of the active compound of the invention is provided which has an extended half-life or other beneficial pharmacokinetic properties that can be achieved by in vivo stabilization of albumin. In some embodiments, the implementation of the acylated analogue may include several fragments linked in a linear, branched or cyclic manner. In some embodiments, one or more amino acids are used as the fatty acid-terminated linker. In one non-limiting example, a non-natural amino acid, such as described below, for example, 8-amino-3,6-dioxaoctanoic acid (one or more in sequence), is covalently linked to a selected complement factor D inhibitor of the present invention through a functional group, such as a carboxylic acid, sulfonyl, hydroxyl or amino group. See, in general, Lau, et al., Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semiglutide, J. Med. Chem., 2015, 58, 73707380. In this embodiment, 8-amino-3,6-dioxaoctanoic acid or the like is covalently linked to an aliphatic acid, including but not limited to C ₁₆ , C ₁₈ , C ₂₀ aliphatic acid, or dicarboxylic acid, including, but not limited to, C ₈ , C ₁₀ , C ₁₂ , C ₁₄ , C ₁₆ , C ₁₈ or C ₂₀ diacid. One or more amino acids may also be used in the selected configuration to add length or functionality. More generally, non-limiting embodiments include the use of a divalent linker moiety, such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, dihydroxy compound, or other compound that has at least two functional groups that can link the parent molecule to another binding moiety, and which can be stabilized by albumin in vivo. In some embodiments, 2, 3, 4, or 5 linking moieties are covalently linked in a sequential, branched, or cyclic manner to the parent compound. In some embodiments, the R ³⁰¹ acyl group is located at a position of the active compound that does not significantly adversely affect complement factor D inhibition of the molecule, such as (i) a substituent on the R ³² group or (ii) a substituent on

- 9 041794

C-ring, such as proline, or as a substituent on a C-ring substituent, such as R ¹ , R ² or R ³ , including, for example, a bridge moiety such as a fused cyclopropyl on a proline ring. In some embodiments, the acyl group has an aliphatic or heteroaliphatic carbon range of C ₁₂ , C ₁₄ , C ₁₆ , C ₁₈ , C ₂₀ , C _{22 ,} or C ₂₄ .

In one embodiment, the disorder is associated with an alternative pathway of the complement cascade. In yet another embodiment, the disorder is associated with the classical complement pathway. In a further embodiment, the disorder is associated with the lectin complement pathway. Alternatively, the active compound, or a salt or prodrug thereof, may act by a different mechanism of action than the complement cascade, or in particular as a complement factor D inhibitor, to treat the disorder described herein.

In one embodiment, a method of treating C3 glomerulonephritis (C3G) is provided which comprises administering to a patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or an N-oxide thereof. isolated isomer, optionally in a pharmaceutically acceptable composition. In one embodiment, a method of treating paroxysmal nocturnal hemoglobinuria (PNH) is provided which comprises administering to a patient an effective amount of a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or its isolated isomer, optionally in a pharmaceutically acceptable composition. In another embodiment, a method of treating wet or dry age-related macular degeneration (AMD) in a patient is provided, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog , N-oxide or its isolated isomer, optionally in a pharmaceutically acceptable composition. In another embodiment, a method of treating rheumatoid arthritis in a patient is provided, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof. , optionally in a pharmaceutically acceptable composition. In another embodiment, a method of treating multiple sclerosis in a patient is provided, which comprises administering to the patient an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof. , optionally in a pharmaceutically acceptable composition.

In other embodiments, the active compound, or a salt or prodrug thereof, as described herein, can be used to treat fatty liver and conditions resulting from fatty liver, non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis and liver failure, dermatomyositis, or amyotrophic lateral sclerosis.

The active compound or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide or isolated isomer thereof, optionally in a pharmaceutically acceptable composition as described herein, is also useful for administration in combination (in the same or different dosage form) or for alternating with a second pharmaceutical agent for use in reducing or reducing the side effects of the second pharmaceutical agent. For example, in one embodiment, the active compound can be used in combination with adoptive cell transfer therapy to reduce the inflammatory response associated with such therapy, for example, a cytokine-mediated response such as cytokine response syndrome. In one embodiment, the adoptive cell transfer therapy is a chimeric antigen receptor (CAR T) or dendritic cell therapy used to treat a hematologic or solid tumor, eg, B-cell associated hematologic cancer. In one embodiment, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or cancer that expresses CD19. In one embodiment, the inflammatory response elicited is a cytokine-mediated response. Another embodiment is provided which comprises administering an effective amount of the active compound, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, to a patient for the treatment of an ocular, pulmonary, gastrointestinal, or other disorder, in which you can get a therapeutic effect from external or local delivery.

Any of the compounds described herein (e.g., Formula I, Formula II, Formula III, Formula IV, or Formula V) may be administered to the eye in any desired form of administration, including intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, choroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior parascleral, scleral, pericorneal, and nasolacrimal injections or via mucus, mucin, or mucus barrier, by immediate or controlled release. In some embodiments, the active compound comprises a lipophilic group, such as a lipophilic acyl group, that is delivered to the eye in a polymeric drug delivery system, such as polylactic acid, polylactide-co-glycolide, polyglycolide, or another degradable polymer, or a combination thereof, or other type of lipophilic material to be delivered to the eye. In some embodiments, the lipophilic active molecule is more soluble in the polymeric or other form of the delivery system than in the ocular fluid. In other embodiments, the active compound provided herein may be used to treat or prevent a disorder in a patient mediated by complement factor D or an excess or disruptive amount of complement component C3 of the complement enhancement loop. As examples, the invention includes methods for treating or preventing complement-related disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder, or ischemic injury. The invention also relates to methods for reducing inflammation or an immune response, including an autoimmune response, mediated or dependent on factor D.

In another embodiment, a method of treating a patient, usually a human, with a complement system-mediated disorder is provided, which comprises administering a prophylactic antibiotic or vaccine to reduce the likelihood of bacterial infection during treatment using one of the compounds described herein. In embodiments, the patient, usually a human, is administered a prophylactic vaccine before, during, or after treatment with one of the compounds described herein. In some embodiments, a prophylactic antibiotic is administered to a patient, usually a human, before, during, or after treatment with one of the compounds described herein. In some embodiments, the infection is a meningococcal infection (eg, sepsis and/or meningitis), aspergillosis, or an infection caused by an encapsulated organism, such as Streptococcus pneumoniae or Haemophilus influenza type b (Hib), especially in children. In other embodiments, the vaccine or antibiotic is administered to the patient following infection with an infection due to or concomitant with inhibition of the complement system.

The present disclosure provides a compound of formula I, formula II or formula III

or a pharmaceutically acceptable salt, isotopic analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

where A is selected from A1, A2 and A3;

B is selected from B1, B2 and B3;

or B is B4;

B4 is defined separately below;

C is selected from C1, C2, C3 and C4;

or C is C5;

C5 is defined separately below;

and where for compounds of formula I there is at least one of the following restrictions: A is A3, B is B3, or C is C4;

C1 is ;

Q ¹ is N(R1), C(R'r'), C(R ¹ R ¹ ')C(R ¹ R ¹ '), C(R'r')C(R'r')C( R'r''), S or O;

Q ² is C(R ² R ² '), C(R ² R ² ')C(R ² R ² '), C(R ² R ² ')C(R ² R ² ')C(R ² R ² '), N(R ² ), S, O or C(R ² R ² ')O;

Q ³ is N(R ³ ), S, O, C(R ³ R ³ '), C(R ³ R ³ ')C(R ³ R ³ ') or C(R ³ R ³ ')C( R ³ R ³ ')C(R ³ R ³ ');

X ¹ and X ² are independently N, CH or CZ;

or X ¹ and X ² together represent C=C;

where X ¹ is directly connected to L3, and X ² is directly connected to L; and where Q ¹ , Q ² , Q ³ , X ¹ and X ² are selected to result in a stable compound;

Z represents . F, Cl, NH ₂ , CH ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

R ¹ , R ¹ , R ² , R ² , R ³ and R ³ are independently selected in each case, if necessary, and only in the case of the formation of a stable compound, from hydrogen, R ²⁰¹ , R ³⁰¹ , halogen (and, as a rule, fluorine, chlorine, bromine), hydroxyl, nitro, cyano, amino, alkyl, including C1- _C6 alkyl, alkenyl, including _C2 - _C6 alkenyl, alkynyl, including _C2 - _C6 alkynyl, alkoxy, including C1 -C ₆ -alkoxy, alkanoyl, including C ₂ -C ₆ alkanoyl, thioalkyl, including C1-C ₆ -alkylthio, hydroxy-C1-C ₆ -alkyl, amino-C1-C ₆ -akyl, -C ₀ -C ₄ -alkylNR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OR', -NR'R, -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ ,

- 11 041794

-NR ⁹ C(O)OR ¹⁰ , haloalkyl, including C ₁ -C ₆ -haloalkyl, and C ₁ -C ₆ -haloalkoxy;

or R ¹ and R ¹ are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

or R ³ and R ³ are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

or R ² and R ² are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring;

where each of the above spiro rings may be optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ -alkyl (and , in particular methyl), alkenyl, including C ₂ -C ₄ -alkenyl, alkynyl, including C ₂ -C ₄ -alkynyl, alkoxy, including C ₁ -C ₆ -alkoxy, alkanoyl, including C ₂ -C ₄ -alkanoyl , hydroxy-C ₁ -C ₄ alkyl, (mono- and dialkylamino) C ₁ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-alkyl (C ₃ - C ₇ cycloalkyl), haloalkyl including C ₁ -C ₆ haloalkyl, and haloalkoxy including C ₁ -C ₆ haloalkoxy;

or, in an alternative embodiment, each of the above spiro rings may be optionally substituted with an aryl ring;

or R ¹ and R ² are taken together to form a 3-membered carbocyclic ring, a 4- to 6-membered carbocyclic or aryl ring, or a 4- to 6-membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S;

or R ² and R ³ are taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring;

where each of these fused R ¹ and R ² or R ² and R ³ rings, or, as a rule, R ¹ , R ² , R ³ , R ¹ , R ² or R ³ , is optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ -alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ -alkenyl , alkynyl, including C ₂ -C ₄ -alkynyl, alkoxy, including C ₁ -C ₄ -alkoxy, alkanoyl, including C ₂ -C ₄ -alkanoyl, hydroxy-C ₁ -C ₄ -alkyl, (mono- and dialkylamino) C ₀ -C ₄ -alkyl, alkyl (C ₃ -C ₇ -cycloalkyl), including -C ₁ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O- (C ₃ -C ₇ -cycloalkyl) , haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

or R ¹ and R ¹ are taken together to form a carbonyl group;

or R ² and R ² are taken together to form a carbonyl group;

or R ³ and R ³ are taken together to form a carbonyl group;

or R ¹ and R ² are taken together to form a carbon-carbon double bond;

or R ² and R ³ are taken together to form a carbon-carbon double bond;

R and R' are independently selected from H, R ²⁰¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;

or, in an alternative embodiment, R, R' and R are independently selected from R ³⁰¹ , heteroalkyl, H, R ²⁰¹ , alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, and a heteroaliphatic moiety;

R ⁹ and R ¹⁰ are independently selected from hydrogen, alkyl, including C ₁ -C ₆ -alkyl, (C ₃ -C ₇ -cycloalkyl)C ₀ -C ₄ alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), and -OC ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl);

C2 is selected from:

q is 0, 1, 2, or 3;

r is 1, 2, or 3;

R ⁴⁴ , R ⁴⁴ , R ⁴⁵ , R ⁴⁵ are independently selected in each case, if necessary and only in the case of the formation of a stable compound, from hydrogen, R ²⁰¹ , halogen (and in particular fluorine, chlorine, bromine), hydroxyl, nitro , cyano, amino, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alkenyl, alkynyl including C2-C6 alkynyl, alkoxy including C1-C6 alkoxy, alkanoyl including C2-C6 alkanoyl, thioalkyl, including C1-C6-alkylthio, hydroxy-C1-C6-alkyl, amino-C1-C6-alkyl, -C0-C4-alkyl-NR ⁹ R ¹⁰ , -C(O)OR ⁹ , -OC(O) R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , haloalkyl including C1-C6 haloalkyl, and C1- _C6 haloalkoxy;

or R ⁴⁴ and R ⁴⁴ or R ⁴⁵ and R ⁴⁵ or two R ⁴⁷ groups are taken together to form a carbonyl group;

or R ⁴⁴ and R ⁴⁴ or R ⁴⁵ and R ⁴⁵ are substituted with a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O or S;

where each of the above spiro rings may be optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH; al- 12 041794 kyla, including C ₁ -C ₄ -alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ -alkenyl, alkynyl, including

C ₂ -C ₄ -alkynyl, alkoxy, including C ₁ -C ₆ -alkoxy, alkanoyl, including C ₂ -C ₄ -alkanoyl, hydroxy-C ₁ -C ₄ alkyl, (mono - and dialkylamino) C _g C ₄ - alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-alkyl (C ₃ -C ₇ cycloalkyl), haloalkyl, including CrC ₆ -haloalkyl, and haloalkoxy, including C 1 -C ₆ - haloalkoxy;

or R ⁴⁴ and R ⁴⁵ or R ⁴⁴ and R ⁴⁵ are taken together to form a 4 to 6 membered carbocyclic or aryl ring or a 4 to 6 membered heterocyclic or heteroaryl ring; each of which may be optionally substituted with 1 or more substituents;

each of the fused rings or typically R ⁴⁴ , R ^44' , R ⁴⁵ or R ^45' is optionally substituted with 1 or more substituents independently selected from R ²⁰¹ , halogen (and in particular F), hydroxyl, cyano, -COOH, alkyl, including C ₁ -C ₄ -alkyl (and in particular methyl), alkenyl, including C ₂ -C ₄ -alkenyl, alkynyl, including C ₂ -C ₄ -alkynyl, alkoxy, including C 1 -C ₄ -alkoxy , alkanoyl, including C ₂ -C ₄ -alkanoyl, hydroxy-C ₁ -C ₄ -alkyl, (mono- and dialkylamino)C ₀ -C ₄ -alkyl, alkyl (C ₃ -C ₇ -cycloalkyl), including -C1 -C4 alkyl (C ₃ -C ₇ -cycloalkyl), -O-(C ₃ -C ₇ -cycloalkyl), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C _g C ₆ -haloalkoxy;

C3 selected from:

X ³ is C(R ¹ R ¹ );

X ⁴ is N or CH;

X ^4a is N, CH or CZ;

X ⁵ and X ⁶ are C(R1R1);

or X ⁴ and X ⁵ or X ⁵ and X ⁶ together represent C=C;

X ⁷ is SO or SO2;

X ⁸ is C(R1R1) or N(R ⁴³ );

X ^5a is independently selected from C(R1R1) and O;

Q ⁴ is N or CH;

Q ⁵ is N(R ⁴⁷ ) or C(R ⁴⁶ R ⁴⁶ ');

Q ^5a is independently selected from C(R ⁴⁷ R ⁴⁷ ), N(R ⁴⁷ ), O, S, SO and SO2;

Q ⁶ is N(R ⁴⁷ ), C(R ⁴⁶ R ^46' ), S or O;

Q ⁷ is C(R ⁴⁶ R ^46' ), S or N(R ⁴⁷ );

Q ⁸ , Q ⁹ , Q ¹⁰ , Q ¹¹ and Q ¹² are independently C(R2R ² ), S, SO, SO2, O, N(R ² ), B(R ⁵⁰ ) or Si(R ⁴⁹ )2;

R ⁴⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

R ⁴² is halo, hydroxy, alkoxy, including C ₁ -C ₆ -alkoxy, haloalkoxy, including C1C ₆ -haloalkoxy, -SH or -S(C ₁ -C ₆ -alkyl);

- 13 041794

R ⁴³ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

R ⁴⁶ and R ⁴⁶ are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

or R ⁴⁶ and R ⁴⁶ are taken together to form an optionally substituted 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

R ⁴⁷ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, where each group may be optionally substituted;

or two R ⁴⁷ groups are taken together to form a carbonyl group;

R ⁴⁹ is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, where each group may be optionally substituted;

R ⁵⁰ is hydroxy or C ₁ -C ₆ alkoxy;

or X ¹ and Q ⁸ or Q ⁸ and Q ⁹ or Q ⁹ and Q ¹⁰ or Q ¹⁰ and Q ¹¹ or Q ¹¹ and Q ¹² or Q ¹² and X ² may form a carbon-carbon double bond;

or two Q ^5a groups or X ^4a and Q ^5a groups may form a carbon-carbon double bond;

and if any of these groups may be further optionally substituted, as that term is defined in the Terminology section below, if desired, a stable compound is obtained to achieve the desired effect that is chemically meaningful to the skilled artisan and the group is not redundant (i.e. as is known in the art, alkyl substituted with alkyl is excessive; however, for example, alkoxy substituted with alkoxy is not;

or the C3 central core fragment is a small beta-turn mimetic such as a benzodiazepine, Friedinger's lactam, 2-oxo-1,3-oxazolidine-4-carboxylate, or an e-D-glucose backbone. See De Marco, R. et al., In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as β-turn inducers, J. Org. Biomol. Chem., 2013, 11, 4316-4326, Hirschmann, R.F. et al., The β-D-Glucose Scaffold as a β-Turn Mimetic, Accounts Chem. Res., 2009, 42, 1511-1520 and Smith, A.B., et al., Accounts of Chem. Res., 2011, 44,180-193. In another embodiment, the central core fragment C may contain a reverse-rotation mimetic, which may include, but is not limited to; a non-peptide residue, a metal chelate mimetic, or a foldamer. See Nair, R.V. et al., Synthetic turn mimetics and hairpin nucleators: Quo Vadimus?, Chem. Comm., 2014, 50, 13874-13884. In other embodiments, the central core fragment C may comprise a cyclic amino acid with limited conformational freedom, including, but not limited to, a derivative of (S)- or (R)α-trifluoromethylpyroglutamic acid. See Chaume, G. et al., Concise access to enantiopure (S)- or (R)-a-trifluoromethyl pyroglutamic acids from ethyl trifluoropyruvate-base chiral CF3-oxazolidines (Fox), J.

Fluor. Chem., 2008, 129, 1104-1109 and Andre, C. et al., (S)-ABOC: A Rigid Bicyclic β-Amino Acid as Turn Inducer, Org. Lett., 2012, 14, 960-963. In other embodiments, the central core fragment C may contain a foldamer monomeric unit such as, but not limited to, oxazolidin-2-one. See Tomasii, C, Angelicim G. and Castellucci, N., Foldamers Based on Oxazolidin-2-ones, Eur. J. Org. Chem., 2011, 3648-3669;

C4 selected from:

or C4 is selected from:

- 14 041794

or A1 is selected from:

·' represents a single or double bond; C5 selected from:

A1 selected from:

- 15 041794

A2 selected from:

- 16 041794

- 17 041794

A3 selected from:

or A3 is selected from:

- 18 041794

or A3 is selected from:

or A3 is selected from:

- 19 041794 or A3 selected from:

or A3 is selected from:

or A3 is selected from:

where at least one of X ⁵¹ , X ⁵² and X ⁵³ is selected from CR ²⁰¹ ;

X ⁵⁴ , X ⁵⁵ and X ⁵⁶ are independently selected from N, CR ³¹ and CR ²⁰¹ ;

R ¹⁰⁴ is selected from R ²⁰¹ , C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, deuterium, -CO ₂ H, CO ₂ R ⁹ , heteroaryl, F, Cl, Br and cyano;

R ²⁰¹ is selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl- and hydroxyalkyl; -alkyl-O alkyl, including -CH ₂ OCH ₃ , -alkyl-S-alkyl, -alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic moiety-O-aliphatic moiety, -aliphatic moiety- S-aliphatic fragment, -aliphatic fragment-N(aliphatic fragment)-aliphatic fragment, -aliphatic fragment-NH-aliphatic fragment, -aliphatic fragment-O-heterocycle, -aliphatic fragment-S-heterocycle, -aliphatic fragment-N(aliphatic fragment)heterocycle, -aliphatic fragment-NH-heterocycle, -alkyl-NHC(O)haloalkyl, -alkylNR ⁹ C(O)haloalkyl, -alkyl-C(O)NH-haloalkyl, -alkyl-C(O)NR ⁹ -haloalkyl, -alkylNHC(O)haloalkyl, -alkyl-NR ⁹ C(O)aliphatic, -alkyl-C(O)NH-aliphatic, -alkyl-NR9C(O)-aliphatic, -alkyl-NHC( O)-aliphatic fragment,

- 20 041794

-substituted alkyl-N(R ⁹ )-substituted alkyl, alkyl-heteroaryl, -alkyl-O-haloalkyl, heteroaryl, heterocycle, alkyl-heterocycle, -M(aliphatic moiety)2; and where each R ²⁰¹ may be optionally substituted as defined in the terminology section below, and where R ²⁰¹ may be optionally substituted with R ³⁰¹ which may be directly linked to R ²⁰¹ or may be linked to R ²⁰¹ via amino, hydroxyl, thio, a carboxylic acid, phosphate, phosphonate or sulfonate bond;

In an alternative embodiment, R ²⁰¹ is selected from R ³⁰¹ , -alkyl-CN, -alkylNH ⁹ C(O)alkenyl, -alkyl-SO ₂ -alkyl, and -alkyl-S(O)NR ⁹ -alkyl; In an alternative embodiment, R ²⁰¹ is substituted with oxime and —C(O)Oalkyl; R ²⁰² is selected from aryl, heteroaryl and heterocycle, where the aryl, heteroaryl or heterocyclic ring is substituted with R ²⁰¹ ; R ³⁰¹ is selected from the following.

i. fatty acid residue. Examples are short chain fatty acids with 3, 4 or 5 carbon atoms in aliphatic moieties, medium chain fatty acids with aliphatic tails of 6, 7, 8, 9, 10, 11 or 12 carbon atoms, long chain fatty acids which contain aliphatic tails of 13 , 14, 15, 16, 17, 18, 19, 20, 21, or 22 carbon atoms, or a very long fatty acid that contains 22, 23, 24, 25, 26, 27, or 28 or more carbon atoms in aliphatic moieties. The chain of the aliphatic moiety can be saturated, monounsaturated, diunsaturated, triunsaturated, polyunsaturated or alkynyl.

ii. Unsaturated fatty acids can be used in cis or trans configuration and include, but are not limited to, oleic acid, ω6 fatty acid such as linoleic acid, ω3 fatty acid such as α-linolenic acid, docosahexaenoic acid, stearidonic acid, eicosapentaenoic acid , docosapentaenoic acid, eicosatetraenoic acid, myristolenic acid, palmitoleic acid, sapienic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, nervonic acid, eicosadienoic acid, docosadienoic acid, linolenic acid, t-linolenic acid, pinoleic acid, eleosteuric acid , β-eleostearic acid, midic acid, eicosatrienoic acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, erucic acid, and docosahexaenoic acid. Non-limiting examples of saturated fatty acids that can be used to prepare the prodrugs of the present invention are caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and cerotic acid.

iii. An amino acid residue that occurs naturally or is synthetic and includes, for example, α, β, γ or δ amino acids. Naturally occurring amino acids include those found in proteins, such as glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. . In some embodiments, the implementation of the amino acid is in the L-configuration. Alternatively, the amino acid may be used in the D-configuration or in a mixture of the L and D- configurations. Alternatively, the amino acid may be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl , β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β -glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. Additional amino acids include selenocysteine, pyrrolysine, N-formylmethionine, γ-aminobutyric acid (GABA), 5-aminolevulinic acid, aminobenzoic acid (including 4-aminobenzoic acid), aminoisobutyric acid, dehydroalanine, cystathionine, lanthionine, diencolic acid, diaminopimelic acid, norvaline , alloisoleucine, tleucine, α-aminoheptanoic acid, pipecolic acid, α,β-diaminopropionic acid, α,γdiaminobutyric acid, ornithine, glutamic acid, allothreonine, homocysteine, βaminobutyric acid, α-aminoisobutyric acid, isovaline, sarcosine, N-ethylglycine, N-propylglycine, N-isopropylglycine, N-methylalanine, N-ethylalanine, N-methyl-β-alanine, isoserine, norleucine, homoserine, O-methylhomoserine, O-ethylhomoserine, homonorleucine, carboxyglutamic acid, hydroxyproline, hypusine, pyroglutamic acid and α- hydroxy-γ-aminobutyric acid.

iv. An extended unnatural amino acid residue between the amino group and the carboxylic acid, which can be used either alone or as a linker to another prodrug moiety. Examples include amino acids where the amino acid and carboxylic acid are separated by an aliphatic or heteroaliphatic moiety (a non-limiting example is 8-amino-3,6-dioxaoctanoic acid), e.g., alkyl, alkenyl, alkynyl, ethylene glycol, propylene glycol, alkylene glycol, or the like, a moiety, e.g. , with 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more straight, branched, or cyclic atoms or moieties (eg, alkylene glycol moieties) to provide the desired properties, if desired. In some embodiments, the amino acid contains one or more internal amino acids.

- 21 041794 nyh, carbonyl, carboxyl, oxo, thio, phosphate or phosphonate fragments in the chain of the heteroaliphatic fragment.

v. A residue of one or more amino acids linked to a terminal fatty acid or to a terminal moiety such as hydrogen or alkyl. In one non-limiting example, 8-amino-3,6dioxaoctanoic acid (one or more in sequence) is covalently linked to a selected complement factor D inhibitor of the present invention through a functional group such as a carboxylic acid, sulfonyl, hydroxyl, or amino group. See, in general, Lau, et al., Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semiglutide, J. Med. Chem., 2015, 58, 7370-7380. 8-Amino-3,6-dioxaoctanoic acid is covalently bonded to an aliphatic acid including but not limited to C16, C18, C20 aliphatic acid or dicarboxylic acid including but not limited to C8, C10, C12, C14, C16 , C18 or C20 diacid. One or more amino acids may also be used in the selected configuration to add length or functionality.

R ⁴ , R ⁵ and R ⁶ are selected from hydrogen, -JCHO, -JC(O)NH2, -JC2-C6-alkanoyl, -JC(O)NH(CH3), -J-COOH, -JP(O)( OR ⁹ )2, -JOC(O)R ⁹ , -JC(O)OR ⁹ , -JC(O)N(CH2CH2R ⁹ )(R ¹⁰ ), -JNR ⁹ C(O)R ¹⁰ , -JSO2NH2, - JS(O)NH2, -JC(CH ₂ ) ₂ F, -JCH(CF ₃ )NH ₂ , -JC(O)C ₀ -C ₂ -alkyl(C ₃ -C ₇ -cycloalkyl), -JNR ⁹ ( C ₂ -C ₆ -alkanoyl),

-JNR ⁹ C(O)NR ⁹ R ¹⁰ , -JSO2(C1-C6-alkyl), -JSO2(C1-C6-haloalkyl), -JSO2NR7R ⁷ , -JSO=NH(C1-C ₆ -alkyl), - Jnitro, -J-halogen, -J-hydroxyl, -J-phenyl, 5- to 6-membered heteroaryl, -J-cyano, -J-cyanoimino, -J-amino, -J-imino, -C ₁ - C ₆ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -heterocycloalkyl), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl),

each of R ⁴ , R ⁵ and R ⁶ other than hydrogen, nitro, halogen, cyano, cyanoimino or -CHO is optionally substituted with one or more amino, imino, halogen, hydroxyl, cyano, cyanoimino, alkyl, including C ₁ -C ₆ -alkyl, alkoxy, including C ₁ -C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono - and di-C 1 -C ₄ alkylamino), -C ₁ -C ₆ -haloalkyl and haloalkoxy, including C 1 - C ₆ haloalkoxy;

J is independently selected from a covalent bond, alkylene, including C1-C ₄ alkylene, O-alkylene, including -OC ₁ -C ₄ alkylene, alkenylene, including C ₂ -C ₄ alkenylene, and alkynylene, including C ₂ -C ₄ -alkynylene;

R ⁶ represents hydrogen, halogen, hydroxyl, C1-C ₄ alkyl, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) or C 1 -C ₄ alkoxy;

or R ⁶ and R ⁶ may be taken together to form an oxo, vinyl or imino group;

R ⁷ represents hydrogen, alkyl, including C 1 -C ₆ -alkyl or -C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl);

R ⁸ and R ⁸ are selected from hydrogen, halogen, hydroxyl, alkyl, including C1-C ₆ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ C ₇ -cycloalkyl), alkoxy, including C 1 -C ₆ -alkoxy, and (C1-C ₄ -alkylamino)C ₀ -C ₂ -alkyl;

or R ⁸ and R ⁸ are taken together to form an oxo group;

or R ⁸ and R ⁸ are taken together with the carbon atom to which they are attached to form a 3-membered carbocyclic ring;

R ¹⁶ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -C1-C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -alkenyl, alkanoyl, including C ₂ -C ₆ -alkanoyl, alkoxy, including C 1 - C ₆ -alkoxy, -C0-C4 alkyl (mono- and di-C1-C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), haloalkyl, including C1-C6 haloalkyl, and haloalkoxy including C1- _C6 haloalkoxy;

R ¹⁹ is hydrogen, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alkenyl, alkanoyl including C2-C6 alkanoyl, -SO2C1-C6-alkyl, (mono- and di-C1-C6- alkylamino)C1-C4-alkyl, -C0-C4-alkyl(C3-C7-cycloalkyl), -C0-C4-alkyl(C3-C7-heterocycloalkyl), -C0-C4-alkyl(aryl), or C0-C4-alkyl(heteroaryl) where each R ¹⁹ other than hydrogen is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C(O)OC1-C ₄ -alkyl;

X ¹¹ is N or CR ¹¹ ;

X ¹² is N or CR ¹² ;

X ¹³ is N or CR ¹³ ;

X ¹⁴ is N or CR ¹⁴ ;

where no more than 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ are N;

where one of R ¹² and R ¹³ is R ³² and the other is R ³¹ or R ³² ;

and where in the absence of R ¹³ and R ³² on ring A, then R ¹² is R ³² ;

and where in the absence of R ¹² and R ³² on ring A, then R ¹³ is R ³² ;

R ³¹ is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, haloalkyl including C1-C6 haloalkyl, haloalkoxy including C1-C6 haloalkoxy, alkyl including C1-C6 alkyl, -C0C4- alkyl (C3-C7-cycloalkyl), alkenyl, including C2-C6-alkenyl, alkanoyl, including C2-C6-alkanoyl, alkoxy, including C1-C6-alkoxy, alkenyloxy, including C2-C6-alkenyloxy, -C(O) OR ⁹ , thioalkyl, including C1-C6-thioalkyl, -C ₀ -C ₄ -alkyl-NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO2R ⁹ , -SO2NR9R ¹⁰ , -OC(O)R ⁹ , and -C(NR ⁹ )NR ⁹ R ¹⁰ , each of R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, haloalkyl, including C1-C6 haloalkyl and C1-C6 haloalkoxy, is optionally substituted one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -C(O)NR ⁹ R ¹⁰ , haloalkyl, including C1C6-haloalkyl, haloalkoxy, including C ₁ -C ₆ -haloalkoxy, phenyl and 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; each phenyl or 4- to 7-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C 2 -C 6 alkenyl, alkanoyl, including C2-C6-alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ -alkylamino) C ₀ C4-alkyl, alkyl ether including C ₁ -C ₆ -alkyl ether, (-C ₀ -C4-alkyl)(C ₃ -C ₇ -cycloalkyl), C ₁ -C6 -haloalkyl and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

R ³² is selected from aryl, heteroaryl and heterocycle, where aryl, heteroaryl or heterocyclic ring may be optionally substituted;

in one embodiment, R ³² is substituted with R ³⁰¹ , -CH2-R ³⁰¹ , or R ²⁰¹ ;

R ¹¹ , R ¹⁴ and R ¹⁵ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -O(PO)(OR ⁹ )2, -(PO)(OR ⁹ )2, alkyl, including C ₁ -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -alkenyl, alkynyl, including C 2 -C 6 alkynyl, C ₂ -C ₆ -alkenyl (aryl), C ₂ -C ₆ -alkenyl (cycloalkyl), C ₂ -C ₆ -alkenyl (heterocycle), C2-C6 alkenyl (heteroaryl), C ₂ -C ₆ alkynyl (aryl), C ₂ -C ₆ alkynyl (cycloalkyl), C ₂ -C ₆ alkynyl (heterocycle), C ₂ C ₆ alkynyl (heteroaryl), alkanoyl, including C ₂ -C ₆ -alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, thioalkyl, including C ₁ -C ₆ -thioalkyl, -C ₀ -C ₄ -alkyl (mono- and di -C ₁ -C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), -C ₀ -C ₄ -alkoxy (C ₃ -C ₇ -cycloalkyl), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

X ¹⁵ represents NH, O or S;

X ¹⁶ is CR ¹² ;

X ¹⁷ is N or CR ¹³ ;

X ¹⁸ is CR ¹² ;

X ¹⁹ is N or CR ¹³ ;

X ²⁰ is NH or O;

X ²¹ is N or CR ¹⁴ ;

X ²² is N or CR ¹³ ;

X ²³ is CR ¹² ;

X ²⁴ is O or S;

X ²⁶ is N or CR ⁴¹ ;

X ²⁷ is CR ¹² , NH, or O;

X ²⁸ is N or CH;

X ³⁰ is N or CR ⁵ ;

X ³¹ is N, C(R ⁵⁴ )2, or CR ⁵⁴ ;

X ³² is NH, C(R ⁵⁴ )2 or CR ⁵⁴ ;

X ³³ represents -CO-, -SO- or -SO ₂ -;

X ³⁴ is CHR ¹³ , NH, O or S;

where no more than 2 of X ²⁸ are N;

R ⁴¹ represents hydrogen, alkyl, including C ₁ -C ₆ -alkyl, or -(C ₀ -C ₂ -alkyl)(C ₃ -C ₅ cycloalkyl);

R ⁴⁸ and R ^48a are selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, alkyl including C1-C6 alkyl, haloalkyl including C ₁ -C ₆ haloalkyl, alkenyl including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ C ₆ -alkynyl, thioalkyl, including C ₁ -C ₆ -thioalkyl, alkoxy, including C ₁ -C ₆ -alkoxy, -JC ₃ -C ₇ -cycloalkyl, -B (OH) 2, -JC (O )NR ⁹ R ²³ , -JOSO2OR ²¹ , -C(O)(CH2)1-4S(O)R ²¹ , -O(CH2)1-4S(O)NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ), -JP(O)(OR ²¹ )(OR ²² ), -JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , -JOP(O) R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)(OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ),

-JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC(O)NR ²¹ SO2R ²² , -JC(NH2)=NR ²² , -JCH(NH2)NR ⁹ S(O) 2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH2)1-4C(O)NR ²¹ R ²² , -JC (O)NR ²⁴ R ³⁰ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O)NR ¹⁰ R ²² , -CCR ²¹ , -(CH2)1-4OC( O)R ²¹ , -JC(O)OR ²³ and R ¹⁰³ ; each R ⁴⁸ may be optionally substituted with one or more substituents selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CONR9R ¹⁰ , -P (O)(OH)2, alkyl, including C ₁ -C ₆ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₆ -alkoxy, -C ₀ -C ₄ -alkyl (mono- and di-C ₁ -C ₄ -alkyl-NR ⁹ R ¹⁰ ), alkyl ether, including C 1 -C 6 alkyl ether, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, haloalkyl, including C 1 -C 6 haloalkyl , -OC(O)R ⁹ , -NR ⁹ C(O)R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -OC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)OR ¹⁰ , haloalkyl , including C1C6-haloalkyl, S(O)=NHR ²¹ , SF5, JC(R ⁹ )=NR ²¹ , SO2OR ²¹ and haloalkoxy, including C1-C ₆ -haloalkoxy;

R ¹⁰³ is independently C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, fluorine, chlorine, or bromine;

R ⁵⁴ is hydrogen, alkyl including C ₁ -C ₆ alkyl, alkenyl including C ₂ -C ₆ alkenyl, alkynyl including C ₂ -C ₆ alkynyl, alkoxy including C ₁ -C ₆ alkoxy, C ₂ -C ₆ -alkynyl, alkanoyl, including C ₂ C ₆ -alkanoyl, thioalkyl, including C ₁ -C ₆ -thioalkyl, hydroxy-C ₁ -C ₆ -alkyl, amino-C ₁ -C ₆ -alkyl, - C ₀ -C ₄ - 23 041794 alkyl (C ₃ -C ₇ -cycloalkyl), (phenyl) C ₀ -C ₄ -alkyl-, (heterocycloalkyl) C ₀ -C ₄ -alkyl or (heteroaryl) C ₀ -C ₄ alkyl, where each R ⁵⁴ is optionally substituted;

s is 1 or 2;

L is selected from L1 and L2;

About p18 p18'

^R17

L1 is a bond,

R ¹⁷ represents hydrogen, alkyl, including C1-C ₆ -alkyl or -C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl);

R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl;

m is 0, 1, 2, or 3;

L2 is selected from:

or L2 is selected from an optionally substituted monocyclic or bicyclic carbocyclic moiety; an optionally substituted monocyclic or bicyclic carbocyclic hydroxy group; optionally substituted monocyclic or bicyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms per ring, optionally substituted with -(C ₀ -C ₄ -alkyl) (aryl); optionally substituted -(C ₀ -C ₄ -alkyl)(5-membered heteroaryl); optionally substituted -(C ₀ -C ₄ -alkyl)(6-membered heteroaryl); optionally substituted -(C ₀ -C ₄ -alkyl)(8-membered heteroaryl); optionally substituted (C ₀ -C ₄ -alkyl)(9-membered heteroaryl); and -(C ₀ -C ₄ -alkyl)(10-membered heteroaryl);

q is 1, 2, or 3;

R ⁵¹ is CH ₃ , CH ₂ F, CHF2 or CF ₃ ;

R ⁵³ is cyano, nitro, hydroxyl or alkoxy, including C1- _C6 alkoxy;

X ²⁹ may be O or S;

L3 is -C(O)-, -C(S)-, -P(O)OH-, -S(O)-, -S(O) ₂ - or -C(R ⁵² ) ₂ -;

each R ⁵² is independently selected from halo, hydrogen, or optionally substituted alkyl, including C1- _C6 alkyl;

or two R ⁵² groups are taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O, or S;

B1 is heteroaryl; aryl; biphenyl, monocyclic or bicyclic carbocycle; a monocyclic or bicyclic carbocyclic hydroxy group; a monocyclic, bicyclic or tricyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from boron, Si, N, O and S and from 4 to 8 ring atoms per ring; alkenyl, including C ₂ C ₆ -alkenyl; or alkynyl, including C ₂ -C ₆ alkynyl; each of B1 is optionally substituted with one or more substituents independently selected from R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

R ³³ is independently selected from halogen, hydroxyl, -COOH, cyano, alkyl including C1-C6 alkyl, alkanoyl including C2-C6 alkanoyl, alkoxy including C1-C6 alkoxy, -C0-C4 alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , haloalkyl including C1-C6 haloalkyl, S(O)=NHR ²¹ , SF ₅ , and JC(R ⁹ )=NR ²¹ , and haloalkoxy including C1-C6 haloalkoxy;

- 24 041794

R ³⁴ is independently selected from nitro, alkenyl including C ₂ -C ₆ alkenyl, alkynyl including C 2 -C 6 alkynyl, thioalkyl including C ₁ -C ₆ -thioalkyl, -JC ₃ -C ₇ -cycloalkyl, -JB(OH) 2, -JC(O)NR ⁹ R ²³ , -JOSO2OR ²¹ ,

-JC(O)(CH2)i-4S(O)R ²¹ , -O(CH2)Si-4(O)NR ²¹ R ²² , -JOP(O)(OR ²¹ )(OR ²² ), -JP( O)(OR ²¹ )(OR ²² ),

-JOP(O)(OR ²¹ )R ²² , -JP(O)(OR ²¹ )R ²² , -JOP(O)R ²¹ R ²² , -JP(O)R ²¹ R ²² , -JSP(O)( OR ²¹ )(OR ²² ), -JSP(O)(OR ²¹ )(R ²² ), -JSP(O)(R ²¹ )(R ²² ), -JNR ⁹ P(O)(NHR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(NHR ²² ), -JNR ⁹ P(O)(OR ²¹ )(OR ²² ), -JC(S)R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S(O)NR ¹⁰ R ²² , -jnr ⁹ so2nr ¹⁰ r ²² , -jso2nr ⁹ cor ²² , -jso2nr ⁹ conr ²¹ r ²² , -jnr ²¹ so2r ²² , -JC(O)NR ²¹ SO2R ²² , -JC (NH2)=NR ²² , -JCH(NH2)NR ⁹ S(O)2R ²² , -JOC(O)NR ²¹ R ²² , -JNR ²¹ C(O)OR ²² , -JNR ²¹ OC(O)R ²² , -(CH2)1-4C(O)NR ²¹ R ²² , -JC(O)R ²⁴ R ³⁰ , -JNR ⁹ C(O)R ²¹ , -JC(O)R ²¹ , -JNR ⁹ C(O )NR ¹⁰ R ²² , -ccr ²¹ , -(CH2) _1-4 OC(O)R ²¹ , -S(O)2OR ²¹ , and -JC(O)OR ²³ ; where each R ³⁴ may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B(OH)2, -Si(CH3)3, -COOH, -CONR9R ¹⁰ , -P (O) (OH) 2, C ₁ -C ₆ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), alkoxy, including C ₁ -C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono - and di-C ₁ -C ₄ -alkylamino), C ₁ -C ₆ -alkylether, Ci-C ₄ alkylamino, C ₁ -C ₄ -hydroxylalkyl, haloalkyl, including C ₁ -C ₆ -haloalkyl, and C ₁ -C ₆ -haloalkoxy;

R ³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C0-C4-alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S and containing 4 to 8 ring atoms in each ring; where each R ³⁵ is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -alkenyl, alkanoyl, including C ₂ -C ₆ -alkanoyl , alkoxy, including C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylether, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -SO2R ⁹ , haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C6-haloalkoxy;

R ³⁶ is independently selected from tetrazolyl, (phenyl)C0-C2-alkyl, (phenyl)C1-C6-alkoxy, phenoxy, and 5 or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, boron , Si and S, where each R ³⁶ is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C 1 -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -alkenyl, alkanoyl, including C ₂ -C ₆ -alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ -cycloalkyl), -SO2R ⁹ , - OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , haloalkyl including C ₁ -C ₆ haloalkyl, and haloalkoxy including C ₁ -C ₆ haloalkoxy;

in an alternative embodiment, R ³⁶ is a bicyclic heteroaryl such as 9-membered heteroaryl;

R ²¹ and R ²² are independently selected from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ -alkyl, haloalkyl, including C ₁ -C ₆ -haloalkyl, alkoxy, including C ₁ -C ₆ -alkoxy, (C ₃ - C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ C ₄ -alkyl, -C ₁ -C ₄ -alkyl-OC (O) OC ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkyl-OC(O)C ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkyl-C(O)OC ₁ C ₆ -alkyl, (4- to 8-membered heterocycloalkyl)C ₀ -C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C ₀ C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and each R ²¹ and R ²² may be optionally substituted;

or R ²¹ and R ²² may be taken together to form a carbocyclic or heterocyclic ring;

R ²³ is independently selected at each occurrence from alkyl, including C ₁ -C ₆ -alkyl, haloalkyl, including C1C ₆ -haloalkyl, (aryl)C ₀ -C ₄ -alkyl, (C ₃ -C ₇ -cycloalkyl)C ₀ - C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, (4- to 8-membered heterocycle) C ₀ -C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 - or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, where each R ²³ may be optionally substituted; R ²⁴ and R ³⁰ are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered monocyclic heterocycle, or a 6- to 10-membered bicyclic heterocyclic group containing fused, spiro, or bridged rings, where each ring may be optionally substituted;

B2 is selected from:

a) a 4-membered carbocycle fused to a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; where the 4-5 or 4-6 ring system may be optionally substituteda;

b) (optionally substituted alkyl)-(optionally substituted cycloalkyl), (optionally substituted alkenyl)-(optionally substituted cycloalkyl), or (optionally substituted alkynyl)-(optionally substituted cycloalkyl);

c) a 4-membered carbocycle fused to a 6-membered aryl ring, where the 4-6 ring system may be optionally substituted;

d) (cycloalkyl)-(optionally substituted aryl), (cycloalkyl)-(optionally substituted heteroaryl), (cycloalkyl)-(optionally substituted heterocycle), (alkyl)-alkenyl), cycloalkylalkenyl;

e) alkyl, alkyl(alkynyl), where each may be optionally substituted;

where B2 may be further substituted with 1, 2, 3, or 4 times or more substituents, regardless

- 25 041794 selected from R ³³ , R ³⁴ , R ³⁵ , R ³⁶ and R ⁴⁸ ;

B3 is a monocyclic or bicyclic carbocycle; a monocyclic or bicyclic carbocyclic hydroxy group; a monocyclic, bicyclic or tricyclic heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from boron, Si, N, O and S and from 4 to 8 ring atoms per ring; alkenyl, including C ₂ -C ₆ -alkenyl; alkynyl, including C ₂ -C ₆ alkynyl; -(C ₀ -C ₄ -alkyl)(aryl); -(C ₀ -C ₄ -alkyl)(heteroaryl); or -(C ₀ -C ₄ -alkyl)(biphenyl), where each B3 is substituted with at least one R ²⁰¹ and optionally substituted with one or more substituents independently selected from R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

B4 is a six-membered heteroaryl ring with at least two substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ;

or B4 is a six-membered heteroaryl ring with at least three substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ;

or B4 is pyridine with at least two substituents selected from R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ ; or B4 is selected from:

R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from halo, hydroxyl, nitro, cyano, alkyl including C1C6 alkyl, alkenyl including C2-C6 alkenyl, alkanoyl including C2-C6 alkanoyl, alkoxy including C1C6-alkoxy, thioalkyl, including C1-C6-thioalkyl, (mono- and di-C1-C6-alkylamino)C0-C4-alkyl, (C3-C7cycloalkyl)C0-C4-alkyl, (aryl)C0-C4-alkyl -, (heteroaryl)C0-C4-alkyl-, and -C0-C4-alkoxy(C3-C7-cycloalkyl); where each R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C1-C ₆ -alkoxy, haloalkyl, including C ₁ -C ₆ -haloalkyl, (C ₃ C ₇ -cycloalkyl)C ₀ -C ₄ -alkyl-, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

or R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from tetrazole, halogen, hydroxyl, nitro, cyano, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alkenyl, alkanoyl including C2-C6- alkanoyl, alkoxy, including C1-C6-alkoxy, thioalkyl, including C1-C6-thioalkyl, (mono- and di-C1-C6-alkylamino)C0-C4alkyl, (C3-C7-cycloalkyl)C0-C4-alkyl, ( aryl)C0-C4-alkyl-, (heteroaryl)C0-C4-alkyl-, and -C0-C4-alkoxy(C3-C7-cycloalkyl); where each R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C1-C ₆ -alkoxy, haloalkyl, including C _r C ₆ -haloalkyl, (C ₃ -C ₇ -cycloalkyl)C ₀ -C ₄ -alkyl-, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

and where any of these groups may be further optionally substituted in the manner that the term is defined in the terminology section below, if desired, to achieve the desired effect, resulting in a stable compound that is chemically meaningful to the skilled artisan and the group is not redundant (ie, as is known in the art, alkyl substituted with alkyl is excessive; however, for example, alkoxy substituted with alkoxy is not; and where any of the structures shown here, for example, A1, A2, A3, B1, B2, OT, B4, C1, C2, C3, C4, C5, L, L3, or any of the R moieties, may optionally be independently substituted 0, 1, 2, 3 or 4, if necessary, R ⁴⁸ substituents.

In another aspect, the invention relates to a compound of formula IV

λ ³ A (IV) or a pharmaceutically acceptable salt, isotopic analog, prodrug or isolated isomer thereof, optionally in a pharmaceutically acceptable carrier;

where R ³² group on ring A is selected from

and where all other variables have the meanings defined herein.

In another aspect, the invention relates to a compound of formula V

L3

A4(V) or a pharmaceutically acceptable salt, isotopic analog, prodrug, N-oxide or you

- 26 041794 divided isomer, optionally in a pharmaceutically acceptable carrier;

where B is as defined above. C is as defined above.

L is as defined above.

L3 is as defined above.

A4 selected from:

- 27 041794

where all other variables have the meanings defined in this document.

Also disclosed are pharmaceutical compositions containing a compound or salt of formula I, formula II, formula III, formula IV or formula V together with a pharmaceutically acceptable carrier.

The present invention thus includes at least the following features:

a) a compound of formula I, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide or isolated isomer thereof, optionally in a pharmaceutically acceptable composition,

b) a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, for use in the treatment or prevention of a disorder, including but not limited to, the development of fatty liver disease and conditions associated with fatty liver, such as non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis, or liver failure; dermatomyasitis; amyotrophic lateral sclerosis; cytokine or inflammatory responses to biotherapeutic agents (eg, CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (eg, geographic retinal atrophy), respiratory disease, or cardiovascular disease;

c) a pharmaceutically acceptable composition of a compound of formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, in a pharmaceutically acceptable carrier;

d) a compound selected from formula I, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, for use in treatment, or preventing a disorder mediated by complement activation and, for example, the Factor D cascade;

e) using a compound of formula I, formula II, formula III, formula IV, or formula V as described herein, or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition, when the manufacture of a medicinal product for the treatment or prevention of a disorder, including,

- 28 041794 but not limited to the development of fatty liver disease and conditions associated with fatty liver, such as non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis, liver failure; dermatomyasitis; amyotrophic lateral sclerosis; cytokine or inflammatory responses to biotherapeutic agents (eg, CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (eg, geographic retinal atrophy), respiratory disease, or cardiovascular disease;

f) a process for the manufacture of a medicinal product intended for therapeutic use in the treatment or prevention of a disorder, or generally in the treatment or prevention of disorders mediated by the factor D complement cascade, characterized in that the compound selected from formula I, formula II, formula III , formula IV or formula V or an embodiment of this active compound is used in the manufacture;

g) a compound selected from formula I, formula II, formula III, formula IV or formula V, or a salt thereof, as described herein, in substantially pure form (for example, at least 90 or 95%):

h) a compound of formula I, formula II, formula III, formula IV, or formula V as described herein, or a pharmaceutically acceptable salt, prodrug, isotopic analog, Noxide, or isolated isomer thereof, optionally in a carrier, to form a pharmaceutically acceptable composition for use in the treatment of a medical disorder that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), a disorder or pathological change in a cell that adversely affects the cell's ability to participate in or respond to normal complement activity, or an unwanted complement mediated response medical treatment, such as surgery or other medical procedure, or administration of medicinal or biopharmaceuticals, blood transfusion, or administration of other allogeneic tissue or fluid;

i) for each of (a)-(i) above and otherwise herein, each group of moieties in the figures and each active compound derived therefrom or use thereof are contemplated and considered to be specifically and individually disclosed as such description is provided for convenience. location only and is not intended to describe only a genus or even a subgenus for such a display.

Terminology

Compounds are described using standard nomenclature. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

Compounds in any of the formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each were specifically described unless otherwise noted or otherwise excluded by context.

The term or means and/or. The indication of ranges of values is intended only to serve as a concise way of referring independently to each individual value falling within that range, unless otherwise noted here, and each individual value is included in the description as if it were separately specified here. The endpoints of all ranges are included in the range and can be independently combined. All methods described herein can be performed in an appropriate order, unless otherwise specified herein or otherwise contrary to the context. The use of examples or introductory words (eg, such as) is only intended to better illustrate the invention and does not limit the scope of the invention unless otherwise stated. Unless otherwise indicated, the technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

The present invention includes compounds of formula I, formula II, formula III, formula IV or formula V with at least one desired isotopic substitution of an atom in excess of the natural abundance of the isotope, i.e. enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e. same number of protons, but different number of neutrons.

Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ CI, ¹²⁵ I, respectively. In one embodiment, isotopically labeled compounds can be used in metabolic studies (with ¹⁴ C), reaction kinetics studies (for example, with ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including studies of the distribution of drugs or substrate in tissues, or in the radioactive treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs, as a rule, can be obtained by carrying out the procedures described in the schemes or in the examples and methods of obtaining,

- 29 041794 described below, by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

As a general example and without limitation, isotopes of hydrogen, such as deuterium ( ² H) and tritium ( 3 H), may optionally be used anywhere in the described structures, which allows you to achieve the desired result. Alternatively or in addition, isotopes of carbon, e.g., ¹³ C and ¹⁴ C, can be used. In one embodiment, isotope substitution is the replacement of hydrogen with deuterium at one or more sites on a molecule to improve drug performance, e.g., pharmacodynamics, pharmacokinetics , biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can be bound to carbon at the site of the bond break during metabolism (kinetic isotope effect of α-deuterium) or near or near the site of the bond break (kinetic isotope effect of β-deuterium).

Isotopic substitutions, such as deuterium, may be partial or complete. Partial substitution by deuterium means that at least one hydrogen atom is replaced by deuterium. In some embodiments, the isotope is 80%, 85%, 90%, 95%, or 99% or more enriched in the isotope at any location of interest. In one embodiment, the deuterium is enriched to 80%, 85%, 90%, 95%, or 99% at any point of interest. Unless otherwise indicated, enrichment at any point exceeds natural abundance, and in one embodiment, it is sufficient to change the detectable property of the drug in humans.

In one embodiment, the substitution of a hydrogen atom for a deuterium atom can be carried out in any of A1, A1', A2, B1, B1', B2, B3, B4, C1, C1', C2, C3, C4, L1, L1', L2 , L2', L4 or L5. In one embodiment, the replacement of a hydrogen atom by a deuterium atom occurs within any R group. In one embodiment, the R group is selected from any of R ¹ , R ¹ , R ² , R ² , R ³ , R ³ , R ⁴ , R ⁴ , R ^{5 ,} R ⁶ , R ⁶ , R 7 R ⁸ R ⁸ 'R ⁹ R ¹⁰ R ¹¹ R ¹² R ¹³ R ¹⁴ R ¹⁵ R ¹⁶ R ¹⁷ R ¹⁸ R ¹⁸ ' R ¹⁹ R ²¹ R ²² R ²³ R ²⁵ R ²⁶ R ²⁷ R ²⁸ R ³⁰ R ³¹ R ³² R33 R34 R35 R36 R40 R41 R42 R43 R44 R44' R45 R45' R46 R46' R47 R48 R48a r49 R50 R51 R52 R53 R54 R103 R ¹⁰⁴ , R ²⁰¹ , R ²⁰² and R ³⁰¹ . For example, when any of the R groups are or contain, for example, when substituted with methyl, ethyl, or methoxy, the alkyl moiety can be deuterated (in non-limiting embodiments, CD ₃ , CH ₂ CD ₃ , CD ₂ CD ₃ , CDH ₂ , CD ₂ H, CD ₃ , CHDCH2D, Ch ₂ CD ₃ , CHDCHD2, OCDH2, OCD2H or OCD ₃ , etc.). In some other embodiments, the R group has the designation ' or a, which in one embodiment may be deuterated. In some other embodiments, when two central ring substituents combine to form a cyclopropyl ring, the unsubstituted methylene carbon may be deuterated. The compound of the present invention can form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound. The term solvate refers to a molecular complex of a compound of the present invention (including its salt) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term hydrate refers to a molecular complex containing a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those in which the solvent of crystallization can be isotopically substituted, for example, D ₂ O, d ₆ -acetone, d ₆ - DMSO. The solvate may be in liquid or solid form.

A dash (-) that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH ₂ is attached through the carbon of the keto group (C=O).

As used herein, the term substituted means that any one or more hydrogen atoms in the specified atom or group is replaced by a fragment selected from the specified group, provided that the normal valence of the specified atom is not exceeded, and the resulting compound is stable. For example, when a substituent is oxo (ie =O), then two hydrogen atoms on that atom are substituted. For example, a pyridyl group substituted with oxo is pyridone. Combinations of substituents and/or variables are allowed only if such combinations result in the formation of stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and put into dosage form with a shelf life of at least one month. A stable manufacturing intermediate or active compound precursor is stable if it does not degrade within the time required for the reaction or other use. A stable moiety or substituent group is a group that does not decompose, react or disintegrate within the period required for use. Non-limiting examples of unstable moieties are those that combine a heteroatom in an unstable arrangement, as commonly known and identified by those skilled in the art.

Any suitable group may be present at a substituted or optionally substituted position that forms a stable molecule and is consistent with the desired object of the invention, and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br, or I); cyano;

- 30 041794 hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including one or more thioether bonds; alkylsulfinyl; alkylsulfonyl groups, including those containing one or more sulfonyl bonds; aminoalkyl groups, including groups containing more than one N atom; aryl (eg phenyl, biphenyl, naphthyl or the like, each ring is either substituted or unsubstituted); arylalkyl containing, for example, from 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, the benzyl group being an example of an arylalkyl group; arylalkoxy, for example containing from 1 to 3 separate or fused rings, benzyloxy being an example of an arylalkoxy group; or a saturated or partially unsaturated heterocycle containing from 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl containing from 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, iperazinyl, piperazinyl . Such groups may be further substituted with, for example, hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, optionally substituted includes one or more substituents independently selected from halo, hydroxyl, amino, cyano, -CHO, -COOH, -CONH2, alkyl, including C ₁ -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -alkenyl, alkynyl, including C ₂ -C ₆ -alkynyl, -C ₁ -C ₆ -alkoxy, alkanoyl, including C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkyl ether, (mono - and di-C ₁ -C ₆ -alkylamino)C ₀ -C ₂ -alkyl, haloalkyl, including C1C ₆ -haloalkyl, hydroxy-C ₁ -C ₆ -alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl (heterocyclo), C ₁ -C ₆ -alkyl (heteroaryl), -C ₁ -C ₆ -alkyl (C ₃ -C ₇ -cycloalkyl), OC ₁ -C ₆ -alkyl (C ₃ -C ₇ cycloalkyl), B (OH) ₂ , phosphate, phosphonate and haloalkoxy, including C ₁ -C ₆ haloalkoxy.

Alkyl is a saturated aliphatic hydrocarbon group with a branched or straight chain. In one embodiment, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, alkyl contains from 1 to about 8 carbon atoms. In some embodiments, alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1- _C6 . The indicated ranges used in this description denote an alkyl group in which each member of the range is described as an independent group. For example, the term C ₁ -C ₆ alkyl as used herein means a straight or branched alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each is described as an independent group. For example, the term C ₁ -C ₄ alkyl as used herein denotes a straight or branched alkyl group containing 1, 2, 3, or 4 carbon atoms and is intended to mean that each is described as an independent group. When C^Cn-alkyl is used here together with another group, for example, (C ₃ -C ₇ -cycloalkyl)C ₀ -C ₄ -alkyl or -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl, specified the group, in this case cycloalkyl, is either directly linked by a single covalent bond (C ₀ alkyl), or attached by an alkyl chain in this case with 1, 2, 3 or 4 carbon atoms Alkyls can also be attached through other groups such as a heteroatom, as in -O-C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl) Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl In one embodiment, the alkyl groups are optionally substituted, as above In one embodiment, trimethylsilyl can be used instead of tert-butyl.

Aliphatic refers to a saturated or unsaturated, straight, branched or cyclic hydrocarbon. Aliphatic is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus includes each of these definitions. In one embodiment, aliphatic is used to refer to those aliphatic groups that contain 1-20 carbon atoms. The aliphatic chain may be, for example, monounsaturated, diunsaturated, triunsaturated, polyunsaturated or alkynyl. Unsaturated aliphatic groups may be in the cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The indicated ranges used herein denote an aliphatic group in which each member of the range is described as an independent group. For example, the term C1-C6 aliphatic as used herein means a straight or branched alkyl, alkenyl, or alkynyl group containing from 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that each of them is described as an independent group. For example, the term C1-C4 aliphatic moiety as used herein means a straight or branched alkyl, alkenyl, or alkynyl group, with

- 31 041794 holding from 1, 2, 3 or 4 carbon atoms, and is intended to indicate that each of them is described as an independent group. In one embodiment, the aliphatic group is substituted with one or more functional groups, resulting in a stable moiety. The term heteroaliphatic refers to an aliphatic moiety that contains at least one heteroatom in the chain, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron in place of a carbon atom. In one embodiment, the only heteroatom is a nitrogen atom. In one embodiment, the only heteroatom is an oxygen atom. In one embodiment, the only heteroatom is a sulfur atom.

The term heteroaliphatic is intended to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, heteroaliphatic is used to refer to a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) containing 1-20 carbon atoms. In one embodiment, if the heteroaliphatic group is optionally substituted, a stable moiety is formed. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, and others.

In one embodiment, when a term is used that includes alk, it should be understood that cycloalkyl or carbocyclic may be considered part of the definition, unless the context expressly excludes this. For example, and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenoxy, haloalkyl, aminoalkyl, alkylene, alkenylene, alkynylene, etc., may be considered to include alkyl cyclic forms unless expressly excluded from the context.

Alkenyl is a branched or straight chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds that may occur at a stable point along the chain. Non-limiting examples are C ₂ -C ₈ alkenyl, C 2 -C 7 alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl, and C ₂ -C 4 alkenyl. The indicated ranges used in this description denote an alkenyl group in which each member of the range is described as an independent group, as described above for the alkyl fragment. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above.

Alkynyl is a branched or straight chain aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds that can occur at any stable point along the chain, such as C ₂ -C ₈ alkynyl or C ₂ -C ₆ alkynyl. The specified ranges used in this description, denote alkynyl group containing each group of the range, described as an independent group, as described above for the alkyl fragment. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl , 4-hexynyl and 5hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above.

Alkylene is a divalent saturated hydrocarbon. Alkylenes, for example, can be 1, 2, 3, 4, 5, 6, 7-8 carbon moiety, 1 to 6 carbon moiety or with the specified number of carbon atoms, for example, C ₁ -C ₂ -alkylene, C ₁ -C ₃ alkylene, C ₁ -C 4 alkylene, C 1 -C 5 alkylene, or C ₁ -C ₆ alkylene.

Alkenylene is a divalent hydrocarbon containing at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2-8 carbon moiety, a 26 carbon moiety, or the number of carbons indicated, eg C ₂ -C4 alkenylene.

Alkynylene is a divalent hydrocarbon containing at least one triple carbon-carbon bond. Alkynylenes, for example, may be a fragment with from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or with the specified number of carbon atoms, for example, C ₂ -C4-alkynylene.

Alkoxy is an alkyl group, as defined above, covalently linked through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy , 2-hexoxy, 3-hexoxy and 3-methylpentoxy. Similarly, an alkylthio or thioalkyl group is an alkyl group, as defined above, with the number of carbon atoms indicated covalently bonded through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

Alkenyloxy is an alkenyl group, as defined above, covalently linked to the group it replaces by an oxygen bridge (-O-). Alkanoyl is an alkyl group, as defined above, covalently linked through a carbonyl bridge (C=O).

- 32 041794

Carbonyl carbon is included in the number of carbon atoms, i.e. C2alkanoyl is a CH ₃ (C=O) group. In one embodiment, the alkanoyl group is optionally substituted as described above. An alkyl ether is an alkyl group, as defined herein, covalently linked through an ester bond. The ester bond may be in any position, for example, a group of formula -O(C=O)alkyl or a group of formula -(C=O)O-alkyl.

The amide or carboxamide is -C(O)NR ^a R ^b , where R ^a and R ^b are independently selected from hydrogen, alkyl, e.g., alkyl, including C1-C6 alkyl, alkenyl, e.g., C2-C6 alkenyl, alkynyl , for example, C2-C6-alkynyl, -C0-C4-alkyl(C3-C7-cycloalkyl), -C0-C4-alkyl(C3-C7-heterocycloalkyl), -C0-C4-alkyl(aryl) and -C0-C4- alkyl(heteroaryl); or together with the nitrogen atom to which they are attached, R ^a and R ^b may form a C3-C ₇ heterocyclic ring. In one embodiment, the R ^a and R ^b groups are independently optionally substituted as described herein.

A carbocyclic group, carbocyclic ring, or cycloalkyl is a saturated or partially unsaturated (ie, non-aromatic) group containing all carbon atoms of the ring. The carbocyclic group usually contains 1 ring of 3-7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may contain a cycloalkyl group that is attached as a spiro group. Examples of carbocyclic rings include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropyl rings. In one embodiment, the carbocyclic ring is optionally substituted as described above. In one embodiment, cycloalkyl is a partially unsaturated (ie, non-aromatic) group containing all carbon ring atoms. In another embodiment, cycloalkyl is a saturated group containing all carbon atoms of the ring.

A carbocyclic hydroxy group is a monocyclic carbocyclic ring or a mono- or bicyclic carbocyclic group as defined above attached to the group it replaces via an oxygen, -O-, linker.

Haloalkyl refers to both branched and straight chain alkyl groups substituted by 1 or more halogen atoms up to the maximum number of halogen atoms allowed. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2fluoroethyl, and pentafluoroethyl.

Haloalkoxy refers to a haloalkyl group, as defined herein, attached via an oxygen bridge (the oxygen of the alcohol radical).

Hydroxyalkyl is an alkyl group, as previously described, substituted with at least one hydroxyl substituent.

Aminoalkyl is an alkyl group, as previously described, substituted with at least one amino substituent.

Halo or halogen independently denotes any of the fluorine, chlorine, bromine or iodine atoms.

Aryl refers to an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl group contains from 1 to 3 separate or fused rings and is from 6 to about 14 or 18 ring atoms, with no heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may include condensation with a 4-7 or 5-7 membered saturated or partially unsaturated cyclic group which optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and/or S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl groups are pendent. An example of a side ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.

The term heterocycle or heterocyclic ring as used herein refers to a saturated or partially unsaturated (i.e. containing one or more double and/or triple bonds in the ring without aromaticity) carbocyclic moiety of 3 to about 12, and more typically 3, 4 , 5, 6, 7, 8-10 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, while the remaining ring atoms are C, where one or more ring atoms are optionally independently substituted with one or more substituents described above. The heterocycle may be a monocycle containing 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, S, Si and B) or a bicycle containing 6 to 10 ring members. members (from 4 to 9 carbon atoms and from 1 to 6 heteroatoms selected from N, O, P, S, Si and B), for example: bicyclo [4.5], [5.5], [5.6] or [6,6] system. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur, boron, or silicon. Heterocycles are described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), in particular sections 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19 and 28; and J. Am. Chem. soc. (1960) 82:5566. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, oxepanyl, thiepanyl diazepinyl, thiazepinyl, 2-pyrrolinyl, 3pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imimidazolinyl, 2 oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8azabicyclo[3.2.1]octane, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1] heptane, 2-oxa-5azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl, quinolisinyl, N- pyridylureas and pyrrolopyrimidine. Spiro fragments are also included within the scope of this definition. Examples of a heterocyclic group in which 1 or 2 ring carbons are substituted by oxo (=O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocyclic groups here are optionally substituted independently with one or more of the substituents described herein, for example 1, 2 or 3 substituents.

The heterocyclic hydroxy group is a monocyclic heterocyclic ring or a bicyclic heterocyclic group, as previously described, linked to the group it replaces via an oxygen, -O-, linker.

Heteroaryl refers to a stable monocyclic, bicyclic, or polycyclic aromatic ring that contains 1 to 3, or in some embodiments, 1, 2, or 3 heteroatoms selected from N, O, S, B, or P, with the remaining ring atoms being carbon , or a stable bicyclic or tricyclic system containing at least one 5-, 6-, or 7-membered aromatic ring that contains 1 to 3, or in some embodiments, 1 to 2, heteroatoms selected from N, O , S, B or P, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups usually contain from 5, 6 or 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are 8-10 membered heteroaryl groups, i. groups containing 8 or 10 ring atoms in which one 5-, 6- or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, , 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl . The heteroaryl groups are optionally substituted independently with one or more of the substituents described herein. Heteroaryloxy is a heteroaryl group, as described, linked to the group it replaces via an oxygen, -O-, linker.

Heterocycloalkyl is a fully saturated heterocycle as defined herein. For example, it may include 1, 2, 3, or 4 heteroatoms independently selected from N, S, O, Si, and B, while the remaining ring atoms are carbon. In a typical embodiment, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically contain 3 to about 8 ring atoms, or 4 to 6 ring atoms. The term mono- and/or dialkylamino means a secondary or tertiary alkylamino group, where the alkyl groups are independently selected as defined herein. The point of attachment of the alkylamino group is on the nitrogen atom. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino and methyl-propyl-amino. Dosage form means the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. The dosage form may also include an implant, such as an ocular implant. Pharmaceutical compositions are compositions containing at least one active agent and at least one other substance, such as but

- 34 041794 Pharmaceutical combinations are combinations of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein. The pharmaceutically acceptable salt is a derivative of the disclosed a compound in which the parent compound has been modified by obtaining its inorganic and organic, pharmaceutically acceptable acid or base addition salts. Salts of the present compounds can be synthesized from a parent compound that contains a basic or acid moiety using conventional chemical techniques. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate of Na, Ca, Mg or K, or the like) or by reacting the free base forms of these compounds with stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or in an organic solvent, or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical where practicable. Salts of the present compounds further include solvates of the compounds and salts of the compounds.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include salts that are acceptable for human consumption and quaternary ammonium salts of the parent compound derived, for example, from inorganic or organic acids. Examples of such salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesyl, esyl, benzyl, sulfanyl, 2acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC-(CH ₂ ) _n -COOH, where n is 0-4, and the like, or using another acid that forms the same counterion. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term carrier as applied to the pharmaceutical compositions/combinations of the invention refers to the diluent, excipient or vehicle with which the active compound is provided.

A pharmaceutically acceptable excipient means an excipient that is useful in formulating a pharmaceutical composition/combination that is generally safe, acceptable for human consumption, and neither biologically nor otherwise unacceptable for administration to a patient, usually a human. In one embodiment, an excipient is used that is acceptable for veterinary use.

A patient or host or subject is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, including, but not limited to, by modulating the factor D complement activation pathway or with the condition, which is treatable with one of the compounds described herein. Typically, the host is a human.

The term patient or host or subject also refers to, for example, a mammal, primate (eg, human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, bird, and the like.

A prodrug, as used herein, means a compound that, when administered to a host in vivo, is converted to the parent drug. As used herein, the term parent drug means any of the chemical compounds described herein. Prodrugs can be used to achieve any desired effect, including improving the properties of the parent drug or improving the pharmaceutical or pharmacokinetic properties of the parent drug, including increasing the in vivo half-life of the drug. Prodrug strategies provide a choice of modulating conditions for creating the parent drug in vivo. Non-limiting examples of prodrug strategies include covalent attachment of leaving groups or leaving portions of groups, such as but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others. In some embodiments, the prodrug makes the parent compound more lipophilic. In some embodiments, a prodrug may be provided that has multiple prodrug groups in a linear, branched, or cyclic form. For example, non-limiting embodiments include using a divalent linker moiety such as

- 35 041794 dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compound that has at least two functional groups that can link the original molecule to another prodrug moiety, and, as a rule, is biodegradable in vivo. In some embodiments, 2, 3, 4 or 5 prodrug biodegradable moieties are covalently linked in series, branched or cyclic form to the parent compound. Non-limiting examples of prodrugs of the present invention are formed with:

i) a carboxylic acid in the parent drug and a hydroxylated prodrug moiety to form an ester;

ii) a carboxylic acid in the parent drug and an amine prodrug to form an amide;

iii) an amine in the parent drug and a prodrug carboxylic acid moiety to form an amide;

iv) an amine in the parent drug and a sulfonic acid to form a sulfonamide;

v) sulfonic acid in the parent drug and an amine on the prodrug moiety to form a sulfonamide;

vi) a hydroxyl group in the parent drug and a carboxylic acid in the prodrug moiety to form an ester;

vii) hydroxyl in the parent drug and a hydroxylated prodrug moiety to form an ether;

viii) a phosphonate in the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester;

ix) phosphoric acid in the parent drug and a hydroxylated prodrug moiety to form a phosphate ester;

x) hydroxyl in the parent drug and phosphonate in the prodrug to form a phosphonate ester;

xi) hydroxyl in the parent drug and the phosphate moiety of the prodrug to form a phosphate ester;

xii) a carboxylic acid in the parent drug and a prodrug of the structure HO(CH ₂ ) ₂ -O-(C _{2 .2} 4αlipatic group), e.g. HO-(CH ₂ ) ₂ -O-(C _{2 .2} 4alkylα group), with the formation of an ester;

xiii) a carboxylic acid in the parent drug and a prodrug of the structure HO(CH ₂ ) ₂ -S-(C _{2 .2} 4aliphatic group), e.g. HO-(CH ₂ ) ₂ -S-(C _{2 .2} 4alkylα group), with the formation of thioether;

xiv) hydroxyl in the parent drug and a prodrug of the structure H0-(CH ₂ ) ₂ -0-(C _{2 .2} 4 aliphatic group), e.g. HO-(CH ₂ ) ₂ -O-(C ₂ . ₂ 4 alkyl group) with ether formation;

xv) a carboxylic acid in the parent drug and a prodrug of the structure HO(CH ₂ ) ₂ -S-(C _{2 .2} 4aliphatic group), e.g. HO-(CH ₂ ) ₂ -S-(C _{2 .2} 4alkylα group), with the formation of thioether; and xvi) a carboxylic acid, oxime, hydrazide, hydrazone, amine, or hydroxyl in the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer, including, but not limited to, polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyganhydride, polyester, polyamide or peptide. An exemplary synthesis of oxime bonds is presented in an article published by Jin et al. and titled Oxime Linkage: A Robust Tool for the Design of PH-Sensitive Polymeric Drug Carriers in BioMacromolecules, 2011, 12(10), 3460-3468.

In one embodiment, the prodrug is provided by attaching a naturally occurring or non-naturally occurring amino acid to the appropriate functional moiety in the parent compound, e.g., oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually such that the amino acid can be cleaved in vivo to produce original drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve desired characteristics such as increased half-life, lipophilicity, or other drug delivery, or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes aliphatic amino acids, an alkyl amino acid, an aromatic amino acid, a heteroaliphatic amino acid, a heteroalkyl amino acid, or a heterocyclic amino acid or a heteroaryl amino acid.

Providing a compound with at least one additional active agent, for example, in one embodiment, may mean that the compound and additional active agent(s) are provided simultaneously in a unit dosage form, provided

- 36 041794 are administered simultaneously in separate dosage forms, or are provided in separate dosage forms for administration. In one embodiment, the administrations of the compounds are separated by some amount of time, which is within the time that both the compound and at least one additional active agent are in the patient's bloodstream. In some embodiments, the compound and the additional active agent must not be administered to the patient by the same healthcare professional. In some embodiments, the implementation of additional active agent or agents do not require appointment. Administration of the compound or at least one additional active agent may be by any suitable route, e.g., oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, parenteral, sublingual, buccal, intravenous, intra-aortic, transdermal, polymer-controlled system. delivery, non-polymeric controlled delivery system, nano or microparticles, liposomes and/or topical contact. In one embodiment, the instructions for use in the form of combination therapy are provided in the labeling of the medicinal product.

A therapeutically effective amount of a pharmaceutical composition/combination of the present invention means an amount effective when administered to a patient to provide a therapeutic benefit, such as reduction in symptoms or reduction or amelioration of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase or significantly decrease the detectable level of complement factor D in the blood, serum, or tissues of a patient.

Detailed description of active compounds

N-oxides

In some embodiments, any of the active compounds may be provided in the form of its N-oxide to a patient in need thereof. In one embodiment, the production scheme uses the N-oxide of the active compound or a precursor of the active compound. In yet another embodiment, the N-oxide is an administration metabolite of one of the active compounds provided herein and may have independent activity. The N-oxide can be formed by treating the compound of interest with an oxidizing agent, such as a suitable peroxyacid or peroxide, to form the N-oxide compound. For example, a heteroaryl group, such as a pyridyl group, can be treated with an oxidizing agent such as sodium percarbonate in the presence of a rhenium-based catalyst under mild reaction conditions to form an N-oxide compound. One of skill in the art will appreciate that appropriate protecting groups may be necessary to carry out the chemical reaction.

See Jain, SL et al., Rhenium-Catalyzed Highly Efficient Oxidations of Tretiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006. In one embodiment, the N-oxide is in ring A. In one embodiment, the N-oxide is in the B ring. In one embodiment, the N-oxide is in the R ³² group.

In other embodiments, any of the active sulfur compounds may be provided in its sulfoxide or sulfone form to a patient in need thereof. In another embodiment, a sulfoxide or sulfone of one of the active compounds, or a precursor of the active compound, is used in a manufacturing scheme. The sulfur atom in the selected compound, as described here, o can be oxidized to form a sulfoxide T ^s "5" or a sulfone ⁰ . using known techniques. For example, the compound 1,3,5-triazo-2,4,6-triphosphorin-2,2,4,4,6,6-tetrachloride (TAPC) is an effective promoter for the oxidation of sulfides to sulfoxides. See, Bahrami, M. et al., TAPC Promoted Oxidation of sulfides and Deoxygenation of Sulfoxides, J. Org. Chem., 75, 6208-6213 (2010). Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalum carbide gives sulfoxides in high yields, see, Kirihara, A., et al., Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones, Synlett, 1557-1561 (2010). Sulfides can be oxidized to sulfones using, for example, niobium carbide as a catalyst, see Kirihara, A., et al., Tantalum Cardide or Niobium Carbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses of Sulfoxides and Sulfones, Synlett, 1557-1561 (2010). The adduct of urea and hydrogen peroxide is a stable, inexpensive and easily processed reagent for the oxidation of sulfides to sulfones, see Varma, RS and Naicker, KP, The Urea - Hydrogen Peroxide Complex: Solid-State Oxidative Protocols for Hydroxylated Aldehydes and Ketones (Dakin Reaction) , Nitriles, Sulfides, and Nitrogen Heterocycles, Org. Lett., 1, 189-191 (1999). One of ordinary skill in the art will appreciate that another heteroatom, such as nitrogen, may need to be protected and then deprotected when the sulfur atom is oxidized to give the desired compound.

Embodiments alkyl.

In one embodiment, alkyl is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C 1 -C 8

- 37 041794 alkyl, C1- _C7 alkyl, C1- _C6 alkyl, C1-C5 alkyl, C1- _C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

In one embodiment, the alkyl contains one carbon atom.

In one embodiment, the alkyl contains two carbon atoms.

In one embodiment, the alkyl contains three carbon atoms.

In one embodiment, the alkyl contains four carbon atoms.

In one embodiment, the alkyl contains five carbon atoms.

In one embodiment, the alkyl contains six carbon atoms.

Non-limiting examples of alkyl include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

Additional non-limiting examples of alkyl include: isopropyl, isobutyl, isopentyl and isohexyl.

Additional non-limiting examples of alkyl include: sec-butyl, sec-pentyl, and sec-hexyl.

Additional non-limiting examples of alkyl include: t-butyl, t-pentyl and t-hexyl.

Additional non-limiting examples of alkyl include: neopentyl, 3-pentyl and active pentyl.

In one embodiment, alkyl is substituted alkyl.

In one embodiment, alkenyl is a substituted alkenyl.

In one embodiment, alkynyl is a substituted alkynyl.

Embodiments haloalkyl.

In one embodiment, haloalkyl is _C1 - _C10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1- _C7 haloalkyl, C1- _C6 haloalkyl, C1-C5 haloalkyl, C1- _C4- haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

In one embodiment, the haloalkyl contains one carbon atom.

In one embodiment, the haloalkyl contains one carbon atom and one halogen atom.

In one embodiment, the haloalkyl contains one carbon atom and two halogen atoms.

In one embodiment, the haloalkyl contains one carbon atom and three halogen atoms.

In one embodiment, the haloalkyl contains two carbon atoms.

In one embodiment, the haloalkyl contains three carbon atoms. In one embodiment, the haloalkyl contains four carbon atoms. In one embodiment, the haloalkyl contains five carbon atoms. In one embodiment, the haloalkyl contains six carbon atoms.

Non-limiting examples of haloalkyl include

Additional non-limiting examples of haloalkyl include

Additional non-limiting examples of haloalkyl include

Additional non-limiting examples of haloalkyl include

Embodiments aryl.

In one embodiment, aryl is a 6 carbon aromatic group (phenyl).

In one embodiment, the aryl is a 10 carbon aromatic group (naphthyl).

In one embodiment, the aryl is a substituted aryl.

Embodiments heteroaryl.

In one embodiment, heteroaryl is a 5-membered aromatic group containing 1, 2, or 3 nitrogen atoms.

Non-limiting examples of 5-membered heteroaryl groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, ochatriazol, isothiazole, thiazole, thiadiazole, and thiatriazole.

Additional non-limiting examples of 5-membered heteroaryl groups include:

- 38 041794

In one embodiment, heteroaryl is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6-membered heteroaryl groups with 1 or 2 nitrogen atoms include:

In one embodiment, heteroaryl is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heteroaryl groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

bicyclic

Additional non-limiting examples of heteroaryl groups that are sky include:

bicyclic

Additional non-limiting examples of heteroaryl groups that are sky include:

Additional non-limiting examples of heteroaryl groups that are sky include:

bicyclic In one embodiment, heteroaryl is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of heteroaryl groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of heteroaryl groups that are bicyclic include:

In one embodiment, the heteroaryl is a substituted heteroaryl.

In an alternative embodiment, the heteroaryl is a tetrazole.

Embodiments cycloalkyl.

In one embodiment, cycloalkyl is C ₃ -C ₈ cycloalkyl, C ₃ -C 7 cycloalkyl, C 3 -C ₆ cycloalkyl, C ₃ -C ₅ cycloalkyl, C ₃ -C ₄ cycloalkyl, C ₄ -C ₈ cycloalkyl , C5-C8 cycloalkyl or C ₆ -C ₈ cycloalkyl.

In one embodiment, the cycloalkyl contains three carbon atoms.

In one embodiment, the cycloalkyl contains four carbon atoms.

In one embodiment, the cycloalkyl contains five carbon atoms.

In one embodiment, the cycloalkyl contains six carbon atoms.

In one embodiment, the cycloalkyl contains seven carbon atoms.

In one embodiment, the cycloalkyl contains eight carbon atoms.

In one embodiment, the cycloalkyl contains nine carbon atoms.

- 39 041794

In one embodiment, the cycloalkyl contains ten carbon atoms.

Non-limiting examples of cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

In one embodiment, the cycloalkyl is a substituted cycloalkyl.

Embodiments heterocycle.

In one embodiment, the term heterocycle refers to a cyclic ring with one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment, the term heterocycle refers to a cyclic ring with one nitrogen atom and one oxygen atom and 3, 4, 5, 6, 7 or 8 carbon atoms.

In one embodiment, the term heterocycle refers to a cyclic ring with two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment, the term heterocycle refers to a cyclic ring with one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment, the term heterocycle refers to a cyclic ring with one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of heterocycles include aziridine, oxirane, thiirane, azetidine, 1,3 diazetidine, oxetane, and thietane.

Additional non-limiting examples of heterocycles include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of heterocycles include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

Additional non-limiting examples of heterocycles include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thian, 1,3-dithian, 1,4-dithian, morpholine, and thiomorpholine.

Non-limiting examples of heterocycles also include:

Additional non-limiting examples of heterocycles include:

Additional non-limiting examples of heterocycles include:

Non-limiting examples of heterocycles also include:

Non-limiting examples of heterocycles also include:

Additional non-limiting examples of heterocycles include:

Additional non-limiting examples of heterocycles include:

In one embodiment, the heterocycle is a substituted heterocycle.

Embodiments R ²⁰¹ .

In one embodiment, R ²⁰¹ is selected from -(CH ₂ ) _m -O-heterocycle, -(CH ₂ ) _m -NH-heterocycle or -(CH ₂ ) _m -NH ⁹ -heterocycle.

In one embodiment, R ²⁰¹ is selected from -(CH2)m-NR ⁹ R ¹⁰ , -(CH2) _m -OR ⁹ or -(CH ₂ ) _m heterocycle.

In one embodiment, R ²⁰¹ is selected from -CH ₂ -O-heterocycle, -CH ₂ -NH-heterocycle, or CH ₂ -NH ⁹ -heterocycle.

In one embodiment, R ²⁰¹ is selected from -CH2-NR ⁹ R ¹⁰ , -CH2-OR ⁹ or -CH2 heterocycle;

- 40 041794

In one embodiment, R ²⁰¹ is selected from -(CH ₂ )m-NH2, -(CH ₂ )m-OH, or -(CH ₂ ) _m -OC ₁ -C6 alkyl.

In one embodiment, m is 1, 2, or 3.

In one embodiment, m is 1.

In one embodiment, m is 2.

In one embodiment, m is 3.

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R'' ¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R'' ¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

- 41 041794

Embodiments C.

In one embodiment, C5 is

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

In one embodiment, R ²⁰¹ is selected from:

- 42 041794

In one embodiment, C5 is

In one embodiment, C5 is

In one embodiment, C5 is

In one embodiment, C1 is selected from:

In one embodiment, C1 is selected from:

- 43 041794

In one embodiment, the methyl group in the structure shown above may be replaced by another alkyl group as defined herein. In another embodiment, the fluorine atoms in the above structures can be replaced by any other halogen. Any of the structures illustrated above or otherwise may be optionally substituted with 0, 1, 2, 3 or 4, optionally and independently, with an R ⁴⁸ substituent.

Examples of beta-turn central core small mimetics, beta-turn inducers, reverse-turn mimetics, and foldamer monomers include:

In one embodiment, C is selected from:

- 44 041794

where R ¹⁰¹ represents C1-C4-alkyl or C3-C7-cycloalkyl; and R ¹⁰² is C1- _C4 alkyl, fluorine, chlorine or bromine.

In one embodiment, C4 is selected from:

- 45 041794

In one embodiment, C is selected from:

In one embodiment, C4 is selected from:

In one embodiment, C4 is selected from:

In one embodiment, C4 is selected from:

- 46 041794

- 47 041794

In one embodiment, R ¹ is selected from F, Cl, Br and C _g C ₆ alkyl.

In one embodiment, R ¹ is selected from hydroxyl and C ₁ -C ₆ alkoxy.

In one embodiment, R ¹ is selected from C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkanoyl, and C ₁ -C ₆ thioalkyl.

In one embodiment, R ¹ is selected from amino-C ₁ -C ₆ -alkyl and -C ₀ -C ₄ -alkyl-NR ⁹ R ¹⁰ .

In an alternative embodiment, C is selected from

Embodiments A.

Non-limiting examples of A1 include:

In one embodiment, A1 is selected from:

HN HN

_NH2

In one embodiment, A3 is selected from:

- 48 041794

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

- 49 041794

In one embodiment, A3 is selected from:

- 50 041794

In one embodiment, A3 is selected from:

In one embodiment, A3 is selected from:

- 51 041794

In one embodiment, A1 is selected from:

In one embodiment, A3 is selected from:

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

- 52 041794

In one embodiment, A1 is selected from:

In one embodiment, A1 is selected from:

C ₁ -C ₄ -alkyl or C ₃ -C ₇ -cycloalkyl.

In another embodiment, A1 is selected from:

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- 54 041794

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- 56 041794

- 57 041794

- 58 041794

In another embodiment, A is selected from:

- 59 041794

In one embodiment, A4 is selected from:

- 60 041794

In one embodiment, L1 is selected from:

- 61 041794

In one embodiment, L1 is selected from:

- 62 041794

In one embodiment, L1 is selected from:

- 63 041794

In one embodiment, L1 is selected from:

In one embodiment, L1 is selected from:

- 64 041794

In one embodiment, the methyl groups in the above structures may be replaced by another alkyl group as defined herein.

In one embodiment, L2 is selected from:

- 65 041794

OH ₅ OH , OH , OO 0 ¹ Η , Η , Η , η , η V ⁷ Η , Η , Η Η Η , O and 0 . Non-limiting examples of L2 include: ^ζ γ ⁴ _ν > τ ^{ζ 1} ο ο ο ο Ζγ-Α xJ<a / _Η ζ^ΚΑα χ,^Αα ζ _υ \ 0 Ο S Η ^ΟΗ Α _Η ^yY s SS Η --on Γ _Η γχΑ >γ4Α s SS . . Η-one η Z^>Ay χ^ S ss 4- ^H v g H ₄ ΖγΑ-xA X^CxA z^ s S and θ Non-limiting examples of L2 include: H H OH3 X>C^A / _V Ny /^Ny /. J 0% ' o ^z 'b ^f 0 HHH bAA As'M o ^z 'b H'' o ^z 'b Hn 0 ^z 'b Λ CH ₃ CH ₃ CH ₃ bA-A 6s ^z M O ^z 'b /'' o ^z 'b H o ^z 'b G'' LaA %aA OH , OH ₅ OH , 0 HHH ^^A ^N -y HH \ , H , O , 0 _4? H ₄ -OH ^ri 5fZ o o O n _h -on 5 0 o 0 x ^N g _{n g} -on < H ^a 5> C~a zAC-a 0 o Η ..-', ν kg Vv Vv ssss HA A. X--' Xa ''γ^ ''γ^ sss XX /Xzy vl^Z ss ¹ Z \ ss K—OH Y 1 v X ^N y />Ay '% O% 0 0 Η Η As^- A As^xA . O ^z 'b H ^z | 0 'ο (η As' ^N A he he ⁰ o CH ₃ CH ₃ yy As ^zN _y \ a _S ' ⁿ a Y 0 ^Z 'b Η ^Z | ⁰ 0 \ H As' ^N A OH OH ° ^z 'o

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Non-limiting examples of L2 include:

He

Non-limiting examples of L2 include:

- 67 041794

Non-limiting examples of L2 include:

- 68 041794

In one embodiment, the methyl groups in the above structures may be replaced by another alkyl or acyl as defined herein. In another embodiment, carbocyclic, heterocyclic, aryl or heteroaryl rings may be optionally substituted. As indicated above, any of the structures shown above or below may optionally be replaced by 0, 1, 2, 3 or 4, optionally and independently, with an R ⁴⁸ substituent.

In a specific embodiment, L2 is a bond. In some embodiments, if L2 is heterocyclic or heteroaryl, then B may be hydrogen.

Embodiments B.

In one further alternative embodiment, B is selected from:

In one further alternative embodiment, R ³⁶ is selected from:

In another embodiment, B1 is selected from:

In one embodiment, B is selected from:

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where R ²⁷ represents hydrogen, methyl or trifluoromethyl; R ²⁸ is hydrogen or halogen; and R ²⁹ is hydrogen, methyl, trifluoromethyl or —Si(CH3) ₂ C(CH ₃ )3.

In one embodiment, B is selected from:

Examples of Fragments B include, but are not limited to:

^R27

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In one embodiment, B4 is selected from:

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is

In one embodiment, B4 is selected from:

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In one embodiment, B4 is selected from:

- 72 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 73 041794

In one embodiment, B4 is selected from:

- 74 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 75 041794

In one embodiment, B4 is selected from:

R ²⁵ R ²⁵ R ²⁵ FR ²⁵

-¼¼ ⁶

R ²⁷ R28 F R28 R ²⁷ R28 R ²⁷ _c / R ²⁷

In one embodiment, B4 is selected from:

- 76 041794

In one embodiment, B4 is selected from:

- 77 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 78 041794

In one embodiment, B4 is selected from: R ²⁵ ι\

R ²⁵ Br H ₃ C _R 25 r25 fy ^ ^R26 b ^ H ²⁶ b ^ - ^{s h} n ^ s ^{n \u003d}

Br CH _{3 R} 28 CH _{3 R} 28 Br _R 28 Br _B / R ²⁷

In one embodiment, B4 is selected from:

- 79 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

CH ₃ F CH ₃ FF H ₃ C F

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 80 041794

r28 Br R ²⁸ CH3 R ^2S F r28 F r28 Br r28 CH3

In one embodiment, B4 is selected from:

F

Vg

Vg

H H H H H

N:

- 81 041794 ^Br Br F Br FF

F BrF

N=( N={N=<

Π-Ζ HZHHZH

In one embodiment, B4 is selected from:

nc-h chc k

H

Ή” Ch” ky k”'

In one embodiment, B4 is selected from: Br Br FF to A L ^to to Ά

Br Br F ’F

Bg Br Br Br Br _Br

I ^wi ya'

I ^r

- 82 041794

In one embodiment, B4 is selected from:

- 83 041794

In one embodiment, B4 is selected from:

- 84 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

R ²⁵ R ²⁵ R ²⁰¹ R ²⁵ R ²⁶ R ²⁵ R ²⁶ R ²⁵

- 85 041794

In one embodiment, B4 is selected from:

^R201FFFF

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 86 041794

In one embodiment, B4 is selected from:

- 87 041794

In one embodiment, B4 is selected from:

- 88 041794

In one embodiment, B4 is selected from:

- 89 041794

In one embodiment, B4 is selected from:

In one embodiment, B4 is selected from:

- 90 041794

In one embodiment, B4 is selected from:

- 91 041794

R ²⁸ are independently selected from hydrogen, halogen and

In one embodiment, R ²⁵ , R ²⁶ , R ²⁷ and C ₁ -C ₆ alkyl.

In another embodiment, B4 is selected from:

- 92 041794

In another embodiment, B4 is selected from:

In an alternative embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

In another embodiment, B4 is selected from:

- 93 041794

In another alternative embodiment, B4 is selected from:

In another alternative embodiment, B4 is -alkyl-Si(alkyl) ₃ or

-alkyl-SF ₅ .

In another alternative embodiment, B4 is ring B substituted with oxo. In this embodiment, if Ring B is a nitrogen containing a heteroaryl group, then the nitrogen may also be substituted as defined herein. For example-NH )=O measures:

, substituted by oxo, can be selected from the following compounds: ^r27

R ²⁷ measures include:

In another alternative embodiment, B4 is selected from:

^r27 , and

In another alternative embodiment, R ³² is a heteroaryl ring substituted with oxo according to valency. In this embodiment, if the R ³² ring is a nitrogen containing a heteroaryl group, then the nitrogen may also be substituted as defined herein. For example:

connections:

blowing

And

In another alternative embodiment, R ³² is selected from:

> substituted oxo, can be selected from blind primers

include:

In another alternative embodiment, B4 is an alkyl group. In another alternative embodiment, B4 is an alkenyl group.

In another embodiment, C4 is selected from:

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of formula I is:

- 94 041794

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of formula II is:

In one embodiment, L2 is a spirocyclic linker attached to ring C such that the resulting compound of formula III is:

(c)-\L3

In one embodiment, a compound of formula ^A3 is provided

In one embodiment, R ³² is selected from:

In an alternative embodiment, R ³² is selected from:

In one embodiment, R ³² is selected from:

In an alternative embodiment, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is -alkyl-R ³² or -O-alkyl-R ³² .

In an alternative embodiment, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is

In one embodiment, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ or R ¹⁵ is

In one embodiment, X ³¹ is selected from N and CR ⁵⁴ ;

In another embodiment, X ³¹ is C(R ⁵⁴ ) ₂ ;

In one embodiment, X ²⁵ is O or S;

In one embodiment, R ⁴ is selected from -JCHO, -JCONH2, -JCONR9R ¹⁰ , JC2-C6-alkanoyl, -JSO2NH2, -JSO2NR ²¹ R ²² , -JC(CH2) ₂ F, -JCH(CF ₃ )NH ₂ . -J-haloαalkyl-NH ₂ , -J-haloalkyl-NR ⁹ R ¹⁰ , alkyl including C1-C6-alkyl, -C0-C4-alkyl(C3-C7-cycloαalkyl), -JC(O)C0-C2- alkyl (C3-C7-cycloalkyl), -JNR ⁹ (C2C ₆ -alkanoyl), -JNR ⁹ C(O)NR ⁹ R ¹⁰ ,

- 95 041794

where each R ⁴ other than -CHO is optionally substituted with one or more amino, imino, halogen, hydroxyl, cyano, cyanoimino, alkyl, including C ₁ -C ₆ -alkyl, alkoxy, including C ₁ -C ₆ -alkoxy, - C ₀ -C ₂ -alkyl (mono - and di-C ₁ -C ₄ -alkylamino), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy.

Additional embodiments R ³² .

In one embodiment, R ³² is Embodiments B.

In one embodiment, B is selected from:

Embodiments R ³⁰¹ .

Examples of R ³⁰¹ are shown below. In the compounds of the present invention, R ³⁰¹ is monovalently attached to the molecule. The bivalent moieties below are provided to illustrate that R ³⁰¹ may be attached at any point and may be limited to, for example, H, alkyl, halogen, haloalkyl, aryl, heteroaryl and heterocycle, where each may be optionally substituted as described Here. In one embodiment, R ³⁰¹ is selected from:

- 96 041794

where, if this fragment is presented as a divalent group, it may also be limited to hydrogen, methyl, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, another blocking fragment of another biologically active fragment, or an additional prodrug fragment. In one embodiment, R ³⁰¹ is selected from:

- 97 041794

native amino acid,

R ³⁰⁹ is selected from: alkyl, hydrogen, alkyl alkyl

n2 is independently selected at each occurrence from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20; And

X ³⁰⁰ is selected from the bond, -NH-, -N(alkyl)-, O, -CH ₂ -O-, -CH2-NH- and -CH ₂ -N(alkyl).

In one embodiment, only 1, 2, 3, 4 or 5 R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, none of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for

- 98 041794 communications.

In one embodiment, only 1 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ is selected for communication.

In one embodiment, only 2 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 3 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 4 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

In one embodiment, only 5 of R ³⁰² , R ³⁰³ , R ³⁰⁴ , R ³⁰⁵ , R ³⁰⁶ , R ³⁰⁷ and R ³⁰⁸ are selected for communication.

Non-limiting examples of compounds of the present invention with an R ³⁰¹ group include:

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- 102 041794

Br

- 103 041794

- 104 041794

- 105 041794

- 106 041794

- 107 041794

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- 109 041794

- 110 041794

- 111 041794

- 112 041794

- 113 041794

- 114 041794

- 115 041794

- 116 041794

- 117 041794

- 118 041794

- 119 041794

- 120 041794

- 121 041794

- 122 041794

- 123 041794

- 124 041794

- 125 041794

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

- 126 041794

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

- 127 041794

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

- 128 041794

Non-limiting examples of compounds of the present invention with the group R ³⁰¹ include:

- 129 041794 _R 301 _R 301

Br Br Br

Br Br Br

In one embodiment, C is selected from:

In one embodiment, A is selected from:

- 130 041794

In one embodiment, B is selected from:

In one embodiment, R ³² is:

Additional formulas.

In one aspect, the disclosure includes compounds and salts of the formulas in table. 1 for any application and in any composition described in the present invention.

In some of the formulas below, for the sake of convenience and location, R ³² is denoted as

'however, each described or illustrated R ³² in this invention is considered to be independently shown in each of these claims.

Table 1

Additional exemplary formulas within the scope of the present invention

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- 132 041794

- 133 041794

- 134 041794

- 135 041794

- 136 041794

- 137 041794

- 138 041794

- 139 041794

- 140 041794

- 141 041794

- 142 041794

- 143 041794

- 144 041794

- 145 041794

- 146 041794

- 147 041794

- 148 041794

- 149 041794

- 150 041794

- 151 041794

- 152 041794

- 153 041794

- 154 041794

- 155 041794

- 156 041794

- 157 041794

Formula 1-238 Formula 1-239 wherein R ¹⁰³ is C ₁ -C ₄ alkyl, C ₃ -C 6 cycloalkyl, fluorine, chlorine or bromine.

- 158 041794

table 2

Additional exemplary formulas within the scope of the present invention

- 159 041794

- 160 041794

- 161 041794

- 162 041794

- 163 041794

- 164 041794

- 165 041794

- 166 041794

- 167 041794

- 168 041794

- 169 041794

- 170 041794

- 171 041794

- 172 041794

- 173 041794

- 174 041794

- 175 041794

where R ¹⁰³ represents C1- _C4 -alkyl, C3-C6-cycloalkyl, fluorine, chlorine or bromine.

- 176 041794

Table 3

Additional exemplary formulas within the scope of the present invention

- 177 041794

- 178 041794

- 179 041794

- 180 041794

Formula PT-47 where R ¹⁰³ is independently C ₁ -C ₄ alkyl, C ₃ -C 6 cycloalkyl, fluorine, chlorine or bromine.

- 181 041794

Table 4

Additional exemplary formulas within the scope of the present invention

- 182 041794

- 183 041794

- 184 041794

hh ₂

- 185 041794

- 186 041794

- 187 041794

- 188 041794

- 189 041794

- 190 041794

Table 5 Additional exemplary formulas within the scope of the present invention

- 191 041794

- 192 041794

R ¹² and R ¹³ heteroaryl and heterocyclic substituents.

The invention includes a compound of formula I, formula II, formula III, formula IV or formula V in the form of its pharmaceutically acceptable salt, prodrug, isotopic analogue, N-oxide or isolated R ¹² and R ¹³ isomer, optionally in a pharmaceutically acceptable composition, where at least at least one of R ¹² or R ¹³ in group A is heteroaryl or heterocycle, eg R ³² .

One of R ¹² and R ¹³ is selected from R ³¹ and the other of R ¹² and R ¹³ is selected from R ³² . In another embodiment, each of R ¹² and R ¹³ may be independently selected from R ³² . R ³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, haloalkyl including C1-C6 haloalkyl, haloalkoxy including C1^-haloalkoxy, alkyl including C1-C6-αalkyl, -C0-C4- alkyl (C3-C7-cycloalkyl), alkenyl including C2-C6 alkenyl, alkanoyl including C2-C6 alkanoyl, alkoxy including C1-C6 alkoxy, alkenyloxy including C2C6 alkenyloxy, -C(O)OR ⁹ , thioalkyl , including C1-C ₆ -thioalkyl, -C ₀ -C ₄ -alkyl-NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ ,

-SO ₂ R ⁹ , -SO2NR ⁹ R ¹⁰ , -OC(O)R ⁹ and -C(NR ⁹ )NR ⁹ R ¹⁰ where each R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, haloalkyl, including C1- _C6 haloalkyl, and haloalkoxy including C1-C6 haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, nitro, cyano, amino, -COOH, -CONH2, haloalkyl, including _C1- C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy, and where each R ³¹ also optionally substituted with one substituent selected from phenyl and from 4 - to 7-membered heterocycle containing 1, 2 or 3 heteroatoms, independently selected from N, O and S; where phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ -α-alkenyl, alkanoyl, including C ₂ C ₆ -alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ -alkylamino)C ₀ -C ₄ -alkyl, C1-C6 alkyl ether, -C ₀ -C ₄ -alkyl)(C ₃ -C ₇ -cycloalkyl), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy;

R ³² is selected from heteroaryl; a saturated heterocycle or a partially unsaturated heterocycle; where heteroaryl, saturated heterocycle or partially unsaturated heterocyclic ring may be optionally substituted.

Non-limiting R ¹² /R ¹³ embodiments.

In one embodiment, R ¹² is R ³² .

In one embodiment, R ¹³ is R ³² .

In one embodiment, R ¹² is an optionally substituted heteroaryl.

In one embodiment, R ¹³ is an optionally substituted heteroaryl.

In one embodiment, R ¹² is R ³² .

In one embodiment, R ¹² is R ³² which is (4- to 7-membered heterocycloalkyl) containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

In one embodiment, the disclosure provides compounds of formula I, where one of R ¹² and R ¹³ is H, and the other of R ¹² and R ¹³ is R ³² , where R ³² is selected from heteroaryl; a saturated heterocycle or a partially unsaturated heterocycle; where heteroaryl; a saturated heterocycle or a partially unsaturated heterocyclic ring may be optionally substituted.

In another embodiment, the disclosure provides compounds of formula I, formula II, formula III, formula IV, or formula V, wherein

R ¹ , R ¹ , R ² and R ³ are all hydrogen;

R ² is fluoro and R ³ is hydrogen, -C ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl) or -OC ₀ -C ₄ alkyl(C ₃ -C ₇ cycloalkyl);

R ⁵ represents hydrogen, halogen or C ₁ -C ₆ -alkyl;

R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ , if present, are independently selected at each occurrence from hydrogen, halogen, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, -C ₀ -C _2- alkyl (mono- and di-C ₁ -C ₆ -alkylαmino), trifluoro- 193 041794 methyl and trifluoromethoxy;

X ¹² is CR ¹² ; And

R ¹² is selected from heteroaryl; a saturated heterocycle or a partially unsaturated heterocycle;

where heteroaryl; a saturated heterocycle or a partially unsaturated heterocyclic ring may be optionally substituted.

In one embodiment, the disclosure provides compounds of formula I, where m is 0 or 1;

R ² is halogen, R ² is hydrogen or halogen, and R ³ is hydrogen, halogen, -C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl) or -OC ₀ -C ₄ -alkyl( C ₃ -C ₇ -cycloalkyl);

R ⁶ is -C(O)C ₁ -C ₄ -alkyl, -C(O)NH ₂ , -C(O)CF ₃ , -C(O)(C ₃ -C ₇ -cycloalkyl) or -ethyl (cyanoimino);

one of R ¹² and R ¹³ is selected from hydrogen, halogen, C ₁ -C4 alkyl, C ₁ -C4 alkoxy, trifluoromethyl and trifluoromethoxy; the other of R ¹² and R ¹³ is R ³² where R ³² is selected from aryl, heteroaryl; saturated or unsaturated heterocycle; where aryl, heteroaryl, saturated or unsaturated heterocyclic ring may be optionally substituted.

In one embodiment, the disclosure provides compounds of formula I, formula II, formula III, formula IV, or formula V, wherein one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R ¹² and R ¹³ is R ³² , where R ³² is selected from heteroaryl; a saturated heterocycle or a partially unsaturated heterocycle; where heteroaryl; a saturated heterocycle or a partially unsaturated heterocyclic ring may be optionally substituted.

In one embodiment, R ³² may be unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, nitro, cyano, amino, oxo, -B(OH) ₂ , -Si(CH ₃ ) ₃ , -COOH, - CONH2, -P(O)(OH) ₂ , C ₁ -C ₆ -alkyl, alkoxy, including C ₁ -C ₆ -alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ - alkylamino), C ₁ -C ₆ alkyl ether, C ₁ -C ₄ alkylamino, C ₁ -C ₄ hydroxylalkyl, haloalkyl, including C ₁ -C ₆ haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy.

In one embodiment, R ³¹ is hydrogen and R ³² is pyrimidinyl.

In another embodiment, R ³¹ is hydrogen and R ³² is a pyrimidine substituted with a methyl group.

Non-limiting embodiments of the central core.

In some embodiments, R ¹ and R ¹ or R ³ and R ³ may be taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O or S; R ² and R ² may be taken together to form a 3- to 6-membered carbocyclic spiro ring; or R ² and R ² may be taken together to form a 3- to 6-membered heterocyclic spiro ring; where each ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, C ₁ -C ₄ -alkyl (including in particular methyl), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy, C ₂ -C ₄ -alkanoyl, hydroxy-C ₁ -C ₄ -alkyl, (mono di-C ₁ -C ₄ -alkylamino)C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -OC ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy.

In other embodiments, R ¹ and R ² may be taken together to form a 3-membered carbocyclic ring; R ¹ and R ² may be taken together to form a 4, 5 or 6 membered carbocyclic or aryl ring, or a 4, 5 to 6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R ² and R ³ , if bonded to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic or aryl ring or a 3- to 6-membered heterocyclic or heteroaryl ring; where each ring may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (and in particular F), hydroxyl, cyano, -COOH, C ₁ -C ₄ -alkyl (including in particular methyl), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy, C ₂ -C ₄ -alkanoyl, hydroxy-C ₁ C ₄ -alkyl, (mono- and di-C ₁ -C ₄ -αkylamino)C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-C0-C4 alkyl (C ₃ -C ₇ -cycloalkyl), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ haloalkoxy.

In one embodiment, the central core fragment is a proline.

In one embodiment, the central core moiety is 4-fluoroproline.

In one embodiment, R ¹ , R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen; and R ² is fluorine.

In one embodiment, R ¹ , R ¹ , R ² and R ³ , if present, are all hydrogen; and R ² is fluoro and R ³ is -C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl) or -0-C0C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl).

In one embodiment, R ¹ and R ² are taken together to form a 3- to 6-membered cycloalkyl group, and R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen. In one embodiment, the bicycle is fused in the cis position. In one embodiment, the bicycle

- 194 041794 is condensed in the trans position.

In one embodiment, R ¹ and R ² are taken together to form a 3- to 6-membered cycloalkyl group that is cis with respect to the carboxy group of L-proline, as shown below:

In one embodiment, R ¹ and R ² are taken together to form a 3- to 6-membered cycloalkyl group that is trans to the carboxy group of L-proline, as shown below:

In one embodiment, R ¹ , R ¹ , R ³ and R ³ , if present, are all hydrogen, and R ² and R ² are taken together to form a 5- or 6-membered heterocycloalkyl group containing 1 or 2 oxygen atoms.

In one embodiment, R ¹ is hydrogen and R ² is fluoro.

In one embodiment, R ¹ and R ² are combined to form a 3-membered ring.

In one embodiment, R ¹ and R ² are taken together to form a 3-membered cycloalkyl group that is cis with respect to the carboxy group of L-proline, as shown below:

In one embodiment, R ¹ and R ² are taken together to form a 3-membered cycloalkyl group that is trans to the carboxy group of L-proline, as shown below:

In one embodiment, R ² and R ³ are taken together to form a 3- to 6-membered cycloalkyl group, and R ¹ , R ¹ , R ² and R ³ , when present, are selected from hydrogen, C ₁ -C ₃ -alkyl or C1C ₃ alkoxy.

In one embodiment, R ² and R ³ are taken together to form a 3- to 6-membered cycloalkyl group that is cis with respect to the carboxy group of L-proline, as shown below:

In one embodiment, R ² and R ³ are taken together to form a 3- to 6-membered cycloalkyl group that is trans to the carboxy group of L-proline, as shown below:

In one embodiment, R ² and R ³ are taken together to form a 3-membered cycloalkyl group that is cis with respect to the carboxy group of L-proline, as shown below:

In one embodiment, R ² and R ³ are taken together to form a 3-membered cycloalkyl group that is trans to the carboxy group of L-proline, as shown below:

- 195 041794

In one embodiment, R ¹ , R ¹ , R ³ and R ³ , if present, are all hydrogen, and R ² and R ² are taken together to form a 5- or 6-membered heterocycloalkyl group containing 1 or 2 oxygen atoms.

In one embodiment, R ¹ is hydrogen and R ² is fluoro.

In one embodiment, R ¹ and R ² are combined to form a 3-membered ring.

L-B substituents of the central core.

Exemplary L core substituents and B substituents in Formula I are described below:

L is a bond or is selected from the formulas:

where R ¹⁷ represents hydrogen, C ₁ -C ₆ -alkyl or -C ₀ -C ₄ -alkyl(C ₃ -C ₇ -cycloalkyl), and R ¹⁸ and R ¹⁸ are independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2, or 3.

Non-limiting Embodiments L-B.

In one embodiment, -L1-B1- is:

where R ¹⁸ and R ¹⁸ ' value 0 or 1; And

R ²⁶ , R ²⁷ and R ²⁸

independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, thioalkyl, including C ₁ -C ₆ -thioalkyl, (mono - and di-C ₁ -C ₆ -alkylamino)C ₀ -C ₄ -alkyl, (C ₃ C ₇ - cycloalkyl) C ₀ -C ₄ -alkyl, (aryl) C ₀ -C ₄ -alkyl-, (heteroaryl) C ₀ -C ₄ -alkyl- and -C ₀ -C ₄ -alkoxy (C ₃ -C ₇ cycloalkyl) ; where each R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C ₁ -C ₆ -alkoxy , haloalkyl, including C ₁ -C ₆ -haloalkyl, (C ₃ -C ₇ -cycloalkyl)C ₀ -C ₄ alkyl and haloalkoxy, including C ₁ -C ₆ -haloalkoxy; And

R ²⁹ is hydrogen, alkyl including C ₁ -C ₆ alkyl, C ₁ -C ₂ haloalkyl, or Si(CH ₃ )2C(CH ₃ ) ₃ .

In one embodiment, the -L-B1- fragment is selected from:

- 196 041794

Br Br

In one embodiment, the -L1-B1- fragment is selected from:

In one embodiment, the -L2-B1- fragment is selected from:

- 197 041794

In one embodiment, the -L2-B1- fragment is selected from:

In one embodiment, m is 0.

In one embodiment, the disclosure further includes compounds and salts of Formula I wherein B1 is 2-fluoro-3-chlorophenyl. In another embodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl group is used, such as 2-bromopyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 2,2-dichlorocyclopropylmethyl or 2-fluoro-3trimethylsilylphenyl.

In another embodiment, B1 is phenyl, pyridyl, or indanyl, where each is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, alkyl, including C ₁ -C ₆ -alkyl, alkenyl, including C ₂ -C ₆ alkenyl, alkanoyl, including C ₂ -C ₆ -alkanoyl, alkoxy, including C ₁ -C ₆ -alkoxy, thioalkyl, including C1C ₆ -thioalkyl, (mono- and di-C ₁ -C ₆ - alkylamino) C ₀ -C ₄ -alkyl, (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ alkoxy (C ₃ -C ₇ -cycloalkyl), (phenyl) C ₀ - C ₂ -alkyl, (pyridyl)C ₀ -C ₂ -alkyl; where each substituent other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkyl, including C ₁ -C ₆ -alkyl, alkoxy, including C ₁ - C ₆ alkoxy, -OSi(CH ₃ ) ₂ C(CH ₃ ) ₃ , -Si(CH ₃ ) ₂ C(CH ₃ ) ₃ , haloalkyl including C1-C6 haloalkyl, and haloalkoxy including C ₁ -C ₆ - haloalkoxy.

In another embodiment, B1 is phenyl or pyridyl substituted with 1, 2, or 3 substituents selected from chlorine, bromine, hydroxyl, -SCF ₃ , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, trifluoromethyl, phenyl and trifluoromethoxy, wherein each substituent other than chlorine, bromine, hydroxyl, SCF ₃ may be optionally substituted.

In some embodiments, B1 is a 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B1 is pyridyl optionally substituted with halogen, C ₁ -C ₆ alkoxy, and trifluoromethyl.

In one embodiment, B1 is phenyl substituted with 1, 2, or 3 substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R ²³ is independently selected at each occurrence from (C ₃ -C ₇ cycloalkyl)C ₀ C ₄ alkyl, (phenyl)C ₀ -C ₄ alkyl, (4- to 7-membered heterocycloalkyl)C ₀ -C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5 - or 6-membered unsaturated or aromatic heterocycle)C ₀ -C ₄ -alkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S.

In one embodiment, L1-B3 is:

- 198 041794

R ²⁷ and R ²⁸ are independently selected from hydrogen, fluorine, bromine, iodo, hydroxyl, nitro, cyano, alkyl including C1-C6 alkyl, alkenyl including C2-C6 alkenyl, alkanoyl including C2-C6 alkanoyl, C2 -C6-alkoxy, C2-C6-thioalkyl, (mono- and di-C1-C6-alkylamino)C0-C4-alkyl, (C3-C7-cycloalkyl)C0-C4-alkyl, (aryl)Co-C4-alkyl-, (heteroaryl)Co-C4-alkyl- and -Co-C4-alkoxy(C3-C7-cycloalkyl); where each R ²⁷ and R ²⁸ other than hydrogen, fluorine, bromine, iodine, hydroxyl, nitro and cyano is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, alkoxy, including C 1 -C ₆ - alkoxy, haloalkyl, including C ₁ -C ₆ -haloalkyl, (C ₃ -C ₇ -cycloalkyl)C ₀ -C ₄ -alkyl and haloalkoxy, including C ₁ -C ₆ -haloalkoxy.

Substituents (L3)-A of the central core.

The (L3)-A substituents of the central nucleus in the formula are illustrated below:

In one embodiment, R ⁵ and R ⁶ are independently selected from -CHO, -C(O)NH2, -C(O)NH(CH ₃ ), C2- _C6 alkanoyl, and hydrogen.

In one embodiment, each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, amino, imino, cyano, cyanoimino, alkyl, including C ₁ -C ₆ -alkyl, C1 -C 4 -alkoxy, -Co -C ₂ -alkyl (mono - and di-C ₁ -C ₄ -alkylamino), haloalkyl, including C ₁ -C ₆ -haloalkyl, and haloalkoxy, including C ₁ -C ₆ -haloalkoxy.

In one embodiment, R ⁸ and R ⁸ are independently hydrogen or methyl.

In one embodiment, R ⁸ and R ⁸ are hydrogen.

In one embodiment, R ⁷ is hydrogen or methyl.

In one embodiment, R ⁷ is hydrogen.

Additional compounds of the present invention.

In one embodiment, the compound of the present invention is selected from:

- 199 041794

- 200 041794

In one embodiment, the compound of the present invention is selected from: Br

Vg

Vg

- 201 041794

In one embodiment, the compound of the present invention is selected from:

- 202 041794

- 203 041794

In one embodiment, the compound of the present invention is selected from:

Medications

The active compounds described herein may be administered to a patient in need thereof as a pure chemical, but more commonly they are administered as a pharmaceutical composition which contains an effective amount of the active compound to a patient, usually a human, in need of such treatment as described herein, or to his pharmaceutical acceptable salt, prodrug, isotopic analogue, N-oxide, or isolated isomer. Thus, in one embodiment, the present invention provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, together with at least one pharmaceutically acceptable carrier for any of the uses, described in this document. The pharmaceutical composition may contain the compound or salt as the sole active agent, or alternatively, the compound and at least one additional active agent.

An effective amount of the active compound described herein, or the active compound described herein, in combination or alternating with the preceding or accompanying or following other active agent, may be used in an amount sufficient to (a) inhibit the development of a complement-mediated disorder, including an inflammatory, immune, including an autoimmune disorder, or a disorder,

- 204 041794 associated with complement factor D; (b) cause regression of an inflammatory, immune, including autoimmune, disorder, or disorder associated with factor D; (c) cause a cure for an inflammatory, immune, including autoimmune, disorder or disorder associated with factor D; or inhibit or prevent the development of an inflammatory, immune, including autoimmune, factor D-associated disorder or disorder. Accordingly, an effective amount of the active compound or salt or composition thereof described herein will provide a sufficient amount of the active agent when administered to a patient to provide clinical benefit.

The exact amount of the active compound or pharmaceutical composition described herein to be delivered to a patient, typically a human in need thereof, will be determined by the healthcare provider to achieve the desired clinical benefit. In some embodiments, the pharmaceutical composition is in a dosage form that contains about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the additional active agent in unit dosage form. Examples are dosage forms with at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250 , 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500 or 1600 mg of the active compound or a salt or prodrug thereof . In one embodiment, the dosage form contains at least about 1, 5, 10, 25, 50, 75, 100, 200, 400, 500, 600, 1000, 1200, or 1600 mg of the active compound, or a salt thereof. The amount of active compound in the dosage form is calculated without salt. The dosage form can be administered, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), once every other day (Q2d), once every third day (Q3d), as needed, or any dosage regimen that provides treatment for the disorder described here.

The pharmaceutical composition may, for example, include a molar ratio of the active compound and additional active agent, which allows you to achieve the desired result. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 of an additional active agent in combination with an active compound (additional active agent : active compound) or its salts described here. In one embodiment, the additional active agent is an anti-inflammatory agent or an immunosuppressant.

The compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via an implant, including an ocular implant, transdermally, buccally, rectally, as an ophthalmic solution, by injection , including injection into the eye, intravenously, intra-aortically, intracranially, subcutaneously, intraperitoneally, subcutaneously, transnasally, sublingually, intrathecally or rectally, or by other means in unit dosage preparations containing conventional pharmaceutically acceptable carriers. For delivery to the eye, the compound may be administered as desired, e.g., as a solution, suspension, or other formulation via intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, periocular , transscleral, retrobulbar, posterior mucoscleral, pericorneal, or lacrimal duct injections, or via mucus, mucin, or mucosal barrier, by immediate or controlled release, or via an ophthalmic device, injection, or topical preparation, such as a solution or suspension presented in the form of eye drops.

The pharmaceutical composition may be formulated in any pharmaceutically acceptable form, e.g., aerosol, cream, gel, gelatin capsule, pill, microparticle, nanoparticle, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, formulation for inhalation, in a medical device, suppositories, buccal or sublingual preparation, parenteral preparation or ophthalmic solution or suspension. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing appropriate amounts of active ingredients, such as an effective amount to achieve the desired purpose.

Pharmaceutical compositions and methods for making such compositions suitable for administration as provided herein are known in the art. Примеры известных методик включают, например, патенты США № 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296, 7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252, incorporated herein by reference.

The pharmaceutical compositions contemplated herein may optionally contain a carrier. Carriers must be of sufficiently high purity and low enough toxicity to be

- 205 041794 suitable for administration to the patient being treated. The carrier may be inert or have its own pharmaceutical advantages. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material to be administered per unit dose of the compound. Carrier classes include, but are not limited to, binders, buffering agents, colorants, diluents, disintegrants, emulsifiers, fillers, flavoring agents, flow regulators, lubricants, pH modifiers, preservatives, stabilizers, surfactants, solubilizers, tabletting agents, and wetting agents. agents. Some carriers may belong to more than one class, for example, vegetable oil may be used as a lubricant in some formulations and a diluent in others. Typical pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc and vegetable oils. Examples of other matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include polyethylene glycols, caffeine, xanthene, gentisic acid, and cyclodextrins. Examples of disintegrants include sodium starch, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide and the like; and buffers, usually containing mixtures of acids and salts of these acids. Optional other active agents may be included in the pharmaceutical composition which do not substantially interfere with the activity of the compound of the present invention.

In some embodiments, the pharmaceutical composition for administration further comprises a compound or salt of Formula I, II, or III, and optionally contains one or more phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleylphosphatidylethanolamine (DOPE); diolyloxypropyltriethylammonium (DOTMA); diolylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexadecanol; a fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9 lauryl ether; a surfactant fatty acid such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20); polysorbate 20 (Tween® 20); polysorbate 60 (Tween® 60); polysorbate 65 (Tween® 65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; poloxamer; an ester of sorbitan fatty acids such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetyl phosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; acetyl palmitate; glyceryl ricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol; poly(ethylene glycol) 5000 phosphatidylethanolamine; poly(ethylene glycol) 400 monostearate; phospholipids; synthetic and/or natural detergent with high surface-active properties; deoxycholate; cyclodextrin; chaotropic salt; an ion pairing agent; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuraminic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycone, amylose, chitosan, N,O-carboxymethylchitosan, algin and alginic acid, starch , chitin, inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid, curdlan and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, block copolymer of polyoxyethylene and polyoxypropylene, polyethylene, polycarbonate (for example, poly(1,3-dioxane -2one)), polyanhydride (e.g. poly(sebacic anhydride)), polypropyl fumarate, polyamide (e.g. polycaprolactam), polyacetal, polyester, polyester (e.g. polylactide, polyglycolide, polylactide-coglycolide, polycaprolactone, polyhydroxy acid (e.g. poly(in -hydroxyalkanoate)), poly(orthoether), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene and polyamine, polylysine, polylysine-PEG -copolymer and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, vitamin E TPGS (also known as d-a-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), Hydroxypropylcellulose (HPC), Methylcellulose (MC), Ethylene oxide-propylene oxide block copolymers (PEO/PPO), Polyethylene glycol (PEG), Sodium carboxymethylcellulose (NaCMC), Hydroxypropyl methyl succinate

- 206 041794 cellulose (HPMCAS).

In some embodiments, the pharmaceutical formulation may contain controlled delivery polymers of the described compounds, including but not limited to pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3 -dioxan-2-one)); polyanhydrides (for example, poly(sebacic anhydride)); polyethers (eg polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates. In some embodiments, polymers may be modified with polyethylene glycol (PEG), carbohydrate, and/or acyclic polyacetals derived from polysaccharides. See, for example, Papisov, 2001, ACS Symposium Series, 786:301, incorporated herein by reference.

The compounds of the present invention may be in the form of particles. In one embodiment, the particles are or include microparticles. In an alternative embodiment, the particles are or include nanoparticles.

In a further alternative embodiment, common particle preparation methods include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable particle preparation methods are briefly described below. Pharmaceutically acceptable excipients, including pH modifying agents, disintegrants, preservatives and antioxidants, may optionally be included in the particles during their formation.

In one embodiment, the particles are obtained by solvent evaporation. In this method, a compound described here (or a polymer matrix and one or more compounds described here) is dissolved in a volatile organic solvent such as methylene chloride. An organic solution containing a compound described herein is then suspended in an aqueous solution which contains a surface active agent such as polyvinyl alcohol. The resulting emulsion is stirred until most of the organic solvent has evaporated, leaving solid nanoparticles or microparticles. The resulting nanoparticles or microparticles are washed with water and dried overnight in a lyophilizer. Nanoparticles with different sizes and morphologies can be obtained by this method.

Pharmaceutical compositions that contain labile polymers, such as certain polyanhydrides, may degrade during the manufacturing process due to the presence of water. For these polymers, methods can be used to obtain particles that are carried out in completely or substantially anhydrous organic solvents. Solvent removal can also be used to prepare particles from a compound that is hydrolytically unstable. In this method, a compound (or a polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent such as methylene chloride. This mixture is then suspended by stirring in an organic oil (such as silicone oil) to form an emulsion. Solid particles are formed from the emulsion, which can subsequently be separated from the supernatant. The external morphology of the spheres obtained using this technique is highly dependent on the identity of the drug product.

In one embodiment, the active compound, as described herein, is administered to a patient in need thereof in the form of particles formed by removal of the solvent. In another embodiment, the present invention relates to particles formed by removal of the solvent, containing the compound of the present invention and one or more pharmaceutically acceptable excipients, as defined here. In another embodiment, the particles formed by removal of the solvent contain the compound of the present invention and an additional therapeutic agent. In a further embodiment, the particles formed by removal of the solvent comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the described solvent removal particles may be formulated into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed by removing the solvent are formulated into a tablet, but the tablet is uncoated.

In one embodiment, the particles are obtained by spray drying. In this method, a compound (or a polymer matrix and one or more compounds) is dissolved in an organic solvent such as methylene chloride. The solution is pumped through a micronizing nozzle driven by a compressed gas flow, and the resulting aerosol is suspended in a heated air cyclone, leaving the solvent to evaporate from the microdroplets, forming particles. Microparticles and nanoparticles can be obtained using this technique.

In one embodiment, the active compound as described herein is administered to a patient in need thereof as a spray dried dispersion (SDD). In another embodiment, the present invention provides a spray-dried dispersion (SDD) containing a compound of the present invention and one or more pharmaceutically acceptable excipients as described.

- 207 041794 redistributed in this document. In another embodiment, the SDD contains a compound of the present invention and an additional therapeutic agent. In a further embodiment, the SDD comprises a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the spray-dried dispersions described may be coated to form a coated tablet. In an alternative embodiment, the spray-dried dispersion is formulated into a tablet but uncoated.

Particles can be obtained from the active compound, as described herein, using the technique of phase inversion. In this method, a compound (or a polymer matrix and one or more active compounds) is dissolved in a suitable solvent and the solution is poured into a strong compound precipitant that can spontaneously form microparticles or nanoparticles under favorable conditions. The method can be used to obtain nanoparticles in a wide range of sizes, including, for example, from nanoparticles to microparticles, usually having a narrow particle size distribution.

In one embodiment, the active compound as described herein is administered to a patient in need thereof in the form of particles formed by phase inversion. In another embodiment, the present invention relates to particles formed by phase inversion, containing the compound of the present invention and one or more pharmaceutically acceptable excipients, as defined herein. In another embodiment, the phase inversion particles comprise a compound of the present invention and an additional therapeutic agent.

In a further embodiment, the phase inversion particles comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the phase inversion particles described can be formed into a tablet and then coated to form a coated tablet. In an alternative embodiment, the phase inversion particles are formed into a tablet, but the tablet is uncoated.

Methods for forming particles using coacervation are known in the art, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S. Patent Nos. 3,266,987, 4,794,000 and 4,460,563. Coacervation involves the separation of a solution of a compound (or a polymer matrix and one or more compounds) into two immiscible liquid phases. One phase is a dense coacervate phase which contains a high concentration of the compound, while the second phase contains a low concentration of the compound. In the dense coacervate phase, the compound forms nanosized or microsized droplets that solidify into particles. Coacervation can be caused by a change in temperature, the addition of a precipitant or the addition of a microsalt (simple coacervation) or the addition of another polymer, resulting in the formation of an interpolymer complex (complex coacervation).

In one embodiment, the active compound, as described herein, is administered to a patient in need thereof in the form of particles formed as a result of coacervation. In another embodiment, the present invention relates to particles formed as a result of coacervation, containing the compound of the present invention and one or more pharmaceutically acceptable excipients, as defined herein. In another embodiment, the particles formed as a result of coacervation contain a compound of the present invention and an additional therapeutic agent. In a further embodiment, the coacervation particles comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the described coacervation particles may be formed into a tablet and then coated to form a coated tablet. In an alternative embodiment, the coacervation particles are formulated into a tablet, but the tablet is uncoated.

Methods for molding controlled release microspheres at very low temperatures are described in US Patent No. 5,019,400 to Gombotz et al. In this method, the compound is dissolved in a solvent. The mixture is then sprayed into a vessel containing a liquid precipitant at a temperature below the freezing point of the drug solution, which freezes fine droplets of the compound. When the fine droplets and the precipitant for the compound are heated, the solvent in the droplets thaws and is extracted into the precipitant, solidifying the microspheres.

In one embodiment, a compound of the present invention is administered to a patient in need thereof in the form of particles formed by low temperature casting. In another embodiment, the present invention relates to low temperature molded particles containing a compound of the present invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, the particles formed during low temperature casting contain a compound of the present invention

- 208 041794 nii and additional therapeutic agent. In a further embodiment, the cold molded particles comprise a compound of the present invention, an additional therapeutic agent, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the cold molded particles described can be formed into a tablet and then coated to form a coated tablet. In an alternative embodiment, the particles formed from the low temperature molding are formed into a tablet, but the tablet is uncoated.

In one aspect of the present invention, an effective amount of the active compound as described herein is incorporated into the nanoparticle, for example for ease of delivery and/or sustained release delivery. The use of materials at the nanoscale makes it possible to modify fundamental physical properties such as solubility, diffusivity, circulating half-life, drug release characteristics and/or immunogenicity. A number of nanoparticle-based therapeutics and diagnostics have been developed to treat cancer, diabetes, pain, asthma, allergies, and infections. These nanoscale agents can provide more efficient and/or more convenient routes of administration, reduce therapeutic toxicity, extend product life cycle, and ultimately reduce healthcare costs. As therapeutic delivery systems, nanoparticles can provide targeted delivery and controlled release.

In addition, delivery of nanoparticle-based compounds can be used to release compounds at a constant rate and thus reduce the frequency of administration, deliver drugs in a targeted manner to minimize systemic side effects, or deliver two or more drugs simultaneously for combination therapy for creating a synergistic effect and suppressing drug resistance. A number of nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposome drugs and polymer-based conjugates make up the bulk of the products. See Zhang, L., et al., Nanoparticles in Medicine: Therapeutic Applications and Developments, Clin. Pharm. and Ther., 83(5):761-769, 2008.

Methods for producing nanoparticles are known in the art. For example, see Muller, R.H., et al., Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art, Eur. H. Pharm. Biopharm., 50:161-177, 2000; US 8,691,750 from Consien et al.; WO 2012/145801 from Kanwar. US 8,580,311 from Armes, S. et al.; Petros, R.A. and DeSimone, J.M., Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews/Drug Discovery, vol. 9:615-627, 2010; US 8,465,775; US 8,444,899; US 8,420,124; US 8,263,129; US 8,158,728; 8,268,446; Pellegnno et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sc. 30:545; and Trindade et al., 2001, Chem. Mat. 13:3843; all are incorporated into this application by reference. Additional methods have been described in the literature (see, for example, Doubrow, Ed., Microcapsules and Nanoparticles in Medicine and Pharmacy, CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6:275, and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755, US Pat. modified PLGAbased Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles Nanomedicine.5(6):843-853 (2010)), U.S. Patent No. 5,543,158 to Gref et al., or WO publication WO2009/051837 from Von Andrian et al. Zauner et al., 1998, Adv. drugdel. Rev. 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703; nHaensler et al., 1993, Bioconjugate Chem. , 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989, Macromolecules, 22:3250 ; Lim et al., 1999, J. Am. Chem. Soc., 121:5633; and Zhou et al., 1990, Macromolecules, 23:3399). Examples of these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ether) (Zhou et al., 1990 , Macromolecules, 23:3399), poly(4-hydroxy-L-proline ether) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633), and poly(4-hydroxy-L-proline ether) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121: 5633, U.S. Patent No. 6,123,727, U.S. Patent No. 5,804,178, U.S. Patent No. 5,770,417, U.S. Patent No. 5,736,372, U.S. Patent No. 5,716,404, U.S. Patent No. 6,095,148, U.S. Patent No. 5,837,752, U.S. Patent No. 5,902,599; U.S. Patent No. 5,696,175; U.S. Patent No. 5,514,378; U.S. Patent No. 5,512,600; U.S. Patent No. 5,399,665; U.S. Patent No. 5,019,379; U.S. Patent No. 5,010,167; U.S. Patent No. 4,806,621; U.S. Patent No. 4,638,045; US No. 4,946,929 Wang et al., 2001, J. Am. Chem. Soc., 123:9480; Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc Chem. Res. 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev. 99:3181; Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press, 1980; Principles of Polymerization by Odian, John Wiley & Sons, Fourth Edition, 2004; Contemporary Polymer Chemistry by Allcock et al., PrenticeHall, 1981; Deming et al., 1997, Nature 390:386; and US Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete et al., Synthesis and characterization of PLGA nanoparticles J. Biomater. sci. Polymer Edn, Vol. 17, no. 3, pp. 247-289 (2006); K. Avgoustakis Pegylated Poly(Lactide) and Poly(Lactide-CoGlycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery Current Drug

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Delivery 1:321-333 (2004); C. Reis et al., Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles Nanomedicine 2:8-21 (2006); P. Paolicelli et al., Surface-modified PLGA-based Nanoparticles that can Efficiently Associate and Deliver Virus-like Particles Nanomedicine. 5(6):843-853 (2010); US Patent No. 6,632,671 from Unger Oct. 14, 2003, all incorporated herein by reference.

In one embodiment, the polymer particle size ranges from about 0.1 to about 10000 nm, between about 1 to about 1000 nm, between about 10 and 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm, between about 1 and 50 nm, between about 100 and 800 nm, between about 400 and 600 nm, or about 500 nm. In one embodiment, the microparticles are no larger than about 0.1, 0.5, 1.0, 5.0, 10, 25, 50, 75, 100, 150, 200, 250, 300, 400, 450, 500, 550, 600, 650, 700 , 750, 800, 850, 900, 950, 1000, 1250, 1500, 1750 or 2000 nm. In some embodiments, a compound described herein may be covalently linked to a polymer used in a nanoparticle, such as a polystyrene particle, PLGA particle, PLA particle, or other nanoparticle. Pharmaceutical compositions may be formulated for oral administration. These compositions may contain any amount of active compound that achieves the desired result, for example, from 0.1 to 99% by weight (wt.%) of the compound and usually at least about 5 wt.% of the compound. Some embodiments contain at least about 10, 15, 20, 25 to about 50% by weight, or from about 5 to about 75% by weight of the compound.

Pharmaceutical compositions suitable for rectal administration are usually presented as unit dose suppositories. They can be prepared by mixing the active compound with one or more conventional solid carriers such as cocoa butter and then molding the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more of these. Pharmaceutical compositions suitable for transdermal administration may be presented as individual patches adapted to remain in close contact with the epidermis of the recipient for an extended period of time. Pharmaceutical compositions suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and are usually in the form of an optionally buffered aqueous solution of the active compound. In one embodiment, patches or microneedle devices are provided for delivering drugs through or into biological tissues, particularly the skin. Microneedle patches or devices allow the delivery of drugs at a clinically significant rate through or into the skin or other tissue barriers with little or no tissue damage, pain, or irritation.

Pharmaceutical compositions suitable for administration to the lungs can be delivered using a wide variety of dry powder inhalers (DPI) with single/multiple dose (DPI) driven by passive breathing and an active source. Devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating screen technology nebulizers. The selection of an appropriate device for delivery to the lungs depends on such parameters as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lung.

Additional non-limiting examples of inhaled drug delivery devices and methods include, for example, US Pat. No. 7,383,837 entitled Inhalation device (SmithKline Beecham Corporation); WO2006/033584 entitled Powder inhaler (Glaxo SmithKline Pharmaceuticals SA); WO2005/044186 entitled Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same (Glaxo Group Ltd and SmithKline Beecham Corporation); US Patent 9,095,670 entitled Inhalation device and method of dispensing medicament; US Patent 8,205,611 entitled Dry powder inhaler (Astrazeneca AB); WO2013/038170 entitled Inhaler (Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 entitled Inhalation Device with Feedback System, US 8,910,625 and US/2015/0165137 entitled Inhalation Device for Use in Aerosol Therapy (Vectura GmbH); U.S. Patent 6,948,496 entitled Inhalers, US/2005/0152849 entitled Powders comprising anti-adherent materials for use in dry powder inhalers for use in dry powder inhalers, US Pat. , titled Inhaler, US/2012/0114709 and US Pat. Composition, US/2015/0174343 entitled Mixing Channel for an Inhalation Device, US Patent 7,744,855 and

- 210 041794

US/2010/0285142 entitled Method of making particles for use in a pharmaceutical composition, US Patent 7,541,022, US/2009/0269412, and US/2015/0050350 entitled Pharmaceutical formulations for dry powder inhalers (Vectura Limited).

A variety of methods and devices for delivering drugs to the eye are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein by reference in their entirety). Examples are US Pat. No. 8,192,408 entitled Ocular trocar assembly (Psivida Us, Inc.); U.S. Patent 7,585,517 entitled Transcleral delivery (Macusight, Inc.); US Pat. No. 5,710,182 and US Pat. No. 5,795,913 entitled Ophthalmic composition (Santen OY); US Pat. 7,455,855 entitled Delivering substance and drug delivery system using the same (Santen Pharmaceutical Co., Ltd.); WO2011/050365 entitled Conformable Therapeutic Shield For Vision and Pain and WO2009/145842 entitled Therapeutic Device for Pain Management and Vision (Forsight Labs, LLC); патент США 9,066,779 и патент США 8,623,395, озаглавленные Implantable therapeutic device, WO2014/160884, озаглавленная Ophthalmic Implant for Delivering Therapeutic Substances, патент США 8,399,006, патент США 8,277,830, патент США 8,795,712, патент США 8,808,727, патент США 8,298,578, и WO2010/088548, entitled Posterior segment drug delivery, WO2014/152959 and US20140276482 entitled Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant, US Patent 8,905,963 and US Patent 9,033,911 entitled Injector apparatus and method for drug delivery, WO2015/057554 titled Formulations and Methods for Increasing or Reducing Mucus, US Patent 8,715,712 and US Patent 8,939,948 titled Ocular insert apparatus and methods, WO2013/116061 titled Insertion and Removal Methods and Apparatus for Therapeutic Devices, WO2014/066775 titled Ophthalmic System for Sustained Release of Drug to the Eye, WO2015/085234 and WO2012/019176 entitled Implantable Therapeutic Device, WO2012/065006 entitled Methods and Apparatus to determine Porous Structures for Drug Delivery, WO2010/141729 entitled Anterior Segment Drug Delivery, WO2011/050327 entitled Corneal Denervation for Treatment of Ocular Pain, WO2013/ 022801, titled Small Molecule Delivery with Implantable Therapeutic Device, WO2012/019047, titled Subconjunctival Implant for Posterior Segment Drug Delivery, WO2012/068549, titled Therapeutic Agent Formulations for Implanted Devices, WO2012/019139, titled Combined Delivery Methods and Apparatus, WO2046/04013/019139 , entitled Ocular Insert Apparatus and Methods, WO2012/019136, entitled Injector Apparatus and Method for Drug Delivery, WO2013/040247, entitled Fluid Exchange Apparatus and Methods (ForSight Vision4, Inc.). Additional non-limiting examples of active compound delivery are provided in WO2015/085251 entitled Intracameral Implant for Treatment of an Ocular Condition (Envisia Therapeutics, Inc.); WO2011/008737 entitled Engineered Aerosol Particles, and Associated Methods, WO2013/082111 entitled Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses, WO2009/132265 entitled Degradable compounds and methods of use thereof, particularly with particle replication in non- wetting templates, WO2010/099321 entitled Interventional drug delivery system and associated methods, WO2008/100304 entitled Polymer particle having high fidelity order, composite size, and shape particles, WO2007/024323 entitled Nanoparticle fabrication methods, systems, and materials (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO2010/009087 entitled Iontophoretic Delivery of a Controlled-Release Formulation in the Eye, (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO2009/132206 entitled Compositions and Methods for Intracellular Delivery and Release of Cargo, WO2007/133808 entitled Nanoparticles for cosmetic applications, WO2007/056561 entitled Medical device, materials, and methods, WO2010/065748 entitled Method for producing patterned materials, WO2007/081876 entitled Nanostructured surfaces for biomedical/biomaterial applications and processes thereof (Liquidia Technologies, Inc.).

Additional non-limiting examples of methods and devices for delivering drugs to the eye include, for example, WO2011/106702 and US Pat. No. 8,889,193 entitled Sustained delivery of therapeutic agents to an eye compartment, WO2013/138343 and US Pat. HIF-1 inhibitors, WO2013/138346 and US2013/0272994 entitled Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents, WO2005/072710 and US Patent 8,957,034 entitled Drug and Gene Carrier Particles that Rapidly Move Through Mucus Barriers, WO2008/030557, US2010/0215580, US2013/0164343 entitled Compositions and Methods for Enhancing Transport Through Mucous, WO2012/061703, US2012/0121718, and US2013/0236556 entitled Compositions and Methods Relating to 0183244 entitled Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain, WO2012/109363 and US2013/0323313 , entitled Mucus Penetrating Gene Carriers, WO 2013/090804 and US2014/0329913, entitled Nanoparticles with enhanced mucosal penetration or

- 211 041794 decreased inflammation, WO2013/110028 entitled Nanoparticle formulations with enhanced mucosal penetration, WO2013/166498 and US2015/0086484 entitled Lipid-based drug carriers for rapid penetration through mucus linings (The Johns Hopkins University); WO2013/166385 entitled Pharmaceutical Nanoparticles Showing Improved Mucosal Transport, US2013/0323179 entitled Nanocrystals, Compositions, And Methods that Aid Particle Transport in Mucus (The Johns Hopkins University and Kala Pharmaceuticals, Inc.); WO2015/066444 entitled Compositions and methods for ophthalmic and/or other applications, WO2014/020210 and WO2013/166408 entitled Pharmaceutical nanoparticles showing improved mucosal transport (Kala Pharmaceuticals, Inc.); US Pat. entitled Injectable aqueous ophthalmic composition and method of use therefor, US2007/0149593 entitled Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye, US Patent 8,632,809 entitled Water insoluble polymer matrix for drug delivery (Alcon, Inc. .).

Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 entitled Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor (Abbott Laboratories); US20050009910 entitled Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug, US20130071349 entitled Biodegradable polymers for lowering intraocular pressure US Patent 8,481,069 entitled Tyrosine kinase microspheres US Patent 8,465,778 entitled Method of making tyrosine kinase microspheres, US 8,409,607 entitled Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods, US 8,512,738 and US 2014/0031408 entitled Biodegradable intravitreal tyrosine kinase implants, US 2014/0294986 entitled Microsphere Drug Delivery System for Sustained Intraocular Release, US Patent 8,911,768 entitled Methods For Treating Retinopathy With Extended Therapeutic Effect (Allergan, Inc.); U.S. Patent 6,495,164 entitled Preparation of injectable suspensions having improved injectability (Alkermes Controlled Therapeutics, Inc.); WO 2014/047439 entitled Biodegradable Microcapsules Containing Filling Material (Akina, Inc.); WO 2010/132664 entitled Compositions And Methods For Drug Delivery (Baxter International Inc. Baxter Healthcare SA); US20120052041 entitled Polymeric nanoparticles with enhanced drugloading and methods of use thereof (The Brigham and Women's Hospital, Inc.); US20140178475, US20140248358, and US20140249158 entitled Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same (BIND Therapeutics, Inc.); U.S. Patent 5,869,103 entitled Polymer microparticles for drug delivery (Danbiosyst UK Ltd.); US Pat. No. 8,628,801 entitled Pegylated Nanoparticles (Universidad de Navarra); US2014/0107025 entitled Ocular drug delivery system (Jade Therapeutics, LLC); U.S. Patent 6,287,588 entitled Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof U.S. Patent 6,589,549 entitled Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles (Macromed, Inc.) ; U.S. Patent 6,007,845 and U.S. Patent 5,578,325 entitled Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers (Massachusetts Institute of Technology); US20040234611, US20080305172, US20120269894, and US20130122064 entitled Ophthalmic depot formulations for periocular or subconjunctival administration (Novartis Ag); U.S. Patent 6,413,539 entitled Block polymer (Poly-Med, Inc.); US 20070071756 entitled Delivery of an agent to ameliorate inflammation (Peyman); US 20080166411 entitled Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Compressing Nanoparticles (Pfizer, Inc.); U.S. Patent 6,706,289 entitled Methods and compositions for enhanced delivery of bioactive molecules (PR Pharmaceuticals, Inc.); and US Patent 8,663,674 entitled Microparticle containing matrices for drug delivery (Surmodics).

The use of active compounds for the treatment of certain diseases

In one aspect, an effective amount of an active compound, or a salt or composition thereof, as described herein, is used to treat a disease that is an inflammatory or immune condition, a disorder mediated by the complement cascade (including a dysfunctional cascade), including a disorder associated with factor D complement, or an alternative complement pathway disorder, a disorder or abnormality of a cell that adversely affects the cell's ability to participate in or respond to normal complement activity, or an unwanted complement-mediated response, to medical treatment such as surgery or other medical procedure, or administration of a pharmaceutical or biopharmaceutical drug, blood transfusion, or other administration of an allogeneic tissue or fluid.

In one embodiment, the disorder is selected from fatty liver and fatty liver conditions such as non-alcoholic steatohepatitis (NASH), inflammation of the liver, cirrhosis, and liver failure. In one embodiment of the present

- 212 041794 of the invention provides a method of treating fatty liver in a patient by administering an effective amount of the active compound or its salt or composition, as described here.

In another embodiment, an active compound, or a salt or composition thereof, as described herein, is used to modulate an immune response before or during surgery or other medical procedure. One non-limiting example is the use in connection with acute or chronic graft versus host disease, which is a common complication of allogeneic tissue transplantation and may also occur as a result of blood transfusion.

In one embodiment, the present invention relates to a method of treating or preventing dermatomyositis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing amyotrophic lateral sclerosis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing an abdominal aortic aneurysm, complications of hemodialysis, hemolytic anemia, or hemodialysis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In another embodiment, a method is provided for treating or preventing cytokine or inflammatory responses in response to the administration of a pharmaceutical or biotherapeutic agent (e.g., CAR T cell therapy or monoclonal antibody therapy) to a patient by administering an effective amount of the active compound, or a salt thereof, or a composition, such as described here. Various types of cytokine or inflammatory responses may occur in response to a number of factors, such as administration of biotherapeutic agents. In one embodiment, the cytokine or inflammatory response is a cytokine release syndrome. In one embodiment, the cytokine or inflammatory response is tumor lysis syndrome (which also results in the release of cytokines). Symptoms of cytokine release syndrome range from fever, headache, and skin rashes to bronchospasm, hypotension, and even cardiac arrest. Severe cytokine release syndrome is described as a cytokine storm, and can be fatal.

Fatal cytokine storms have been observed in response to infusion using several monoclonal antibodies. See, Abramowicz D, et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients Transplantation (1989) 47(4):606-8; Chatenoud L, et al. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids Transplantation (1990) 49(4):697-702; and Lim LC, Koh LP, and Tan P. Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia J. Clin Oncol. (1999) 17(6): 1962-3.

This document also contemplates the use of an active compound, or a salt thereof, or a composition as described herein, to mediate an adverse immune response in patients receiving bi-specific T cell recruiters (BiTE). A bi-specific T cell recruiter directs T cells to target and bind to a specific antigen on the surface of a cancer cell. For example, Blinatumomab (Amgen), BiTE, has recently been approved as a second-line therapy for relapsed or refractory Philadelphia chromosome acute lymphoblastic leukemia. Blinatumomab is given as a continuous intravenous infusion in 4-week cycles. The use of BiTE agents has been associated with adverse immune responses, including cytokine release syndrome. The most significantly elevated cytokines in CRS associated with ACT include IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/ CD3-bispecific BiTE antibody blinatumomab Blood (2012) 119:6226-6233).

In another embodiment, the disorder is episcleritis, idiopathic episcleritis, anterior episcleritis, or posterior episcleritis. In one embodiment, the disorder is idiopathic anterior uveitis, HLA-B27 associated uveitis, herpetic keratouveitis, Posner-Schlossmann syndrome, Fuchs heterochromic iridocyclitis, or cytomegalovirus anterior uveitis. In one embodiment, the present invention provides a method of treating or preventing C3 glomerulopathy by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, the disorder is selected from Dense Deposit Disease (DDD) and C3 glomerulonephritis (C3GN).

In one embodiment, the present invention relates to a method of treating or preventing IC-MPGN by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, the present invention relates to a method of treating or preventing paroxysmal nocturnal hemolybinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method for treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing myasthenia gravis by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing atypical hemolytic uremic syndrome (aHUS) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In one embodiment, the present invention relates to a method of treating or preventing myelitis optica (NMO) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein.

In yet another embodiment, the present invention relates to a method of treating or preventing a disorder as described below by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein, including:

vitritis, sarcoidosis, syphilis, tuberculosis or Lyme disease; retinal vasculitis, Eales' disease, tuberculosis, syphilis, or toxoplasmosis; neuroretinitis, viral retinitis or acute retinal necrosis;

varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, lichen planus, or a disease associated with dengue (eg, dengue hemorrhagic fever); masquerade syndrome, contact dermatitis, inflammation caused by trauma, inflammation caused by ultraviolet light, eczema, anular granuloma or acne.

In a further embodiment, the disorder is selected from: acute myocardial infarction, aneurysm, cardiopulmonary bypass, dilated cardiomyopathy, complement activation during cardiopulmonary bypass surgery, coronary artery disease, post-stent restenosis or percutaneous transluminal coronary angioplasty (PTCA); antibody-mediated graft rejection, anaphylactic shock, anaphylaxis, allogeneic graft rejection, humoral and vascular graft rejection, graft dysfunction, graft-versus-host disease, Graves' disease, adverse drug reactions, or chronic graft vasculopathy; allergic bronchopulmonary aspergillosis, allergic neuritis, drug allergy, radiation damage to the lungs, eosinophilic pneumonia, allergy to radiopaque substance, bronchiolitis obliterans or interstitial pneumonia; parkinsonism-dementia complex, sporadic frontotemporal dementia, frontotemporal dementia with parkinsonism associated with chromosome 17, frontotemporal lobar degeneration, tangle-only dementia, cerebral amyloid angiopathy, cerebrovascular disorder, some forms of frontotemporal dementia, chronic traumatic encephalopathy (CTE), PD with dementia (PDD), argyrophilic grain dementia, boxer dementia, Lewy body dementia (DLB), or multi-infarct dementia; Creutzfeldt-Jakob disease, Huntington's disease, multifocal motor neuropathy (MMN), prion cerebral amyloid angiopathy, polymyositis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, non-Guam motor neuron disease with neurofibrillary tangles, neuronal regeneration, or diffuse neurofibrillary tangles with calcification.

In one embodiment, the disorder is selected from: atopic dermatitis, dermatitis, dermatomyositis, bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic arthritis, pemphigus vulgaris, discoid lupus erythematosus, cutaneous lupus erythematosus, lupus pernio, or crossed lupus erythematosus-lichen planus syndrome, cryoglobulinemic lichen planus, vasculitis, mesenteric/intestinal vascular disorder, peripheral vascular disorder, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), IL-2-induced vascular leak syndrome, or immune complex-associated vasculitis, angioedema, low platelet syndrome (HELLP), sickle cell anemia, platelet refractoriness, erythrocyte casts, or typical or infectious hemolytic uremic syndrome (tHUS); hematuria, hemorrhagic shock, drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA), azotemia, inflammation

- 214 041794 blood vessels and/or lymphatic vessels, rotational atherectomy or delayed hemolytic transfusion reaction; British type amyloid angiopathy, Buerger's disease, bullous pemphigoid, C1q nephropathy, cancer, or catastrophic antiphospholipid syndrome.

In another embodiment, the disorder is selected from: wet (exudative) AMD, dry (non-exudative) AMD, chorioretinal dystrophy, choroidal neovascularization (CNV), choroiditis, loss of RPE function, loss of vision (including loss of visual acuity or visual field), loss of vision from AMD, retinal damage in response to light exposure, retinal degeneration, retinal detachment, retinal dysfunction, retinal neovascularization (RNV), retinopathy of prematurity, pathologic myopia, or RPE degeneration; pseudophakic bullous keratopathy, symptomatic disorder associated with macular degeneration, optic nerve degeneration, photoreceptor degeneration, cone degeneration, photoreceptor cell loss, pars planitis, scleritis, proliferative vitreoretinopathy, or ocular drusen formation; chronic urticaria, Churg-Strauss syndrome, cold agglutination syndrome (CAD), corticobasal degeneration (CBD), cryoglobulinemia, cyclitis, Bruch's membrane damage, Degos disease, diabetic angiopathy, elevated liver enzymes, endotoxemia, epidermolysis bullosa or acquired epidermolysis bullosa; essential mixed cryoglobulinemia, excess blood urea nitrogen-BUN, focal segmental glomerulosclerosis, Gerstmann-Straussler-Scheikner disease, giant cell arteritis, gout, Hallervorden-Spatz disease, Hashimoto's thyroiditis, Henoch-Scheonlein nephritis, or atypical urinary sediment; hepatitis, hepatitis A, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), a viral infection more generally, e.g., selected from Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae, Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae, Togaviridae, Orthomyxoviridae , Rhabdoviridae or Hepadnaviridae, Neisseria meningitidis, E. coli Shiga toxin associated with hemolytic uremic syndrome (STEC-HUS), hemolytic uremic syndrome (HUS); streptococcus or post-streptococcal glomerulonephritis.

In a further embodiment, the disorder is selected from: hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic shock, hypocomplementemic urticarial vasculitis, hypophosphatasia, hypovolemic shock, idiopathic pneumonia syndrome, or idiopathic pulmonary fibrosis; inclusion body myositis, intestinal ischemia, iridocyclitis, iritis, juvenile chronic arthritis, Kawasaki disease (arteritis), or lipiduria; membranoproliferative glomerulonephritis (MPGN) I, microscopic polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency (MoCD) type A, pancreatitis, panniculitis, Pick's disease, polyarteritis nodosa (PAN), progressive subcortical gliosis, proteinuria, reduced glomerular filtration rate (GFR), or renovascular disorders; multiple organ failure, multiple system atrophy (MSA), myotonic dystrophy, Niemann-Pick type C disease, chronic demyelinating diseases, or progressive supranuclear palsy; spinal cord injury, spinal muscular atrophy, spondyloarthropathy, Reiter's syndrome, spontaneous fetal loss, recurrent fetal loss syndrome, preeclampsia, synucleinopathy, Takayasu's arteritis, postpartum treoiditis, thyroiditis, cryoglobulinemia type I, mixed cryoglobulinemia type II, mixed cryoglobulinemia type III, ulcerative colitis , uremia, urticaria, venous gas embolism (VGE) or Wegener's granulomatosis; Hippel-Lindau disease, ocular histoplasmosis, hard drusen, soft drusen, pigment clumping, or loss of photoreceptors and/or retinal pigment epithelium (RPE).

In one embodiment, the active compound or salt or composition thereof as described herein is useful for treating or preventing a disorder selected from autoimmune oophoritis, endometriosis, autoimmune orchitis, Orda's thyroiditis, autoimmune enteropathy, celiac disease, Hashimoto's encephalopathy, antiphospholipid syndrome ( APLS) (Hughes syndrome), aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia, pure erythrocyte aplasia, thrombocytopenia, neurolipomatosis (Derkum's disease), Still's disease, developed in adults, ankylosing spondylitis , CREST syndrome, drug-induced lupus, eosinophilic fasciitis (Schulman syndrome), Felty syndrome, IgG4-associated disease, mixed connective tissue disease (MCTD), palindromic rheumatism (Hensch-Rosenberg syndrome), Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsing polychondritis (Me syndrome Jenburg-Altter-Uhlinger), retroperitoneal fibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia, neuromyotonia (Isaac's disease), paraneoplastic degeneration, autoimmune inner ear disease, Meniere's disease, interstitial cystitis, autoimmune pancreatitis, Zika virus disorders, disorders associated with chikungunya virus, subacute bacterial endocarditis (SBE), IgA nephropathy, IgA vasculitis, polymyalgia rheumatica, rheumatoid vasculitis, alopecia, autoimmune progesterone dermatitis, dermatitis herpetiformis, erythema nodosum, gestational pemphigoid, hidradenitis suppurativa, lichen sclerosus, IgA dependent, dermatosis (LAD), focal scleroderma, myositis, acute lichenoid and varioliform parapsoriasis, vitiligo, syndrome after myocardial infarction (Dressler's syndrome), postpericardiotomy syndrome, autoimmune retinopathy, Cogan's syndrome, Graves' ophthalmopathy, woody skin njunctivitis, corneal ulcer, opso-myoclonal syndrome, optic neuritis, retinocochleo-celebral vasculopathy (Susak syndrome), sympathetic ophthalmia, Tolos-Hunt syndrome, interstitial lung disease, antisynthetase syndrome, Addison's disease, autoimmune polyendocrine syndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II, autoimmune polyendocrine syndrome (APS) type III, multiple sclerosis (multiple sclerosis, pattern II), rapidly progressive glomerulonephritis (RPGN), juvenile rheumatoid arthritis, enthesitis-associated arthritis, reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoid hepatitis, primary biliary cirrhosis (PBS), primary sclerosing cholangitis, microscopic colitis, latent lupus (undifferentiated connective tissue disease (UCTD)), acute disseminated encephalomyelitis (ADEM), acute motor axonal neuropathy, encephalitis with antititis elami to anti-n-methyl-D-aspartate receptors, Balo's concentric sclerosis (Schilder's disease), Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton's myasthenic syndrome, Austoran's syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), progressive inflammatory neuropathy, restless legs syndrome, stiff person syndrome, Sydenham syndrome, transverse myelitis, non-lupus vasculitis, leukocytoclastic vasculitis, microscopic polyangiitis, polymyositis, or ischemia-reperfusion eye injury.

Examples of ocular diseases that can be treated according to the compositions and methods disclosed herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercal keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs endothelial corneal dystrophy syndrome , Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune diseases dry eye syndrome, environmentally induced dry eye syndrome, corneal neovascularization, prevention and treatment of corneal transplant rejection, autoimmune uveitis, infectious uveitis, posterior uveitis (including toxoplasmosis), pan-uveitis, inflammatory disease of the vitreous or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, autoimmune disease retinal disease, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open-angle glaucoma, angle-closure glaucoma, pigmentary glaucoma, and combinations thereof.

In a further embodiment, the disorder is selected from glaucoma, diabetic retinopathy, blistering skin diseases (including bullous pemphigoid, pemphigus, and epidermolytic bullosis), cicatricial ocular retinitis pigmentosa, uveitis, adult macular degeneration, diabetic retinitis pigmentosa, macular edema, diabetic macular edema, Behçet uveitis, multifocal choroiditis, Vogt-Kojangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, bilobed ocular pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation and retinal vein occlusion or central retinal vein occlusion (CVRO) ).

In some embodiments, complement-mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic retinal atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases. In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

Disorders that can be treated or prevented with an active compound, or a salt thereof, or a composition as described herein also include, but are not limited to: hereditary angioedema, capillary leak syndrome, hemolytic uremic syndrome (HUS), neurological disorders, Guillain-Barré syndrome, diseases of the central nervous system and other neurodegenerative conditions, glomerulonephritis (including membranoproliferative glomerulonephritis), SLE nephritis, proliferative nephritis, liver fibrosis, tissue regeneration and neuronal regeneration, or Barraquer-Simons syndrome;

inflammatory responses of sepsis, systemic inflammatory response syndrome (SIRS), inappropriate or unwanted complement activation disorders, interleukin-2-induced toxicity with IL-2 therapy, inflammatory disorders, inflammation in autoimmune diseases, systemic lupus erythematosus (SLE), lupus nephritis, arthritis, immune complex diseases and autoimmune diseases, systemic lupus erythematosus or lupus erythematosus; ischemia/reperfusion injury (I/R injury), myocardial infarction, myocarditis, postischemic reperfusion, balloon angioplasty, atherosclerosis, posthemodialysis syndrome in cardiopulmonary bypass

- 216 041794 or renal bypass, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, antiphospholipid syndrome, autoimmune heart disease, ischemia-reperfusion injury, obesity or diabetes; dementia in Alzheimer's disease, stroke, schizophrenia, traumatic brain injury, trauma, Parkinson's disease, epilepsy, transplant rejection, prevention of fetal loss, biomaterial reactions (eg, hemodialysis, implants), hyperacute allograft rejection, xenograft rejection, transplantation, psoriasis, trauma burns, thermal injuries, including burns or frostbite, or crush injuries; asthma, allergies, acute respiratory distress syndrome (ARDS), cystic fibrosis, adult respiratory distress syndrome, dyspnea, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarcts, pneumonia, fibrogenic pneumoconiosis, inert dust disease and minerals (e.g. silicon, coal dust, beryllium and asbestos), pulmonary fibrosis, organic dust diseases, chemical damage (due to irritating gases and chemicals, e.g. chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid), smoke injury, thermal injury (eg, burns, frostbite), bronchospasm, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's syndrome (antiglomerular basement membrane nephritis), pulmonary vasculitis, spider-immune vasculitis, or inflammation associated with immune complexes.

In one embodiment, a method for treating sickle cell anemia in a patient is provided, which comprises administering an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, a method of treating immunothrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathic thrombocytopenic purpura (ITP) in a patient is provided, which comprises administering an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, a method for treating ANCA vasculitis in a patient is provided, which comprises administering an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, a method for treating IgA nephropathy in a patient is provided, which comprises administering an effective amount of an active compound, or a salt or composition thereof, as described herein. In one embodiment, a method for treating rapidly progressive glomerulonephritis (RPGN) in a patient is provided, which comprises administering an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, a method of treating lupus nephritis in a patient is provided, which comprises administering an effective amount of an active compound, or a salt thereof, or a composition as described herein. In one embodiment, a method of treating dengue hemorrhagic fever in a patient is provided, which comprises administering an effective amount of the active compound, or a salt thereof, or composition as described herein.

In a further alternative embodiment, an active compound, or salt or composition thereof, as described herein, is used in the treatment of an autoimmune disorder.

The complement pathway enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body. It is part of the innate immune system and is a necessary process in healthy people. Inhibition of the complement pathway will decrease the response of the body's immune system. Therefore, it is an object of the present invention to treat autoimmune disorders by administering an effective active compound, or salt or composition thereof, as described herein, to a subject in need thereof.

In one embodiment, the autoimmune disorder is caused by the activity of the complement system. In one embodiment, the autoimmune disorder is caused by the activity of the alternative complement pathway. In one embodiment, the autoimmune disorder is caused by activity of the classical complement pathway. In another embodiment, the autoimmune disorder is caused by a mechanism of action that is not directly related to the complement system, such as excessive proliferation of T-lymphocytes or excessive production of cytokines.

Non-limiting examples of autoimmune disorders include: lupus, allograft rejection, autoimmune thyroid diseases (such as Graves' disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis , regional ileitis and terminal ileitis), diabetes, multiple sclerosis, pernicious anemia, psoriasis, rheumatoid arthritis, sarcoidosis and scleroderma.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, is used in the treatment of lupus. Non-limiting examples of lupus include lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, lupus pernio, lupus erythematosus and lichen planus overlap syndrome. Lupus erythematosus is a general category of diseases that includes both systemic and cutaneous disorders. The systemic form of the disease can have both skin and systemic manifestations. However, there are also

- 217 041794 forms of the disease that are only cutaneous without systemic involvement. For example, SLE is an inflammatory disease of unknown etiology that occurs predominantly in women and is characterized by articular symptoms, butterfly erythema, recurrent pleurisy, pericarditis, generalized adenopathy, splenomegaly, as well as CNS involvement and progressive renal failure. Serum of the majority of patients (more than 98%) contains antinuclear antibodies, including anti-DNA antibodies. High titers of anti-DNA antibodies are essentially specific to SLE. The traditional treatment for this disease is the administration of corticosteroids or immunosuppressants.

There are three forms of cutaneous lupus: chronic cutaneous lupus (also known as discoid lupus erythematosus or DLE), subacute cutaneous lupus, and acute cutaneous lupus. DLE is a disfiguring chronic disease primarily affecting the skin with sharply defined macules and plaques that exhibit erythema, follicular blockage, scaling, telangiectasia, and atrophy. The condition is often aggravated by sun exposure, and early lesions are erythematous, round, scaly papules 5 to 10 mm in diameter and with follicular occlusion. Lesions in DLE appear most often on the cheeks, nose, scalp, and ears, but they can also spread to the upper trunk, extensor surfaces of the extremities, and mucous membranes of the mouth. If left untreated, the central lesion atrophies and leaves a scar. Unlike SLE, double-stranded DNA antibodies (eg, DNA-binding test) are almost always absent in DLE.

Multiple sclerosis (PC) is an autoimmune demyelinating disease believed to be dependent on T-lymphocytes. MS usually exhibits a relapsing or chronic progressive course. The etiology of MS is unknown, however viral infections, genetic predisposition, environment, and autoimmunity appear to contribute to the disorder. Lesions in patients with MS contain infiltrates of predominantly T lymphocyte-mediated microglial cells and infiltrating macrophages. CD4+ T lymphocytes are the predominant cell type present in these lesions. The hallmark of a PC lesion is the plaque, an area of demyelination that is sharply demarcated from the normal white matter seen on MRI.

The histological appearance of MS plaques varies with different stages of the disease. In active lesions, the blood-brain barrier is damaged, allowing extravasation of serum proteins into extracellular spaces. Inflammatory cells can be seen in the perivascular cuffs and throughout the white matter. CD4+ T cells, especially Th1, accumulate around postcapillary venules at the margin of the plaque and also disperse into the white matter. Active lesions also show upregulation of adhesion molecules and lymphocyte and monocyte activation markers such as IL2-R and CD26. Demyelination in active lesions is not accompanied by destruction of oligodendrocytes. In contrast, during the chronic phases of the disease, lesions are characterized by the loss of oligodendrocytes and hence the presence of antibodies to oligodendrocyte myelin glycoprotein (MOG) in the blood.

Diabetes can refer to either type 1 or type 2 diabetes. In one embodiment, the active compound, or salt or composition thereof, as described herein, is provided as an effective dose for the treatment of a patient with type 1 diabetes. In one embodiment, the active compound, or salt or composition thereof, as described herein, is provided as an effective dose for the treatment of a patient with type 2 diabetes. Type 1 diabetes is an autoimmune disease. An autoimmune disease occurs when the body's infection-fighting system (the immune system) attacks a part of the body. In type 1 diabetes, the pancreas produces little or no insulin.

Combination Therapy

In one embodiment, the active compound, or a salt thereof, or a composition as described herein, may be provided in combination or alternation, together with or before, simultaneously with or with subsequent addition, with an effective amount of at least one additional therapeutic agent, for example, for the treatment of disorders listed here. Non-limiting examples of second active agents for such combination therapy are given below.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination or alternation with at least one additional complement system inhibitor or a second active compound with a different biological mechanism of action. In the description below and in this document, as a general rule, whenever any terms are used referring to an active compound, or a salt thereof, or a composition as described herein, it should be understood that pharmaceutically acceptable salts, prodrugs, or compositions are considered included unless otherwise noted or in accordance with the text. In non-limiting embodiments, an active compound or salt or composition thereof as described herein may be provided together with a protease inhibitor, soluble complement regulator, therapeutic antibody (monoclonal

- 218 041794 or polyclonal), complement component inhibitor, receptor agonist or siRNA.

In other embodiments, the active compound described herein is administered in combination or in alternation with an anti-tumor necrosis factor (TNF) antibody, including, but not limited to, infliximab (Remicade), adalimumab, certolizumab, golimumab, or a receptor fusion protein such as etanercept (Embrel).

In another embodiment, the active compound described herein may be administered in combination or in alternation with an anti-CD20 antibody, including, but not limited to, rituximab (Rituxan), adalimumab (Humira), ofatumumab (Arzerra), tositumomab (Bexxar) , obinutuzumab (Gazyva) or ibritumomab (Zevalin).

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with an anti-IL6 antibody, including, but not limited to, tocilizumab (Actemra) and siltuximab (Sylvant).

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with an IL17 inhibitor, including but not limited to secukinumab (Cosentyx).

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with a p40 (IL12/IL23) inhibitor, including but not limited to ustekinumab (Stelara).

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with an IL23 inhibitor, including, but not limited to, risankizumab.

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with an anti-interferon a antibody, including, but not limited to, sifalimumab.

In an alternative embodiment, the active compound as described herein may be administered in combination or in alternation with a kinase inhibitor, such as, but not limited to, a JAK1/JAK3 inhibitor, such as, but not limited to, tofacitinib (Xelianz). In an alternative embodiment, the active compound as described herein may be administered in combination or in alternation with a JAK1/JAK2 inhibitor, such as, but not limited to, baricitinib.

In an alternative embodiment, the active compound described herein may be administered in combination or in alternation with an anti-VEGF agent, for example, but not limited to: aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche); lapatinib (Tykerb); sunitinib (Sutent); axitinib (Inlyta); pazopanib; sorafenib (Nexavar); ponatinib (Inclusig); regorafenib (Stivarga); cabozantinib (Abometyx; Cometriq); vandetanib (Caprelsa); ramucirumab (Cyramza); lenvatinib (Lenvima); civ-aflibercept (Zaltrap); cediranib (Recentin); ancortan acetate, squalamine lactate, and corticosteroids.

In another embodiment, the active compound described herein may be administered in combination or in alternation with an immune checkpoint inhibitor.

Non-limiting examples of checkpoint inhibitors include anti-PD-1 or anti-PDL1 antibodies, e.g., nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca). ), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and PDL1/VISTA inhibitor CA-170 (Curis Inc.), atezolizumab, durvalumab and KN035, or anti-CTLA4 antibodies such as ipilimumab, tremelimumab, AGEN1884 and AGEN2041 (Agenus).

Non-limiting examples of active agents that can be used in combination with the active compounds described herein are:

protease inhibitors: plasma-derived C1-INH concentrates, eg Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma) and Cinryze®; recombinant human O-inhibitors such as Rhucin®; ritonavir (Norvir®, Abbvie, Inc.);

soluble complement regulators: soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLe ^X /TP-20 (Avant Immunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals); Myrocept (Inflazyme Pharmaceuticals);

therapeutic antibodies: eculizumab/Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutramazab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A/S);

complement component inhibitors: compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas); PDGF inhibitors: Sorafenib Tosylate; Imatinib Mesilate (STI571); Sunitinib Malate; Ponatinib (AP24534); axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258,

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CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) Lactyl lactic acid; MK-2461; Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate; Sennoside B; sunitinib; AZD2932; and Trapidil; Anti-factor H or anti-factor B agents: anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMA measures for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas);

molecules targeting complement C3 or CAP C3 convertase: TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Opthenon); H17 C3 (C3b/iC3b) (EluSys Therapeutics); mini-CFH (Amyndas) Myrocept (APT070); sCR1 (CDX-1135) (Celldex); CRIg/CFH; anti-CR3, anti-MASP2, anti-C1s, and anti-C1n molecules: Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera);

receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini);

others: recombinant human MBL (rhMBL; Enzon Pharmaceuticals); imides and glutarimide derivatives such as thalidomide, lenalidomide, pomalidomide. Additional non-limiting examples that can be used in combination or alternation with an active compound or salt or composition as described herein include the following.

Non-limiting Examples of Potential Combination Therapy Medicines Name Target Company Molecule class LFG316 C5 N ovartis/Morphosy s monoclonal antibody 4(1MEW)APL-1, APL- 2 C3/C3b Apellis Family Compstatin 4(lMeW)POT-4 C3/C3b Potentia Family Compstatin Anti-C5 siRNA C5 Alnylam SiRNA Anti-FB siRNA CFB Alnylam SiRNA ARC 1005 C5 Novo Nordisk Aptamers

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ΑΤΑ C5 N.A. Chemical compound Coversin C5 Volution Immuno- Pharmaceuticals Small animal protein CP40/AMY-101,PEG- Cp40 C3/C3b Amyndas Family Compstatin CRIg/CFH CAP C3 convertase NA CFH protein Cynryze Cln/Cls ViroPharma/Baxter Purified human protein FCFD4514S CFD Genentech/Roche monoclonal antibody H17 C3 (C3b/iC3b) EluSys Therapeutics monoclonal antibody mini CFH CAP C3 convertase Amyndas CFH protein Myrocept (APT070) CAP and SSR NW NA Protein CR1 Mubodina C5 Adienne monoclonal antibody RA101348 C5 Rapharma small molecule sCRl (CDX-1135) CAP and SR C3 celldex CR1 protein SOBI002 C5 Swedish Orphan Biovitrum Affitelo 8OMAmeasures C5 SomaLogic Aptamers ZOMAmeasures CFBs and CFDs SomaLogic Aptamers (SELEX) TAI 06 CFB Alexion Pharmaceuticals monoclonal antibody TNT003 Cis true north monoclonal antibody TT30 (CR2/CFH) CAP C3 convertase Alexion CFH protein

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TT32 (CR2/CR1) CAP and SSR NW Alexion Pharmaceuticals Protein CR1 Nafamostat (FUT-175, Futhan) Cis, CFD, other proteases Torri Pharmaceuticals small molecule OMS721 MASP-2 Omeros monoclonal antibody OMS906 MASP-2 Omeros monoclonal antibody Bikaciomab, NM9308 CFB Novelmed monoclonal antibody NM9401 properdin Novelmed monoclonal antibody CVF, HC-1496 C3 code Recombinant peptide ALXN1102/ALXN1103 (TT30) C3-conv, C3b Alexion Pharmaceuticals Regulator rFH C3-conv, C3b Optherion Regulator 5C6, AMY-301 CFH Amyndas Regulator Erdigna C5 Adienne Pharma Antibody A.R.C. 1905 C5 Optotech monoclonal antibody MEDI7814 C5/C5a Medlmmune monoclonal antibody NOX-D19 C5a Noxxon Aptamer (Spiegelmer) IFX-1, CaCP29 C5a InflaRx monoclonal antibody PMX53, PMX205 C5aR Cephalon, Teva Peptidomimetic CCX168 C5aR ChemoCentryx small molecule ADC-1004 C5aR Alligator Bioscience small molecule

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Anti-C5aK-151, NN8209; Anti-S5aK215, NN8210 C5aR Novo Nordisk monoclonal antibody Imprime PGG CR3 Biothera Soluble betaglucan ANX005; ANX007 Clq Annexion monoclonal antibody Lampalizumab fD Roche monoclonal antibody avacincaptad pegol C5 Optotech Aptamer regenemab C6 regeneration monoclonal antibody BIW020 Cis Bioverative monoclonal antibody PRO-02 C2 Broteio/Argen-x monoclonal antibody 5С6, compsorbin fH Amyndas Peptide SOBI005 C5 sobi Protein ISU305 C5 ISU ABXIS monoclonal antibody Mubodina C5 Adienne monoclonal antibody IFX-2, IFX-3 C5a InflaRx monoclonal antibody ALS-205 C5aRl Alsonex Peptide DF2593A C5aRl Dompe small molecule IPH5401 C5aRl Innate Pharma monoclonal antibody C6-LNA C6 regeneration Oligonucleotide SKY59 C5 Roche monoclonal antibody REGN3918 C5 Regeneron monoclonal antibody Aptamers to Factor D fD Vitrisa Therapeutics Aptamer CLG561 properdin Novartis monoclonal antibody Tesidolumab; LFG316 C5 Novartis and MorphoSys monoclonal antibody

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in conjunction with a compound that inhibits an enzyme that metabolizes an administered protease inhibitor. In one embodiment, the compound or salt may be co-administered with ritonavir.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with a C5 complement inhibitor or C5 convertase inhibitor. In another embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with eculizumab, a monoclonal antibody directed to complement factor C5 and manufactured and sold by Alexion Pharmaceuticals under the brand name Soliris. Eculizumab has been approved by the U.S. FDA for the treatment of PNH and aHUS. In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in conjunction with a compound that inhibits Complement Factor D.

In one embodiment of the invention, an active compound, or a salt thereof, or a composition as described herein, as described herein, may be used in combination or alternation with a compound described in US Patent No. 6,653,340, Biocryst Pharmaceuticals, entitled Compounds useful in the complement, coagulate and kallikrein pathways and method for their preparation, which describes fused bicyclic ring compounds that are potential factor D inhibitors; Novartis PCT, Patent Publication WO2012/093101, os

- 223 041794 chapter Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration describing certain inhibitors of factor D; NOVARTIS, PCT patent publications WO2013/164802, Wo2013/192345, Wo2014/002051, Wo2014/002052, Wo2014/002053, Wo2014/002054, Wo2014/002057, Wo2014/002059, Wo2014/2014/2014/2014/2014, Wo2014/2014/2014/2014/20 /143638, WO2015/009616, WO2015/009977, WO2015/066241, Bristol-Myers Squibb PCT, patent publication WO2004/045518 entitled Open chain prolyl urea-related modulators of androgen receptor function; Japan Tobacco Inc., PCT Patent Publication WO1999/048492 entitled Amide derivatives and nociceptin antagonists; Ferring B.V. and Yamanouchi Pharmaceutical Co. LTD., PCT Patent Publication WO1993/020099 entitled CCK and/or gastrin receptor ligands; Alexion Pharmaceuticals, PCT Patent Publication WO1995/029697 entitled Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases; or Achillion Pharmaceuticals, PCT Patent Application No. PCT/US2015/017523 and US Patent Application No. 14/631,090 entitled Alkyne Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017538 and US Patent Application No. 14/631,233 entitled Amide Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017554 and US Patent Application No. 14/631,312 entitled Amino Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017583 and US Patent Application No. 14/631,440 entitled Carbamate, Ester, and Ketone Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017593 and US Patent Application No. 14/631,625 entitled Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017597 and US Patent Application No. 14/631,683 entitled Ether Compounds for Treatment of Complement Mediated Disorders; PCT Patent Application No. PCT/US2015/017600 and US Patent Application No. 14/631,785 entitled Phosphonate Compounds for Treatment of Complement Mediated Disorders; and PCT Patent Application No. PCT/US2015/017609 and US Patent Application No. 14/631,828 entitled Compounds for Treatment of Complement Mediated Disorders.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, is administered in combination with an anti-inflammatory drug, antimicrobial agent, antiangiogenic agent, immunosuppressant, antibody, steroid, ophthalmic antihypertensive drug, or combinations thereof. Examples of such agents include amikacin, anecortane acetate, anthracenedione, anthracycline, azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clotrimazole, cephalosporin, corticosteroids, dexamethasone, econazole, ceftazidime, epipodophyllotoxin, fluconazole-cytoxin, , fluoroquinolones, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone, prednisolone acetate, pegaptanibmycin, platinum analogs, poly propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, anti-vascular endothelial growth factor (VEGF) agents, anti-VEGF antibodies, anti-VEGF antibody fragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonide in, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamicin, tobramycin, cefazolin, voriconazole, ganciclovir, cidofovir, foscarnet, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluorometholone, rimexolone, anecortava, cyclosporine, methotrexate, molecules -PDGFR, as well as their combinations.

In one embodiment of the present invention, the active compound, or a salt or composition thereof, as described herein, can be administered in combination or alternately with at least one immunosuppressive agent. Non-limiting examples of an immunosuppressant may be a calcineurin inhibitor such as cyclosporine or ascomycin such as Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor such as rapamycin or a derivative thereof such as sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalogue eg ridaforolimus, azathioprine, campate 1H, S1P receptor modulator eg fingolimod or analogue, anti-IL-8 antibody, mycophenolic acid or salt thereof e.g. sodium salt or its prodrug e.g. Mycophenolate mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, Thymoglobulin®, Brekinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualine, tresperimus, leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT®), daclizumab (ZENAPAX®), mizorbin, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel® ), CTLA4lg (abatacept), belatacept, LFA3lg, et anercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), anti-LFA-1 antibody, natalizumab (Antegren®), enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, alefacept, efalizumab, pentase, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, tocilizumab (Actemra), siltuximab (Sylvant), secuquibumab (Cosentyx), ustekinumab (Stelara), risankizumab, sifali

- 224 041794 mumab, aspirin and ibuprofen. Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluorometholone acetate, fluorometholone alcohol, loteprednol etabonate, medrisone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, aspirin, suprofene, ibuprofen , piroxicam, meloxicam, flubiprofen, naproxen, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac and any combination thereof. In one embodiment, the active compound or salt or composition thereof as described herein is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril) , oxaprozin (Daypro), salsalate (Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol ), naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren) and combinations thereof.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, is administered in combination or alternating with an omega-3 fatty acid or a peroxisome proliferator-activated receptor (PPAR) agonist. Omega-3 fatty acids are known to reduce serum triglyceride levels by inhibiting DGAT and stimulating peroxisomal and mitochondrial beta-oxidation. Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have high affinity for both PPARalpha and PPARgamma. Seafood oils, such as fish oil, are a good source of EPA and DHA, which have been shown to regulate lipid metabolism. Omega-3 fatty acids have been found to have a beneficial effect on risk factors for cardiovascular disease, especially mild hypertension, hypertriglyceridemia, and on the activity of the coagulation factor VII phospholipid complex. Omega-3 fatty acids reduce serum triglyceride levels, increase serum HDL-cholesterol levels, lower systolic and diastolic blood pressure and pulse rate, and reduce the activity of blood coagulation factor VII - the phospholipid complex. In addition, omega-3 fatty acids appear to be well tolerated without causing any major side effects. One such form of omega-3 fatty acids is a concentrate of omega-3, long-chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and sold under the brand name Omacor®. This form of omega3 fatty acid is described, for example, in US Pat. Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear ligand-activated transcription factor receptors that are associated with retinoid, steroid, and thyroid thyroid hormone receptors. There are three different PPAR subtypes that are products of different genes and are commonly referred to as PPAR alpha, PPAR beta/delta (or simply delta), and PPAR gamma. General classes of pharmacological agents that stimulate peroxisomal activity are known as PPAR agonists, for example, PPAR alpha agonists, PPAR gamma agonists, and PPAR delta agonists. Some pharmacological agents are combinations of PPAR agonists such as alpha/gamma agonists, etc., and some other pharmacological agents have dual agonist/antagonist activity. Fibrates such as fenofibrate, bezafibrate, clofibrate, and gemfibrozil are PPAR-alpha agonists and are used in patients to reduce triglyceride-rich lipoproteins, to increase HDL levels, and to decrease atherogenic LDL density. Fibrates are usually administered orally to such patients. Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, has been known for many years as a medical agent for its effectiveness in lowering blood triglycerides and cholesterol levels.

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); bevacizumab (Avastin; Genentech/Roche); lapatinib (Tykerb); sunitinib (Sutent); axitinib (Inlyta); pazopanib; sorafenib (Nexavar); ponatinib (Inclusig); regorafenib (Stivarga); cabozantinib (Abometyx; Cometriq); vandetanib (Caprelsa); ramucirumab (Cyramza); lenvatinib (Lenvima); civ-aflibercept (Zaltrap); cediranib (Recentin); anecortan acetate, squalamine lactate, and corticosteroids, including but not limited to triamcinolone acetonide.

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein in

- 225 041794 in combination with a complement C5 inhibitor, for example, a complement C5 inhibitor described here and in the table above entitled Non-limiting examples of potential therapeutic agents for combination therapy, including, but not limited to, eculizumab; LFG316 (Novartis/Morphosys); Anti-C5 siRNA (Alnylam); ARC1005 (Novo Nordisk); coversin (Volution ImmunoPharmaceuticals); Mubodin (Adienne Pharma); RA101348 (Ra Pharma); SOBI002 (Swedish Orphan Biovitrum); SOMAmers (SomaLogic); Erdigna (Adienne Pharma); ARC1905 (Opthotech); MEDI7814 (MedImmune); NOX-D19 (Noxxon); IFX-1, CaCP29 (InflaRx); PMX53, PMX205 (Cephalon, Teva); CCX168 (ChemoCentryx); ADC-1004 (Alligator Bioscience); and anti-C5aR-151, NN8209; Anti-C5aR-215, NN8210 (Novo Nordisk).

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein, in combination with an anti-properdin agent, for example, an anti-properdin agent as described above, including but not limited to NM9401 (Novelmed).

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of the active compound, or a salt or composition thereof, as described herein, in combination with a complement C3 inhibitor, e.g. , the complement C3 inhibitor described above, including but not limited to compstatin or compstatin analogs, eg compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-l,APL-2 (Appelis); CP40/AMY-101, PEGCp40 (Amyndas) molecules targeting complement C3 or CAP C3 convertase: TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Opthenon); H17 C3 (C3b/iC3b) (EluSys Therapeutics); mini-CFH (Amyndas), mirocept (APT070); sCR1 (CDX-1135) (Celldex); and CRIg/CFH.

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination with an anti-factor B agent. H or an anti-factor selected from Anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche), SOMAmers for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6 and AMY-301 (Amyndas). In one embodiment, the present invention relates to a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or salt or composition thereof, as described herein, in combination with an anti-MASP2, anti -C1s or anti-CR3 molecules such as but not limited to Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

In one embodiment, the present invention relates to a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination with a PDGF inhibitor, for example, as described herein, including but not limited to Sorafenib Tosylate; Imatinib Mesilate (STI571); Sunitinib Malate; Ponatinib (AP24534); axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258), Lactyl lactic acid; MK-2461; Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate; Sennoside B; sunitinib; AZD2932; and Trapidil.

In one embodiment, the present invention relates to a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound, or a salt thereof, or a composition as described herein, with an additional inhibitor of the complement system or other active compounds with different biological mechanisms of action. In another embodiment, the present invention relates to a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of the active compound, or a salt or composition thereof, as described herein, in combination or alternating with eculizumab. In another embodiment, the present invention relates to a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of an active compound, or a salt or composition thereof, as described herein, in combination or in alternation with CP40. In one embodiment, the additional agent is pegylated CP40. CP40 is a peptide inhibitor that shows strong affinity for C3b and inhibits hemolysis of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes. In one embodiment, the additional agent is a complement component inhibitor such as, but not limited to, Compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix);

- 226 041794

4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101, PEG-Cp40 (Amyndas); a PDGF inhibitor such as but not limited to Sorafenib Tosylate; Imatinib Mesilate (STI571); Sunitinib Malate; Ponatinib (AP24534); axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); TSU-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) Lactyl lactic acid; MK-2461; Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate; Sennoside B; sunitinib; AZD2932; and Trapidil; an anti-factor H or anti-factor B agent, eg anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche), SOMA Merc for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas); a molecule targeting complement C3 or CAP C3 convertase, such as but not limited to TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode), ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Opthenon); H17 C3 (C3b/iC3b) (EluSys Therapeutics); Mim-CFH (Amyndas) Myrocept (APT070); sCR1 (CDX-1135) (Celldex); CRIg/CFH, an anti-CR3, anti-MASP2, anti-C1s, or anti-C1n molecule, such as, but not limited to, Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

In one embodiment, the present invention relates to a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition containing an active compound, or a salt thereof, or a composition as described herein, in combination or alternating with additional a complement system inhibitor, or an active agent that functions through a different mechanism of action. In another embodiment, the present invention relates to a method of treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of the active compound, or a salt or composition thereof, as described herein, in combination or alternating with methotrexate. In some embodiments, the active compound, or a salt thereof, or a composition as described herein, is administered in combination or in alternation with at least one additional therapeutic agent selected from: salicylates, including aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalat (Mono-Gesic, Salgesic); non-steroidal anti-inflammatory drugs (NSAIDs); non-selective inhibitors of cyclooxygenase enzymes (COX-1 and COX-2), including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine) , indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective cyclooxygenase-2 (COX2) inhibitors, including celecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex), penicillamine (Cuprimine) and sulfasalazine (Azulfidine); biologics, including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroids, including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), and triamcinolone (Aristocort); gold salts, including auranofin (Ridaura); Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combination of them.

In one embodiment, the present invention relates to a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of the active compound, or a salt or composition thereof, as described herein, in combination or in alternation with an additional complement system inhibitor, or an active agent that functions through a different mechanism of action. In another embodiment, the present invention relates to a method of treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of the active compound, or a salt or composition thereof, as described herein, in combination or alternating with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone. In one embodiment, the active compound or salt or composition thereof as described herein is combined with at least one multiple sclerosis drug, for example selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a ), Betaseron (interferon beta-1b), Sorahope (glatiramer acetate), extavia (interferon beta-1b), gilenia (fingolimod), lemtrada (alemtuzumab), novantrone (mitoxantrone), plegridy (peginterferon beta-1a), rebif (interferon beta-1a), Tecfidera (dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol (methylprednisolone), high dose oral deltazone (prednisone), H.P. Acthar Gel (ACTH), or combinations thereof.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, is useful in combination with another pharmaceutical agent to improve or reduce the side effects of the agent. For example, in one embodiment, an active compound, or a salt or composition thereof, as described herein, may be used in a combination

- 227 041794 nations with adaptive cell transfer therapy to reduce the associated inflammatory response associated with such therapies, for example, a cytokine-mediated response such as cytokine release syndrome. In one embodiment, adaptive cell transfer therapy comprises the use of chimeric antigen receptor T cells (CAR T). In one embodiment, adaptive cell transfer therapy comprises the use of a chimeric antigen receptor (CAR T) cell or dendritic cell to treat a hematologic or solid tumor, such as a B cell-associated hematologic cancer. In one embodiment, the hematologic or solid tumor is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreatic cancer, glioblastoma, or a tumor that expresses CD19.

In a further alternative embodiment, an active compound or salt or composition thereof as described herein may be provided in combination with eculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA vasculitis, AMD, CAD, C3 glomerulopathy, for example, DDD or C3GN, chronic hemolysis, optic neuromyelitis, or transplant rejection. In one embodiment, an active compound or salt or composition thereof as described herein may be provided in combination with compstatin or compstatin derivatives for the treatment of PNH, aHUSs, STEC-HUS, ANCA vasculitis, AMD, CAD, C3 glomerulopathy, for example, DDD or C3GN, chronic hemolysis, optic neuromyelitis, or transplant rejection. In one embodiment, the additional agent is a complement component inhibitor such as, but not limited to, compstatin/POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix); 4(1MEW)APL-1,APL-2 (Appelis); CP40/AMY-101,PEG-Cp40 (Amyndas); a PDGF inhibitor such as but not limited to Sorafenib Tosylate; Imatinib Mesilate (STI571); Sunitinib Malate; Ponatinib (AP24534); axitinib; Imatinib (STI571); Nintedanib (BIBF 1120); Pazopanib HCl (GW786034 HCl); Dovitinib (TKI-258, CHIR-258); Linifanib (ABT-869); Crenolanib (CP-868596); Masitinib (AB1010); Tivozanib (AV-951); Motesanib Diphosphate (AMG-706); Amuvatinib (MP-470); tSu-68 (SU6668, Orantinib); CP-673451; Ki8751; Telatinib; PP121; Pazopanib; KRN 633; Dovitinib (TKI-258) lactyl lactic acid; MK-2461; Tyrphostin (AG 1296); Dovitinib (TKI258) Lactate; Sennoside B; sunitinib; AZD2932; and Trapidil; an anti-factor H or anti-factor B agent, eg anti-FB siRNA (Alnylam); FCFD4514S (Genentech/Roche) SOMA measures for CFB and CFD (SomaLogic); TA106 (Alexion Pharmaceuticals); 5C6, and AMY-301 (Amyndas); a molecule targeting complement C3 or CAP C3 convertase, such as but not limited to TT30 (CR2/CFH) (Alexion); TT32 (CR2/CR1) (Alexion Pharmaceuticals); Nafamostat (FUT-175, Futhan) (Torri Pharmaceuticals); Bikaciomab, NM9308 (Novelmed); CVF, HC-1496 (InCode) ALXN1102/ALXN1103 (TT30) (Alexion Pharmaceuticals); rFH (Opthenon); H17 C3 (C3b/iC3b) (EluSys Therapeutics); mini-CFH (Amyndas) Myrocept (APT070); sCR1 (CDX-1135) (Celldex); CRIg/CFH, anti-CR3, anti-MASP2, anti-ds, or anti-C1n molecules such as, but not limited to, Cynryze (ViroPharma/Baxter); TNT003 (True North); OMS721 (Omeros); OMS906 (Omeros); and Imprime PGG (Biothera).

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with Rituxan for the treatment of a complement-mediated disorder. In one embodiment, the complement mediated disorder is, for example, rheumatoid arthritis, granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis), and microscopic polyangiitis (MPA). In one embodiment, the disorder is lupus.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with cyclophosphamide for the treatment of a complement-mediated disorder. In one embodiment, the disorder is an autoimmune disease. In one embodiment, the complement mediated disorder is, for example, rheumatoid arthritis, granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis), and microscopic polyangiitis (MPA). In one embodiment, the disorder is lupus.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, is dosed in combination with conventional DLE treatment to treat lupus in a subject in need thereof.

Examples of conventional treatments for DLE include topical corticosteroid ointments or creams such as triamcinolone acetonide, fluocinolone, flurandrenolide, betamethasone valerate, or betamethasone dipropionate. Resistant plaques can be injected with an intradermal corticosteroid. Other possible treatments for DLE include calcineurin inhibitors such as pimecrolimus cream or tacrolimus ointment. Particularly persistent cases can be treated with systemic antimalarial drugs such as hydroxychloroquine (PLAQUENIL).

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with methotrexate for the treatment of lupus.

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In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with azathioprine for the treatment of lupus.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with a non-steroidal anti-inflammatory drug for the treatment of lupus.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with a corticosteroid for the treatment of lupus.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with belimumab (Benlysta) for the treatment of lupus.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with hydroxychloroquine (Plaquenil) for the treatment of lupus.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with sifalimumab for the treatment of lupus.

In one embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with OMS721 (Omeros) for the treatment of a complement-mediated disorder. In one embodiment, an active compound, or salt or composition thereof, as described herein, may be provided in combination with OMS906 (Omeros) for the treatment of a complement-mediated disorder. In one embodiment, the complement mediated disorder is, for example, thrombotic thrombocytopenic purpura (TTP) or aHUS.

In one embodiment, an active compound, or a salt thereof, or a composition as described herein, may be provided in combination with an anti-inflammatory agent, immunosuppressive agent, or anti-cytokine agent to treat or prevent cytokine or inflammatory responses in response to administration of pharmaceuticals. or biotherapeutic agents (eg adaptive T cell therapy (ACT) such as CAR T cell therapy or monoclonal antibody therapy). In one embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with a corticosteroid, e.g. IL-10, IL-11, IL-13 and TGFe.

In one embodiment, the active compound, or a salt or composition thereof, as described herein, may be provided in combination with a cytokine inhibitor, including, but not limited to, adalimumab, infliximab, etanercept, protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab, ustekinumab, golimumab and tocilizumab, or combinations thereof. Additional anti-inflammatory agents that can be used in combination with the active compound, or a salt thereof, or composition as described herein include, but are not limited to, non-steroidal anti-inflammatory drug(s) (NSAID); cytokine-suppressing anti-inflammatory drug(s) (CSAID); CDP-571/BAY-10-3356 (humanized anti-TNFa antibody; Celltech/Bayer); cA2/infliximab (chimeric anti-TNFa antibody; Centocor); 75 kdTNFR-IgG/etanercept (75 kD TNF-IgG receptor fusion protein; Immunex); 55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche); IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody; IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins; Seragen); Anti-Tac (humanized anti-IL-2Rα; Protein Design Labs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering); IL-4 agonists; IL-10 and/or IL-4 (eg, agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra (Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein); R973401 (phosphodiesterase type IV inhibitor); MK-966 (COX-2 inhibitor); Iloprost, leflunomide (anti-inflammatory and cytokine inhibition); tranexamic acid (an inhibitor of plasminogen activation); T-614 (cytokine inhibitor); prostaglandin E1; Tenidap (non-steroidal anti-inflammatory drug); Naproxen (non-steroidal anti-inflammatory drug); Meloxicam (non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidal anti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatory drug); Diclofenac (non-steroidal anti-inflammatory drug); Indomethacin (non-steroidal anti-inflammatory drug); sulfasalazine; azathioprine; ICE inhibitor (interleukin-1b converting enzyme inhibitor); zap-70 and/or lck inhibitor (zap-70 or lck tyrosine kinase inhibitor); TNF convertase inhibitors; anti-Gk-12 antibodies; anti-IL-18 antibodies; interleukin-11 inhibitors; interleukin-13; interleukin-17; gold; penicillamine; chloroquine; chlorambucil; hydroxychloroquine; cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4 antibodies; CD5 toxins; orally administered peptides and collagen; lobenzarite disodium; cytokine regulators (CRAB) HP228 and HP466 (Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioate oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone; orgotein; glycosaminoglycan polysulfate; minocycline; anti-IL2R antibodies; marine and vegetable lipids (fatty acids of marine animals and plants); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid; immune globulin for intravenous administration; zileuton; mycophenolic acid (RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose (terafectin); cladribine (2-chlorodeoxyadenosine).

In a particular embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with a corticosteroid to treat or prevent cytokine or inflammatory responses in response to administration of pharmaceuticals or biotherapeutic agents. In another embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with etarnecept for the treatment or prevention of cytokine or inflammatory reactions in response to administration of pharmaceuticals or biotherapeutic agents. In another embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with tocilizumab for the treatment or prevention of cytokine or inflammatory reactions in response to administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with etarnecept and tocilizumab to treat or prevent cytokine or inflammatory responses in response to administration of pharmaceuticals or biotherapeutic agents. In another embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with infliximab for the treatment or prevention of cytokine or inflammatory responses in response to administration of pharmaceuticals or biotherapeutics. In another embodiment, an active compound, or a salt or composition thereof, as described herein, may be provided in combination with golimumab to treat or prevent cytokine or inflammatory responses in response to administration of pharmaceuticals or biotherapeutics.

Combinations for prophylactic or concomitant antibiotic therapy

In one aspect, the present invention provides a method of treating a patient in need thereof, which comprises administering an effective amount of a prophylactic antibiotic vaccine prior to administering the active compound, salt or composition thereof for any of the disorders described herein. In another aspect, the present invention provides a method of treating a patient in need thereof, which comprises administering an effective amount of a prophylactic antibacterial drug, such as a pharmaceutical drug, prior to administering the active compound or salt thereof, or a composition for any of the disorders described herein. In one aspect, the present invention provides a method of treating a patient in need thereof, which comprises administering an effective amount of an antibacterial vaccine following administration of the active compound, or salt thereof, or composition for any of the disorders described herein. In another aspect, the present invention provides a method of treating a patient in need thereof, which comprises administering an effective amount of an antibacterial drug, such as a pharmaceutical drug, following administration of the active compound, or salt thereof, or composition for any of the disorders described herein. In one embodiment, the disorder is PNH, C3G, or aHUS. In one embodiment, the patient has received an organ or other tissue or biological fluid for transplantation. In one embodiment, the patient is also administered eculizumab.

In one aspect of the present invention, an active compound, or a salt or composition thereof, as described herein, is administered to a patient concurrently with a subject following prophylactic administration of a vaccine against a bacterial infection. In one embodiment, the complement mediated disorder is PNH, C3G, or aHUS. In one embodiment, the subject has received an organ or other tissue or body fluid transplant. In one embodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound, or a salt or composition thereof, as described herein, is administered to a subject concurrently with prophylactic administration of a vaccine against a bacterial infection. In one embodiment, the complement mediated disorder is PNH, C3G, or aHUS. In one embodiment, the subject has received an organ or other tissue or body fluid transplant. In one embodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound, or a salt or composition thereof, as described herein, is administered to a subject, and during the period of administration of the compound or salt, the subject is vaccinated against a bacterial infection. In one embodiment, a disorder mediated

- 230 041794 complement is PNH, C3G or aHUS. In one embodiment, the subject has received an organ or other tissue or body fluid transplant. In one embodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound, or a salt or composition thereof, as described herein, is administered to a subject in combination with an antibiotic compound during administration of a factor D inhibitor. In one embodiment, the complement mediated disorder is PNH, C3G, or aHUS . In one embodiment, the subject has received an organ or other tissue or body fluid transplant. In one embodiment, the subject is also administered eculizumab.

In one aspect of the present invention, an active compound, or a salt or composition thereof, as described herein, is administered to a subject following prophylactic administration of a vaccine against a bacterial infection and in combination with an antibiotic compound during administration of a factor D inhibitor. In one embodiment, the disease mediated complement is PNH or aHUS. In one embodiment, the subject has received an organ or other tissue or body fluid transplant. In one embodiment, the subject is also administered eculizumab. In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium Neisseria meningitidis before receiving the active compound, or a salt thereof, or composition as described herein. In one embodiment, the subject is given a vaccine against a bacterial infection caused by the bacterium Haemophilus influenzae. In one embodiment, the Haemophilus influenzae is Haemophilus influenzae serotype B (Hib). In one embodiment, the subject is given a vaccine against a bacterial infection caused by Streptococcus pneumoniae. In one embodiment of the present invention, the subject is given a vaccine against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae. In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae.

In other embodiments, the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-negative bacterium. In one embodiment, the subject is vaccinated against a bacterial infection caused by a bacterium selected from a Gram-positive bacterium. In one embodiment, the subject is vaccinated against a bacterial infection caused by the bacterium Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneunemoniae, or a combination of one or more of Nisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae and one or more of, but not limited to, Bacillus anthracis , Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheria, Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibrio cholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichia chaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacterium leprae, Borrelia Borrelia, Borrelia burgonii garinii, Mycobacterium bovis, Staphylococcus aureus, Streptococcus pyogenes, Treponema pallidum, Francisella tularensis, Yersinia pestis.

In one embodiment, the subject is vaccinated with one or more vaccines selected from, but not limited to, typhoid vaccine, live (Vivotif Berna Vaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi), pneumococcal 23 polyvalent vaccine, PCV13 (Pneumovax 23, Merck), pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal 13-valent vaccine, PCV13 (Prevnar 13, Pfizer), haemophilus influenzae type b conjugate vaccine (prp-t) (ActHIB, Sanofi; Hibrix, GSK), hemophilic type b conjugate vaccine (hboc) (HibTITER, Neuron Biotech), hemophilic type b conjugate vaccine (prp-omp) (PedvaxHIB, Merck), hemophilic type b conjugate vaccine (prp-1)/meningococcal conjugate vaccine (MenHibrix, GSK), haemophilus influenzae type b conjugate vaccine (prpt)/meningococcal conjugate vaccine/hepatitis B vaccine (Comvax, Merck), meningococcal polysaccharide vaccine (Menomune A/C/Y/W-135, Sanofi), meningococcal occa conjugate vaccine/diphtheria conjugate CRM197 (Menveo, GSK; Menactra, Sanofi), meningococcal group B vaccines (Bexsero, GSK; Trumenba, Pf), adsorbed anthrax vaccine (Biothrax, Emergent Biosolutions), tetanus toxoid (Te Anatoxal Berna, Hendricks Regional Health), Bacillus Calmette-Guérin, live, intravesical (TheraCys, Sanofi; Tice BCG, Organon), cholera vaccine, live, oral (Vachora, Sanofi; Dukoral, SBL Vaccines; ShanChol, Shantha Biotec; Micromedex, Truven Health), tetanus toxoids and diphtheria (Tdap; Decavac, Sanofi; Tenivac , Sanofi; td, Massachusetts Biological Labs), diphtheria and tetanus toxoids and pertussis (DTap; Daptacel, Sanofi; Infanrix, GSK; Tripedia, Sanofi), diphtheria and tetanus toxoids, pertussis/polio (Kinrix, GSK; Quadracel, Sanofi ), diphtheria and tetanus toxoids, pertussis/hepatitis B/polio (Pediarix, GSK), diphtheria and tetanus toxoids, whooping cough/polio, Haemophilus influenzae type b (Pentacel, Sanofi), and/or diphtheria and pertussis (Tdap; Boostrix, GSK; Adacel, Sano fi), or combinations thereof.

As described above, a subject receiving a compound of the present invention for treatment

- 231 041794 disorders, an antibiotic compound is prophylactically administered in addition to the factor D inhibitor described herein. In one embodiment, an antibiotic compound is administered to the subject at the time of administration of the active compound to reduce the development of a bacterial infection. The antibiotic compounds for co-administration with a factor D inhibitor described herein can be any antibiotic useful in preventing or reducing the effects of a bacterial infection. Antibiotics are well known in the art and include, but are not limited to, amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Heo-Fradin), netilmicin (Netromycin), tobramycin (Nebcin), paromomycin (Humatin) , streptomycin, spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan), loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax), imipenem/cilastatin (Primaxin), meropenem (Merrem), cefadroxil (Duricef), cefazolin (Ancef), cephalothin (Keflin), cephalexin (Keflex), cefaclor (Distaclor), cefamandol (Mandol), cefoxitin (Mefoxin), cefprozil (Cefzil), cefuroxime (Ceftin, Zinnat), cefixime (Cefspan), cefdinir (Omnicef, cefdiel), cefditoren (Spectracef, Meiact), cefoperazone (Cefobid), cefotaxime (Claforan), cefpodoxime (Vantin), ceftazidime (Fortaz), ceftibuten (Cedax), ceftizoxime (Cefizox), ceftriaxone (Rocephin), cefepime (Maxipime), ceftaroline fosamil (Teflaro), ceftobiprole (Zeftera), teicoplanin (Targocid), vancomycin (Vancocin), tel avancin (Vibativ), dalbavancin (Dalvance), oritavancin (Orbactiv), clindamycin (Cleocin), lincomycin (Lincocin), daptomycin (Cubicin), azithromycin (Zithromax, Sumamed, Xithrone), clarithromycin (Biaxin), dirithromycin (Dynabac), erythromycin (Erythocin, Erythroped), roxithromycin, troleandomycin (Tao), telithromycin (Ketek), spiramycin (Rovamycine), aztreonam (Azactam), furazolidone (Furoxone), nitrofurantoin (Macrodantin, Macrobid), linezolid (Zyvox), posizolid, radezolid, torezolid , amoxicillin (Novamox, Amoxil), ampicillin (Principen), azlocillin, carbenicillin (Geocillin), cloxacillin (Tegopen), dicloxacillin (Dynapen), flucloxacillin (Floxapen), mezlocillin (Mezlin), methicillin (Staphcillin), nafcillin (Unipen), oxacillin (Prostaphlin), penicillin G (Pentids), penicillin V (Veetids (Pen-Vee-K), piperacillin (Pipracil), penicillin G (Pfizerpen), temocillin (Negaban), ticarcillin (Ticar), amoxicillin/clavulanate (Augmentin) , ampicillin/sulbactam (Unasyn), piperacillin/tazobactam ( Zosyn), ticarcillin/clavulanate (Timentin), bacitracin, colistin (Coly-Mycin-S), polymyxin B, ciprofloxacin (Cipro, Ciproxin, Ciprobay), enoxacin (Penetrex), gatifloxacin (Tequin), gemifloxacin (Factive), levofloxacin ( Levaquin), Lomefloxacin (Maxaquin), Moxifloxacin (Avelox), Nalidixic Acid (NegGram), Norfloxacin (Noroxin), Ofloxacin (Floxin, Ocuflox), Trovafloxacin (Trovan), Grepafloxacin (Raxar), Sparfloxafine (Zagam), Temafloxacin (Omniflox) , mafenide (Sulfamylon), sulfacetamide (Sulamyd, Bleph-10), sulfadiazine (Micro-Sulfon), silver sulfadiazine (Silvadene), sulfadimethoxine (Di-Methox, Albon), sulfamethizole (Thiosulfil Forte), sulfamethoxazole (Gantanol), sulfanilamide, sulfasalazine (Azulfidine), sulfisoxazole (Gantrisin), trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim, Septra), sulfonamidochrysoidine (Prontosil), demeclocycline (Declomycin), doxycycline (Vibramycin), minocycline (Minocin), oxytetracycline (Terramycin), tetracycline (Sumycin, A chromycin V, Steclin), clofazimine ((Lamprene), dapsone (Avlosulfon), capreomycin (Capastat), cycloserine (Seromycin), ethambutol (Myambutol), ethionamide (Trecator), isoniazid (I.N.H.), pyrazinamide (Aldinamide), rifampicin (Rifadin , Rimactane), rifabutin (Mycobutin), rifapentin (Priftin), streptomycin, arsphenamine (Salvarsan), chloramphenicol (Chloromycetin), fosfomycin (Monurol, Monuril), fusidic acid (Fucidin), metronidazole (Flagyl), mupirocin (Bactroban), platen mycin , quinupristin/dalfopristin (Synercid), thiamphenicol, tigecycline (Tigacyl), tinidazole (Tindamax Fasigyn), trimethoprim (Proloprim, Trimpex), and/or teixobactin, or a combination thereof.

In one embodiment, the subject is administered a prophylactic antibiotic selected from a cephalosporin, e.g., ceftriaxone or cefotaxime, ampicillin-sulbactam, penicillin G, ampicillin, chloramphenicol, fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin, vancomycin, clindamycin, cetronemycin, meraziopefazolin, ceftaroline, tigecycline, clarithromycin, moxifloxacin, trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin, rifampin, minocycline, spiramycin and cefixime, or a combination of two or more of them.

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Process for preparing the compounds of the present invention

ACN Abbreviations Acetonitrile ace Acetyl ASGO AcOEt, EtOAc Acetic anhydride Ethyl acetate ASON Acetic acid WOSGO di-more/i-butyl dicarbonate In and Butyl CAN Cerium ammonium nitrate CBz Carboxybenzyl CDI Carbonyldiimidazole CH3OH, MeOH methanol CsF cesium fluoride Cui copper iodide DCM, CH2CI2 dichloromethane DIEA, DIPEA Ν,Ν-diisopropylethylamine DMA Ν,Ν-dimethylacetamide DMAP 4-Dimethylaminopyridine DMF Ν,Ν-dimethylformamide DMS dimethyl sulfide DMSO Dimethyl sulfoxide DPPA Diphenylphosphorylazide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EEDQ N-Ethoxy carbonyl-2-ethoxy-1,2-dihydroquinoline Et Ethyl Et _3N , TEA Triethylamine EtOAc ethyl acetate EtOH ethanol

HATU 1 - [Bis (dimethylamino) methyl it] -1 Η-1,2,3 -triazolo [4,5 -b] pyridinium-3 hexafluorophosphate oxide HC1 Hydrochloric acid NOVT Hydroxybenzotriazole iBu, z-Bu, isoBu Isobutyl iPr, z-Pr, isoPr *Pr ₂ NEt Isopropyl Ν,Ν-diisopropylethylamine K2CO3 Potassium carbonate

- 233 041794

LiOH lithium hydroxide Me Methyl Mel methyl iodide Ms Mezil MsCl Mesyl chloride MTBE Methyl ''butyl ether _{Na2SO4 _} Sodium sulfate NaCl Sodium chloride NaH sodium hydride _NaHCO3 Bicarbonate of soda NBS N-bromosuccinimide NCS N-chlorosuccinimide NET ₃ Trimethylamine NMP M-methyl-2-pyrrolidone PCC Pyridinium chlorochromate Pd (OAc) ₂ Pd(dppf)Cl ₂ Pd(PPh ₃ ) ₂ Cl ₂ Pd(PPh ₃ ) ₄ Pd/C Palladium acetate [1,G-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) Bis(triphenylphosphine)palladium(II) dichloride Tetrakis(triphenylphosphine)palladium (0) Palladium on charcoal Pd ₂ (dba) ₃ Tris(dibenzylideneacetone)dipalladium (0) PMB 4-Methoxybenzyl ether PPh ₃ Triphenylphosphine Pr Propil Ru, py RT pyridine Room temperature T3P Propane-phosphonic acid anhydride TBAF Tetra-n-butylammonium fluoride TBAT Tetrabutylammonium difluorotriphenyl silicate tBu, f-Bu tBuOK trash butyl tert-Butoxy d potassium TEA Trimethylamine _Tf2O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF T tetrahydrofuran TMS Trimethylsilane TMSBr Bromotrimethylsilane & retention time Troc 2,2,2-Trichloroethoxycarbonyl chloride Zn(CN) ₂ zinc cyanide General Methods

All non-aqueous reactions were carried out under dry argon or nitrogen gas using anhydrous solvents. The progress of the reactions and the purity of the target compounds were determined using one of the two liquid chromatography (LC) methods listed below. The structure of starting materials, intermediates and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry.

Method A LC.

Device: Waters Acquity Ultra Performance LC.

Column: ACQUITY UPLC BEH C18 2.1 x 50 mm, 1.7 µm.

Column temperature: 40°C.

- 234 041794

Mobile phase: solvent A: H2O + 0.05% FA; solvent B: CH3CN + 0.05% FA.

Flow rate: 0.8 ml/min.

Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then 0.5 min α 85% B.

Detection: UV (PDA), ELS and MS (SQ in electron ionization (EI) mode).

Method B LC.

Instrument: Shimadzu LC-2010A HT.

Column: Athena, C18-WP, 50 x 4.6 mm, 5 µm.

Column temperature: 40°C.

Mobile phase: solvent A: H ₂ O/CH ₃ OH/FA=90/10/0.1; solvent B:

H ₂ O / CH ₃ OH / FA \u003d 10/90 / 0.1.

Flow rate: 3 ml/min.

Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min α 100% B.

Detection: UV (220/254 nm).

Method C LC.

Instrument: Agilent 1100/1200 Series LC system with DAD detector.

Column: Atlantis dC18 (250 x 4.6) mm, 5 µm.

Column temperature: ambient temperature.

Mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile.

Flow rate: 1.0 ml/min.

Gradient: _________________ __________________

time (min) 0.0 15 20 23 thirty %IN 10 100 100 10 10

Detection: (210-400 nm).

Method D LC.

Instrument: Shimadzu LC 20AD system with PDA detector.

Column: Phenomenex Gemini NX C18 (150 x 4.6) mm, 5 µm.

Column temperature: ambient temperature.

Mobile phase A: 10 mM NH4OAC in water, mobile phase B: acetonitrile.

Flow rate: 1.0 ml/min.

Gradient:

time (min) 0.0 15 20 23 thirty %IN 10 100 100 10 10

Detection: (210-400 nm).

Example 1. General synthesis route.

The compound of the present invention can be obtained, for example, from the central core. In one embodiment, for example, Core structure 1 is an N protected amino acid, where X ¹ is nitrogen and PG = a protecting group. In one embodiment, the central core is linked to an amine to form an amide of structure 2 (where LB includes a C(O)N moiety). Structure 2 can then be deprotected to form structure 3. Structure 3 binds to structure 4 (A-COOH) to form a second amide bond, forming a compound of formula I. The mechanism of the chemical reaction is illustrated using route 1 as an example.

He

PG

Activation fCO ₂ H amine

About ¹ A

L l .v removal

PG binding

PG

STRUCTURE 1 STRUCTURE 2 _Q 1-Q\ A-COOH _Q 1-Q\

I (STRUCTURE 4) I

STRUCTURE h

Formula I

Path 1.

In an alternative embodiment, structure 5 of the central core reacts with a heterocyclic or heteroaryl compound to form a compound of structure 6. In one embodiment, structure 6 is deprotected to form a carboxylic acid, structure 7. In one embodiment, structure 7 is coupled to an amine to form compounds of formula I. This chemical reaction mechanism is illustrated using route 2 as an example.

- 235 041794

Structure ₆

Structure 5

Structure 7

Formula |

Path 2.

In an alternative embodiment, structure 8 is deprotected to form an amine, which is structure 9. Structure 9 is then coupled to form an amide, which is structure 6. Structure 6 is then deprotected to form a carboxylic acid, which is structure 7. Structure 7 then binds to form an amide, which corresponds to formula I. The mechanism of the chemical reaction is illustrated by the example of route 3.

OPG ^Q 4'

removal

I o pg ₂ pg ₂

O

A-COOH (structure 4) binding

Structure 9

Structure 8

Structure 6 Structure 7 Formula

Path 3.

In an alternative embodiment, the 4-1 heteroaryl or aryl moiety binds to the central core to form 4-2. Protected acid 4-2 is deprotected to form carboxylic acid 4-3. The carboxylic acid then binds to form an amide (LB) which is 4-4. The heteroaryl or aryl moiety A' can then be further derivatized to add substituents at positions X ¹¹ , X ¹² , X ¹³ and X ¹⁴ to give compounds of formula I. The mechanism of the chemical reaction is illustrated using route 4 as an example.

binding

OPG_________

OPG

PG removal

amine about

binding activation CO ₂ H

V

A'

4-4 binding

V

Path 4

In an alternative embodiment, Structure 5-1 is coupled to an acid, Structure 5-2, to form Structure 5-3. The carboxylic acid, Structure 5-3, is deprotected to form the carboxylic acid, which is Structure 5-4. The carboxylic acid of Structure 5-4 is coupled to an amine to form an amide product (L-B) which is a compound of Formula I. The mechanism of the chemical reaction is illustrated using route 5 as an example.

- 236 041794

Q ¹ ^ ^Q \ °'-/ Ύ o

Structure 5-1

А-СООН _0PG Structure 5-2 α ¹ Λ ? \^^ ^{0PG Qk} x ^l/ Π __/ o

Q ^{1 Q} \ removal I _z ,ΟΗ

PG

A

Structure 5-3

Structure 5-4 CO ₂ H activation

Amine binding

F ^q \< _l / ^b

Q< _Y i ^L

7=°

TO

Formula I

Path 5.

In an alternative embodiment, a heteroaryl compound of structure 10 is acylated to form a compound of structure 11, where LG is the leaving group. By way of example, the leaving group may be a halide, such as a bromide. Structure 11 binds to structure 12 to form structure 13. In some embodiments, LG1 is a leaving group. In some embodiments, LG1 is a halide. Structure 13 is coupled to an aryl, heteroaryl, or heterocyclic compound to form structure 14. In some embodiments, structure 13 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 14 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to form structure 15. Structure 15 is coupled to structure 3 from route 1 to form a compound of formula I. This chemical reaction mechanism is illustrated using route 6 as an example.

Path 6.

In an alternative embodiment, a heteroaryl compound of structure 17 is acylated to form a compound of structure 18, where LG is the leaving group. By way of example, the leaving group may be a halide, such as bromide. Pattern 18 couples to an activated ester, Pattern 12 from pathway 6, where LG1 may be halogen, to form pattern 19. Pattern 19 couples to an aryl, heteroaryl, or heterocyclic compound to form pattern 20. In some embodiments, pattern 19 is treated with an aryl, heteroaryl or heterocyclic boronic acid, an organometallic catalyst, a base and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 20 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to form structure 21. Structure 21 binds to

- 237 041794 structure 3 from route 1 to form a compound of formula I. This chemical reaction mechanism is illustrated by the example of route 7.

Path 7.

In an alternative embodiment, a heteroaryl compound of structure 8-1 is acylated to give a compound of structure 8-2, where LG is a leaving group. By way of example, the leaving group may be a halide, such as bromide. Structure 8-2 binds to structure 8-3 to form structure 8-4. In some embodiments, LGj is a leaving group. In some embodiments, LGj is a halide.

Structure 8-4 binds to an aryl, heteroaryl, or heterocyclic compound to form structure 8-5. In some embodiments, Structure 8-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 8-5 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to give structure 8-6. Structure 8-6 couples to structure 3 from route 1 to give a compound of formula I. The mechanism of the chemical reaction is illustrated using route 8 as an example.

- 238 041794

Path 8.

In an alternative embodiment, a heteroaryl compound of structure 9-1 is acylated to give a compound of structure 9-2, wherein LG is the leaving group. By way of example, the leaving group may be a halide, such as bromide. Structure 9-2 couples to an activated ester, structure 9-3, where LG1 may be a halide, to form structure 9-4. Structure 9-4 is coupled to an aryl, heteroaryl, or heterocyclic compound to form structure 9-5. In some embodiments, Structure 9-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis(triphenylphosphine)palladium(0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 9-5 is treated with an organic acid, such as, but not limited to, trifluoroacetic acid, to obtain structure 9-6. Structure 9-6 binds to structure 3 from the reaction illustrated in route 1 to give a compound of formula I. Mechanism of the chemical route 9.

Path 9.

In an alternative embodiment, structure 10-1 is coupled to an amine to form an amide (L-B) and structure 10-2. Structure 10-2 binds to an amine to form compounds of formula I. The mechanism of the chemical reaction is illustrated using pathway 10 as an example.

- 239 041794

Path 10.

Example 2. Examples of central synthons

^R3

LOEt

Vos

Vos _and Vos

Z ^A is halogen.

In one embodiment, deuterated synthons of L-proline are disclosed. Deuterated synthons include, but are not limited to, for example, the following compounds:

Structure A can be treated with deuterium oxide to form structure B. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO 2014/037480 (p. 103). Structure B can be recovered to give structure C. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be processed under Mitsunobu reaction conditions to give structure D. Structure B can be processed with DAST to give structure E. See WO

- 240 041794

2014/037480. Structure A can be treated with sodium borodeutheride to give structure F. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Compound F can be used to form structure K. See Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can be treated with a deuterated reducing agent such as sodium boron deuteride to give structure G. Structure G can be treated with DAST to give structure H. Structure F can be used to give structure K. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure G can be used to create structure I. Structure J can be obtained according to Hruby, V. J. et al. J. Am. Chem. soc. 1979, 101, 202-212. Structures A-J can be used to prepare compounds of formula I.

Example 3. Obtaining synthons central nucleus-L-B

(1s)

Paths 1a, 1b and 1c.

In route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid, 5-(1,1-dimethylethyl)ether, (4S)-, CAS 209269-08-9, can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 11391144. In step 2, protected azaspiro[2.4]heptane is coupled to an amine in the presence of an organic solvent, a base, and a coupling agent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent.

In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane. In route 1b(4S), 4oxazolidinecarboxylic acid, hydrochloride, is treated with an amine protecting reagent. In one embodiment, the amine protectant is di-tert-butyl dicarbonate. In another embodiment, 3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl)ether, (4S)-, is commercially available from JPM2 Pharmaceuticals. In one embodiment, the reaction is carried out in an organic solvent in the presence of a base. In one embodiment, the organic solvent is acetonitrile. In one embodiment, the base is 4-dimethylaminopyridine (DMAP). In step 2, a protected 4oxazolidinecarboxylic acid is coupled to an amine in the presence of an organic solvent, a base, and a coupling agent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane.

In route 1c, (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid, CAS 112963444-1, is commercially available from Ark Pharm. In step 2, a carboxylic acid is coupled to an amine in the presence of an organic solvent, a base, and a coupling agent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 3, the protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is di

- 241 041794 oksan.

Paths 2a, 2b, 2c and 2d.

In route 2a, commercially available Boc-L-proline is coupled to an amine in the presence of an organic solvent, a base, and a coupling reagent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane.

In route 2b, commercially available (1R,3S,5R)-2-[(tert-butoxy)carbonyl]-2azabicyclo[3.1.0]hexane-3-carboxylic acid, from Enamine, is coupled to an amine in the presence of an organic solvent, a base, and a binding reagent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane.

In route 2c, commercially available (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2carboxylic acid, from Manchester Organics, is coupled to an amine in the presence of an organic solvent, a base and a coupling reagent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane.

In route 2d, commercially available (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex, is coupled to an amine in the presence of an organic solvent, a base, and a coupling reagent to form an amide bond; fragment L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment, the binding reagent is HATU. In step 2, the Boc protecting group is removed. In one embodiment, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment, the acid is 4N. hydrochloric acid. In one embodiment, the organic solvent is dioxane. This reaction mechanism is illustrated in Scheme 2.

Additional starting materials that can be readily converted to central-LB synthons include, but are not limited to: (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole2-carboxylic acid, CAS 90104- 21-5, available from Ark Pharm; cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid, 1-(1,1-242 041794 dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commercially available from FCH Group; Boc-L-

octahydroindole-2-carboxylic acid can be purchased from Chem Impex. The connection can be obtained in accordance with the methods described in WO 2004/111041; (S)-Boc-5oxopyrrolidine-2-carboxylic acid is available from Aldrich Chemical Co.; (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylic acid available from Ark Pharm; (S)-3-Bocthiazolidine-2-carboxylic acid available from Alfa Aesar; (2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid available from Arch Bioscience; (1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid available from Ark Pharm; 1,2pyrrolidinodicarboxylic acid, 3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl)ether, (2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz group may be removed and the amino group may be alkylated to give the core compounds of the present invention.

1^0

The n ^OH compound can be prepared as disclosed by Braun, JV; Heymons, Albrecht Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930) 63B, 502-7. (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and pyrrolidine-1,2-dicarboxylic acid can be prepared as a mixture according to WO 2012/093101, Novartis, and the regioisomers can be eventually separated after coupling to obtain central core-LB synthons. Compound (S)-Boc5-oxopyrrolidine-2-carboxylic acid is available from Aldrich Chemical Co. Example 4 Synthesis of LB Fragments.

Diagram 4-1

NSG^ON

Scheme 4-1: in step 1, appropriately substituted dibrom molecules are coupled with the corresponding boronic acid, as is known in the art, to form a mixture of biaryl and triaryl products from which the desired biaryl compound is isolated. In step 2, the suitably substituted biaryl is converted into an activated magnesium Grignard reagent. In step 3, the suitably substituted aldehyde is treated with a pre-prepared Grignard reagent to form an alcohol. In step 4, the appropriately substituted alcohol is converted to the bromide, as is known in the art, with carbon tetrabromide and triphenylphosphine. In step 5, the suitably substituted bromide is converted into an activated magnesium Grignard reagent.

- 243 041794

Example 5 Synthesis of C-L-B Fragments.

Diagram 5-1

D1EA, DCM, 0°С TO F'

DIEA, DCM, 0°C to room temp.

Stage 1

DIEA, DCM, 0°C TO room temp.

Stage 1

DIEA, DCM, 0°C TO room temp.

Stage 1

- 244 041794

Diagram 5-1 continued

DIEA, DCM, 0°C to room temp.

Stage 1

Stage 1

1. Herdeis, C., et al. (1994). Liebigs Ann. Chem. (11): 1117-1120.

Scheme 5-1: In step 1, an appropriately substituted carboxylic acid is coupled to an appropriately substituted amine, as is known in the art, to form an amide. In step 2, the suitably substituted Boc-protected molecules are deprotected with acid to release the free amine. In step 3, the suitably substituted amine is Cbz-protected, as is known in the art, to form a protected carboxylic acid. In step 4, an appropriately substituted carboxylic acid may be orthogonally protected, as is known in the art, to form an ester. In step 5, an appropriately substituted and protected alkene is exposed to a carbene to form a bicyclic ring. In step 6, the suitably substituted ester is saponified with acid to isolate the carboxylic acid. In step 7, the appropriately substituted Cbz-protected molecules are deprotected with hydrogen to isolate the free amine.

Diagram 5-2

1. Vasil'eva, T. P. (2003). Russ. Chem. Bull. 52(4): 958-960.

Scheme 5-2: In step 1, an appropriately substituted sulfide is oxidized to a sulfoxide, as is known in the art. Alternatively, in step 2, the suitably substituted sulfide is oxidized to the sulfone, as is known in the art. In step 3, an appropriately substituted carboxylic acid is coupled to an appropriately substituted amine,

- 245 041794 as known in the art, to form an amide. In step 4, the suitably substituted Boc-protected molecules are acid deprotected to isolate the free amine.

Diagram 5-3

Scheme 5-3: In step 1, an appropriately substituted carboxylic acid is converted to an acyl chloride, as is known in the art. In step 2, the suitably substituted acyl chloride is converted to Weinreb amide, as is known in the art. In step 3, an appropriately substituted Weinreb amide is reacted with a Grignard reagent to form a ketone. The synthesis of the Grignard reagent complex is described in Example 4. In step 4, the appropriately substituted carbamate-protected amine is deprotected to isolate the free amine.

Diagram 5-4

Scheme 5-4: In step 1, an appropriately substituted amide is converted to a thioamide with Lawesson's reagent. In step 2, the suitably substituted Boc-protected amine is acid deprotected to isolate the free amine.

Diagram 5-5

Scheme 5-5: In step 1, a suitably substituted carboxylic acid is converted to a Weinreb amide, as is known in the art. In step 2, the suitably substituted Weinreb amide is reduced, as is known in the art, to give the aldehyde. In step 3, an appropriately substituted aldehyde is reacted with an amine to form a Schiff base, which is then quenched in step 4. In step 4, an appropriately substituted Schiff base is reacted with an appropriate nucleophile to form an amine complex. In step 5, the suitably substituted Boc-protected molecules are deprotected with acid to isolate the free amine.

- 246 041794

Diagram 5-6

1. Prosser, A. R. and D. C. Liotta (2015). Tetrahedron Lett. 56(23): 3005-3007.

Scheme 5-6: In step 1, an appropriately substituted alcohol is subjected to TMS-Cl, as is known in the art, to give a silyl ether. In step 2, an appropriately substituted silyl ether is exposed to sodium cyanide to give cyan moieties. In step 3, suitably substituted cyano moieties are reduced, as is known in the art, to give the aldehyde. In step 4, the appropriately substituted aldehyde is further reduced with borane to give an alcohol. In step 5, the suitably substituted alcohol is oxidized, as is known in the art, to give the carboxylic acid. In step 6, an appropriately substituted carboxylic acid is coupled with an appropriately substituted amine, as is known in the art, to form an amide. In step 7, the appropriately substituted apropyl ester is converted to methyl ketone directly by formation of the Weinreb amide followed by exposure to a methyl Grignard reagent. In step 8, the suitably substituted methyl ketone is reacted with bromine to give bromide. By choosing an appropriate starting material, all mixtures of chiral centers can be prepared as described.

Example 6. Synthesis of fragments A.

Diagram 6-1

- 247 041794

Scheme 6 continued .o

1. Babler, J. H. (1987). Synth. commun. 17(1): 77-84.

2. Mas, T., et al. (2002). ARKIVOC (Gainesville, F.L., U.S.)(5): 48-61.

3. Lebedev, A. Y., et al. (2005). J. Org. Chem. 70(2): 596-602.

Scheme 6-1: In step 1, suitably substituted nitro moieties are reduced with palladium as is known in the art to give an amine. In step 2, suitably substituted alkene molecules are brominated with the simultaneous addition of ethanol, as is known in the art, to produce bromide moieties. In step 3, a suitably substituted mixture of tautomers is subjected to pre-formed bromide compounds, as is known in the art, to give two isomers. Appropriately substituted isomers corresponding to each tautomer can either be separated or used as a mixture in subsequent reactions with separation at a later stage. In step 4, appropriately substituted ketal molecules are deprotected and then cyclized in the presence of an acid, as is known in the art. In step 5, appropriately substituted cyano molecules are attacked by a strong acid to form a primary amide. In step 6, the suitably substituted heterocycle is exposed to bromide compounds of the appropriate linker to give suitably protected compounds. Various 5-5 fused bicyclic systems can be prepared appropriately by minor modifications to this synthetic protocol, another non-limiting example is provided in steps 5 to 12 with the same conditions for primary amide formation and linker installation. In step 7, the suitably substituted aryl is brominated as is known in the art. In step 8, the suitably substituted ester molecules are deprotected with palladium, as is known in the art, to give the alcohol. In step 9, the appropriately substituted alcohol is oxidized, as is known in the art, to form an aldehyde. In step 10, an appropriately substituted aldehyde is treated with hydrazine to first give a Schiff base and then cyclized to form a bicyclic iodinate, as is known in the art. In step 12, the suitably substituted iodide is exposed to sodium cyanide to give cyano compounds.

- 248 041794

Diagram 6-2

Scheme 6-2: Non-limiting examples of aryl substituents are shown, demonstrating the robust nature of the synthesis protocol. Boronic acids 1-8 are treated with a suitably substituted aryl bromide to form a biaryl system.

Diagram 6-3

Scheme 6-3: In step 1, the suitably substituted and protected aniline is converted, as is known in the art, to a sulfonamide. In step 2, the suitably substituted alcohol is converted, as is known in the art, to trifluorosulfonamide. In step 3, the pre-prepared reagents are exposed to sodium hydride to form their adduct. In Step 4, the suitably substituted ketal is subjected to a strong Lewis acid to deprotect and then cyclize to a biaryl compound. In step 5, the suitably substituted sulfonamide is deprotected in the presence of a base to give the free amine. In an alternative embodiment, this synthetic protocol can be applied to other aniline isomers to provide substituents at alternative positions.

Diagram 6-4

1. Thompson, A.L.S., et al. (2005). Synthesis(4): 547-550.

Scheme 6-4: In step 1, the substituted indole is acylated as is known in the art. In step 2, the suitably substituted heterocycle is exposed to bromide compounds of the appropriate linker to give suitably protected molecules. In step 3, a suitably substituted aryl bromide is treated with boronic acid to form an aryl. In step 4, the suitably substituted benzyl alcohol is deprotected in the presence of suitably hydrogen gas and palladium to give the free alcohol. In step 5, a suitably substituted phenol is treated with sulfonic anhydride to form a leaving group. In step 6, the suitably substituted aryl is converted to boronic acid, as is known in the art. In step 7, an appropriately substituted boronic acid is treated with copper bromide to form an aryl bromide. In an alternative embodiment, this synthetic protocol can simply be applied to other indole isomers to produce substituents at alternative positions.

- 250 041794

Diagram 6-5

Scheme 6-5: non-limiting examples of aryl substituents are shown, demonstrating the robust nature of the synthesis protocol. Boronic acids 1-8 are treated with a suitably substituted aryl bromide to form an aryl system.

Example 7 Synthesis of L3-A Fragments.

Diagram 7-1

Scheme 7-1: In step 1, a suitably substituted aryl compound is exposed to bromide to form a sulfonic acid-substituted compound. In step 2, suitably substituted sulfonic acid molecules are chlorinated, as is known in the art.

Diagram 7-2

Scheme 7-2: In step 1, a suitably substituted aryl compound is exposed to chloride to form a phosphonic acid-substituted compound. At stage 2 suitable

- 251 041794 the substituted phosphonic acid molecule is chlorinated, as is known in the art.

Example 8. Non-limiting examples of the synthesis of prodrugs of the present invention.

Scheme 1. Synthesis of (((2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4fluoropyrrolidine-2-carbonyl )amino)methyl)-o-carborane (1) and lithium salt (2S,4R)-1-(2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1 H-indazol-1 -yl) acetyl)-4-fluoropyrrolidine-2-carbonyl)amino)methyl)-nidododecahydroundecaborate (8) but

and he

EUN

Stage-2 'O N'

Step 1. (((2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4fluoropyrrolidine-2-carbonyl) amino)methyl)-o-carborane (1): to a solution of (((2S,4R)-4-fluoropyrrolidine-2carbonyl)amino)methyl)-o-carborane hydrochloride (8-S1, 1 eq.) in DMF (10 vol.) at 0°C in a nitrogen atmosphere was added 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indαzol-1-yl)acetic acid (8-S2, 1.2 eq.), HATU (1.5 equiv.) and DIPEA (3 equiv.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 1.

1H NMR (400 MHz, DMSO-d6) δ: 9.04 (s, 2H), 8.86 (t, J=6.2 Hz, 1H), 8.43 (s, 1H), 7.88-7.81 (m, 2H), 5.86-5.82 (m, 1H), 5.61-5.47 (m, 2H), 4.68-4.67 (m, 1H), 4.38 (t, J=8.6 Hz, 1H), 4.25-4.16 (m, 1H), 3.92-3.77 (m , 4H), 2.69 (s, 3H), 2.65 (s, 3H), 2.30–1.30 (br, 10H).

Step 2 Lithium (2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4fluoropyrrolidine-2-carbonyl)amino )methyl)-nido-dodecahydrooundecaborate (8): to a solution of compound 1 (1 equiv.) in EtOH (10 vol.) at room temperature was added lithium hydroxide monohydrate (0.9 equiv.). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was purified using preparative HPLC to obtain compound 8.

Ή NMR (400 MHz, D2O) δ: 8.30 (s, 2H), 7.66-7.60 (m, 1H), 7.16-6.95 (m, 2H), 5.47-4.99 (m, 3H), 4.674.65 (m, 2H), 4.62-3.95 (m, 2H), 3.49-3.09 (m, 3H), 2.49 (s, 3H), 2.47 (s, 3H), 2.02-1.30 (br, 10H).

Scheme 2. Synthesis of (1S,3aS,6aR)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromopyridine -2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (2)

- 252 041794

Stage 1. (S)-Methyl 4-(methylthio)-2-(prop-2-yn-1-ylamino)butanoate (2-S2): to a mixture of LiOH-H ₂ O (6.6 g, 157.7 mmol), 4 A molecular sieve (39 g) and DMF (70 ml) which was stirred at 0°C for 20 min was added L-methionine methyl ester hydrochloride (2-S1, 15.0 g, 75.1 mmol). The mixture was stirred for 45 min at 0°C and then 3-bromoprop-1-yne (10.6 g, 90.1) was added to this mixture. The resulting mixture was stirred at room temperature overnight and filtered. The filtrate was partitioned between EtOAc (100 ml) and water (200 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=20:1 to 15:1) to give 2-S2 (8.8 g, 58.6% yield) as a clear oil. LC/MS (ESI) m/z: 202 (M+H)+.

Step 2. (S)-Methyl 2-(((benzyloxy)carbonyl)(prop-2-yn-1-yl)amino)-4-(methylthio)butanoate (2S3): to a mixture of (S)-methyl 4- (methylthio)-2-(prop-2-yn-1-ylamino)butanoate (2-S2, 8.8 g, 43.8 mmol), K ₂ CO ₃ (18.1 g, 131.4 mmol), EtOAc (150 ml) and water ( 150 ml) was added CbzCl (11.2 g, 65.7 mmol) dropwise at 0°C. The reaction mixture was stirred at 0° C. overnight. The mixture was quenched by adding 10% aqueous HCl to pH ~3 at 0°C. The mixture was extracted with EtOAc (2 x 100 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 10:1) to give 2-S3 (12.9 g, 87.9% yield) as a clear oil. LC/MS (ESI) m/z: 336 (M+H) ⁺ .

Step 3. (2S)-Methyl 2-(((benzyloxy)carbonyl)(prop-2-yn-1-yl)amino)-4(methylsulfinyl)butanoate (2-S4): to (S)-methyl 2 solution -(((benzyloxy)carbonyl)(prop-2-yn-1yl)amino)-4-(methylthio)butanoate (2-S3, 12.9 g, 38.5 mmol) in MeOH (100 ml) and water (100 ml) was added NaIO4 (8.7 g, 40.4 mmol) in portions at 0°C. The mixture was stirred at this temperature for 4 hours. The mixture was extracted with EtOAc (2 x 50 ml) and the combined layers were washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give S4 (12 g, 88.8% yield) as yellow oil. This crude product was carried to the next stage of the synthesis without further purification. LC/MS (ESI) m/z: 352 (M+H) ⁺ .

Step 4. (S)-Methyl 2-(((benzyloxy)carbonyl)(prop-2-yn-1-yl)amino)but-3-enoate (2-S5): solution of (2S)-methyl 2-( ((benzyloxy)carbonyl)(prop-2-yn-1-yl)amino)-4-(methylsulfinyl)butanoate (2-S4, 2.0 g, 5.69 mmol) in xylene (8 mL) was stirred at 140°C for 2 days. The mixture was evaporated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 25:1 to 20:1) to give 2-S5 (480 mg, 23.5% yield) as yellow oils.

LC/MS (ESI) m/z: 288 (M+H)+.

Step 5. (1S)-2-Benzyl 1-methyl 5-oxo-1,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,2-(3H)dicarboxylate (2-S6): to solution (S) -methyl 2-(((benzyloxy)carbonyl)(prop-2-yn-1-yl)amino)but-3enoate (2-S5, 480 mg, 1.65 mmol) in THF (8 ml) was added Co ₂ (CO) ₈ (81.4 mg, 0.24 mmol). The reaction mixture was subjected to compression in an atmosphere of CO (50 psi) and stirred at 100°C overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 4:1 to 2:1) to give 2-S6 (130 mg, 18.8% yield) as a brown oil. LC/MS (ESI) m/z: 316 (M+H) ⁺ .

Step 6. (1S,3aS,6aR)-2-Benzyl 1-methyl 5-oxohexahydrocyclopenta[c]pyrrole-1,2(1H)dicarboxylate (2-S7): to (1S)-2-benzyl 1-methyl solution Pd/ C (13 mg) and the reaction mixture was stirred at 0° C. under a hydrogen atmosphere (balloon) for 30 min. The mixture was filtered and the filtrate was evaporated under reduced pressure to give 2-S7 (120 mg, 92.6% yield) as a yellow oil. This crude product was carried to the next stage of the synthesis without further purification. LC/MS (ESI) m/z: 318 (M+H) ⁺ .

Step 7. (1S,3aS,6aR)-2-Benzyl 1-methyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-1,2(1H)dicarboxylate (2-S8): to a solution of (1S,3aS,6aR)-2- benzyl 1-methyl 5-oxohexahydrocyclopenta[c]pyrrole 1,2(1H)-dicarboxylate (2-S7, 120 mg, 0.38 mmol) in MeOH (3 ml) was added NaBH ₄ (14.3 mg) at 0°C under nitrogen atmosphere, and the reaction mixture was stirred at 0°C for 30 min. The mixture was quenched by adding an aqueous solution of NH ₄ Cl (15 ml) and was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 3:1 to 2:1) to give 2-S8 (90 mg, 74.4% yield) as a yellow oil. LC/MS (ESI) m/z: 320 (M+H) ⁺ .

Step 8. (1S,3aS,6aR)-2-Benzyl 1-methyl 5-(((4-fluorophenoxy)carbonothioyl)oxy)hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate (2-S9): 4- fluorophenylthionochloroformate (127.7 mg, 0.67 mmol) and DMAP (164.3 mg, 1.34 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 ml), washed successively with 0.5N. aqueous HCl (10 ml), water (10 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (PE/EtOAc=20:1 to 4:1) to give 2-S9 (110 mg, 51.6% yield) as a white solid. LC/MS (ESI) m/z: 496 (M+Na)+.

Step 9. (1S,3aS,6aR)-2-Benzyl 1-methyl hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate (2S10): to a solution of (1S,3aS,6aR)-2-benzyl 1- methyl 5-(((4-fluorophenoxy)carbonothioyl)oxy)hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate (2-S9, 110 mg, 0.23 mmol) in 1,4-dioxane (3 ml) was added 1,1'-azobis(cyclohexanecarbonitrile) (Vazo, 18.9 mg, 0.12 mmol) and tris(trimethylsilyl)silane (86.8 mg, 0.35 mmol). The reaction mixture was stirred at 105°C for 40 min. The reaction mixture was concentrated to dryness and the remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 40:1 to 10:1) to give 2-S10 (68 mg, 97.5% yield) as a clear oil. LC/MS (ESI) m/z: 304 (M+H) ⁺ .

Step 10. (1S,3aS,6aR)-2-((Benzyloxy)carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (2-S11): to a solution of (1S,3aS,6aR)-2-benzyl 1- methyl hexahydrocyclopenta[c]pyrrole-1,2(1H)dicarboxylate (2-S10, 68 mg, 0.22 mmol) in THF (3 ml) was added 1 M aqueous NaOH solution (0.44 ml, 0.44 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (15 ml) and concentrated under reduced pressure. The remaining residue was washed with Et ₂ O (2 x 10 ml). The aqueous layer was acidified with 2N. aqueous HCl to pH ~3 and was extracted with EtOAc (2 x 15 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2-S11 (40 mg, 61.7% yield) as a clear oil. This crude product was carried on without further purification. LC/MS (ESI) m/z: 290 (M+H) ⁺ .

Step 11. (1S,3aS,6aR)-Benzyl 1-((6-bromopyridin-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2-S12): to mixture (1S,3aS ,6aR)-2-((benzyloxy)carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (2-S11, 40 mg, 0.14 mmol), 6-bromopyridine-2-amine (25 mg, 0.14 mmol), and EEDQ (69.2 mg, 0.28 mmol) in DCE (4 ml) was added DIPEA (54.2 mg, 0.42 mmol) and the reaction mixture was stirred at 90°C under nitrogen atmosphere overnight. The mixture was concentrated to dryness and the remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 20:1 to 10:1) to give 2-S12 (30 mg, 48.4% yield) as a clear oil. LC/MS (ESI) m/z: 444 (M+H) ⁺ .

Step 12: (1S,3aS,6aR)-N-(6-Bromopyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (2S13): to a solution of (1S,3aS,6aR)-benzyl 1-(( 6-bromopyridin-2-yl)carbamoyl)hexahydrocyclopenta[c]pyr- 254 041794 roll-2(1Н)-carboxylate (2-S12, 30 mg, 0.07 mmol) in AcOH (1.5 mL) was added 30% HBr/AcOH solution (0.3 ml) at 0°C and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice-cold aqueous NaHCO ₃ and extracted with EtOAc (2 x 15 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2S13 (25 mg, crude) as a brown oil. This crude product was used directly in the next reaction without further purification. LC/MS (ESI) m/z: 310 (M+H)+.

Step 13: (1S,3aS,6aR)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromopyridin-2 -yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (2): to a mixture of (1S,3aS,6aR)-N-(6bromopyridin-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (2-S13, 25 mg, 0.08 mmol) DMF (2 ml) was added with DIPEA (31 mg, 0.24 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give 2 (5 mg, 16.6% yield) as a white solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 9.04 (s, 2H), 8.43 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.877.85 (m , 2H), 7.72 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.7 Hz, 1H), 5.74 (d, J=17.3 Hz, 1H), 5.62 (d, J=17.2 Hz, 1H ), 4.42 (d, J=2.8 Hz, 1H), 4.09-4.03 (m, 1H), 3.67-3.63 (m, 1H), 2.87-2.84 (m, 1H), 2.69 (s, 3H), 2.65 ( s, 3H), 1.981.58 (m, 7H). LC/MS (ESI) m/z: 602 (M+H) ⁺ .

Scheme 3. Synthesis of (S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridin- 2-yl)-2-azabicyclo [2.2.2] octan-3-carboxamide (3)

Vg

3-S1 Stage 1 ^B ° ^C 3-S2 Stage 2

The above scheme and the following detailed description depict one non-limiting method for synthesizing compounds by the following steps: 1) formation of an amide bond between the B-ring and C-ring using a coupling reagent such as EEDQ or HATU; 2) removal of the Boc group using acid; and 3) formation of an amide bond between the C-ring (already linked to the B-ring) and the A-ring using HATU. One skilled in the art will appreciate that the C- and B-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention. One skilled in the art will also appreciate that the A-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention.

Stage 1. (S)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-2-azabicyclo[2.2.2]octane-2carboxylate (3-S2): to a mixture of 3-S1 (230 mg, 0.902 mmol), 6-bromo-3-methylpyridin-2-amine (169 mg, 0.902 mmol) and EEDQ (446 mg, 1.80 mmol) in DCE (10 mL) DIPEA (0.6 mL, 3.61 mmol) was added. The reaction mixture was stirred at 90°C overnight. The mixture was then concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 20:1 to 10:1) to give 3-S2 (100 mg, 26.2% yield) as a yellow solid. LC/MS (ESI) m/z: 424 (M+H) ⁺ .

Step 2. (S)-N-(6-Bromo-3-methylpyridin-2-yl)-2-azabicyclo[2.2.2]octane-3-carboxamide (3-S3): to 3-S2 solution (100 mg , 0.236 mmol) in dioxane (2 mL), a solution of HCl/dioxane (1 mL, 2 M) was added at 0°C and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness to give 3-S3 (105 mg , 100% yield) as a brown solid, which was used in the next step of the synthesis without further purification. LC/MS (ESI) m/z: 324 (M+H) ⁺ .

Step 3. (S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2 -yl)-2-azabicyclo[2.2.2]octane-3-carboxamide (3): to a mixture of 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (24 mg, 0.078 mmol) DI-255 041794 was added to DMF

PEA (0.03 ml, 0.195 mmol), HATU (37.0 mg, 0.097 mmol) and 3-S3 (21.0 mg, 0.065 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give 3 (2.5 mg, 6.27% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.54 (s, 1H), 7.79 (s, 2H), 7.54 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 5.63 (q, J=16.8 Hz, 2H), 4.50 (s, 1H), 4.22 (s, 1H), 2.75 (s, 3H), 2.71-2.66 (m, 3H), 2.41 (s , 1H), 2.30 (d, J=15.1 Hz, 1H), 2.09 (m, 3H), 1.88 (m, 5H), 1.69 (d, J=6.7 Hz, 1H), 1.34 (m, 1H). LC/MS (ESI) m/z: 616 (M+H)+.

(1 R,3S,5S)-2-(2-(3-Acetyl-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-(6-bromo- 3 (methoxymethyl)pyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (49):

¹ H NMR (400 MHz, CD3OD) δ 9.01 (d, J=6.9 Hz, 2H), 8.54 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.80 (d, J=9.8 Hz, 2H), 7.27 (d, J=8.1 Hz, 1H), 5.81 (d, J=17.2 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 4.76 (s, 1H), 4.46 (s, 2H), 3.79 (s, 1H), 3.74-3.69 (m, 1H), 3.63 (d, J=10.2 Hz, 1H), 3.51 (d, J=10.3 Hz, 1H), 3.43 (s, 3H), 3.40 (s, 3H), 2.75 (s, 3H), 2.70 (s, 3H), 2.59 (dd, J=16.6, 6.7 Hz, 2H), 2.19 (t, J=7.6 Hz, 1H), 1.16-1.11 (m, 1H), 0.90 (t, J=6.8 Hz, 1H). LC/MS (ESI) m/z: 662 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(2 -(3-chloro-2-fluorophenyl)propan-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, chloroform-d) δ 0.87 (dd, J=2.3, 5.4 Hz, 1H), 1.14 (t, J=5.5 Hz, 1H), 1.32 (s, 3H), 1.62 (s, 3H ), 1.68 (s, 3H), 2.07 (dd, J=8.6, 13.3 Hz, 1H), 2.55 (dd, J=2.7, 13.3 Hz, 1H), 2.72 (s, 3H), 2.76 (s, 3H) , 2.80 (s, 3H), 3.05 (dd, J=2.3, 5.5 Hz, 1H), 4.58 (dd, J=2.7, 8.7 Hz, 1H), 5.68 (s, 2H), 7.01 (t, J=8.0 Hz, 1H), 7.10 (s, 1H), 7.23-7.29 (m, 2H), 7.35 (s, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.90 (s, 2H). ¹⁹ F δ -115.9.

(S)-2-((1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl )-5methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-4-methylpentanoic acid:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.53 (s, 1H), 5.90-5.94 (d, J=17.6 Hz, 1H), 5.735.78 (d , J=17.6 Hz, 1H), 4.43-4.35 (m, 2H), 3.46-3.44 (m, 1H), 2.72 (s, 6H), 2.68 (s, 3H), 2.48 (m, 1H), 2.17 ( dd, J=13.2, 4.4 Hz, 1H), 1.65 (m, 1H), 1.62-1.53 (m, 2H), 1.35 (s, 3H), 1.09 (m, 1H), 0.90 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H). LC/MS (ESI) m/z: 561 (M+H) ⁺ .

(S)-2-((1R,3R,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl )-5methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-3-phenylpropanoic acid:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.32 (t, J=4.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.35-7.04 (m, 5H), 5.95-5.99 (d, J=18 Hz, 1H), 5.61-5.66 (d, J=17.6 Hz, 1H), 4.28-4.41 (m, 2H ), 3.43-3.44 (m, 1H), 3.01 (dd, J=14, 5.2 Hz, 1H), 2.89 (dd, J=14.4, 6 Hz, 1H), 2.68 (s, 3H), 2.65 (s, 3H), 2.64 (s, 3H), 2.34 (dd, J=13.2, 9.6 Hz, 2H), 1.91 (m, 1H), 1.17 (s, 3H), 0.97-1.00 (m, 1H), 0.82-0.84 (m, 1H). LC/MS (ESI) m/z: 595 (M+H) ⁺ .

(R)-2-(( 1R,3 S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl )acetyl)-5methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-4-methylpentanoic acid:

¹ H NMR (400 MHz, CD3OD) δ 8.98 (s, 2H), 8.39 (s, 1H), 7.52 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.78 (d, J=18.0 Hz, 1H), 4.46-4.37 (m, 2H), 3.46-3.48 (m, 1H), 2.74 (s, 3H), 2.73 (s, 3H), 2.67 (s, 3H), 2.48-2.54 (m, 1H), 2.09-2.14 (m, 1H), 1.61-1.64 (m, 3H), 1.36 (s, 3H), 1.12-1.07 (m, 1H), 1.00 (m, 1H), 0.92-0.87 (m, 6H). LC/MS (ESI) m/z: 561 (M+H) ⁺ .

(2R)-2-{[(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}- 5methyl-2-azabicyclo[3.1.0]hexan-3-yl]formamido}-3-phenylpropanoic acid:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.52 (s, 1H), 7.30-7.16 (m, 5H), 5.88 (d, J=17.7 Hz, 1H ), 5.75 (d, J=17.8 Hz, 1H), 4.72-4.68 (m, 1H), 4.37-4.32 (m, 1H), 3.38-3.36 (m, 1H), 3.25-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.81-2.65 (m, 9H), 2.34-2.28 (m, 1H), 1.75-1.70 (m, 1H), 1.22 (s, 3H), 1.07-1.02 (m, 1H ), 0.87–0.83 (m, 1H). LC/MS (ESI) m/z: 595 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(3 chloro-2-fluorobenzyl)-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.52 (s, 1H), 7.29 (dd, J=11.0, 4.1 Hz, 1H), 7.21 (t, J =6.9 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 5.93 (d, J=17.7 Hz, 1H), 5.79 (d, J=17.7 Hz, 1H), 4.57-4.35 (m, 3H ), 3.79 (dd, J=5.7, 2.7 Hz, 1H), 3.12 (d, J=16.0 Hz, 1H), 2.75 (s, 3H), 2.69 (d, J=6.1 Hz, 3H), 2.65 (d , J=11.2 Hz, 3H), 2.62-2.55 (m, 1H), 2.37 (s, 3H), 2.29 (dd, J=13.8, 4.6 Hz, 1H), 1.36 (m, 1H), 1.13 (m, 1H). LC/MS (ESI) m/z: 671 [M+H] ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(3 chloro-2-fluorobenzyl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.42-8.45 (t, 1H), 8.32 (s, 1H), 7.62 (s, 1H), 7.41-7.45 (t, 1H ), 7.17-7.20 (t, 1H), 7.04-7.08 (t, 1H), 5.97-6.01 (d, J=17.6 Hz, 1H), 5.67-5.71 (d, J=17.6 Hz, 1H), 4.25- 4.33 (m, 3H), 3.73-3.76 (m, 1H), 3.15-3.16 (d, J=16 Hz, 1H), 3.02-3.06 (d, J=16 Hz, 1H), 2.68 (s, 3H) , 2.65 (s, 3H), 2.63 (s, 3H), 2.48 (s, 3H), 2.46-2.47 (m, 1H), 2.06-2.10 (m, 1H), 1.24-1.25 (m, 1H), 1.07 -1.09 (m, 1H). LC/MS (ESI) m/z: 671 (M+H) ⁺ .

- 256 041794 (1R,2S,5S)-3-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-[(3 -chloro-2fluorophenyl)methyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (d, J=2.0 Hz, 1H), 7.53-7.50 (m, 1H), 7.31-7.24 (m, 2H), 6.94 (td, J=1.2, 1.2Hz, 1H), 5.65(s, 2H), 4.57(d, J=6.0Hz, 1H), 4.47(d, J=15.2Hz, 1H), 4.37(d, J=15.6Hz, 1H), 4.03 (dd, J=5.6, 5.6 Hz, 1H), 3.90 (d, J=10.0 Hz, 1H), 2.74 (s, 3H), 2.71 (s, 3H), 2.66 (s, 3H), 2.04-2.00 (m, 1H), 1.95-1.90 (m, 1H), 0.89 (q, J=4.6 Hz, 1H), 0.83-0.79 (m, 1H). LC/MS (ESI) m/z: 575 (M+H)+.

(2S,4R)-N-(5'-Acetyl-2'-chloro-2-fluoro-[1,Γ-biphenyl]-3-yl)-1-(2-(3-acetyl-5-(2 -methylpyrimidin-5yl)-1H-indazol-1-yl)acetyl)-4-fluoropyrrolidine-2-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.03 (s, 2H), 8.43 (s, 1H), 8.02-8.00 (m, 2H), 7.98 (s, 1H), 7.97-7.96 (m, 2H), 7.76-7.73 (m, 1H), 7.28-7.24 (m, 1H), 7.14-7.11 (m, 1H), 5.86 (d, J=17.2 Hz, 1H), 5.66 ( d, J=17.2 Hz, 1H), 4.79-4.75 (m, 1H), 4.30-4.21 (m, 1H), 4.08-3.97 (m, 1H), 2.69 (s, 3H), 2.64 (s, 3H) , 2.61-2.60 (m, 2H), 2.58 (s, 3H), 2.26-2.22 (m, 1H).

Scheme 4. Synthesis of (3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3- methylpyridin-2-yl)-5-(piperidin-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4)

The above scheme and the following detailed description show one non-limiting method for the synthesis of compounds with R ²⁰¹ nucleophilic groups on the C-ring. One skilled in the art will appreciate that piperidine may be substituted with other nucleophilic reagents to provide additional compounds of the present invention. Non-limiting examples of groups that a person skilled in the art can use in place of piperidine include azetidine, 6azaspiro[2.5]octane, and 2-azaspiro[3.3]heptane.

Step 1. (3S)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-(piperidin-1-ylmethyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (4-S2): to a mixture of 4-S1 (25 mg, 0.05 mmol) in MeCN (2 mL) were added DIPEA (0.035 mL, 0.2 mmol), piperidine (4 mg, 0.055 mmol), and NaI at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated, diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 40:1 to 30:1) to give the title compound (8 mg, 33.3% yield) as a yellow solid. LC/MS (ESI) m/z: 493 (M+H) ⁺ .

Step 2. (3S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-(piperidin-1-ylmethyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (4-S3): HCl/dioxane (1 ml) was added to a solution of 4-S2 (8 mg, 0.016 mmol) in dioxane (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound (10 mg, 100% yield) as a brown solid. The crude material was carried to the next stage of the synthesis without further purification. LC/MS (ESI) m/z: 393 (M+H) ⁺ .

Step 3. (3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo3-methylpyridine -2-yl)-5-(piperidin-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (4): to a solution of 4-S3 (10 mg, 0.025 mmol) and 4-S4 ( 7.75 mg, 0.025 mmol) in DMF (2 mL) were added HATU (17.1 mg, 0.045 mmol) and DIPEA (0.018 mL, 0.10 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 4 (2.1 mg, 12.3% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.56 (s, 1H), 7.81 (s, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.9 Hz , 1H), 5.82 (d, J=17.2 Hz, 1H), 5.67 (d, J=17.2 Hz, 1H), 5.35-5.33 (m, 1H), 4.68 (t, J=7.2 Hz, 1H), 3.04 (d, J=7.3Hz, 2H), 2.75 (s, 3H), 2.70 (d, J=2.0Hz, 4H), 2.66 (d, J=8.4Hz, 2H), 2.20 (t, J=7.2Hz , 2H), 2.13 (s,

- 257 041794

3H), 2.04 (s, 2H), 1.83 (s, 4H), 1.60 (s, 4H). LC/MS (ESI) m/z: 685 (M+H)+.

(3S)-5-(6-Azaspiro[2.5]octan-6-ylmethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (5):

¹ H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.57 (s, 1H), 7.80 (s, 2H), 7.59 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 5.82 (d, J=17.1 Hz, 1H), 5.67 (d, J=16.9 Hz, 1H), 2.75 (s, 3H), 2.70 (s, 3H), 2.67 (s, 1H), 2.13 (s, 3H), 1.48 (s, 2H), 1.33 (s, 2H), 1.29 (s, 6H), 0.90 (s, 3H), 0.51 (s, 3H). LC/MS (ESI) m/z: 711 (M+H) ⁺ .

(3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-III-indazol-1-yl)acetyl)-5-(azetidin-1-ylmethyl)X-(6 -bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (6):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.56 (s, 1H), 7.80 (s, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.43 (d, J=8.0 Hz , 1H), 5.81 (d, J=17.2 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 5.35 (d, J=5.0 Hz, 1H), 4.72-4.65 (m, 1H), 4.30 (s, 2H), 3.53 (d, J=13.3 Hz, 1H), 3.46 (t, J=6.8 Hz, 2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.66-2.59 (m, 1H), 2.54-2.50 (m, 1H), 2.20 (dd, J=15.8, 8.3 Hz, 2H), 2.12 (s, 3H), 2.04 (s, 2H), 1.60 (s, 2H), 1.41 (d , J=6.2 Hz, 1H), 1.10-1.08 (m, 1H). LC/MS (ESI) m/z: 657 (M+H) ⁺ . (3S)-5-(3-Azabicyclo[3.1.1]heptan-3-ylmethyl)-2-(2-(3-acetyl-5(2-methylpyrimidin-5-yl)-1H-indazol-1-yl )acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (13):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.55 (s, 1H), 7.84-7.76 (m, 2H), 7.59 (d, J=8.2 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 5.88 (d, J=17.2 Hz, 1H), 5.64 (d, J=17.2 Hz, 1H), 4.64 (dd, J=9.0, 4.2 Hz, 1H), 4.22 (s, 3H) , 4.01 (d, J=3.2 Hz, 1H), 3.52-3.37 (m, 2H), 2.75 (s, 3H), 2.69 (s, 3H), 2.61 (d, J=9.2 Hz, 1H), 2.54 ( d, J=3.8 Hz, 1H), 2.34 (s, 4H), 2.12 (s, 3H), 1.90 (t, J=7.6 Hz, 2H), 1.40 (s, 1H), 1.10-1.08 (m, 1H ). LC/MS (ESI) m/z: 697 (M+H) ⁺ .

(3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2-yl) -5-((4-methylpiperazin-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (24):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.56 (s, 1H), 7.80 (d, J=1.2 Hz, 2H), 7.56 (d, J=7.8 Hz, 1H), 7.40 (d , J=7.9 Hz, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.66 (d, J=17.2 Hz, 1H), 4.65-4.61 (m, 4.7 Hz, 1H), 3.66-3.64 (m , 1H), 3.28 (s, 3H), 2.99 (s, 4H), 2.75 (s, 4H), 2.72 (s, 1H), 2.69 (s, 4H), 2.65 (s, 3H), 2.54-2.44 ( m, 2H), 2.12 (s, 3H), 1.20–1.02 (m, 2H). LC/MS (ESI) m/z: 700 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo- 3-methylpyridin-2-yl)-5-((4-methylpiperazin-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (69):

1H NMR (400 MHz, CD ₃ OD) δ 8.99 (s, 2H), 8.40 (s, 1H), 7.50-7.53 (m, 2H), 7.35 (d, J=8.0 Hz, 1H), 5.87 (s, 2H), 4.85-5.03 (m, 1H), 3.63-3.66 (m, 1H), 3.29-3.33 (m, 5H), 2.67-2.92 (m, 17H), 2.32-2.48 (m, 2H), 2.04 ( s, 3H), 1.72-1.74 (m, 1H), 1.03-1.06 (m, 1H). LC/MS (ESI) m/z: 714/716 (M+H) ⁺ .

Scheme 5. Synthesis of (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5(azetidin-1-ylmethyl)- N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (9) but

The above scheme and the following detailed description depict one non-limiting method for synthesizing compounds by forming an amide bond between the C-ring (already linked to the B-ring) and the A-ring using HATU or another peptide coupling reagent such as TBTU. One skilled in the art will appreciate that the C- and B-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention. One skilled in the art will also appreciate that the A-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention.

To a solution of 9-S1 (45 mg, 0.086 mmol) and 9-S2 (26.7 mg, 0.086 mmol) in DMF (2 mL) were added HATU (58.9 mg, 0.155 mmol) and DIPEA (0.06 mL, 0.344 mmol) at 0°C C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 9 (23 mg, 41.5% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.51 (s, 1H), 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.63 (d, J=8.1Hz, 1H), 7.45(d, J=7.9Hz, 1H), 5.94(d, J=17.3Hz, 1H), 5.62(d, J=17.3Hz, 1H), 4.47(dd, J= 9.0, 5.0

- 258 041794

Hz, 1H), 2.82 (s, 2H), 2.69 (s, 3H), 2.66 (s, 3H), 2.66-2.64 (m, 1H), 2.51 (d, J=1.7 Hz, 6H), 2.42-2.31 (m, 2H),

2.04 (s, 3H), 2.00 (d, J=7.7 Hz, 1H), 1.34 (d, J=6.1 Hz, 1H). LC/MS (ESI) m/z: 645 (M+H)+.

(2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-III-indazol-1-yl)acetyl)-N-(cuban-1-ylmethyl)4- fluoropyrrolidine-2-carboxamide (16):

¹ H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 2H), 8.44 (s, 1H), 8.02-8.01 (m, 1H), 7.89-7.82 (m, 2H), 5.825.78 (m , 1H), 5.61-5.43 (m, 2H), 4.39 (t, J=8.3 Hz, 1H), 4.22-3.80 (m, 4H), 3.73-3.72 (m, 3H), 3.51-3.36 (m, 2H ), 3.17-3.10 (m, 3H), 2.69 (s, 3H), 2.64 (s, 3H), 2.11-1.98 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N(6 -bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (30):

1H NMR (400 MHz CD3OD) δ 9.05 (s, 2H), 8.68 (t, J=1.9 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.87 (dd, J=3.1, 1.7 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 5.60-6.05 (m, 4H), 4.52 (dd, J=9.0, 5.8 Hz, 1H), 3.56 (dd, J=5.5, 2.4 Hz, 1H), 2.77 (s, 3H), 2.73 (s, 3H), 2.61 (dd, J=13.4, 9.3 Hz, 1H), 2.18-2.24 (m, 1H) , 1.41 (s, 3H), 1.10–1.16 (m, 1H), 1.01–1.04 (m, 1H). LC/MS (ESI) m/z: 620/622 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(2fluoro -3-(trifluoromethoxy)phenyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (33):

1H NMR (400 MHz, CD3OD) δ: 9.01 (s, 2H), 8.42 (s, 1H), 7.92-7.89 (m, 1H), 7.54 (s, 1H), 7.21-7.19 (m, 2H), 5.98 (d, J=17.6 Hz, 1H), 5.82 (d, J=17.6 Hz, 1H), 4.60 (m, 1H), 3.57-3.55 (m, 1H), 2.76 (s, 3H), 2.74 (s, 3H), 2.71 (s, 3H), 2.63-2.57 (m, 1H), 2.28-2.23 (m, 1H), 1.42 (s, 3H), 1.15-1.13 (m, 1H), 1.00-0.99 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(( S)-3fluoro-4-methylpent-3-en-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (34):

1H NMR (400 MHz, CD3OD) δ: 9.00 (s, 2H), 8.42 (s, 1H), 7.54 (s, 1H), 5.92 (d, J=17.6 Hz, 1H), 5.78 (d, J=17.6 Hz, 1H), 4.36-4.32 (m, 1H), 3.48-3.46 (m, 1H), 2.76 (s, 3H), 2.74 (s, 3H), 2.69 (s, 3H), 2.50-2.47 (m, 1H), 2.12-2.00 (m, 1H), 1.67 (s, 3H), 1.57 (s, 3H), 1.40 (s, 3H), 1.24 (s, 3H), 1.22-1.21 (m, 1H), 1.10 -1.09 (m, 1H), 0.92-0.90 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5-methylN- (1-(2,2,2-trifluoroethyl)-1 H-pyrazol-3-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (35):

1Н NMR (400 MHz, CD3OD) δ: 9.01 (s, 2H), 8.42 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 6.67 (s, 1H), 5.98 (d, J =18.0 Hz, 1H), 5.83 (d, J=18.0 Hz, 1H), 4.81-4.76 (m, 1H), 4.51-4.47 (m, 1H), 3.56-3.54 (m, 1H), 2.77 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.62-2.56 (m, 1H), 2.22-2.17 (m, 1H), 1.40 (s, 3H), 1.22-1.20 (m, 1H) , 1.19–1.10 (m, 1H), 0.97–0.99 (m, 1H). (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-5-methyl-N-( 6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (36):

1H NMR (400 MHz, CD3OD) δ: 9.01 (s, 2H), 8.42-8.36 (m, 2H), 7.99-7.95 (m, 1H), 7.54 (s, 1H), 7.48 (d, J=7.6 Hz , 1H), 6.01 (d, J=18.0 Hz, 1H), 5.81 (d, J=20.0 Hz, 1H), 4.54-4.52 (m, 1H), 3.59-3.58 (m, 1H), 2.78 (s, 3H), 2.75 (s, 3H), 2.68 (s, 3H), 2.61-2.59 (m, 1H), 2.23-2.19 (m, 1H), 1.40 (s, 3H), 1.14-1.11 (m, 1H) , 1.00-0.98 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5-methylN- (6-(trifluoromethoxy)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (37):

1H NMR (400 MHz, CD3OD) δ: 9.05-9.02 (m, 2H), 8.43 (s, 1H), 8.11-8.09 (m, 1H), 7.91-7.87 (m, 1H), 7.54 (s, 1H) , 6.83 (d, J=7.6 Hz, 1H), 6.00 (d, J=18.0 Hz, 1H), 5.80 (d, J=17.6 Hz, 1H), 4.55-4.54 (m, 1H), 3.743.58 ( m, 1H), 3.57-3.56 (m, 1H), 2.77 (s, 3H), 2.75 (s, 3H), 2.74-2.73 (m, 2H), 2.61-2.57 (m, 1H), 2.21-2.16 ( m, 1H), 1.40 (s, 3H), 1.14–1.11 (m, 1H), 0.98–0.97 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(2 'chloro-2-fluoro-[ 1,1 '-biphenyl]-3-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (38):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.80 (s, 1H), 9.01 (s, 2H), 8.31 (s, 1H), 7.95-7.94 (m, 1H), 7.61-7.37 (m, 5H ), 7.13-7.21 (m, 1H), 7.07-7.06 (m, 1H), 6.08 (d, J=18.0 Hz, 1H), 5.67 (d, J=18.0 Hz, 1H), 4.55-4.52 (m, 1H), 3.63-3.61 (m, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 2.63 (s, 3H), 2.11-2.09 (m, 1H), 1.32 (s, 3H), 1.26 -1.24 (m, 1H), 0.94-0.92 (m, 1H), 0.86-0.83 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(2'-chloro-2 -fluoro[1,1 '-biphenyl] -3 -yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (3 9):

1H NMR (400 MHz, DMSO-d6) δ: 9.77 (s, 1H), 9.03 (s, 2H), 8.43 (s, 1H), 7.91-7.80 (m, 3H), 7.57 (d, J=8.0 Hz , 1H), 7.45-7.37 (m, 3H), 7.25-7.21 (m, 1H), 7.08-7.06 (m, 1H), 5.95 (d, J=17.2 Hz, 1H), 5.58 (d, J=17.2 Hz, 1H), 4.58-4.56 (m, 1H), 3.62-3.60 (m, 1H), 2.69 (s, 3H), 2.64 (s, 3H), 2.47-2.46 (m, 1H), 2.11-2.09 ( m, 1H), 1.32 (s, 3H), 1.01–1.00 (m, 1h), 0.86–0.83 (m, 1H). 1-(2-((1R,3S,5R)-3-((6-Bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)- 2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazole-3-carboxamide (55):

1H NMR (400 MHz, DMSO-d6) δ: 10.28 (s, 1H), 9.03 (s, 2H), 8.44 (s, 1H), 7.83-7.76 (m, 3H), 7.62 (d, J=8.0 Hz , 1H), 7.49-7.44 (m, 2H), 5.82 (d, J=17.6 Hz, 1H), 5.49 (d, J=17.2 Hz, 1H), 4.41-4.37 (m, 1H), 3.583.56 ( m, 1H), 2.68 (s, 3H), 2.57-2.54 (m, 1H), 2.04 (s, 3H), 2.03-2.00 (m, 1H), 1.32 (s, 3H), 1.00-0.96 (m, 2H).

1-(2-((1R,2S,5S)-2-((6-Bromo-3-methylpyridin-2-yl)kαrbαmoyl)-3-αzabutyclo[3.1.0]hexan-3-ul)-2oxoethyl) -5-(2-methylpyrimidin-5-yl)-1H-indazole-3-carboxamide (56):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.31 (s, 1H), 9.03 (s, 2H), 8.42 (s, 1H), 7.79-7.74 (m, 2H), 7.69 (s, 1H),

- 259 041794

7.59 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 5.58-5.47 (m, 2H), 4.58-4.57 (m, 1H), 4.01 -4.00(m,

1H), 3.88-3.81 (m, 1H), 2.77 (s, 3H), 2.03 (s, 3H), 2.02-2.01 (m, 1H), 1.89-1.82 (m, 1H), 0.92-0.69 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(( R)-1 ((R)-2,2-dichlorocyclopropyl)ethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (52):

¹ H NMR (400 MHz, DMSO-d6) δ: 9.03 (s, 2H), 8.32 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=18.0 Hz, 1H), 5.70 (d, J=18.0 Hz, 1H), 4.25-4.22 (m, 1H), 3.52-3.51 (m, 2H), 2.68 (s, 3H), 2.65 (s, 6H ), 2.452.42 (m, 1H), 1.96-1.92 (m, 2H), 1.74-1.72 (m, 1H), 1.45-1.43 (m, 1H), 1.41-1.31 (m, 2H), 1.27-1.24 (m, 2H), 1.15-1.13 (m, 2H), 1.09-1.08 (m, 1H), 1.04-0.88 (m, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K -(6bromopyrazine -2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (53):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 11.18 (s, 1H), 9.26 (s, 1H), 9.01 (s, 2H), 8.53 (s, 1H), 8.30 (s, 1H), 7.61 ( s, 1H), 6.07 (d, J=18.0 Hz, 1H), 5.66 (d, J=18.0 Hz, 1H), 4.44 (t, J=14.0 Hz, 1H), 3.65-3.59 (m, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 2.63 (s, 3H), 2.62-2.61 (m, 1H), 2.05-2.00 (m, 1H), 1.35 (s, 3H), 0.99-0.92 ( m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6bromo -5-methylpyrazin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (54):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 11.06 (s, 1H), 9.13 (s, 1H), 9.03 (s, 2H), 8.31 (s, 1H), 7.62 (s, 1H), 6.07 ( d, J=18.0 Hz, 1H), 5.67 (d, J=18.0 Hz, 1H), 4.45-4.41 (m, 1H), 3.65-3.64 (m, 1H), 2.73 (s, 3H), 2.69 (s , 3H), 2.68 (s, 3H), 2.61 (s, 3H), 2.60-2.59 (m, 1H), 2.04-2.00 (m, 1H), 1.31 (s, 3H), 0.99-0.98 (m, 2H ).

1-(2-((1R,3S,5R)-3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)- 2-oxoethyl)-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazole-3-carboxamide (57):

1H NMR (400 MHz, DMSO-d6) δ: 10.33 (s, 1H), 9.02 (s, 2H), 8.32 (s, 1H), 7.73 (s, 1H), 7.62 (d, J=8.0 Hz, 1H ), 7.56 (s, 1H), 7.46-7.42 (m, 2H), 5.94 (d, J=18.0 Hz, 1H), 5.59 (d, J=17.6 Hz, 1H), 4.41-4.37 (m, 1H) , 3.603.58 (m, 1H), 2.68 (s, 3H), 2.66 (s, 3H), 2.66–2.53 (m, 1H), 2.01 (s, 3H), 2.00–1.99 (m 1H), 1.32 ( s, 3H), 1.031.00 (m, 1H), 0.89–0.88 (m, 1H).

1-(2-((1R,3S,5R)-3-((6-Bromopyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2oxoethyl) -7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-3-carboxamide (58):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.82 (s, 1H), 9.00 (s, 2H), 8.30 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.747.70 ( m, 2H), 7.56 (s, 1H), 7.46 (s, 1H), 7.32 (d, J=7.6 Hz, 1H), 5.97 (d, J=18.0 Hz, 1H), 5.57 (d, J=18.0 Hz, 1H), 4.40 (t, J=14.8 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H), 2.67 (s, 6H), 2.00-1.96 (m, 1H), 1.30 (s, 3H ), 1.29–1.27 (m, 1H), 1.00–0.84 (m, 2H).

(2S,4R)-1 -(2-(3-Acetyl-7-methyl-5 -(2-methylpyrimidin-5-yl)-1H-indazol-1 -yl)acetyl)-K-(6-bromo- 3methylpyridin-2-yl)-4-fluoro-4-(fluoromethyl)pyrrolidin-2-carboxamide (66):

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.44 (s, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.39 (d, J=8.0 Hz, 1H), 5.84 (d , J=17.6 Hz, 1H), 5.74 (d, J=17.5 Hz, 1H), 4.74-4.70 (m, 2H), 4.35-4.31 (m, 1H), 4.17-4.15 (m, 1H), 4.104. 07 (m, 1H), 2.77 (s, 6H), 2.70 (s, 3H), 2.50-2.44 (m, 1H), 2.42-2.36 (m, 1H), 2.12 (s, 3H). LC/MS (ESI) m/z: 640 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(3 ,3dimethylbutyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (80):

¹ H NMR (400 MHz, DMSO-d6) δ: 9.03 (s, 2H), 8.32 (s, 1H), 7.75-7.73 (m, 1H), 7.63 (s, 1H), 5.96 (d, J=17.2 Hz, 1H), 5.67 (d, J=17.2 Hz, 1H), 4.14-4.12 (m, 1H), 3.86-3.75 (m, 4H), 3.50-3.49 (m, 1H), 3.06-3.00 (m, 2H), 2.66 (s, 3H), 2.61 (s, 3H), 2.49-2.33 (m, 1H), 1.90-1.89 (m, 1H), 1.30-1.28 (s, 5H), 1.00-0.99 (m, 1H), 0.98 (s, 9H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5-methylK- (2-(trifluoromethoxy)ethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (81):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 9.03 (s, 2H), 8.31 (s, 1H), 8.15-8.12 (m, 1H), 7.62 (s, 1H), 5.96 (d, J=18 Hz, 1H), 5.67 (d, J=18 Hz, 1H), 4.22-4.02 (m, 4H), 3.51-3.49 (m, 1H), 3.36-3.24 (m, 2H), 2.68 (s, 3H) , 2.64 (s, 3H), 2.49-2.33 (m, 3H), 1.89-1.85 (m, 1H), 1.26 (s, 3H), 1.00-0.99 (m, 1H), 0.88-0.87 (m, 1H) .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6methoxypyridine -2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (82):

1H NMR (400 MHz, DMSO-d6) δ: 10.20 (s, 1H), 9.01 (s, 2H), 8.30 (s, 1H), 7.67-7.61 (m, 3H), 6.49 (d, J=7.6 Hz , 1H), 6.08 (d, J=16 Hz, 1H), 5.65 (d, J=17.6 Hz, 1H), 4.51-4.48 (m, 1H), 3.78 (s, 3H), 3.63-3.62 (m, 1H), 2.67 (s, 3H), 2.61 (s, 3H), 2.55 (s, 3H), 2.02–1.97 (m, 1H), 1.31 (s, 3H), 0.88–0.86 (m, 3H).

(2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4-fluoro-N-(6hydroxypyridin-2- yl) pyrrolidine-2-carboxamide (83):

1H NMR (400 MHz, DMSO-d6) δ: 10.38 (s, 1H), 9.04 (s, 2H), 8.43 (s, 1H), 7.89-7.83 (m, 2H), 7.54-7.50 (m, 1H) , 7.25-7.18 (m, 1H), 6.28 (d, J=8.0 Hz, 1H), 5.85 (d, J=17.2 Hz, 1H), 5.65 (d, J=17.2 Hz, 1H), 4.69-4.65 ( m, 1H), 4.28-4.19(m, 1H), 4.06-3.94 (m, 2H), 2.68 (s, 3H), 2.64 (s, 3H), 2.18-2.04 (m, 1H).

(1 R,3S,5S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-K-(6bromo -3-methylpyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (98):

1H NMR (400 MHz CD3OD) δ 9.00 (s, 2H), 8.42 (d, J=1.1 Hz, 1H), 7.57-7.51 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 5.98 ( d, J=16.0 Hz, 1H), 5.82 (d, J=16.0 Hz, 1H), 4.64 (m, 1H), 3.73 (m, 1H), 3.58 (d, J=1.2 Hz, 2H), 3.43

- 260 041794 (s, 3H), 2.76 (s, 6H), 2.70 (s, 3H), 2.62 (m, 1H), 2.54 (m, 1H), 2.14 (s, 3H), 1.34 (t, J= 5.5 Hz, 1H), 1.09 (m, 1H).

LC/MS (ESI) m/z: 646 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6hydroxypyridine -2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (105):

¹ H NMR (400 MHz, DMSO-d6) δ: 10.20 (s, 1H), 9.02 (s, 2H), 8.31 (s, 1H), 7.55 (s, 1H), 7.53-7.50 (m, 1H), 7.21-7.20 (m, 1H), 6.27-6.26 (m, 1H), 6.08 (d, J=20Hz, 1H), 5.66 (d, J=20Hz, 1H), 4.47-4.43 (m, 2H) , 3.773.62 (m, 1H), 2.68 (s, 9H), 2.04-2.00 (m, 1H), 1.24 (s, 3H), 1.01-0.98 (m, 1H), 0.89-0.88 (m, 1H) .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridine -2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (106): 1H NMR (400 MHz, DMSOd6) δ: 10.29 (s, 1H), 8.66 (s, 2H) , 8.30 (s, 1H), 7.90-7.72 (m, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.55 (d, J=17.6 Hz, 1H), 4.42-4.38 (m, 1H), 3.59-3.58 (m, 1H), 2.64 (s, 3H), 2.04 (s, 3H), 1.32-1.24 (m, 5H), 1.03–1.00 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromopyridin-2-yl) -5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (108):

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 10.77 (s, 1H), 8.94 (s, 1H), 8.37 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.857.79 (m, 2H), 7.72-7.70 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 5.94 (d, J=17.2 Hz, 1H), 5.55 (d, J=17.2 Hz, 1H) , 4.434.39 (m, 1H), 3.97 (s, 3H), 3.67-3.61 (m, 1H), 2.68 (s, 3H), 2.00-1.96 (m, 1H), 1.29 (s, 3H), 0.95 -0.83 (m, 3H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromopyridin-2-yl) -5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (109):

1H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 8.74 (s, 2H), 8.30 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.827.69 (m , 2H), 7.33(d, J=8.0 Hz, 1H), 5.94 (d, J=17.2 Hz, 1H), 5.55 (d, J=17.2 Hz, 1H), 4.43-4.39 (m, 1H), 3.643 .62 (m, 1H), 2.67 (s, 3H), 2.01-1.96 (m, 1H), 1.30 (s, 3H), 0.97-0.86 (m, 3H).

(1 R,3S,5S)-2-(2-(3-Acetyl-7-(methoxymethyl)-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)K- (6-bromo-3-methylpyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (114):

1H NMR (400 MHz, CD3OD) δ 9.04 (s, 2H), 8.61 (d, J=2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H ), 7.39 (d, J=8.0Hz, 1H), 6.04 (d, J=16.0Hz, 1H), 5.89 (d, J=16.0Hz, 1H), 4.98 (d, J=12.0Hz, 1H), 4.71 (d, J=12.0 Hz, 1H), 4.63 (m, 1H), 3.69 (m, 1H), 3.58 (m, 2H), 3.43 (s, 3H), 3.39 (s, 3H), 2.77 (s , 3H), 2.71 (s, 3H), 2.58 (m, 2H), 2.15 (s, 3H), 1.33 (m, 1H), 1.15 (m, 1H). LC/MS (ESI) m/z: 676 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-hydroxypyrimidin-5-yl)-7-methyl-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (121):

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.32 (s, 1H), 8.72 (s, 2H), 8.19 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.01 (d, J=17.6 Hz, 1H), 5.66 (d, J=18.0 Hz, 1H), 4.42-4.38 (m, 1H), 2.67 ( s, 3H), 2.64 (s, 3H), 2.63-2.58 (m, 1H), 2.04 (s, 3H), 2.01-1.99 (m, 1H), 1.32 (s, 3H), 1.01-0.94 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-4-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6- bromo3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (130):

1H NMR (400 MHz, CD3OD) δ 8.92 (d, J=1.1 Hz, 2H), 7.60 (m, 3H), 7.38 (d, J=7.9 Hz, 1H), 5.80 (m, 1H), 5.65 (m , 1H), 4.53 (m, 1H), 3.53 (m, 1H), 2.76 (s, 3H), 2.71 (s, 3H), 2.63 (m, 1H), 2.31 (m, 1H), 2.12 (s, 3H), 1.40 (s, 3H), 1.10 (m, 1H), 1.00 (m, 1H). LC/MS (ESI) m/z: 620 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-cyclopropyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N (6-bromo -3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (131):

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.03 (S, 2H), 8.32 (d, J=1.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J=7.6Hz, 1H), 6.14 (d, J=17.6Hz, 1H), 5.87 (d, J=17.6Hz, 1H), 4.42-4.38 (m, 1H) , 3.61-3.59 (m, 1H), 2.68 (s, 3H), 2.65 (s, 3H), 2.58-2.52 (m, 1H), 2.30 (m, 1H), 2.04 (m, 4H), 1.32 (m , 3H), 1.041.00 (m, 4H), 0.91–0.89 (m, 2H). LC/MS (ESI) m/z: 642 (M+H) ⁺ .

(1R,2S,5S)-3-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (141):

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.73-0.89 (m, 2H), 1.88-1.96 (m, 1H), 2.03 (s, 4H), 2.67 (s, 3H), 2.70 (s, 3H) , 3.91 (d, J=9.6 Hz, 1H), 4.02-4.11 (m, 1H), 4.62 (d, J=5.4 Hz, 1H), 5.65-5.80 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 8.60 (s, 1H), 9.26 (d, J=1.3 Hz, 1H), 9.34 (s, 2H), 10.30 (s, 1H).

(1 R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6-bromo- 3 (methoxymethyl)pyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (152):

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.53 (s, 1H), 7.78 (d, J=1.2 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.46 (d , J=8.0 Hz, 1H), 5.81 (d, J=16.0 Hz, 1H), 5.66 (d, J=16.0 Hz, 1H), 4.58 (m, 1H), 4.28 (m, 2H), 3.73 (m , 1H), 3.55 (m, 2H), 3.42 (s, 3H), 3.17 (s, 3H), 2.75 (s, 3H), 2.69 (s, 3H), 2.63-2.50 (m, 2H), 1.32 ( d, J=4.0 Hz, 1H), 1.11 (m, 1H). LC/MS (ESI) m/z: 662 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin- 2-yl)-5-((2,2-difluorocyclopentanecarboxamido)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (159):

1H NMR (400 MHz, CD3OD) δ 8.93 (s, 2H), 8.47 (s, 1H), 7.71 (s, 2H), 7.47 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.9, 2.2 Hz, 1H), 5.69 (m, 1H), 5.57 (m, 1H), 4.54 (m, 1H), 3.67-3.29 (m, 3H), 3.05-2.88 (m, 1H), 2.66 (s, 3H ), 2.61 (s, 3H), 2.18-1.88 (m, 6H), 1.94-1.73 (m, 2H), 1.65 (m, 1H), 1.21 (m, 1H), 1.06-0.93 (m, 1H).

- 261 041794

LC/MS (ESI) m/z: 749 (M+H)+.

(1R,2S,5S)-3-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-5-fluoro-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (172):

1H NMR (400 MHz, DMSO-d6) δ 0.74-0.88 (m, 2H), 1.88-1.98 (m, 1H), 2.02-2.09 (m, 4H), 2.68 (s, 3H), 2.70 (s, 3H ), 3.91 (d, J=9.6 Hz, 1H), 4.01-4.09 (m, 1H), 4.60 (d, J=5.4 Hz, 1H), 5.67-5.83 (m, 2H), 7.80 (d, J= 8.4 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 9.26 (s, 1H), 9.34 (s, 2H), 10.30 (s, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetyl)-N (6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (182):

¹ H NMR (400 MHz, DMSO-d6) δ 0.94-0.98 (m, 1H), 1.02-1.08 (m, 1H), 1.33 (s, 3H), 1.97-2.14 (m, 4H), 2.54-2.60 ( m, 1H), 2.68 (s, 3H), 2.71 (s, 3H), 3.59-3.66 (m, 1H), 4.40 (dd, J=5.1, 9.2 Hz, 1H), 5.62 (d, J=17.0 Hz , 1H), 5.91 (d, J=17.1 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 8.84 (d, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H ), 9.14 (s, 2H), 10.27 (s, 1H).

(1R,2S,5S)-3-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetyl)-N (6-bromo-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (183):

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.73-0.81 (m, 1H), 0.82-0.92 (m, 2H), 1.89 (s, 1H), 2.04 (s, 3H), 2.66 (s, 3H) , 2.71 (s, 3H), 3.93 (d, J=9.8 Hz, 1H), 4.05-4.13 (m, 1H), 4.60 (d, J=5.4 Hz, 1H), 5.59 (s, 2H), 7.40 ( d, J=7.9 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.13 (s, 2H), 10.27(s, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)-N (6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (185):

1H NMR (400 MHz, DMSO-d6) δ 0.96-1.08 (m, 2H), 1.31-1.35 (m, 3H), 2.07 (s, 4H), 2.53-2.60 (m, 1H), 2.73 (s, 3H ), 2.82 (s, 3H), 3.53-3.60 (m, 1H), 4.35-4.43 (m, 1H), 5.61 (d, J=17.2 Hz, 1H), 5.93 (d, J=17.2 Hz, 1H) , 7.83 (d, J=8.4Hz, 1H), 8.23 (d, J=9.0Hz, 1H), 8.35 (d, J=8.9Hz, 1H), 9.44 (s, 2H), 10.26 (s, 1H) .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-3-(morpholinomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (192):

1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.36 (s, 2H), 9.33 (s, 1H), 8.63 (s, 1H), 7.77 (d, 1H, J=8.4 Hz) , 7.47 (d, 1H, J=8.4 Hz), 6.08 (d, 1H, J=17.7 Hz), 5.74 (d, 1H, J=17.7 Hz), 4.44-4.49 (m, 1H), 3.61-3.65 ( m 1H), 3.42-3.46 (m, 4H), 3.28 (s, 2H), 2.70 (s, 3H), 2.69 (s, 3H), 2.54-2.59 (m, 1H), 2.07-2.18 (m, 5H ), 1.35 (s, 3H), 0.99–1.13 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (195):

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.98-1.04 (m, 1H), 1.07-1.12 (m, 1H), 1.33 (s, 3H), 2.01-2.12 (m, 4H), 2.54-2.61 ( m, 1H), 2.67 (s, 3H), 3.56-3.65 (m, 1H), 4.38-4.45 (m, 1H), 5.69 (d, J=17.2 Hz, 1H), 6.00 (d, J=17.2 Hz , 1H), 6.90 (s, 2H), 7.83 (d, J=8.4 Hz, 1H), 8.37 (s, 1H), 8.93 (s, 2H), 9.20 (s, 1H), 10.27 (s, 1H) .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)Na( 6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (198):

1H NMR (400 MHz, DMSO-d6) δ 0.99-1.06 (m, 1H), 1.07-1.12 (m, 1H), 1.34 (s, 3H), 2.00-2.12 (m, 4H), 2.53-2.61 (m , 1H), 2.69 (s, 3H), 3.55-3.63 (m, 1H), 4.01 (s, 3H), 4.29-4.49 (m, 1H), 5.73 (d, J=17.2 Hz, 1H), 6.04 ( d, J=17.3 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 8.55 (d, J=1.3 Hz, 1H), 9.20-9.33 (m, 3H), 10.27 (s, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-1yl)acetyl) ^-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.26 (s, 2H), 8.49 (d, J=6.0 Hz, 2H), 7.82 (d, J=8.3 Hz, 1H), 5.79 (d, J=17.9 Hz, 1H), 5.48 (d, J=17.8 Hz, 1H), 4.39 (m, 1H), 3.57 (m, 1H), 2.82 (s, 3H), 2.67 (s, 3H) , 2.60-2.52 (m, 1H), 2.10-1.97 (m, 4H), 1.33 (s, 3H), 1.02 (m, 1H), 0.91 (m, 1H). LC/MS (ESI) m/z: 634/636 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -4-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.39 (s, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.11 (s, 1H), 5.95-6.00 (d, J=18 Hz, 1H), 5.76-5.80 (d, J=18 Hz, 1H), 4.46-4.50 (m, 1H), 3.53-3.55 (m, 1H), 2.75 (s, 3H), 2.73 (s , 3H), 2.67 (s, 3H), 2.53-2.59 (m, 1H), 2.31 (s, 3H), 2.15-2.19 (m, 1H), 1.38 (s, 3H), 1.08-1.11 (m, 1H ), 0.94–0.96 (m, 1H). LC/MS (ESI) m/z: 616/618 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-4-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 9.31 (s, 2H), 9.20 (s, 1H), 8.63 (s, 1H), 7.90 (s, 1H), 7.10 (s, 1H), 5.93-5.98 (d, J=17.6 Hz, 1H), 5.72-5.77 (d, J=17.2 Hz, 1H), 4.48-4.51 (m, 1H), 3.54-3.56 (m, 1H), 2.74 (s, 3H), 2.70 (s , 3H), 2.53-2.59 (m, 1H), 2.29 (s, 3H), 2.15-2.20 (m, 1H), 1.38 (s, 3H), 1.08-1.11 (m, 1H), 1.00-1.02 (m , 1H). LC/MS (ESI) m/z: 603/605 (M+H) ⁺ .

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6-bromo-4methylpyridin-2-yl )-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.97 (d, J=7.1 Hz, 2H), 8.54-8.48 (m, 1H), 7.90 (s, 1H), 7.77 (d, J=1.2 Hz, 2H), 7.11 (s, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.63 (d, J=17.2 Hz, 1H), 4.53-4.44 (m, 1H), 3.57-3.52 (m, 1H), 2.74 ( s, 3H), 2.69 (s, 3H), 2.59-2.52 (m, 1H), 2.30 (s, 3H), 2.21-2.14 (m, 1H), 1.37 (s, 3H), 1.10-1.04 (m, 1H), 0.99-262 041794

0.95 (m, 1H). LC/MS (ESI) m/z: 602/604 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl) acetyl)-N-(6-bromo-4-fluoroiridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.32 (s, 2H), 8.48 (s, 1H), 7.84-7.87 (dd, J=11.2 Hz, 1.6 Hz, 1H), 7.41-7.43 (dd, J=7.6 Hz, 1.2 Hz, 1H), 6.16-6.20 (d, J=18.0 Hz, 1H) 5.75-5.79 (d, J=18.0 Hz, 1H), 4.354.45 (m, 1H), 3.66-3.67 (m, 1H), 2.92 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 2.64-2.65 (m, 1H), 2.02-2.03 (m, 1H) , 1.31 (s, 3H), 0.99–1.01 (m, 1H), 0.92–0.94 (m, 1H). LC/MS (ESI) m/z: 621/623 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl) acetyl)-N-(6-bromo-5-fluoro-3-methyliiridin-2-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2azabicyclo[3.1. 0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 9.33 (s, 2H), 8.50 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 6.17 (d, J=18.0 Hz, 1H), 5.80 (d, J=18.0 Hz, 1H), 4.45 (m, 1H), 3.86 (m, 1H), 3.25 (d, J=16.0 Hz, 1H), 3.10 (d, J=16.0 Hz, 1H), 2.92 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 2.66-2.62 (m, 1H), 2.46 (s, 3H), 2.18 (m, 1H ), 2.03 (s, 3H), 1.25 (m, 1H), 1.16 (m, 1H). LC/MS (ESI) m/z: 717/719 (M+H) ⁺ .

(2S,4R)-1-{2-[3-Acetyl-7-methyl-5-(2-methyliurimidin-5-ul)irazolo[3,4-c]irudin-1-yl]acetyl}K-( 6-bromo-3-methyliiridin-2-yl)-4-fluoro-4-methyliirrolidin-2-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.33 (d, J=5.4 Hz, 2H), 8.49 (d, J=6.9 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 6.01 (d, J=17.9 Hz, 1H), 5.82 (d, J=17.8 Hz, 1H), 4.68-4.62 (m, 1H) , 4.304.22 (m, 1H), 3.94-3.83 (m, 1H), 2.89 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 2.24-2.16 (m, 1H), 2.13 -2.04 (m, 1H), 1.99 (s, 3H), 1.64 (d, J=21.0 Hz, 3H). LC/MS (ESI) m/z: 623(M+H)+.

(2S,4R)-1 -(2-(3-Acetyl-7-methyl-5 -(2-methylpyrimidin-5-yl)-1H-indazol-1 -yl)acetyl)-K-(6-bromo- 3methylpyridin-2-yl)-4-fluoro-4-methylpyrrolidin-2-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.02 (d, J=6.8 Hz, 2H), 8.30 (d, J=1.1 Hz, 1H), 7.63-7.56 (m, 2H ), 7.42 (d, J=7.9 Hz, 1H), 5.89 (d, J=17.9 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.67-4.62 (m, 1H), 4.28-4.20 (m, 1H), 3.92-3.80 (m, 1H), 2.68 (s, 3H), 2.66 (s, 3H), 2.64 (s, 3H), 2.24-2.14 (m, 1H), 2.13-2.02 (m , 1H), 2.00 (s, 3H), 1.63 (d, J=21.0 Hz, 3H). LC/MS (ESI) m/z: 622(M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl) acetyl)-N-(6-bromo-5-fluoro-3-methyliiridin-2-yl)-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2azabicyclo[3.1. 0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 8.98 (s, 2H), 8.40 (d, J=1.1 Hz, 1H), 7.58-7.48 (m, 2H), 5.98 (d, J=17.7 Hz, 1H), 5.80 (d, J=17.7 Hz, 1H), 4.59-4.56 (m, 1H), 3.85 (dd, J=5.7, 2.7 Hz, 1H), 3.37 (d, J=16.1 Hz, 1H), 3.16 (d , J=16.1 Hz, 1H), 2.73 (dd, J=11.1, 3.4 Hz, 7H), 2.67 (s, 3H), 2.48 (dd, J=13.7, 4.3 Hz, 1H), 2.36 (s, 3H) , 2.12 (s, 3H), 1.37 (t, J=5.7 Hz, 1H), 1.29 (m, 1H), 1.18 (m, 1H). LC/MS (ESI) m/z: 717/719 [M+H] ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methyliurimidin-5-ul)-1H-indazol-1-yl)acetyl)-N(6 -bromo-3-methyliiridin-2-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.07 (s, 2H), 8.58 (s, 1H), 8.01 (s, 1H), 7.62 (d, J=8.3 Hz, 1H ), 7.44 (d, J=7.9 Hz, 1H), 5.72-5.97 (m, 3H), 5.62-5.70 (m, 1H), 4.45 (dd, J=9.3, 5.3 Hz, 1H), 3.82 (dd, J=5.6, 2.7 Hz, 1H), 3.09-3.23 (m, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.51-2.52 (m, 1H), 2.45 (s, 3H), 2.14 -2.21 (m, 1H), 1.99 (s, 3H), 1.22-1.26 (m, 1H), 1.13-1.20 (m, 1H). LC/MS (ESI) m/z: 716/718 (M+H) ⁺ .

(1R,3S,5R)-N-(6-Bromo-3-methyliiridin-2-yl)-2-{2-[3-carbamoyl-5-(2-methyliirimidin-5yl)irazolo[3,4-с ]iiridin-1-yl]acetyl}-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 9.34 (s, 2H), 9.21 (d, J=1.2 Hz, 1H), 8.69 (d, J=1.2 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.90 (d, J=20.0 Hz, 1H), 5.75 (d, J=20.0 Hz, 1H), 4.54 (m, 1H), 3.54 (m, 1H), 2.76 (s, 3H), 2.63 (m, 1H), 2.31 (m, 1H), 2.11 (s, 3H), 1.41 (s, 3H), 1.10 (t, J=4.0 Hz, 1H), 1.00(m, 1H). LC/MS (ESI) m/z: 604/606 (M+H) ⁺ .

(1R,2S,5S)-3-{2-[3-Acetyl-7-methyl-5-(2-methyliirimidin-5-yl)irazolo[3,4-c]iiridin-1yl]acetyl}-K- [(3-chloro-2-fluorophenyl)methyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 2H), 8.49 (s, 1H), 8.43 (t, J=5.7 Hz, 1H), 7.40 (dd, J=14.7, 7.8 Hz, 1H ), 7.23 (dd, J=14.0, 7.4 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 5.87-5.70 (m, 2H), 4.47 (t, J=9.6 Hz, 1H), 4.35 (dd, J=15.6, 5.9Hz, 1H), 4.24 (dd, J=15.6, 5.6Hz, 1H), 4.00 (dd, J=9.7, 5.1Hz, 1H), 3.85 (d, J=9.8Hz, 1H), 2.88 (s, 3H), 2.66 (t, J=9.4 Hz, 6H), 1.93 (d, J=12.2 Hz, 1H), 1.84 (s, 1H), 0.81-0.67 (m, 2H). LC/MS (ESI) m/z: 576 (M+H) ⁺ .

(1R,2S,5S)-3-(2-(3-Acetyl-5 -(2-methyliirimidin-5-yl)-1 H-indazol-1 -yl)αcetyl)-N-(3-chloro-2fluorobenzyl )-3-azabicyclo[3.1.0]hexane-2-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.53 (s, 1H), 7.75 (s, 2H), 7.31-7.23 (m, 2H), 6.97-6.91 (m, 1H), 5.48 (t, J=13.4Hz, 2H), 4.56 (d, J=5.6Hz, 1H), 4.49 (d, J=15.6Hz, 1H), 4.38 (d, J=15.6Hz, 1H), 4.08-4.03 (m, 1H), 3.91 (d, J=9.7 Hz, 1H), 2.75 (s, 3H), 2.67 (s, 3H), 2.05-2.00 (m, 1H), 1.96-1.90 (m, 1H), 0.87-0.78 (m, 2H). LC/MS (ESI) m/z: 561(M+H)+.

(2S)-1-{2-[3-Acetyl-7-methyl-5-(2-methyliirimidin-5-yl)irazolo[3,4-c]iiridin-1-yl]acetyl}-N(6- brom-3-methyliiridin-2-yl)-4-fluoro-4-(fluoromethyl)iirrolidin-2-carboxamide:

- 263 041794

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 9.32 (s, 2H), 8.48 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.42 (d,

J=7.9Hz, 1H), 6.06(d, J=17.9Hz, 1H), 5.88(d, J=17.8Hz, 1H), 4.96(d, J=22.5Hz, 1H), 4.84(d, J= 21.2 Hz

1H), 4.72 (t, J=8.4 Hz, 1H), 4.41-4.31 (m, 1H), 4.14-4.03 (m, 1H), 2.90 (s, 3H), 2.69 (s, 3H), 2.67 (s , 3H), 2.372.15 (m, 2H), 1.99 (s, 3H). LC/MS (ESI) m/z: 641/643 (M+H)+.

2-{2-[3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)inαzol-1-yl]acetyl}-N-(6-bromo-3methylpyridin-2-yl)- 5-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 9.04 (s, 2H), 8.67 (t, J=1.9 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H ), 7.41-7.33 (m, 1H), 5.98-5.64 (m, 4H), 4.59 (dd, J=9.2, 4.9 Hz, 1H), 3.84 (dd, J=5.7, 2.7 Hz, 1H), 3.39 ( d, J=16.1 Hz, 1H), 3.16 (d, J=16.1 Hz, 1H), 2.85-2.62 (m, 6H), 2.52 (dd, J=13.5, 5.2 Hz, 1H), 2.33 (d, J =20.8 Hz, 3H), 2.13-1.98 (m, 3H), 1.60 (s, 1H), 1.42-1.37 (m, 1H), 1.22 (dd, J=5.9, 2.6 Hz, 1H). LC/MS (ESI) m/z: 716 (M+H) ⁺ .

(1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-2-(2-(3-cyano-7-methyl-5-(2-methylpyrimidin-5-yl)1H -indazol-1-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.13 (s, 2H), 8.13 (s, 1H), 7.73 (s, 1H), 7.61 (d, J=8.0 Hz, 1H) , 7.43 (d, J=8.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.17-7.10 (m, 1H), 6.05 (d, J=18.0 Hz, 1H), 5.70 (d, J=18.0 Hz, 1H), 4.40-4.37 (m, 1H), 3.57-3.56 (m, 1H), 2.68 (s, 3H), 2.67 (s, 3H), 2.66-2.65 (m, 1H), 2.02 (s, 3H), 2.01-2.02 (m, 1H), 1.31 (s, 3H), 1.01-0.98 (m, 1H), 0.93-0.92 (m, 1H).

Scheme 6: (1S,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indαzol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (10)

Stage 1. (3S)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((1,3-dioxoisoindolin-2yl)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (10-S2): to a solution of 10-S1 (1 g, 2.34 mmol), isoindoline-1,3-dione (517 mg, 3.52 mmol) and PPh ₃ (1.22 g, 4.68 mmol) in THF ( 15 ml) was added DIAD (0.92 ml, 4.68 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=10:1 to 3:1) to give the title compound (1.25 g, 96.1% yield) as a light yellow solid. LC/MS (ESI) m/z: 555/557 (M+H) ⁺ .

Stage 2. (3S)-tert-Butyl 5-(aminomethyl)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (10-S3): to To a solution of 10-S2 (1.2 g, 2.16 mmol) in EtOH (10 ml) was added hydrazine hydrate (1 ml, 85%). The reaction mixture was stirred at 60°C for 3 h and then cooled to room temperature. The mixture was filtered, the filtrate was concentrated to dryness and the remaining crude product was purified by silica gel column chromatography (eluting with DCM/MeOH = 80:1 to 5:1) to give 10-S3 (500 mg, 52.4% yield) as light yellow oils. LC/MS (ESI) m/z: 425/427 (M+H) ⁺ .

Step 3. (3S)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (10-S4 ): NaBH ₃ CN (148 mg, 2.36 mmol) and 15% aqueous formaldehyde solution (0.3 ml) were added to a solution of 10-S3 (500 mg, 1.18 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 30:1) with

- 264 041794 followed by preparative HPLC to give 10-S4 (90 mg, 16.8% yield) as a white solid. LC/MS (ESI) m/z: 453/455 (M+H)+.

Step 4. (1 R,3 S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide ( 10-S5): TFA (1 ml) was added to a solution of 10-S4 (90 mg, 0.21 mmol) in DCM (3 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 10-S5 (65 mg, 94.6% yield) as a yellow solid. The crude material was carried to the next stage of the synthesis without further purification. LC/MS (ESI) m/z: 353/355 (M+H) ⁺ .

Step 5. (1S,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (10): to a solution of 10-S5 (90 mg, 0.20 mmol), 2-( 3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (75 mg, 0.24 mmol) and HATU (152 mg, 0.40 mmol) in DMF (3 ml) DIPEA was added (0.13 ml, 0.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative TLC to give 10 (35 mg, 27.3% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.52 (s, 1H), 7.75 (s, 2H), 7.53 (d, J=7.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 5.78-5.82 (m, 1H), 5.62-5.67 (m, 1H), 5.10-5.12 (m, 1H), 3.82-3.85 (m, 1H), 3.42-3.48 (m, 1H), 2.73-2.86 (m, 10H), 2.69 (s, 3H), 2.47-2.52 (m, 1H), 2.06 (s, 3H), 1.79-1.81 (m, 1H), 0.89-0.92 (m, 2H). LC/MS (ESI) m/z: 645/647 (M+H) ⁺ .

Scheme 7. Synthesis of (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridin- 2-yl)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (11)

Step 1. (3aR,6aS)-tert-Bugyl 5-(((4-fluorophenoxy)carbonothioyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11-S2): to (3aR,6aS) solution 4-Fluorophenylthionochloroformate (213.5 mg, 1.12 mmol) and DMAP were added to DCM (5 ml) (344.6 mg, 2.82 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 ml), washed with 0.5N. aqueous HCl (10 ml), water (10 ml) and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=20:1 to 10:1) to give 11-S2 (338 mg, 94.3% yield) as a white solid. LC/MS (ESI) m/z: 404 (M+Na) ⁺ .

Step 2. (3aR,6aS)-tert-Butyl hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11-S3): to

- 265 041794 solution of (3aR,6aS)-tert-butyl 5-(((4-fluorophenoxy)carbonothioyl)oxy)hexahydrocyclopenta[c]pyrrole 2(1H)-carboxylate (11-S2, 338 mg, 0.89 mmol) in 1, 4-dioxane (3 ml) was added 1,1'azobis(cyclohexanecarbonitrile) (Vazo, 73.0 mg, 0.45 mmol) and tris(trimethylsilyl)silane (330.9 mg, 1.33 mmol). The reaction mixture was stirred at 105° C. for 40 minutes at room temperature for 30 minutes. The mixture was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 40:1 to 10:1) to give 11S3 (73 mg, 38.8% yield) as a yellow oil. LC/MS (ESI) m/z: 156 (M+H-56)+.

Step 3. (3aR,6aS)-Octahydrocyclopenta[c]pyrrole (11-S4): to a solution of (3aR,6aS)-tert-butyl hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (11-S3, 73 mg , 0.14 mmol) in DCM (3 ml) was added TFA (1 ml) at 0°C, and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated under reduced pressure to obtain 11-S4 (70 mg, 100% yield ). This crude material was carried to the next stage of the synthesis without further purification. LC/MS (ESI) m/z: 112 (M+H) ⁺ .

Step 4. (3S)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-2 -azabicyclo[3.1.0]hexane-2-carboxylate (11-S6): to a mixture of (3aR,6aS)octahydrocyclopenta[c]pyrrole (11-S4, 35 mg, 0.3 mmol) and DIPEA (77.4 mmol, 0.6 mmol) (3S)-tert-butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5(((methylsulfonyl)oxy)methyl)-2-azabicyclo[3.1. 0]hexane-2-carboxylate (S5, 100 mg, 0.20 mmol) and NaI (32 mg, 0.2 mmol) at 0°C. After stirring at room temperature overnight, the mixture was evaporated under reduced pressure and the remaining residue was purified by silica gel column chromatography (PE/EtOAc=5:1 to 1:1) to give 11-S6 (30 mg, 28.9% yield) as brown oil. LC/MS (ESI) m/z: 519 (M+H) ⁺ .

Step 5. (3S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)yl)methyl)-2-azabicyclo[3.1.0] hexane-3-carboxamide (11-S7): to a solution of (3S)-tert-butyl 3-((6-bromo-3methylpyridin-2-yl)carbamoyl)-5-((hexahydrocyclopenta[c]pyrrole-2(1H )-yl)methyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (11-S6, 30 mg) in 1,4-dioxane (1 ml) was added 4n. HCl solution in 1,4-dioxane (1 ml) at 0°C, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness to give 11-S7 (30 mg, 100% yield), which was used in the next synthesis stage without further purification.

Step 6. (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2 -yl)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (11): to a mixture of (3S)-N-(6- bromo-3-methylpyridin-2-yl)-5-((hexahydrocyclopenta[c]pyrrol2(1H)-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (11-S7, 20 mg, 0.05 mmol), 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-III-indazol-1-yl)acetic acid (14.8 mg, 0.05 mmol) and HATU (28.5 mg, 0.08 mmol) in DMF ( 2 ml) DIPEA (19.3 mg, 0.15 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative TLC to give 11 (1.1 mg, 3.1% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.01 (d, J=2.8 Hz, 2H), 8.56 (d, J=5.3 Hz, 1H), 7.79-7.76 (m, 2H), 7.587.54 (m, 1H) , 7.44-7.39 (m, 1H), 5.83-5.79 (d, 1H), 5.69-5.64 (s, 1H), 3.93-3.86 (m, 2H), 3.49-3.46 (m, 1H), 2.97-2.93 ( m, 2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.10 (d, J=18.6 Hz, 3H), 1.40-1.26 (m, 13H). LC/MS (ESI) m/z: 711 (M+H) ⁺ .

Scheme 8. Synthesis of (3S)-5-(3-Azabicyclo[3.1.1]heptan-3-ylmethyl)-2-(2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-indazol- 1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (12)

- 266 041794

About 12-S1

O Cl^^ ⁴ ^ _g BnNH ₂ , THF

Stage 1 ivn ₄ _ thf ' ^but

Stage h

12-S6

12-S4

12-S7

Stage 6

12-1

BHZ-THF

THF

ABOUT

HATU,DIPEA,DMF

MsCl, TEA

Nai, acetone.

Stage 4

Vod.HCl MeOH

Stage 7

Nai, DIPEA, MeCN

HN » A Stage > 8

12-S9

Br

Stage 9

Stage 10

Step 1. Methyl 1-benzyl-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate (12-S2): To a solution of benzylamine (6 g, 56.1 mmol) in THF (50 ml) was added 12- S1 (4.55 g, 56.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and dissolved in THF (100 ml). Acryloyl chloride (5.55 g, 61.7 mmol) was added to the solution at 0°C and the reaction mixture was stirred at room temperature overnight. The solution was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 5:1 to 3:1) to give the title compound (3.5 g, 25.5% yield) as a yellow oil. LC/MS (ESI) m/z: 246 (M+H)+.

Stage 2. Methyl 1-benzyl-6-oxopiperidine-3-carboxylate (12-S3): to a solution of 12-S2 (3.5 g, 14.3 mmol) in EtOH (30 ml) was added Pd/C (10% mol, 151 mg ). The mixture was purged with nitrogen, purged with hydrogen, and stirred under a hydrogen atmosphere (balloon) at room temperature for 1.5 h. The mixture was filtered through a pad of celite and washed with EtOH. The filtrate was concentrated to dryness to give the title compound (3.2 g, 90.2% yield) as a colorless oil. LC/MS (ESI) m/z: 248 (M+H) ⁺ .

Stage 3. 1-Benzyl-5-(hydroxymethyl)piperidin-2-one (12-S4): LiBH4 (566 mg, 26.0 mmol) was added to a solution of 12-S3 (3.2 g, 13.0 mmol) in THF (45 ml) at 0°C. The reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc (50 ml). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 50:1) to give the title compound (2.2 g, 77.3% yield) as a yellow oil. LC/MS (ESI) m/z: 220 (M+H)+.

Stage 4. 1-Benzyl-5-(iodomethyl)piperidin-2-one (12-S5): Et ₃ N (3.47 ml, 25.0 mmol) and MsCl (1.72 g, 15 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight under nitrogen. Ice water was added and the organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and diluted with acetone (25 ml). NaI (4.50 g, 30.0 mmol) was then added, the mixture was stirred at reflux for 24 h. The mixture was cooled to room temperature and concentrated. The remaining residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 5:1 to 3:1) to give the title compound (1.5 g,

45.5% yield) as a yellow oil. LC/MS (ESI) m/z: 330 (M+H)+.

Step 5. 3-Benzyl-3-azabicyclo[3.1.1]heptan-2-one (12-S6): LiHMDS ( 1 M solution in THF, 13.68 ml, 13.68 mmol) at 20°C. The reaction mixture was stirred at -20°C for 1.5 h under nitrogen. The reaction mixture was quenched by adding water and extracted with EtOAc (50 ml). The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 8:1) to give the title compound (600 mg, 65.5% yield) as a colorless oil. LC/MS (ESI) m/z: 202 (M+H) ⁺ .

Step 6. 3-Benzyl-3-azabicyclo[3.1.1]heptane (12-S7): BH3-THF (1 M solution in THF, 8.97 ml, 8.97 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours under nitrogen. The reaction mixture was quenched with MeOH at 0° C. and concentrated. The remaining residue was diluted with EtOH (4.5 ml) and water (0.5 ml) and then stirred at 100°C for 3 h. The mixture was concentrated, diluted with EtOAc and washed with water and brine. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 50:1) to give the title compound (300 mg, 53.7% yield) as a colorless oil. LC/MS (ESI) m/z: 188 (M+H) ⁺ .

Step 7. 3-Benzyl-3-azabicyclo[3.1.1]heptane hydrochloride (12-S8): To a solution of compound 12-S7 (300 mg, 1.6 mmol) and concentrated HCl (0.27 ml) in EtOH (35 ml) was added Pd/C (60 mg). The mixture was purged with nitrogen and stirred under hydrogen atmosphere (balloon) at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated to give the title compound (180 mg, 65.9% yield) as a light brown solid. LC/MS (ESI) m/z: 98 (M+H) ⁺ .

Step 8. (3S)-tert-Butyl 5-(azetidin-1-ylmethyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (12-S10): to a solution of 12-S9 (80 mg, 0.19 mmol) in MeCN (2 mL) were added DIPEA (0.13 mL, 0.76 mmol), 12-S8 (18.5 mg, 0.19 mmol) and NaI at 0°C . The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the remaining residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 50:1) to give the title compound (21 mg, 21.9% yield) as a yellow solid. LC/MS (ESI) m/z: 505 (M+H) ⁺ .

Step 9. (3S)-5-(Azetidin-1-ylmethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (12-S11): HCl/dioxane (1 ml) was added to a solution of 12-S10 (21 mg, 0.042 mmol) in dioxane (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound (25 mg, 100% yield) as a brown solid. LC/MS (ESI) m/z: 405 (M+H) ⁺ .

Step 10 (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-(azetidin-1ylmethyl)-N- (6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (12): to a solution of 12S11 (25 mg, 0.042 mmol) and 12-S12 (13.02 mg, 0.042 mmol) in DMF (2 mL) were added HATU (28.7 mg, 0.076 mmol) and DIPEA (0.029 mL, 0.168 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 12 (2.1 mg, 7.2% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.56 (s, 1H), 7.80 (s, 2H), 7.58 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.0 Hz , 1H), 5.82 (d, J=17.1 Hz, 1H), 5.67 (d, J=17.1 Hz, 1H), 5.34 (t, J=4.6 Hz, 1H), 4.70 (d, J=4.2 Hz, 1H ), 2.75 (d, J=5.0 Hz, 4H), 2.70 (s, 3H), 2.57-2.47 (m, 4H), 2.38-2.27 (m, 4H), 2.22-2.17 (m, 2H), 2.12 ( s, 3H), 2.02 (d, J=7.8 Hz, 2H), 1.49-1.46 (m, 1H), 1.39 (d, J=6.8 Hz, 1H), 1.10-1.08 (m, 1H). LC/MS (ESI) m/z: 697 (M+H) ⁺ .

Scheme 9. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-isopropylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (14)

- 268 041794

Step 1. 2-Bromo-5-isopropyl-1-(oxidanyl)pyridine (14-S2): to a stirred solution of 2-bromo-5-isopropylpyridine (14-S1, 3 g, 1 eq.) in CHCl ₃ (200 ml) 3-chlorobenzooperoxoic acid (10 g, 3 eq.) was added. The reaction mixture was heated to 50°C to complete the reaction. The reaction mixture was cooled and saturated aqueous NaHCO ₃ solution (100 ml) was added. The organic and aqueous layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (100 ml x 3). The combined organic layers were concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM) to give 14-S2 (2.6 g, 80%).

Step 2. 5-Bromo-N-(tert-butyl)-2-isopropylaniline (14-S3): to a stirred solution of 14-S2 (812 mg, 1 eq.) and 2-methylpropan-2-amine (1.97 ml, 5 equiv.) in DCM (100 ml) was added dropwise trifluoroacetic anhydride (0.7 ml, 1.1 equiv.) at 0-5°C in an argon atmosphere. The reaction mixture was stirred at 0-5°C for 1 h and a solution of TFAA (0.7 ml in 5 ml DCM, 1 eq.) was added, followed by the addition of 2-methylpropan-2-amine (0.4 ml, 1 eq.). The reaction mixture was neutralized with an aqueous saturated solution of NaHCO ₃ (50 ml). The organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with hexanes/EtOAc=3:1) to give 14-S3 (397 mg, 39%).

Step 3 5-Bromo-N-(tert-butyl)-2-isopropylaniline (14-S4): TFA (10 ml) was added to 14-S3 (397 mg) and the reaction mixture was heated at 70°C. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (15 ml), washed with aqueous saturated NaHCO ₃ solution (15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness to give 14-S4 (316 mg, quant.).

Step 4. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-isopropylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (14 -S5): to a stirred solution of (1R, 3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (99 mg, 1 eq.), 14- S4 (89 mg, 1 equiv.) in DCM (8 ml) and pyridine (0.17 ml, 5 equiv.) was then added dropwise POCl ₃ (0.04 ml, 2 equiv.) at 0-5°C under argon. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with DCM (10 ml), neutralized with aqueous saturated NaHCO ₃ solution (10 ml) and the aqueous layer was extracted with DCM (1 x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 14-S5 (130 mg, 73%).

Step 5. (1 R,3 S,5R)-N-(6-bromo-3-isopropylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 carboxamide hydrochloride (14-S6 ): to a solution of 14-S5 (130 mg) in DCM (5 ml) was added TFA (5 ml). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness to give 14-S6 as the TFA salt (135 mg, quant.).

Step 6. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-(6bromo -3-isopropylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (14): to a solution of 14S6 (72 mg, 1 equiv.), 2-(3-acetyl- 5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (50 mg, 1.2 equiv.) in DMF (8 ml) and DIPEA (0.17 ml, 5 equiv.) HATU (70 mg, 1.2 equiv.) at 0°C in an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours before being diluted with EtOAc (25 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness.

The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 14 (84 mg, 82%).

1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.75 (d, 1H, J=8.3 Hz) , 7.54 (d, 1H, J=8.3 Hz), 5.91 (d, 1H, J=17.5 Hz), 5.59 (d, 1H, J=17.5 Hz ), 4.41-4.46 (m, 1H), 3.58(t, 1H, J=5.4 Hz), 3.16-3.19 (m, 1H), 2.89-2.97 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.54-2.58 (m, 1H), 2.01 -2.09 (m, 1H), 1.33 (s, 3H), 1.16-1.27 (m, 1H), 1.03-1.09 (m, 6H).

Scheme 10. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (S)

But

The above scheme and the following detailed description depict one non-limiting method for synthesizing compounds by the following steps: 1) forming an amide bond between the B ring and the C ring by first forming an acyl chloride B ring with POCl ₃ ; 2) removal of the Boc group using acid; and 3) formation of an amide bond between the C-ring (already linked to the B-ring) and the A-ring using HATU.

One skilled in the art will appreciate that the C- and B-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention. One skilled in the art will also appreciate that the A-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention. One of skill in the art will also appreciate that the B-ring linked to the C-ring can be further functionalized prior to HATU binding. Additional functionalization includes Stille's cross-matching and Ullmann's cross-matching.

Step 1. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (15 -S3): (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxylic acid (15-S1, 483 mg, 2.0 mmol) and 6- bromo-3-methylpyridine-2amine (15-S2, 374 mg, 2.0 mmol) was dissolved in anhydrous DCM (15 ml). The reaction mixture was cooled in an ice bath and dry pyridine (0.5 ml, 6.0 mmol) was added in one portion followed by POCl ₃ (200 μl, 2.0 mmol). After completion of the addition, the mixture was stirred for 4 h at 0°C, and the reaction was quenched with water (15 ml). The aqueous phase was extracted with DCM (15 ml x 2) and the combined organic layers were washed with brine and dried over MgSO ₄ . The solution was filtered and concentrated and the resulting residue was purified to give 15-S3 (595 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ): (main rotamer) δ 0.61 (dd, J=2.4, 5.3 Hz, 1H), 0.68 (t, J=5.6 Hz, 1H), 1.20 (s, 3H) , 1.38 (s, 9H), 1.88-1.98 (m, 1H), 2.11 (s, 3H), 2.37-2.45 (m, 1H), 3.12 (s, 1H), 4.06 (dd, J=6.6, 8.9 Hz , 1H), 7.44 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 10.17 (s, 1H) ppm.

Step 2. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide hydrochloride (15-S4): tert -Butyl (1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)5-methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (15-S3, 595 mg) was taken in 4n. HCl/dioxane (3.0 ml) and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure. The remaining residue (15-S4) was carried on without further purification and immediately used.

- 270 041794 was called at the next stage.

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl)acetyl)- N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (S): to a solution of (1R,3S,5R)-N-( 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide hydrochloride (15-S4, 87 mg, 0.25 mmol), 2-(3-acetyl-5- HATU (114 mg, 0.3 mmol) followed by dropwise addition of DIEA (4.0 equiv.) at room temperature. The mixture was stirred for 1 hour at room temperature before the volatiles were evaporated. The residue was diluted with 10% sodium carbonate (50 ml) and extracted with EtOAc. The combined organic solutions were washed successively with water, brine and dried over MgSO ₄ . The solution was filtered and the solvent was removed. The residue was purified to give 15 (136.1 mg).

1H NMR (400 MHz, DMSO-d ₆ ): (main rotamer) δ 1.02 (t, J=5.4 Hz, 1H), 1.07-1.13 (m, 1H 1.33 (s, 3H), 2.04 (s, 3H), 2.05-2.11 (m, 1H), 2.56 (dd, J=9.2, 13.3 Hz, 1H), 2.69 (s, 3H), 2.70 (s, 3H), 3.54-3.62 (m, 1H), 4.35-4.48 ( m, 1H), 5.72 (d, J=17.2 Hz, 1H), 6.04 (d, J=17.3 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 8.60 (s, 1H), 9.30 (s, 1H), 9.34 (s, 2H), 10.27 (s, 1H) ppm LC (Method A): & = 1.71 min LC/MS (EI) m /z: [M+H]+ 605.44.

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(3-bromoisoquinolin-1-yl) -5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (73):

¹ H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.04 (s, 2H), 8.46 (s, 1H), 8.09 (s, 1H), 7.82-7.96 (m, 4H), 7.74 -7.80 (m, 1H), 7.51 (t, 1H, J=7.7 Hz), 5.97 (d, 1H, J=17.5 Hz), 5.62 (d, 1H, J=17.5 Hz), 4.51-4.58 (m, 1H), 3.64-3.67 (m, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.61-2.65 (m, 1H), 2.14-2.20 (m, 1H), 1.38 (s, 3H) , 1.00-1.10 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indol-1-yl)acetyl)-K-(6 -bromo3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 0.87 (dd, J=2.4, 5.4 Hz, 1H), 1.15 (t, J=5.4 Hz, 1H), 1.42 (s, 3H), 2.08 (s, 3H) , 2.30-2.36 (m, 1H), 2.53 (s, 3H), 2.67 (d, J=14.8 Hz, 1H), 2.72 (s, 3H), 2.79 (s, 3H), 3.10 (d, J =2.8, 1H), 4.83 (d, J=8.3Hz, 1H), 5.30 (d, J=17.7Hz, 1H), 5.46 (d, J=17.7Hz, 1H), 7.16-7.26 (m, 2H) , 7.34 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 8.55 (s, 1H), 8.56 (brs, 1H), 8.89 (s, 2H).

(1R,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-5-fluoro- 3((methylthio)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 0.97-1.08 (m, 2H), 1.34 (s, 3H), 1.77 (s, 3H), 2.06 (m, 1H), 2.56 (m, 1H), 2.66 ( s, 3H), 2.70 (s, 3H), 3.60 (m, 1H), 4.00-4.80 (m, 2H), 4.40 (m, 1H), 5.59 (m, 1H), 5.92 (m, 1H), 7.85 -7.96 (m, 3H), 8.45 (s, 1H), 9.05 (s, 2H), 10.35 (s, 1H).

(2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4-fluoro-N-(6iodopyridin-2- yl) pyrrolidine-2-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.03 (s, 2H), 8.42 (s, 1H), 8.00-8.02 (d, J=7.2 Hz, 1H), 7.85-7.86 ( m, 2H), 7.51-7.53 (d, J=7.2 Hz, 1H), 7.42-7.46 (t, 1H), 5.82-5.86 (d, J=13.2 Hz, 1H), 5.62-5.66 (d, J= 13.2 Hz, 1H), 5.48-5.61 (m, 1H), 4.65-4.69 (m, 1H), 4.18-4.27 (m, 1H), 3.96-4.08 (m, 1H), 2.68 (s, 3H), 2.64 (s, 3H), 2.51-2.56 (m, 1H), 2.06-2.23 (m, 1H). LC/MS (ESI) m/z: 628 (M+H) ⁺ .

(2S,4R)-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1-H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-4fluoro-K -(pyridin-2-yl)pyrrolidine-2-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (s, 1H), 9.03 (s, 2H), 8.41 (s, 1H), 8.28-8.29 (m, 1H), 8.01-8.03 (d, J= 8.4 Hz, 1H), 7.85 (m, 2H), 7.72-7.76 (m, 1H), 7.06-7.09 (m, 1H), 5.82-5.86 (d, J=17.2 Hz, 1H), 5.63-5.74 (d , J=17.2 Hz, 1H), 5.62 (m, 0.5H), 5.49 (m, 0.5H), 4.69-4.73 (m, 1H), 4.23-4.28 (m, 1H), 3.95-4.08 (m, 1H ), 2.67 (s, 3H), 2.64 (s, 3H), 2.53–2.58 (m, 1H), 2.11–2.21 (m, 1H). LC/MS (ESI) m/z: 502 (M+H) ⁺ .

(2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1-H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N -(6bromopyridin-2-yl)4-fluoro-N-methylpyrrolidin-2-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 2H), 8.43 (s, 1H), 7.77-7.92 (m, 3H), 7.53-7.55 (d, J=8.0 Hz, 1H), 7.45- 7.47 (d, J=8.0 Hz, 1H), 5.76-5.81 (d, J=17.2 Hz, 1H), 5.58-5.62 (d, J=17.2 Hz, 1H), 5.49-5.51 (m, 1H), 4.60 -4.63 (m, 1H), 4.18-4.27 (m, 1H), 3.92-4.05 (m, 1H), 3.23 (s, 3H), 2.72 (s, 1H), 2.71 (s, 1H), 2.63-2.69 (m, 1H), 2.20-2.33 (m, 1H). LC/MS (ESI) m/z: 595/597 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl) acetyl)-N-(6-bromo-4-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.54 (s, 2H), 7.91 (s, 1H), 7.11 (s, 1H), 6.04-6.08 (d, J=17.6 Hz, 1H), 5.845.88 (d, J=17.6 Hz, 1H), 4.48-4.49 (m, 1H), 3.56-3.58 (m, 1H), 2.97 (s, 3H), 2.74 (s, 3H), 2.69 (s, 3H), 2.55-2.60 (m, 1H), 2.31 (s, 3H), 2.16-2.21 (m, 1H), 1.39 (s, 3H), 1.10-1.13 (m, 1H), 0.97-0.99 (m, 1H). LC/MS (ESI) m/z: 617/619 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-methyl-N-(5methyl- [2,2'-bipyridine]-6-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.96 (s, 2H), 8.58 (d, J=4.8 Hz, 1H), 8.52-8.49 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.77-7.69 (m, 3H), 7.36 (t, J=6.4Hz, 1H), 5.79 (d, J= 17.2

- 271 041794

Hz, 1H), 5.63 (d, J=17.2 Hz, 1H), 4.67-4.55 (m, 2H), 3.56-3.52 (m, 1H), 2.74 (s, 3H), 2.69 (s, 3H), 2.35 (dd,

J=13.6, 13.6 Hz, 1H), 2.23 (s, 3H), 1.42 (s, 3H), 1.11 (t, J=5.2 Hz, 1H), 1.03-0.99 (m, 1H). LC/MS (ESI) m/z:

601(M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5-methylK- (6-(pyridin-2-yloxy)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.01 (s, 2H), 8.30 (d, J=2.0 Hz, 1H), 8.18 (m, 1H), 7.917.82 (m , 3H), 7.60 (dd, J=1.6, 1.6 Hz, 1H), 7.16 (m, 1H), 7.07 (m, 1H), 6.81-6.77 (m, 1H), 6.07 (d, J=17.6 Hz, 1H), 5.64 (d, J=17.6 Hz, 1H), 4.41 (dd, J=9.2, 9.2 Hz, 1H), 3.62 (dd, J=5.6, 5.6 Hz, 1H), 2.72-2.62 (m, 9H ), 2.43 (d, J=12.0 Hz, 1H), 1.96 (dd, J=13.2, 13.2 Hz, 1H), 1.29 (s, 3H), 0.98 (t, J=5.2 Hz, 1H), 0.86-0.82 (m, 1H). LC/MS (ESI) m/z: 617 (M+H) ⁺ .

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K{2 -oxo-[1,2'-bipyridine]-6'-yl}-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 9.01 (s, 2H), 8.30 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.987.93 (m , 1H), 7.77 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.52-7.47 (m, 1H), 7.38 (d, J=7.7 Hz, 1H), 6.47 (d, J= 9.2 Hz, 1H), 6.33-6.28 (m, 1H), 6.09 (d, J=17.9 Hz, 1H), 5.66 (d, J=17.8 Hz, 1H), 4.48-4.43 (m, 1H), 3.64 ( m, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.64 (s, 3H), 2.05-1.99 (m, 1H), 1.81 (m, 1H), 1.31 (s, 3H), 1.02 -0.97 (m, 1H), 0.90 (m, 1H). LC/MS (ESI) m/z: 617(M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6bromo -5-fluoro-3-methylpyridin-2-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-azabicyclo[3.1.0]hexane3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.33 (s, 2H), 8.50 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 6.17 (d, J= 18.0Hz, 1H), 5.80(d, J=18.0Hz, 1H),4.45(m, 1H),3.86(m, 1H), 3.25(d, J=16.0Hz, 1H), 3.10(d, J= 16.0 Hz, 1H), 2.92 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 2.66-2.62 (m, 1H), 2.46 (s, 3H), 2.18 (m, 1H), 2.03 (s, 3H), 1.25 (m, 1H), 1.16 (m, 1H). LC/MS (ESI) m/z: 717/719 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6bromo -3-chloropyridin-2-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide: ¹ H-NMR( 4OO MHz, CD3OD) δ 9.00 (s, 2H), 8.42 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.43 (d, J=8.3 Hz, 1H) , 6.01 (d, J=17.7 Hz, 1H), 5.83 (d, J=17.8 Hz, 1H), 4.76 (m, 1H), 3.87-3.84 (m, 1H), 3.20 (s, 2H), 2.78 ( s, 3H), 2.74 (s, 3H), 2.69 (s, 3H), 2.67 (d, J=4.3 Hz, 1H), 2.54 (s, 3H), 2.47 (d, J=10.3 Hz, 1H), 1.42 (m, 1H), 1.21 (m, 1H). LC/MS (ESI) m/z: 718/720 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(6-bromopyrazine -2-yl)-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ: 9.27 (s, 1H), 8.98 (s, 2H), 8.42 (s, 1H), 8.40 (d, J=1.1 Hz, 1H), 7.53 (s, 1H), 6.01 (d, J=17.7 Hz, 1H), 5.80 (d, J=17.7 Hz, 1H), 4.68-4.49 (m, 2H), 3.87 (dd, J=5.8, 2.7 Hz, 1H), 3.23 (d , J=1.9 Hz, 2H), 2.77 (s, 3H), 2.73 (s, 3H), 2.68 (s, 3H), 2.67-2.62 (m, 1H), 2.45 (dd, J=13.8, 3.6 Hz, 1H), 2.31 (s, 3H), 1.40 (m, 1H), 1.20 (m, 1H). LC/MS (ESI) m/z: 685/687 [M+H] ⁺ .

(2S,4S)-1-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6-bromopyridin-2-yl)4-fluoro -4-(1,2,3-triazol-1-ylmethyl)pyrrolidin-2-carboxamide:

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.54 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.82-7.79 (m, 2H), 7.55 (d, J=8.3Hz, 1H), 7.38(d, J=7.9Hz, 1H), 5.67-5.55(m, 2H), 5.11(d, J=10.4Hz, 1H), 5.05(d, J=4.8Hz, 1H), 5.01-4.97 (m, 1H), 4.38-4.28 (m, 1H), 4.16-4.08 (m, 1H), 2.76 (s, 3H), 2.70 (s, 3H), 2.67-2.50 (m, 2H), 2.10 (s, 3H). LC/MS (ESI) m/z: 675(M+H)+.

(2S,4R)-1-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazolacetyl}-N-(6-bromo-3-methylpyridin-2yl)-4-[( dimethylamino)methyl]-4-fluoropyrrolidine-2-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 9.05 (s, 2H), 8.44 (s, 1H), 7.92-7.85 (m, 2H), 7.63 (d, J=8.0 Hz , 1H), 7.46 (d, J=7.9 Hz, 1H), 5.74 (d, J=16.4 Hz, 1H), 5.62 (d, J=17.2 Hz, 1H), 4.70 (d, J=9.6 Hz, 1H ), 4.20-4.08 (m, 2H), 2.78-2.71 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 2.47-2.35 (m, 2H), 2.32 (s, 6H), 2.02 (s, 3H), LC/MS (ESI) m/z: 651(M+H)+.

(2S,4R)-1 -(2-(3-Acetyl-7-methyl-5 -(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl)acetyl) -N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 2H), 8.49 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 6.06 (d, J=18.0 Hz, 1H), 5.88 (d, J=17.8 Hz, 1H), 4.85-4.68 (m, 3H), 4.36 (dd, J=19.0, 12.3 Hz, 1H), 4.14-4.05 (m, 1H), 2.90 (s, 3H), 2.68 (d, J=6.5 Hz, 6H), 2.35-2.24 (m, 2H), 2.02 (s, 3H). LC/MS (ESI) m/z: 659 (M+H) ⁺ .

(2S,4R)-1 -(2-(3-Acetyl-7-methyl-5 -(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl)acetyl) -K-(6-bromopyrazin-2-yl)-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 9.32 (s, 2H), 9.25 (s, 1H), 8.56-8.53 (m, 1H), 8.48 (s, 1H), 6.09 (d, J=18.0 Hz, 1H), 5.91 (d, J=17.9 Hz, 1H), 4.94-4.78 (m, 3H), 4.38 (dd, J=18.6, 12.2 Hz, 1H), 4.17-4.06 ( m, 1H), 2.92 (s, 3H), 2.68 (s, 3H), 2.67 (s, 3H), 2.63-2.56 (m, 1H), 2.33-2.23 (m, 1H). LC/MS (ESI) m/z: 628 (M+H) ⁺ .

(2S,4S)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2- yl)-4-fluoro-4-(fluoromethyl)pyrrolidine-2-carboxamide:

- 272 041794 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 9.05 (s, 2H), 8.44 (d, J=1.2 Hz, 1H), 7.64 (d, J=8.4 Hz ,

1H), 7.47 (d, J=7.9 Hz, 1H), 5.75 (d, J=17.3 Hz, 1H), 5.63 (d, J=17.3 Hz, 1H), 4.88-4.72 (m, 3H), 4.30- 4.16(m,

2H), 2.69 (s, 3H), 2.65 (s, 3H), 2.63-2.53 (m, 1H), 2.43-2.34 (m, 1H), 2.03 (s, 3H). LC/MS (ESI) m/z: 626 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -5-fluoro-3-methylpyridin-2-yl)-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (d, J=5.2 Hz, 2H), 8.40 (d, J=1.1 Hz, 1H), 7.61-7.46 (m, 2H), 5.98 (d, J=17.7 Hz, 1H), 5.80 (d, J=17.7 Hz, 1H), 4.57 (dd, J=9.2, 5.0 Hz, 2H), 3.85 (dd, J=5.7, 2.7 Hz, 1H), 3.37 (d, J =16.1 Hz, 1H),

3.16 (d, J=16.1 Hz, 1H), 2.75 (s, 3H), 2.73 (d, J=7.8 Hz, 3H), 2.72-2.68 (m, 1H), 2.67 (s, 3H), 2.48 (dd , J=13.7, 4.3 Hz, 1H), 2.36 (s, 3H), 2.12 (s, 3H), 1.37 (m, 1H), 1.29 (m, 1H), 1.18 (m, 1H). LC/MS (ESI) m/z: 716/718 [M+H] ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-chloropyridin-2-yl)-5-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.42 (s, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.00 (d, J=17.6Hz, 1H), 5.82 (d, J=17.8Hz, 1H), 4.74 (d, J=8.2Hz, 1H), 3.85 (d, J=3.1Hz, 1H), 3.40 (s, 1H), 3.14 (d, J=15.9 Hz, 1H), 2.77 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H), 2.57-2.50 (m, 1H ), 2.35 (s, 3H), 1.41 (t, J=5.5 Hz, 1H), 1.34-1.26 (m, 1H), 1.20 (m, 1H). LC/MS (ESI) m/z: 718/720 [M+H] ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5 -(( 3 methyl-1,2,4-oxadiazol-5-yl)methyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.53 ( s, 1H), 6.00 (M, 1H), 5.82 (M, 1H), 4.66-4.61 (m, 1H), 3.86 (m, 1H), 3.38 (m, 1H), 3.15 (m, 1H), 2.75 (m, 6H), 2.68 (s, 3H), 2.54-2.49 (m, 1H), 2.33 (s, 4H), 2.23 (s, 3H), 1.38 (m, 1H), 1.18 (m, 1H). LC/MS (ESI) m/z: 688 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5 -(( 5methyl-1,3,4-oxadiazol-2-yl)methyl)-N-(3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 9.02 (s, 2H), 8.32 (d, J=0.9 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H) , 7.70 (d, J=7.6 Hz, 1H), 7.62 (s, 1H), 6.08 (d, J=17.6 Hz, 1H), 5.70 (d, J=18.0 Hz, 1H), 5.32 (t, J= 4.4 Hz, 1H), 4.51 (dd, J=9.6, 5.2 Hz, 1H), 3.85 (dd, J=5.2, 2.4 Hz, 1H), 3.27-3.22 (m, 1H), 3.12-3.06 (m, 1H ), 2.92-2.51 (m, 9H), 2.45 (s, 3H), 2.22-2.11 (m, 3H), 2.03-1.96 (m, 2H), 1.48-1.42 (m, 1H), 1.16-1.12 (m , 1H). LC/MS (ESI) m/z: 688 (m+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-3-methylpyridin-2-yl)-5-(2-oxopropyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.35 (s, 2H), 9.32 (d, J=1.2 Hz, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.07 (d, J=17.2 Hz, 1H), 5.74 (d, J=17.2 Hz, 1H), 4.43 ( dd, J=9.6, 5.2Hz, 1H), 3.71 (dd, J=5.6, 2.4Hz, 1H), 2.93 (d, J=16.8Hz, 1H), 2.69 (d, J=3.2Hz, 6H), 2.64-2.56 (m, 2H), 2.16 (s, 3H), 2.11-2.05 (m, 1H), 2.03 (s, 3H), 1.21-1.18 (m, 1H), 1.13-1.08 (m, 1H). LC/MS (ESI) m/z: 646 (M+h) ⁺ .

(1R,2S,5S)-3-(2-(3-Acetyl-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-(6-bromo-3 methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.87 (s, 1H), 9.03 (s, 2H), 8.41 (s, 1H), 7.86-7.85 (m, 2H), 7.59 (d, J=8.0 Hz , 1H), 7.40 (d, J=8.0 Hz, 1H), 5.63-5.53 (m, 2H), 4.59-4.58 (m, 1H), 4.05-4.01 (m, 1H), 3.89-3.87 (m, 1H ), 2.67 (s, 3H), 2.63 (s, 3H), 2.00 (s, 3H), 1.92–1.91 (m, 1H), 1.90–1.85 (m, 1H), 0.86–0.75 (m, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6-bromo-3methylpyridin-2-yl )-5-[(4-ethyl-1,3-thiazol-2-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 8.89 (s, 2H), 8.83 (s, 1H), 8.56 (t, J=1.3 Hz, 1H), 7.61 (d, J=1.3 Hz, 2H), 7.42 (d, J=1.1 Hz, 1H), 7.33 (dd, J=0.8, 7.9 Hz, 1H), 7.20 (s, 0H), 5.58-5.44 (m, 2H), 4.78 (dd, J=3.5, 9.3 Hz, 1H), 3.54 (dd, J=2.7, 5.7 Hz, 1H), 3.41 (d, J=15.8 Hz, 1H), 3.24-3.11 (m, 2H), 2.80 (s, 4H), 2.68 (s , 3H), 2.41 (dd, J=9.0, 13.7 Hz, 1H), 1.33 (d, J=6.8 Hz, 6H), 0.99 (dd, J=2.7, 5.9 Hz, 1H). LC (method A): t _R = 2.20 min. LC/MS (EI) m/z: [M+H]+ 727.

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-3-fluoropyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxami e:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.35 (s, 2H), 9.32 (d, J=1.2 Hz, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.81-7.75 (m, 1H), 7.57 (dd, J=8.4, 3.2 Hz, 1H), 6.06 (d, J=17.2 Hz, 1H), 5.74 (d, J=17.2 Hz, 1H), 4.45 (m ,1H), 3.59 (m, 1H), 2.71 (s, 3H), 2.69 (s, 3H), 2.53-2.60 (m, 1H), 2.03 (dd, J=13.2, 5.2 Hz, 1H), 1.31 ( s, 3H), 1.11 (m, 1H), 1.02 (t, m, 1H). LC/MS (ESI) m/z: 607 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6 -bromo- 273 041794

3-methylpyridin-2-yl)-5-((diisopropylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.43 (s, 1H), 7.54 (d J=7.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 1H), 5.98 (d , J=17.7 Hz, 1H), 5.81 (d, J=17.7 Hz, 1H), 4.59-4.57 (m, 1H), 3.52 (dd, J=4.9, 2.0 Hz, 1H), 3.21-3.19 (m, 1H), 3.14-3.11 (m, 1H), 2.77 (s, 3H), 2.74 (s, 3H), 2.68 (s, 3H), 2.64-2.62 (m, 1H), 2.60-2.58 (m, 1H) , 2.48-2.43 (m, 2H), 2.13 (s, 3H), 1.30-1.29 (m, 1H), 1.20-1.18 (m, 1H), 1.08-1.00 (m, 12H). LC/MS (ESI) m/z: 715 (M+H)+.

Scheme 11. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-n-( (e)-2-fluoro-3-phenylbut-2-en-1-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (17).

The three-part synthesis shown below and the accompanying detailed description depicts one non-limiting method for synthesizing compounds by first forming intermediate 17-S7 using Goses' reagent to form an amide bond. Intermediate 17S7 binds to the A-ring using a coupling reagent such as HATU. One skilled in the art will appreciate that the A-ring synthetic intermediate shown below can be replaced with other A-ring synthetic intermediates to provide additional compounds of the present invention.

Synthesis of tert-butyl (1R,3S,5R)-3-(((E)-2-fluoro-3-phenylbut-2-en-1-yl)carbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (intermediate 17-S7) o $ θ |Ργ% J Lob NaH,DME _Q T O

CP _Stage ,, / \ ⁺ /V

17-S1 ^{17'S2 17-83} ^=/

Step 1 Ethyl (E)-2-fluoro-3-phenylbut-2-enoate (S2) and ethyl (Z)-2-fluoro-3-phenylbut-2-enoate (17-S3): Ethyl 2-(diethoxyphosphoryl )-2-fluoroacetate (5 g) was added dropwise to a stirred solution of NaH (0.9 g, 60% in mineral oil) in DME (50 ml) at 0°C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. Benzaldehyde (3.6 ml) was added at room temperature and the reaction mixture was stirred at 90°C overnight. The reaction mixture was cooled to room temperature, diluted with ether, washed with water, dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by silica gel flash column chromatography (eluent: 0-0.5% EtOAc in hexanes). Ethyl (Z)-2-Φτορ-3phenylbut-2-enoate (17-S3) was eluted first as a colorless liquid (0.37 g) and ethyl (E)-2-fluoro-3phenylbut-2-enoate (17-S2) was eluted the second in the form of a light yellow liquid (1.3 g). (Ref. WO 2014/002052 and J. Org. Chem. 2009, 74, 4124-4131).

Step 2. (E)-2-Fluoro-3-phenylbut-2-en-1-ol (17-S4): Ethyl ( E)-2-fluoro-3-phenylbut-2-enoate (17S2) (1.3 g) in ether (10 ml). The reaction mixture was stirred at room temperature for 1 h and quenched by careful addition of saturated aqueous NH ₄ Cl. The heterogeneous mixture was then extracted with ether, washed with water and brine, and dried over Na ₂ SO ₄ . After concentrating the organic layer, the residue was carried on without further purification to the next stage.

Step 3. (E)-2-(2-Fluoro-3-phenylbut-2-en-1-yl)isoindoline-1,3-dione (17-S5): DEAD (1.52 ml) was added dropwise to the stirred solution (E)-2-fluoro-3-phenylbut-2-en-1-ol (1 g), phthalimide (1.06 g) and triphenylphosphine (2.4 g) in THF (20 ml). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (eluent: 0-2.5% EtOAc in hexanes) to give 1.5 g of 17-S5 as a white solid.

Step 4. (E)-2-Fluoro-3-phenylbut-2-en-1-amine hydrochloride (17-S6): Hydrazine hydrate (0.74 ml) was added to a heterogeneous solution of (E)-2-(2-fluoro- 3-phenylbut-2-en-1-yl)isoindoline-1,3-dione (1.7 g) in EtOH (30 ml) and stirred at room temperature overnight. The precipitate was filtered off and the filtrate was concentrated. The residue was triturated with 4n. HCl in dioxane (10 ml) and the volatiles were removed

- 274 041794 under reduced pressure. The resulting white solid was dried under high vacuum to give 17-S6. Step 5. tert-Butyl (1R,3S,5R)-3-(((E)-2-fluoro-3-phenylbut-2-en-1yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2 -carboxylate (17-S7): To an ice-cold solution of (1R,3S,5R)-2(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (17-S6a) (0.25 g) in 6 ml of CH ₂ Cl ₂ was added dropwise 1-chloro-N,N,2-trimethyl-1-propenylamine (0.16 ml, 1.1 equiv.) with stirring. After stirring for 3 h at the same temperature, solid (E)-2-fluoro-3-phenylbut-2en-1-amine hydrochloride (17-S6) (0.2 g, 1.0 equiv.) was added followed by the addition of 0.7 ml of DIPEA ( 4 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. The solvent was co-evaporated with MeOH (1 ml) and the crude product was purified by silica gel flash column chromatography (eluent: 0-0.5% MeOH in CH ₂ Cl ₂ ) to give 0.18 g of a colorless gum.

Synthesis of tert-Butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (intermediate 17-S12)

Step 6. 7-Methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole (17-S9): A mixture of 0.5 g of bromindazole (1 eq.), 2-methyl-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.782 g, 1.5 equiv.), cesium carbonate (2.315 g, 3 equiv.) in dioxane (10 ml) and water (1.0 ml) were purged argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium (0) (0.550 g, 0.2 equiv.) was then added under argon and the pressure vessel was sealed and heated at 90°C overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 0-3% MeOH in CH ₂ Cl ₂ ) to give 0.395 g of product as a white solid.

Step 7. 3-Bromo-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole (17-S10): To a stirred solution of indazole 17-S9 (1.75 g) in DMF (20 ml) was added NBS (1.05 g). The reaction mixture was stirred at room temperature for 2 h and additional NBS (0.209 g) was added, followed by stirring for 30 min at room temperature. The reaction mixture was poured into water and the precipitate was filtered off, dried and purified by silica gel flash column chromatography (eluent: 0-5% MeOH in CH ₂ Cl ₂ ) to give 17-S10 as a white solid.

Step 8. tert-Butyl 2-(3-bromo-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate 17(S11): mixture of 3-bromo-7- methyl 5-(2-methylpyrimidin-5-yl)-1H-indazole (0.215 g), tert-butyl bromoacetate (115 μl) and potassium carbonate (0.196 g) in anhydrous acetonitrile (10 ml) was heated under reflux for 4 hours The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 0-1% MeOH in CH ₂ Cl ₂ ) to give the product as a white foam.

Step 9 tert-Butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (17S12): tert-butyl 2-(3 -bromo-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (17S11) (0.170 g, 1 equiv.), tert-butyl(1-ethoxyvinyl)tin 0.249 g, 2 equiv.) and PdCl ₂ (PPh ₃ ) ₂ (28 mg, 0.1 equiv.) in DMF (3 ml) were heated at 80°C overnight in an argon atmosphere. The mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ , and washed with cold aqueous HCl (1N). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0-1% MeOH in CH ₂ Cl ₂ ) to give a yellow solid.

Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N((E )-2-fluoro-3-phenylbut-2-en-1-ul)-2-azabicyclo[3.1.0]hexane-3-carboxamide (17)

- 275 041794

Step 10. (1R,3S,5R)-N-((E)-2-Fluoro-3-phenylbut-2-en-1-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide, TFA salt ( 17-S13): tert-butyl (1R,3S,5R)-3-(((E)-2-fluoro-3-phenylbut-2-en-1-yl)carbamoyl)2-azabicyclo[3.1.0] hexane-2-carboxylate (0.1 g) was dissolved in CH ₂ Cl ₂ (1 ml) and an equal volume of TFA was added. The mixture was stirred for 30 min at room temperature, then the volatiles were removed under reduced pressure, and the residue was carried on without further purification to the next stage.

Step 11 2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (17-S14): tert-butyl 2-(3- acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetate (17-S12, 0.13 g) was stirred in CH ₂ Cl ₂ (1 ml) and TFA (2 ml). After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure and the remaining residue was used in the next synthetic step without purification.

Step 12: (1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)acetyl)-N -((E)-2-fluoro-3-phenylbut-2-en-1-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (17): compound 17-S14 was dissolved in DMF (1 ml ) and added iPr ₂ NEt (0.297 ml, 5 equiv.) followed by addition of 17-S13 at 5°C. Then HATU (0.156 g, 1.2 equiv.) was slowly added at 5°C, and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and the precipitate was filtered off. The solid was dried and purified by silica gel flash column chromatography (eluent: 0-2.5% MeOH in CH ₂ Cl ₂ ) to give 17 as an off-white solid.

¹ H NMR (400 MHz, DMSO) δ 0.65-0.71 (m, 1H), 0.78 (s, 0H), 1.02-1.07 (m, 1H), 1.15-1.26 (m, 1H), 1.811.98 (m, 1H), 1.93 (d, J=3.2 Hz, 3H), 2.06-2.12 (m, 1H), 2.23-2.26 (m, 1H), 2.64 (s, 3H), 2.68 (s, 6H), 3.70-3.93 (m, 2H), 4.24 (dd, J=5.0, 9.1 Hz, 1H), 5.70 (d, J=17.7 Hz, 1H), 6.03 (d, J=17.8 Hz, 1H), 7.20-7.33 (m, 5H), 7.63 (s, 1H), 8.15 (t, J=5.3 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 9.02 (s, 2H). ¹⁹ F-NMR (DMSO-d6): δ -113.2.

(1 R,3S,5R)-2-(2-(3 - Acetyl-5 -(2-methylpyrimidin-5 -yl)-1 H-indazol-1 -yl)acetyl)-N-((E)- 2-fluoro-3-phenylbut-2-en-1-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 0.85 (dd, J=2.4, 5.4 Hz, 1H), 1.13 (t, J=5.3 Hz, 1H), 1.41 (s, 3H),

1.95 (d, J=3.7 Hz, 3H), 2.13 (dd, J=8.7, 13.4 Hz, 1H), 2.64-2.68 (m, 1H), 2.72 (s, 3H), 2.81 (s, 3H), 3.11 (dd,

J=2.4, 5.5 Hz, 1H), 3.85-4.07 (m, 2H), 4.55 (dd, J=3.0, 8.7 Hz, 1H), 5.45 (d, J=2.7 Hz, 2H), 6.78 (t, J =5.2 Hz,

1H), 7.08-7.15 (m, 2H), 7.18-7.32 (m, 3H), 7.51 (d, J=8.7 Hz, 1H), 7.61 (dd, J=1.7, 8.7 Hz, 1H), 8.59 (s , 1H),

8.89(s, 2H). ¹⁹ F δ -115.9.

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-C]pyridin-1-yl)acetyl)-N ((E)-2-fluoro-3-phenylbut-2-en-1-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.94 (dd, J=2.4, 5.4 Hz, 1H), 1.00 (t, J=5.4 Hz, 1H), 1.28 (s, 3H), 1.841.97 (m , 1H), 1.94 (d, J=3.2 Hz, 3H), 2.39 (dd, J=9.1, 13.2 Hz, 1H), 2.53 (s, 3H), 2.68 (s, 3H), 3.48 (d, J= 3.2 Hz, 1H), 3.84 (dd, J=5.3, 20.8 Hz, 2H), 4.21 (dd, J=4.9, 9.2 Hz, 1H), 5.36 (d, J=17.1 Hz, 1H), 5.63 (d, J=17.2Hz, 1H), 7.20-7.35(m, 5H), 8.17(t, J=5.4Hz, 1H), 8.52(s, 1H), 8.58(s, 1H), 8.98(s, 1H), 9.29(s, 2H). ¹⁹ F δ -113.6.

(1 R,3S,5R)-2-(2-(3 - Acetyl-7-methyl-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-I-( (E)-2fluoro-3-phenylbut-2-en-1-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 0.87 (dd, J=2.4, 5.5 Hz, 1H), 1.15 (t, J=5.4 Hz, 1H), 1.42 (s, 3H), 1.94 (d, J= 3.6 Hz, 3H), 2.14 (dd, J=8.7, 13.4 Hz, 1H), 2.68 (s, 3H), 2.71 (s, 3H), 2.80 (s, 3H), 3.08 (dd, J=2.4, 5.5 Hz, 1H), 3.96 (dd, J=5.3, 20.9 Hz, 2H), 4.55 (dd, J=3.0, 8.7 Hz, 1H), 5.64 (s, 2H), 6.81 (t, J=5.4 Hz, 1H ), 7.077.14 (m, 2H), 7.18-7.31 (m, 4H), 7.32 (s, 1H), 8.47 (s, 1H), 8.88 (s, 2H). ¹⁹ F δ -115.6.

Scheme 12. Synthesis of (2S,4R)-1-(2-(3-Acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)- N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (19)

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Stage 1. 2-Amino-5-bromo-3-methylbenzoic acid (19-S2): to a solution of 19-S1 (15 g, 0.1 mol) in AcOH (80 ml) was added Br ₂ (5.1 ml, 0.1 mol) drops at 0°C. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc and basified with an aqueous solution of

NaOH (4N) to pH 7. The mixture was extracted with EtOAc, dried and concentrated to give crude product which was purified by silica gel column chromatography (eluting with DCM/MeOH = 100:0 to 50:1) to give 19-S2 (12.0 g, 52.2% yield) as a white solid. LC/MS (ESI) m/z: 230 (M+H)+.

Stage 2. Methyl 2-amino-5-bromo-3-methylbenzoate (19-S3): to a solution of 19-S2 (12 g, 52.2 mmol) in DMF (60 ml) was added Cs ₂ CO ₃ (25.5 g, 78.3 mmol ) and CH ₃ I (7.79 g, 54.8 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc, washed with 5% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 50:1 to 20:1) to give 19-S3 (11.0 g, 86.6% yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) ⁺ .

Stage 3. Methyl 5-bromo-1H-indazole-7-carboxylate (19-S4): to a mixture of 19-S3 (10.9 g, 44.7 mmol) and AcOK (1.32 g, 13.41 mmol) in CHCl ₃ (50 ml) slowly Ac ₂ O (10.6 g, 103 mmol) was added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. The mixture was then heated to 60°C and t-BuONO (10.2 g, 98.3 mmol) was added to the above mixture. The resulting mixture was stirred at 60° C. for 4 hours. After cooling, the mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 100:0 to 10:1) to give 19-S4 (8.0 g, 70.5% yield) as yellow solid. LC/MS (ESI) m/z: 255 (M+H) ⁺ .

Stage 4. (5-Bromo-1H-indazol-7-yl)methanol (19-S5): LiAlH ₄ (1.49 g, 39.2 mmol) in portions at 0°C. The reaction mixture was stirred at 0°C for 30 min and at room temperature for 1 h. The mixture was then quenched with water (1.5 ml), 10% aqueous NaOH solution (3 g) and water (4.5 ml). The mixture was filtered and the filter cake washed with EtOAc. The filtrate was dried and concentrated to give a crude product which was purified by silica gel column chromatography (eluting with DCM/MeOH = 100:0 to 20:1) to give 19-S5 (3.36 g, 76.1% yield) as a white solid. LC/MS (ESI) m/z: 227 (M+H) ⁺ .

Step 5. (5-Bromo-3-iodo-1H-indazol-7-yl)methanol (19-S6): KOH (1.26 g) was added to a solution of 19-S5 (2.27 g, 10 mmol) in DMF (25 ml). , 22.5 mmol) and I ₂ (3.81 g, 15 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was then quenched with 5% aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to give the crude product, which was recrystallized with EtOAc/PE (1:2) to give 19-S6 (2.85 g, 81.0% yield) as a brown solid. LC/MS (ESI) m/z: 353 (M+H) ⁺ .

Step 6. Methyl 2-(5-bromo-7-(hydroxymethyl)-3-iodo-1H-indazol-1-yl)acetate (19-S7): to solution

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19-S6 (1.98 g, 5.6 mmol) in DMF (20 mL) was added K2CO3 (1.38 g, 10 mmol) and methyl 2-bromoacetate (900 mg, 5.88 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was diluted with EtOAc, washed with 10% LiCl aqueous solution, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 10:1 to 3: 1) to obtain 19-S7 (1.34 g, 56.4% yield) as a colorless oil. LC/MS (ESI) m/z: 425 (M+H)+.

Step 7. Methyl 2-(5-bromo-7-(chloromethyl)-3-iodo-1H-indazol-1-yl)acetate (19-S8): to a mixture of 19-S7 (424 mg, 1 mol) in dry DCM (10 ml) was added with Et ₃ N (250 mg, 2.5 mmol) followed by dropwise addition of MsCl (173 mg, 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 100:0 to 15:1) to give 19-S8 (360 mg, 81.1% yield) as a brown solid. LC/MS (ESI) m/z: 443 (M+H) ⁺ .

Step 8. Methyl 2-(5-bromo-7-((dimethylamino)methyl)-3-iodo-1H-indazol-1-yl)acetate (19-S9): to a solution of 19-S8 (360 mg, 0.82 mol ) Et ₃ N (249 mg, 2.46 mmol) and dimethylamine hydrochloride (133 mg, 1.64 mmol) were added to MeCN (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc = 20:1 to 10:1) to give 19-S9 (328 mg, 88.5% yield) as a brown solid. LC/MS (ESI) m/z: 452 (M+H) ⁺ .

Step 9. 2-(3-Acetyl-5-bromo-7-((dimethylamino)methyl)-1H-indazol-1-yl)acetic acid (19S10): to a mixture of 19-S9 (68 mg, 0.15 mol) in dry toluene (10 ml) was added tributyl(1ethoxyvinyl)stannan (82 mg, 0.226 mmol) and Pd(PPh ₃ ) ₄ (14 mg, 0.012 mmol). The reaction mixture was stirred at 95° C. for 16 hours under nitrogen. After cooling, the mixture was quenched with 1N. aqueous HCl solution, and the mixture was stirred at room temperature for 15 minutes. The mixture was extracted with DCM/MeOH (20:1), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH = 20:1) to give 19-S10 (38 mg , 71.7% yield) as a colorless oil. LC/MS (ESI) m/z: 354 (M+H)+.

Step 10 2-(3-Acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (19-S11): to solution 19 -S10 (38 mg, 0.11 mol) in 1,4-dioxane/H ₂ O (7 ml, 6:1) was added 2-methylpyrimidin-5-ylboronic acid (23 mg, 0.162 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(PPh ₃ ) ₄ (12 mg, 0.011 mmol). The reaction mixture was stirred at 90° C. for 16 hours under nitrogen. After cooling, the mixture was acidified with 10% aqueous HCl and extracted with DCM/MeOH (10:1). The organic layer was separated, dried and concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH = 5:1) to give 19-S11 (21 mg, 52.0% yield) as a yellow solid. LC/MS (ESI) m/z: 368 (M+H) ⁺ .

Step 11. (2S,4R)-1-(2-(3-Acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N -(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (19): to a mixture of 19-S11 (21 mg, 0.057 mmol) and (2S,4R)-N-(6-bromopyridine-2- yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (19 mg, 0.057 mmol) in DMF (1 ml) was added with DIPEA (23 mg, 0.171 mmol) followed by addition of HATU (43 mg, 0.114 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by preparative HPLC to give 19 (6 mg, 16.7% yield) in form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.10 (s, 2H), 8.50 (d, J=1.7 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.73 -7.83 (m, 2H), 7.39 (d, J=7.7 Hz, 1H), 6.31 (d, J=17.4 Hz, 1H), 6.09 (d, J=17.3 Hz, 1H), 5.55-5.68 (m, 1H), 4.80 (t, J=8.7 Hz, 1H), 4.30-4.39 (m, 1H), 3.86-3.99 (m, 2H), 3.43-3.48 (m, 1H), 2.73 (s, 3H), 2.68 (s, 3H), 2.57-2.66 (m, 1H), 2.29 (s, 6H), 2.13-2.19 (m, 1H). LC/MS (ESI) m/z: 637 (M+H)+.

Scheme 13. Synthesis of (2S,4R)-1-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (20)

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The above scheme and the following detailed description depict one non-limiting route for synthesizing compounds by 1) Stille's carbonylating cross-coupling using tributyl(1-ethoxyvinyl)stannan to functionalize the R ⁶ position on the A ring; 2) Suzuki cross-coupling to functionalize the R ³² A-ring; and 3) formation of an amide bond between the C-ring (already linked to the B-ring) and the A-ring using HATU. One skilled in the art will appreciate that the C- and B-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention. One of skill in the art will also appreciate that the A-ring synthetic intermediate can be replaced with other synthetic intermediates to provide additional compounds of the present invention.

Stage 1. Methyl 2-(5-bromo-7-(fluoromethyl)-3-iodo-1H-indαzol-1-yl)acetate (20-S2): to a solution of 20-S1 (85 mg, 0.2 mmol) in dry DCM (6 ml) was added DAST (64 mg, 0.4 mmol) dropwise at -30°C. The resulting mixture was stirred at -30° C. to room temperature for 1 hour. The mixture was then quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 20:1 to 10:1) to give 20-S2 (73 mg, 85.7% yield) as a yellow oil. LC/MS (ESI) m/z: 427 (M+H)+.

Stage 2. 2-(3-Acetyl-5-bromo-7-(fluoromethyl)-1H-indazol-1-yl)acetic acid (20-S3): to a mixture of 20-S2 (73 mg, 0.171 mol) in dry toluene (8 ml), tributyl(1-ethoxyvinyl)stannan (87 mg, 0.24 mmol) and Pd(PPh ₃ ) ₄ (16 mg, 0.0137 mmol) were added. The reaction mixture was stirred at 95° C. for 16 hours under nitrogen. After cooling, the mixture was quenched with 1N. aqueous HCl solution, and the mixture was stirred at room temperature for 15 minutes. The mixture was then extracted with DCM/MeOH (15:1), the organic layer was separated, dried and concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH = 15:1) to give 20-S3 (50 mg, 88.8% yield) as a colorless oil. LC/MS (ESI) m/z: 329 (M+H)+.

Step 3. 2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (2-S4) and 2-(3-acetyl -5-(2-methylpyrimidin-5-yl)-7-((2-methylpyrimidin-5-yl)methyl)-1H-indazol-1yl)acetic acid (20-S4A): to 20-S3 mixture (50 mg , 0.152 mol) in 1,4-dioxane/H ₂ O (7 ml, 6:1) was added 2-methylpyrimidin-5-ylboronic acid (26 mg, 0.182 mmol), K ₂ CO ₃ (63 mg, 0.456 mmol) and Pd(PPh ₃ ) ₄ (18 mg, 0.0152 mmol). The reaction mixture was stirred at 90° C. for 16 hours under nitrogen. After cooling, the mixture was acidified with 10% aqueous HCl and extracted with DCM/MeOH (10:1). The organic layer was separated, dried and concentrated to give the crude product, which was purified by preparative TLC (DCM/MeOH = 5:1) to give 20-S4 (30 mg, 57.5% yield) and 20-S4A (25 mg, 39.4% yield) as colorless oils. LC/MS (ESI) m/z: 343(M+H)+, 417(M+H)+.

Step 4. (2S,4R)-1 -(2-(3 - Acetyl-7-(fluoromethyl)-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)αcetyl)-N- (6-bromopyridin-2-yl)-4-fluoropyrrolidin-2-carboxamide (20): to a mixture of 20-S4 (30 mg, 0.088 mmol) and (2S,4R)-N-(6-bromopyridin-2-yl )-4-Fluoropyrrolidine-2-carboxamide hydrochloride (30 mg, 0.088 mmol) in DMF (1 mL) was added with DIPEA (36 mg, 0.264 mmol) followed by addition of HATU (52 mg, 0.132 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product which was purified by prep HPLC to give 20 (6 mg, 11.1% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.06 (s, 2H), 8.55 (s, 1H), 8.06-7.94 (m, 2H), 7.72 (t, J=8.0 Hz, 1H), 7.33 (d, J=7.3 Hz, 1H), 5.94 (d, J=18.0 Hz, 1H), 5.78-5.88 (m, 1H), 5.47-5.71 (m, 3H), 4.68-4.74 (m , 1H), 4.24-4.33 (m, 1H), 3.86-4.02 (m, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 2.18-2.27 (m, 1H), 2.07-2.16 (m , 1H). LC/MS (ESI) m/z: 612 (M+H)+.

3-Acetyl-1-(2-((3S)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexan-2-yl )-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazole-7-carboxylic acid (63):

¹ H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.99 (s, 2H), 8.46 (d, J=1.6 Hz, 1H), 7.96 (s, 1H), 7.58 (d, J =8.0 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 6.08 (d, J=16.8 Hz, 1H), 5.93 (d, J=16.8 Hz, 1H), 5.82-5.85 (m, 1H ), 4.334.40 (m, 1H), 3.62-3.66 (m, 1H), 3.57-3.61 (m, 1H), 2.68 (s, 3H), 2.66 (s, 3H), 2.40-2.44 (m, 1H ), 2.37 (s, 3H), 2.33 (s, 3H), 2.17-2.22 (m, 1H), 2.01 (s, 3H), 1.21-1.25 (m, 1H), 1.10-1.15 (m, 1H). LC/MS (ESI) m/z:

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689/691 (M+H)+.

(1 R,3S,5R)-2-(2-(3-Acetyl-4-fluoro-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-( 6-bromo3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (155):

Ή NMR (400 MHz, CD3OD) δ 8.84 (s, 2H), 7.61-7.44 (m, 3H), 7.30 (d, J=7.9 Hz, 1H), 5.73 (d, J=17.3 Hz, 1H), 5.58 (d, J=17.5 Hz, 1H), 4.55 (m, 1H), 3.63 (m, 1H), 2.96 (m, 1H), 2.67 (s, 3H), 2.62 (s, 3H), 2.59-2.47 ( m, 3h), 2.44 (m, 6H), 2.04 (s, 3H), 1.20 (d, J=19.2 Hz, 2H). LC/MS (ESI) m/z: 662 (M+H) ⁺ .

(1 S,3S,5S)-2-(2-(3-Acetyl-4-fluoro-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-( 6-bromo3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (156):

Ή NMR (400 MHz, CD3OD) δ 8.83 (s, 2H), 7.57-7.44 (m, 3H), 7.28 (d, J=7.9 Hz, 1H), 5.74 (d, J=17.0 Hz, 1H), 5.55 (d, J=17.1Hz, 1H), 4.99 (d, J=9.5Hz, 1H), 3.59 (s, 1H), 2.81 (s, 1H), 2.67 (s, 3H), 2.62 (s, 3H) , 2.33 (m, 9H), 1.99 (m, 3H), 1.60 (m, 1H), 1.01 (m, 1H). LC/MS (ESI) m/z: 662 (M+H) ⁺ .

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-b]pyridin-1-yl)acetyl) -N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo [3.1.0]hexane-3-carboxamide (181):

1H NMR (400 MHz, DMSO-d6) δ 0.93-0.99 (m, 1H), 1.02-1.08 (m, 1H), 1.33 (s, 3H), 2.07 (s, 4H), 2.522.61 (m, 1H ), 2.68 (s, 3H), 2.71 (s, 3H), 3.62 (dd, J=2.4, 5.7 Hz, 1H), 4.42 (dd, J=5.0, 9.3 Hz, 1H), 5.62 (d, J= 17.0 Hz, 1H), 5.91 (d, J=17.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 8.84 (d, J=2.2 Hz , 1H), 9.02 (d, J=2.1 Hz, 1H), 9.14 (s, 2H), 10.26 (s, 1H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[4,3-b]pyridin-1-yl)acetyl) -N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (184):

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.97-1.07 (m, 2H), 1.33 (s, 3H), 2.00-2.10 (m, 4H), 2.53-2.59 (m, 1H), 2.72 (s, 3H), 2.82 (s, 3H), 3.54-3.63 (m, 1H), 4.37-4.50 (m, 1H), 5.61 (d, J=17.2 Hz, 1H), 5.94 (d, J=17.2 Hz, 1H ), 7.45 (d, J=7.9Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 8.23 (d, J=9.0Hz, 1H), 8.34 (d, J=8.9Hz, 1H), 9.44 (s, 2H), 10.26 (s, 1H).

(2S,4R)-N-(6-bromopyridin-2-yl)-1-(2-(3-ethyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-4 -fluoropyrrolidine-2-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.05 (s, 2H), 8.15 (s, 1H), 8.02-8.04 (d, J=8.4 Hz, 1H), 7.68- 7.75 (m, 2H), 7.59-7.62 (d, J=8.8 Hz, 1H), 7.31-7.33 (d, J=7.6 Hz, 1H), 5.45-5.58 (m, 1H), 5.50-5.54 (m, J=17.2 Hz, 1H), 5.30-5.34 (d, J=17.2 Hz, 1H), 4.61-4.65 (m, 1H), 4.13-4.22 (m, 1H), 3.88-3.98 (m, 1H), 2.942 .97 (m, 2H), 2.66 (s, 3H), 2.07-2.17 (m, 1H), 1.29-1.35 (t, 3H). LC/MS (ESI) m/z: 566/568 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-6-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6- bromo3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.91(s, 2H), 8.30 (d, J=8 Hz, 1H), 7.84 (d, J=12 Hz, 1H), 7.64 (d, J=8Hz, 1H), 7.45 (d, J=8Hz, 1H), 5.92 (d, J=20Hz, 1H), 5.56 (d, J=20Hz, 1H), 4.40 (t , J=4 Hz, 1H), 3.57 (t, J=3.2 Hz, 1H), 2.70 (S, 3H), 2.64 (S, 3H), 2.04 (S, 3H), 1.32 (S, 3H), 1.08 -1.05 (m, 2H). LC/MS (ESI) m/z: 620 (M+H) ⁺ .

(1 R,3S,5R)-2-(2-(3-Acetyl-7-chloro-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-( 6-bromo3-((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 9.06 (s, 2H), 8.44 (d, J=1.6 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.71 (d, J=7.2Hz, 1H), 7.43 (d, J=6.8Hz, 1H), 6.02 (d, J=17.6Hz, 1H), 5.87 (d, J=17.6Hz, 1H), 5.32 ( t, J=4.8 Hz, 1H), 4.47-4.34 (m, 1H), 3.64-3.56 (m, 1H), 3.41-3.37 (m, 1H), 3.04-2.52 (m, 6H), 2.08 (s, 3H), 2.041.87 (m, 2H), 1.23 (s, 3H), 1.10–1.00 (m, 1H), 0.99–0.88 (m, 1H). LC/MS (ESI) m/z: 679 (M+H)+.

(1R,3S,5R)-2-{2-[3-Acetyl-6-chloro-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-{6-bromo-3 [(dimethylamino)methyl]pyridin-2-yl }-5-methyl-2-azabicyclo[3.1. 0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.81 (d, J=5.5 Hz, 2H), 8.19 (s, 1H), 8.17 (s, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 5.95 (d, J=17.3 Hz, 1H), 5.60 (d, J=17.2 Hz, 1H), 4.43 (s, 1H), 3.61 -3.59 (m, 1H), 3.23-3.19 (m, 1H), 2.71 (s, 3H), 2.62 (s, 3H), 2.59-2.55 (m, 1H), 2.12-2.09 (m, 1H), 2.06 (s, 6H), 1.34 (s, 3H), 1.23 (m, 1H), 1.11-1.08 (m, 1H), 1.00 (t, J=5.3 Hz, 1H). LC/MS (ESI) m/z: 681(M+H)+.

Scheme 14. Synthesis of (2S,4R)-1-(2-(3-Acetyl-7-((5-methylpyrimidin-2-yl)methyl)-5-(2-methylpyrimidin5-yl)-1H-indazol-1 -yl)acetyl)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (21)

21-S1

The title compound (21) was prepared according to the procedure described in Step 4 of Scheme 13 using the appropriate starting materials.

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1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.94 (s, 2H), 8.55 (s, 2H), 8.37-8.44 (m, 1H), 8.01 (d,

J=8.0Hz, 1H), 7.73(t, J=8.0Hz, 1H), 7.35(d, J=7.3Hz, 1H), 7.24(s, 1H), 5.92(d, J=18.1Hz, 1H) , 5.45-5.61 (m, 2H), 4.67-4.76 (m, 1H), 4.51 (d, J=16.9 Hz, 1H), 4.34 (d, J=16.7 Hz, 1H), 4.23 (dd, J=20.8 , 13.0 Hz, 1H),

3.84-3.94 (m, 1H), 2.68 (s, 3H), 2.62(s, 3H), 2.52 (s, 3H), 2.18-2.26 (m, 1H), 2.06-2.15 (m, 1H). LC/MS (ESI) m/z: 686 (M+H)+.

Scheme 15: (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridine -2-yl)-5-(piperazin-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22)

Stage 1. 1-Allyl 4-tert-butyl-piperazine-1,4-dicarboxylate (22-S2): DIPEA (0.032 ml, 10.10 mmol) and allyl chloroformate (727 mg, 6.06 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was washed with water and brine. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 30:1 to 20:1) to give the title compound (400 mg, 73.4% yield) as a yellow oil. LC/MS (ESI) m/z: 271 (M+H) ⁺ .

Step 2 Allylpiperazine-1-carboxylate hydrochloride (22-S3): To a solution of 22-S2 (400 mg, 1.48 mmol) in dioxane (1 ml) was added HCl/dioxane (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the title compound (450 mg, 100% yield) as a brown oil. LC/MS (ESI) m/z: 171 (M+H) ⁺ .

Step 3. (3S)-tert-Butyl 5-((4-((allyloxy)carbonyl)piperazin-1-yl)methyl)-3-((6-bromo-3methylpyridin-2-yl)carbamoyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (22-S5): DIPEA (0.45 ml, 2.64 mmol), 22-S3 (179 mg, 0.66 mmol) and NaI at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with DCM and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 20:1) to give the title compound (45 mg, 11.8% yield) as a yellow solid. LC/MS (ESI) m/z: 578 (M+H) ⁺ .

Step 4 Allyl 4-(((3S)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5yl)methyl)piperazine-1-carboxylate (22-S6): HCl/dioxane (2 ml) was added to a solution of 22-S5 (45 mg, 0.078 mmol) in dioxane (2 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give the title compound (65 mg,

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100% yield) as a brown oil. LC/MS (ESI) m/z: 477 (M+H)+.

Step 5. Allyl 4-(((3S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-3-( (6bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)methyl)piperazin-1-carboxylate (22-S8): to a solution of 22-S6 (65 mg, 0.078 mmol) and 22-S7 (24.18 mg, 0.078 mmol) in DMF (3 mL) were added HATU (53.4 mg, 0.14 mmol) and DIPEA (0.054 mL, 0.312 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 20:1) to give the title compound (30 mg, 50.0% yield) as a white solid. LC/MS (ESI) m/z: 697 (M+H)+.

Step 6. (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2 -yl)-5-(piperazin-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (22): to a solution of 22-S8 (30 mg, 0.039 mmol) in dry THF (5 ml) morpholine (33.93 mg, 0.39 mmol) and Pd(PPh ₃ ) ₄ (2.3 mg, 0.0020 mmol) were added under nitrogen at 0°C. The reaction mixture continued to stir at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 22 (3.5 mg, 13.1% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.56 (s, 1H), 7.80 (d, J=1.2 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (d , J=7.9 Hz, 1H), 5.80 (d, J=17.2 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 4.65-4.62 (m, 1H), 3.64-3.66 m, 1H), 2.93 (t, J=4.9Hz, 4H), 2.75 (s, 3H), 2.72-2.61 (m, 6H), 2.56 (d, J=6.9Hz, 5H), 2.14 (d, J=8.2Hz, 3H ), 1.15 (t, J=5.6 Hz, 1H), 1.10-1.08 (m, 1H). LC/MS (ESI) m/z: 686 (M+H)+.

Scheme 16. Synthesis of (2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)αcetyl)-N(6-bromo-3 -(cyanomethyl)pyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (23) o Br TFAA n ₂ tert-butyl ιΝΗ S2 Stage 1-2

Step 1. 2-(6-Bromo-1-(1-oxidanyl)pyridin-3-yl)acetonitrile (23-S2): to a stirred solution of 2-(6-bromopyridin-3-yl)acetonitrile (23-S1, 1 g, 1 equiv.) in CHCl ₃ (100 ml) was added 3-chlorobenzeneroxoic acid (1.72 g, 77%, 1.5 equiv.). The reaction mixture was heated to 50°C. The reaction mixture was cooled and neutralized with saturated aqueous NaHCO ₃ (100 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel chromatography (5% CH3OH in DCM, gradient) to give 23-S2 (99 mg, 10%).

Step 2. 2-(6-Bromo-2-(tert-butylamino)pyridin-3-yl)acetonitrile (23-S3): to a stirred solution of 23-S2 (99 mg, 1 eq.) and 2-methylpropan-2 -amine (0.24 ml, 5 equiv.) in DCM (8 ml) was added a solution of trifluoroacetic anhydride (0.08 ml, 1.1 equiv.) in DCM (3 ml) dropwise at 0-5°C in an argon atmosphere. The reaction mixture was stirred at 0-5°C for 1 h and TFAA (0.07 ml, 1 eq.) was added followed by 2-methylpropan-2-amine (0.02 ml, 1 eq.). The reaction mixture was diluted with DCM (25 ml) and neutralized with aqueous saturated NaHCO ₃ solution (10 ml). The organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with hexanes/EtOAc=3/1) to give 23-S3 (80 mg, 30%).

Step 3 2-(2-Amino-6-bromopyridin-3-yl)acetonitrile (23-S4): TFA (10 ml) was added to the solid compound 23-S3 (80 mg) and the reaction mixture was heated at 70°C . The reaction mixture was concentrated to dryness. The residue was dissolved in DCM (15 ml) and washed with aqueous saturated NaHCO ₃

- 282 041794 (8 ml). The organic layer was dried over Na2SO4 and concentrated to dryness to give 23-S4 (63 mg, quant.).

Step 4 tert-Butyl (2S,4R)-2-((6-bromo-3-(cyanomethyl)pyridin-2-yl)carbamoyl)-4fluoropyrrolidine-1-carboxylate (23-S5): to a stirred solution (2S ,4R)-1-(tert-Butoxycarbonyl)-4fluoropyrrolidine-2-carboxylic acid (69 mg, 1 equiv.) and 23-S4 (63 mg, 1 equiv.) 5 equiv.). The reaction mixture was cooled to 0-5°C and POCl ₃ (0.024 ml, 2 equiv.) was added dropwise under argon. The reaction mixture was warmed to room temperature, diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (1x10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 23-S5 (56 mg, 26%).

Step 5. (2S,4R)-N-(6-Bromo-3-(cyanomethyl)pyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (23-S6): To a solution of 23-S5 was added 4N. HCl in dioxane (10 ml). The resulting solution was stirred at room temperature for 6 hours and then concentrated to dryness to give 23-S6 (61 mg).

Step 6. (2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo3-( cyanomethyl)pyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (23): to a solution of 23-S6 (61 mg, 1 equiv.), 2(3-acetyl-5-(2-methylpyrimidin-5-yl )-1H-indazol-1-yl)acetic acid (50 mg, 1.2 equiv.) in DMF (8 ml) and DIPEA (0.12 ml, 5 equiv.) was added HATU (63 mg, 1.2 equiv.) at 0°C in an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours before diluting with EtOAc (25 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with brine (15 ml x 3), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 23.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 9.04 (s, 2H), 8.45 (s, 1H), 7.77-7.90 (m, 3H), 7.63 (d, 1H, J= 8.2 Hz), 5.52-5.89 (m, 3H), 4.57-4.64 (m, 1H), 4.19-4.31 (m, 1H), 3.95-4.13 (m, 1H), 3.61-3.74 (m, 2H), 2.70 (s, 3H), 2.66 (s, 3H), 2.65-2.68 (m, 1H), 2.24-2.33 (m, 1H), 0.84-0.90 (m, 2H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -176.02 (s, 1F).

Scheme 17. Synthesis Methyl 3-acetyl-1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4fluoropyrrolidin-1-yl)-2-oxoethyl)-5- (2-methylpyrimidin-5-yl)-1H-indazole-7-carboxylate (25)

Stage 1. Methyl 5-(2-methylpyrimidin-5-yl)-III-indazole-7-carboxylate (25-S2): mixture of methyl 5-283 041794 bromine-III-indazole-7-carboxylate (0.95 g), 2 -methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidine (1.231 g, 1.5 eq.), cesium carbonate (3.64 g, 3 eq.) in dioxane (20 ml) and water (2.0 ml) were purged with argon in a pressure vessel for 5 min. Tetrakis(triphenylphosphine)palladium (0) (0.842 g, 0.2 equiv.) was added under argon and the pressure vessel was sealed and heated at 90°C overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 0-4.5% MeOH in CH ₂ Cl ₂ ) to give 0.538 g of product as a white solid.

Step 2 Methyl 3-bromo-5-(2-methylpyrimidin-5-yl)-1H-indazol-7-carboxylate (25-S3): To ice-cold methyl 5-(2-methylpyrimidin-5-yl)-1H -indazole-7-carboxylate (0.538 g) in DMF (15 ml) was added dropwise with bromine (113 μl). The resulting slurry was stirred at room temperature for 2 hours and quenched by adding saturated sodium thiosulfate solution. The solid was separated by filtration, washed with water and dried. The material was carried to the next step without further purification.

Step 3 Methyl 3-bromo-1-(2-(tert-butoxy)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazole-7carboxylate (25-S4): methyl mixture 3 -bromo-5-(2-methylpyrimidin-5-yl)-1H-indazol-7-carboxylate (0.150 g), tert-butyl bromoacetate (67 μl) and potassium carbonate (0.090 g) in anhydrous acetonitrile (10 ml) and DMF (1 ml) was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was triturated with water, filtered and dried. The material was carried to the next step without further purification.

Step 4 Methyl 3-acetyl-1-(2-(tert-butoxy)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazole 7-carboxylate (25-S5): methyl 3 solution -bromo-1-(2-(tert-butoxy)-2-oxoethyl)-5-(2-methylpyrimidin-5yl)-1H-indazole-7-carboxylate (0.100 g, 1 equiv.), tri-butyl(1 -ethoxyvinyl)tin (0.15 ml, 2 equiv.) and PdCl ₂ (PPh ₃ ) ₂ (15 mg, 0.1 equiv.) in DMF (2 ml) were heated at 80°C overnight in an argon atmosphere. The reaction was then concentrated under reduced pressure, diluted with CH2Cl2 and washed with cold aqueous HCl (1N). The organic layer was dried (Na ₂ SO ₄ ), filtered, concentrated, and the residue was purified by silica gel flash column chromatography (eluent: 0-1.5% MeOH in CH ₂ Cl ₂ ) to give a yellow solid.

Step 5 2-(3-Acetyl-7-(methoxycarbonyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (25-S6): methyl 3-acetyl- 1-(2-(tert-butoxy)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazole-7-carboxylate (25-S5) (0.08 g) was stirred in CH ₂ Cl ₂ (1 ml) and TFA (2 ml). After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure, and the remaining residue was immediately used in the next stage of the synthesis without purification.

Step 6. Methyl 3-acetyl-1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1yl)-2-oxoethyl)-5-( 2-methylpyrimidin-5-yl)-1H-indazole-7-carboxylate (25): compound 25-S6 from the previous step was dissolved in DMF (1 ml) and iPr ₂ NEt (0.164 ml, 5 eq.) was added followed by 25-S7 at 5°C. Then HATU (86 mg, 1.2 equiv.) was added slowly at 5°C and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and the precipitate was filtered off. The solid was dried and purified by silica gel flash column chromatography (eluent: 0-2.0% MeOH in CH ₂ Cl ₂ ) to give 25 as a white solid.

1H NMR (400 MHz, DMSO) δ 2.05-2.23 (m, 1H), 2.50-2.59 (m, 1H), 2.68 (s, 3H), 2.69 (s, 3H), 3.88-4.03 (m, 1H), 3.94 (s, 3H), 4.19 (dd, J=12.4, 21.8 Hz, 1H), 4.64 (t, J=8.4 Hz, 1H), 5.54 (d, J=52 Hz, 1H), 5.76 (d, J =17.4Hz, 1H), 5.95 (d, J=17.4Hz, 1H), 7.31 (d, J=7.7Hz, 1H), 7.70 (t, J=8.0Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 8.22 (d, J=2 Hz, 1H), 8.70 (d, J=1.8 Hz, 1H), 9.06 (s, 2H), 10.95 (s, 1H). ¹⁹ F NMR (DMSO-d ₆ ): δ -176.1.

Scheme 18. Synthesis of (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5(aminomethyl)-N-(6 -bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (26)

- 284 041794

Step 1. (3S)-3-Benzyl 2-tert-butyl 5-((1,3-dioxoisoindolin-2-yl)methyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate (26-S2) : to a solution of 26-S1 (300 mg, 0.86 mmol), isoindoline 1,3-dione (190 mg, 1.29 mmol) and PPh ₃ (452 mg, 1.72 mmol) in THF (6 ml) was added DIAD (0.34 ml, 1.72 mmol ) dropwise at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 6:1) to give 26-S2 (400 mg, 97.1% yield) as a light yellow viscous oil. LC/MS (ESI) m/z: 377 (M+H-100)+.

Step 2. (3S)-2-(tert-Butoxycarbonyl)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (26-S3): a solution of 26-S2 (400 mg, 0.83 mmol) in MeOH (10 mL) was purged with nitrogen and Pd/C (60 mg, 5 wt %) was added. The mixture was then purged with hydrogen and stirred under a hydrogen atmosphere (balloon) at room temperature for 12 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 40:1) to give 26-S3 (170 mg, 32.3% yield) as a light yellow oil. LC/MS (ESI) m/z: 287 (M+H-100)+.

Stage 3. (3S)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((1,3-dioxoisoindolin-2yl)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (26-S4): DIPEA (0.29 ml, 1.76 mmol) was added to a solution of 26-S3 (170 mg, 0.44 mmol) and 6methylpyridine-2-amine (90 mg, 0.48 mmol) in DCE (5 ml) and EEDQ (217 mg, 0.88 mmol). The reaction mixture was stirred at 90° C. overnight and concentrated under high vacuum. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 4:1) to give 26-S4 (103 mg, 41% yield) as a yellow solid. LC/MS (ESI) m/z: 555/557 (M+H) ⁺ .

Step 4. (3S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2azabicyclo[3.1.0]hexane-3- carboxamide (26-S5): HCl/dioxane (4 M, 1 ml) was added to a solution of 26-S4 (100 mg, 0.18 mmol) in dioxane (1 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated to give 26-S5 (82 mg, 100% yield) as a white solid. The crude material was carried to the next stage of the synthesis without purification.

Step 5. (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3

- 285 041794 methylpyridin-2-yl)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (26-S6): to a solution of 26- S5 (82 mg, 0.18 mmol), 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetic acid (67 mg, 0.21 mmol) and HATU (136 mg, 0.36 mmol) in DMF (2 ml) was added DIPEA (0.12 ml, 0.72 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with DCM/MeOH = 30:1) to give 26-S6 (60 mg, 44.7% yield) as an off-white solid.

Step 6. (3S)-5-(Aminomethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-(2-(3-((Z)-1-hydrazonoethyl)-5(2 -methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (26-S7): to a solution of 26-S6 (60 mg, 0.08 mmol) hydrazine hydrate (0.1 ml, 85%) was added to EtOH (3 ml). The reaction mixture was stirred at 50°C for 12 h and then cooled to room temperature. The mixture was filtered, the filtrate was concentrated to dryness, and the remaining crude product was purified by silica gel column chromatography (eluting with DCM/MeOH = 20:1) to give 26-S7 (30 mg, 60.1% yield) as a yellow oil.

Step 7. (3S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5(aminomethyl)-N-(6- bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (26): to a solution of 26-S7 (30 mg, 0.047 mmol) in THF/H2O (1 ml/1 ml ) copper(II) sulfate (38 mg, 0.24 mmol) was added. The reaction mixture was stirred at 50°C for 12 h and then cooled to room temperature. The mixture was filtered, the filtrate was concentrated to dryness and the remaining crude product was purified by preparative TLC to give 26 (3.6 mg, 12.4% yield) as a yellow solid.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.55 (s, 1H), 7.78 (s, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz , 1H), 5.65-5.79 (m, 2H), 5.14-5.19 (m, 1H), 3.90-3.94 (m, 1H), 3.40-3.43 (m, 1H), 3.01-3.05 (m, 1H), 2.75 (s, 3H), 2.70 (s, 3H), 2.47-2.51 (m, 1H), 2.29-2.39 (m, 1H), 2.08 (s, 3H), 0.83-0.90 (m, 2H). LC/MS (ESI) m/z: 617 (M+H)+.

Scheme 19. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (27)

HO

HATU (128 mg, 1.2 equiv.) was added at 0°C under argon to a solution of 27-S6 (102 mg, 1 equiv.), 2(3-acetyl-7-methyl-5-(2-methylpyrimidine-5- yl)-1H-indazol-1-yl)acetic acid (92 mg, 1.2 eq.) and DIPEA (0.24 ml, 5 eq.) in DMF (8 ml). The reaction mixture was stirred at room temperature for 3 hours before being diluted with EtOAc (30 ml) and water (15 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 27 (70 mg, 39%).

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.03 (s, 2H), 8.35 (s, 1H), 7.82 (d, 1H, J=8.4 Hz), 7.62 (s, 1H) , 6.03 (d, 1H, J=18.0 Hz), 5.69 (d, 1H, J=18.0 Hz), 4.37-4.43 (m, 1H), 3.59-3.62 (m, 1H), 2.69 (s, 6H), 2.65 (s, 3H), 2.53-2.60 (m, 1H), 2.08 (s, 3H), 2.02-2.10 (m, 1H), 1.33 (s, 3H), 0.93-1.05 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6): δ -119.12 (s, 1F).

Scheme 20. Synthesis of (1S,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)5-((allyloxy) methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (29)

- 286 041794

Step 1 2-(tert-Butyl)-3-ethyl-(1S,3S,5R)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (29-S4): Anhydrous DCM (12.5 mL) was cooled in an ice bath, and a solution of ZnEt2 in hexane (1.0 M) (2.27 mL, 2.27 mmol) was added to the flask, followed by careful dropwise addition of CH2I2 (4.54 mmol) under argon. After completion of the addition, the mixture was stirred at 0° C. for 10 min, during which a white precipitate appeared. A solution of 1-(tert-butyl) 2-ethyl (S)4-(hydroxymethyl)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (29-S1, 279 mg, 1.03 mmol) and L-dioxaborolane was quickly added 29-S2 (316 mg, 1.17 mmol) and the mixture was stirred for 30 min at 0°C. The reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH ₄ Cl (15 ml) at 0°C and the aqueous phase was extracted with DCM (15 ml x 2). The combined DCM solutions were washed with brine and dried over MgSO ₄ . The solution was filtered and concentrated and the resulting residue was purified to give 29-S4 (153 mg).

Step 2. 2-(tert-Butyl)-3-ethyl-(1S,3S,5R)-5-((allyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (29-S5) : to a solution of 2-(tert-butyl)-3-ethyl-(1S,3S,5R)-5-(hydroxymethyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate (29-S4, 153 mg, 0.53 mmol) in THF at 0°C was added NaH (60%, 2.65 mmol) under argon. The mixture was stirred for 30 min, allyl bromide (3.0 mmol) was added, and the reaction was heated to 40°C for 4 h. The reaction mixture was cooled in an ice bath and carefully quenched with aqueous NH ₄ Cl. The mixture was extracted with ethyl acetate (15 mlx3) and the combined organic layers were washed with water, brine and dried over MgSO ₄ . The solution was concentrated and the residue was purified to give 29-S5 (137 mg).

1H NMR (400 MHz, DMSO-d6, 300 K): δ 0.77-0.85 (m, 1H), 1.18-1.94 (m, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.41 (s, 9H ), 2.09-2.14 (m, 1H), 2.57-2.71 (m, 1H), 3.33-3.45 (m, 3H), 3.97 (d, J=5.2 Hz, 2H), 4.10-4.20 (m, 2H), 4.52-4.64 (m, 1H), 5.18 (d, J=10.4 Hz, 1H), 5.26 (d, J=17.2 Hz, 1H), 5.84-5.93 (m, 1H) ppm.

Step 3. (1S,3S,5R)-5-((Allyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3carboxylic acid (29-S6): Compound 29-S5 (137 mg, 0.42 mmol) was dissolved in a mixture of CH3OH-THF-H2O (2 ml-2 ml-2 ml) and treated with LiOH (40 mg, 1.67 mmol). The reaction mixture was stirred overnight at room temperature before the volatiles were evaporated under reduced pressure and the remaining residue was acidified with 10% citric acid (10 ml). The mixture was extracted with ethyl acetate (15 ml x 3) and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was concentrated and the residue 29-S6 (108 mg) was dried and carried on without further purification. LC (method A): t _R = 1.66 min. LC/MS (EI) m/z: [M+H]+ 298.4.

Step 4. tert-Butyl (1S,3S,5R)-5-((allyloxy)methyl)-3-((3-((allyloxy)methyl)-6-bromopyridin-2yl)carbamoyl)-2-azabicyclo[3.1 .0]hexane-2-carboxylate (29-S8): (1S,3S,5R)-5-((allyloxy)methyl)-2(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (29-S6, 108 mg, 0.36 mmol), 3((allyloxy)methyl)-6-bromopyridine-2-amine (29-S7, 97 mg, 0.40 mmol) was dissolved in anhydrous DCM (5 ml) in dried flask. The flask was cooled using an ice bath and dry pyridine (0.25 ml) was added in one portion followed by POCl ₃ (100 μl, 1.0 mmol). After

- 287 041794 the addition was completed, the mixture was stirred for 4 hours at 0° C. and the reaction was quenched with water (15 ml).

The DCM layer was removed and the aqueous phase was extracted with DCM (15 ml x 2). The combined DCM solutions were washed with brine and dried over MgSO ₄ . The solution was filtered and concentrated and the resulting residue was purified to give 29-S8 (126 mg).

1H NMR (400 MHz, chloroform-d) δ 0.75-0.92 (m, 1H), 1.02-1.17 (m, 1H), 1.51 (s, 9H), 2.35-2.80 (m, 2H), 3.42 (d, J =10.4 Hz, 1H), 3.52-3.63 (m, 2H), 3.90-4.11 (m, 4H), 4.36-4.44 (m, 2H), 4.74-4.87 (br, 1H), 5.185.31 (m, 4H ), 5.85-5.92 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 9.16 (s, 1H) ppm. LC (method A): tR=2.68 min. LC/MS (EI) m/z: [M+H]+ 524.44.

Step 5. (1S,3S,5R)-5-((Allyloxy)methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-2azabicyclo[3.1.0]hexane-3 -carboxamide, TFA salt (29-S9): tert-butyl (1S,3S,5R)-5-((allyloxy)methyl)-3((3-((allyloxy)methyl)-6-bromopyridin-2-yl )carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (29S8, 104 mg) was dissolved in DCM (4 ml) and treated with TFA (1 ml). The mixture was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure. The resulting material was co-evaporated twice with toluene and the residue (29-S9) was taken to the next step without further purification.

Step 6. (1S,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5((allyloxy)methyl )-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (29): to a solution of (1S,3S,5R)-5- ((allyloxy)methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt (29-S9, 0.2 mmol) , 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid (29-S10, 62 mg, 0.2 mmol) in DMF ( 2.0 ml) was added HATU (114 mg, 0.3 mmol) followed by dropwise addition of DIEA (5.0 eq.) at room temperature. The mixture was stirred for 1 hour at room temperature and the volatiles were evaporated. The residue was diluted with 10% sodium carbonate (50 ml) and extracted with ethyl acetate. The combined organic solution was washed successively with water and brine and dried over MgSO ₄ . The solution was filtered and the solvent was removed. The residue was purified to give 29 (31.1 mg).

1H NMR (400 MHz, DMSO-d ₆ ): (main rotamer) δ 1.05 (t, J=5.7 Hz, 1H), 1.44-1.46 (m, 1H), 2.07 (dd, J=13.5, 3.6 Hz, 1H ), 2.64 (s, 3H), 2.68 (s, 4H), 3.41-3.76 (m, 4H), 3.79 (dd, J=6.0, 2.6 Hz, 1H), 4.03 (d, J=5.5 Hz, 2H) , 4.16 (s, 2H), 4.91 (dd, J=11.4, 3.6 Hz, 1H), 4.96-5.13 (m, 2H), 5.20-5.36 (m, 2H), 5.58 (d, J=17.2 Hz, 1H ), 5.69-5.74 (t 1H), 5.91-5.98 (m, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.75-7.88 (m, 3H), 8.43 (s, 1H), 9.03 (s , 2H), 10.55 (s, 1H) ppm. LC (method A): t _R =2.28 min. LC/MS (EI) m/z: [M+H]+ 714.44, 716.47.

Scheme 21. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-X -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (31)

31-S1 31-S2

Step 1. tert-Butyl 2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (31-S2): to mixture 31-S1 ( 163 mg, 0.38 mmol) in dry DCM (10 ml) was added DAST (124 mg, 0.76 mmol) at -30°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 31-S2 (140 mg, 92% yield) as a white solid which was used in the next synthetic step without further purification. LC/MS (ESI) m/z: 399 (M+H)+.

Stage 2. 2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (31-S3): to a solution of 31-S2 ( 65 mg, 0.16 mmol) in THF/H2O (3:1 v/v, 4 ml) was added NaOH (14 mg,

- 288 041794

0.32 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and washed with diethyl ether twice. The aqueous layer was adjusted to pH 5 with 10% aqueous HCl and extracted twice with DCM. The organic layer was dried over Na ₂ SO ₄ and concentrated to give 31-S3 (35 mg, 63.8% yield) as a white solid which was used in the next synthetic step without further purification. LC/MS (ESI) m/z: 343 (M+H)+.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (31): to a solution of 31-S3 (35 mg, 0.1 mmol) , (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (46 mg, 0.13 mmol) and HATU ( 57 mg, 0.15 mmol) in DMF (3 ml) was added DIPEA (39 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed successively with 10% aqueous LiCl and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 31 (8 mg, 12.6% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.08 (s, 2H), 8.58 (s, 1H), 8.01 (s, 1H), 7.63 (d, J=8.1 Hz, 1H ), 7.45 (d, J=7.9 Hz, 1H), 5.95 (t, J=5.7 Hz, 1H), 5.81-5.91 (m, 1H), 5.72-5.78 (m, 1H), 5.61-5.69 (m, 1H), 4.38-4.44 (m, 1H), 3.58 (d, J=2.9 Hz, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 2.55-2.62 (m, 1H), 1.98-2.13 (m, 4H), 1.33 (s, 3H), 0.97–1.06 (m, 2H). LC/MS (ESI) m/z: 634 (M+H)+.

Scheme 22. Synthesis of (1R,3S,5S)-2-(2-(3-Acetyl-7-(methoxymethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N -(6-bromopyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (32)

Stage 1. 2-(tert-Butyl)-3-ethyl-(3S)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (32-S2): to a solution of 32-S1 ( 500 mg, 1.75 mmol) in THF (5 ml) was added NaH (105.4 mg, 4.39 mmol) at 0°C under nitrogen atmosphere, and the mixture was stirred at 0°C for 20 min. Iodomethane (740 mg, 5.25 mmol) was added and the resulting mixture was stirred at 0° C. under nitrogen for 3 h. The reaction mixture was quenched with aqueous NH4Cl and diluted with EtOAc. The mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 5:1) to give 32-S2 (160 mg, 30.5% yield) as a colorless oil. LC/MS (ESI) m/z: 300 (M+H)+.

Step 2. (3S)-2-(tert-Butoxycarbonyl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (32-S3): to a mixture of 32-S2 (160 mg, 0.5 mmol) in THF (2 mL) and water (2 mL) was added LiOH (62.7 mg, 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated to half volume and washed with EtOAc twice. The mixture was acidified with 2N. aqueous HCl and extracted with DCM twice. The combined organic layers were concentrated to dryness to give 32-S3 (120 mg, 88.9% yield) as a colorless oil. LC/MS (ESI) m/z: 272 (M+H)+.

Step 3. tert-Butyl (3S)-3-((6-bromopyridin-2-yl)carbamoyl)-5-(methoxymethyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (32-S4): to mixture 32-S3 (100 mg, 0.37 mmol) and 6-bromopyridine-2amine (24.6 mg, 0.37 mmol) in DCE (5 ml) were added DIPEA (0.25 ml, 1.48 mmol) and EEDQ (183 mg, 0.74

- 289 041794 mmol) at 0°C. The reaction mixture was stirred at 90°C overnight. The mixture was concentrated to dryness and the remaining residue was purified by silica gel column chromatography (eluting

PE/EtOAc = 1:1) to give 32-S4 (110 mg, 69.8% yield) as a yellow solid. LC/MS (ESI) m/z: 426 (M+H)+.

Step 4. (3S)-N-(6-Bromopyridin-2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32-S5): to a solution of 32-S4 ( 95 mg, 0.223 mmol) in dioxane (2 ml) was added HCl/dioxane (2 ml, 2 M) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give 32-S5 (114 mg, 100% yield) as a brown syrup which was used in the next step of the synthesis without purification. LC/MS (ESI) m/z: 326 (M+H) ⁺ .

Step 5. (3S)-2-(2-(3-Acetyl-7-(methoxymethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6-bromopyridine -2-yl)-5-(methoxymethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (32): to a mixture of 32-S5 (57 mg, 0.11 mmol), 2-(3-acetyl-7 -(methoxymethyl)-5-(2-methylpyrimidin-5-yl)-1N-indazol1-yl)acetic acid (39 mg, 0.078 mmol) and HATU (75 mg, 0.198 mmol) in DMF (3 ml) was added DIPEA ( 0.076 ml, 0.44 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 32 (19 mg, 50.4% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.59 (d, J=1.7 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H ), 7.61 (t, J=8.0 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.04 (d, J=17.5 Hz, 1H), 5.86 (d, J=17.4 Hz, 1H), 4.99 (s, 1H), 4.72 (d, J=12.6 Hz, 1H), 4.56 (d, J=9.0 Hz, 1H), 3.69 (dd, J=5.7, 2.6 Hz, 1H), 3.53 (q, J =10.3 Hz, 2H), 3.39 (d, J=3.1 Hz, 6H), 2.75 (s, 3H), 2.70 (d, J=2.5 Hz, 3H), 2.53 (dd, J=13.5, 9.2 Hz, 1H ), 2.41 (dd, J=12.8, 5.1 Hz, 1H), 1.15-1.11 (m, 1H), 0.90 (t, J=6.8 Hz, 1H). LC/MS (ESI) m/z: 662 (M+H) ⁺ .

Scheme 23 2-methylpyrimidin-5-yl)-1 N-indazole-7-carboxylic acid (41)

To a suspension of methyl 3-acetyl-1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin1-yl)-2-oxoethyl)-5-(2 -methylpyrimidin-5-yl)-1H-indazole-7-carboxylate (25, 0.13 g) in THF (3 ml) was added a solution of LiOH (25 mg) in water (1 ml). The resulting homogeneous solution was stirred overnight at room temperature. The organic solvent was removed and the residue was diluted with water (2 ml). White solid obtained by acidification of an aqueous solution of 2N. aqueous HCl, isolated and purified by reverse phase HPLC to give 41.

1H NMR (400 MHz, DMSO) δ 2.03-2.25 (m, 1H), 2.50-2.58 (m, 1H), 2.68 (s, 3H), 2.69 (s, 3H), 3.56-3.68 (m, 1H), 3.91-4.13 (m, 2H), 4.64 (t, J=8.4Hz, 1H), 5.53 (d, J=52.4Hz, 1H), 5.74 (d, J=17.1Hz, 1H), 6.10 (d, J =17.1 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 9.05 (s, 2H), 10.96 (s, 1H), 13.72 (s, 1H). ¹⁹ P-NMR (DMSO-d6): δ -175.2.

Scheme 24 2-yl)-5-((methylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (42)

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with R ²⁰¹ nucleophilic groups on the C-ring. One skilled in the art will appreciate that MeNH ₂ can be replaced with other nucleophilic reagents to provide additional compounds of the present invention. Non-limiting examples of groups that a person skilled in the art can use instead of MeNH ₂ include ethanamine, 2-fluoroethane-1amine, 2,2,2-trifluoroethanamine, N-ethylpropan-1-amine, cyclopropanamine, piperazine, azetidin, azetidin3-ol, 3,3-difluoroazetidine, 2-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, (3aR,6aS)octahydrocyclopenta[c]pyrrole, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4 ]octane, phenylmethanamine, (2-290 041794 fluorophenyl)methanamine and sodium cyanide.

To a solution of 42-S1 (84 mg, 0.12 mmol) in MeCN (3 mL) was added DIPEA (0.04 mL, 0.24 mmol), NaI (18 mg, 0.12 mmol), and MeNH ₂ -HCl (16 mg, 0.24 mmol). The reaction mixture was stirred at 30° C. overnight. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 10:1) and further purified by preparative HPLC to give 42 (1.5 mg, 3.3% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.57 (s, 1H), 7.76-7.83 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.42 (d, J =8.0 Hz, 1H), 5.65-5.79 (m, 2H), 4.72-4.75 (m, 1H), 3.85-3.87 (m, 1H), 2.61-2.79 (m, 11H), 2.59-2.60 (m, 2H ), 2.12 (s, 3H), 1.28–1.45 (m, 2H). LC/MS (ESI) m/z: 631/633 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-(piperazin-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (88):

¹ H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.55 (s, 1H), 8.45 (s, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.41 (d, J=7.9 Hz, 1H), 6.00 (m, 1H), 5.83 (m, 1H), 4.66 (m, 1H), 3.68 (m, 1H), 3.25 (m, 4H), 2.91 (m, 2H), 2.77 (d , J=4.9 Hz, 6H), 2.74 (d, J=3.9 Hz, 2H), 2.70 (s, 3H), 2.68 (s, 2H), 2.51 (m, 2H), 2.14 (s, 3H), 1.20 (m, 1H), 1.10 (m, 1H). LC/MS (ESI) m/z: 700 (M+H) ⁺ .

(1R,3S,5R)-5-(2-Azaspiro[3.3]heptan-2-ylmethyl)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5yl)-1H- indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (89):

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.45 (s, 1H), 7.64-7.52 (m, 2H), 7.42 (d, J=7.9 Hz, 1H), 5.99 (m, 1H) , 5.82 (m, 1H), 4.64 (m, 1H), 3.79 (m, 4H), 3.16-3.06 (m, 1H), 2.77 (d, J=2.9 Hz, 6H), 2.70 (s, 3H), 2.66 (s, 2H), 2.63-2.49 (m, 2H), 2.26 (m, 4H), 2.15 (s, 3H), 1.93-1.85 (m, 2H), 1.35 (m, 1H), 1.16 (m, 1H). LC/MS (ESI) m/z: 711 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-((methylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (94):

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.45 (d, J=6.7 Hz, 1H), 7.67-7.45 (m, 2H), 7.40 (m, 1H), 6.035.77 (m, 2H), 3.84 (s, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 2.79 (d, J=10.8 Hz, 2H), 2.75 (m, 4H), 2.77-2.68 (m, 4H ), 2.70-2.63 (m, 2H), 2.66-2.56 (m, 1H), 2.47 (dd, J=13.8, 3.5 Hz, 1H), 2.10 (m, 3H), 1.79 (m, 1H), 1.30 ( m, 2H). LC/MS (ERI) m/z: 645 (M+H)+ (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl) -1 H-indazol-1 -yl)acetyl)-N-(6bromo-3-methylpyridin-2-yl)-5-((2-fluoroethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide (113):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.43 (s, 1H), 7.66-7.47 (m, 3H), 7.41 (d, J=7.9 Hz, 2H), 5.99 (m, 1H) , 5.82 (m, 1H), 4.71 (m, 1H), 4.66 (m, 1H), 4.60 (m, 1H), 3.77 (m, 1H), 3.19 (m, 1H), 3.15-3.09 (m, 2H ), 3.00 (d, J=12.9 Hz, 1H), 2.76 (s, 6H), 2.70 (s, 3H), 2.63 (m, 2H), 2.14 (s, 3H), 1.18 (m, 1H), 0.92 (m, 1H). LC/MS (ESI) m/z: 677 (M+h) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-((diethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (118):

1H NMR (400 MHz, CD3OD) δ 8.89 (s, 2H), 8.33 (s, 1H), 7.51-7.42 (m, 2H), 7.30 (d, J=7.9 Hz, 1H), 5.80 (dd, J= 18.0, 18.0 Hz, 2H), 4.59 (dd, J=8.9, 4.5 Hz, 1H), 3.76 (d, J=3.2 Hz, 1H), 3.36 (d, J=14.6 Hz, 1H), 3.10 (s, 5H), 2.65 (d, J=5.3 Hz, 6H), 2.57 (d, J=7.6 Hz, 4H), 2.48 (dd, J=13.3, 4.3 Hz, 1H), 2.06 (s, 6H), 2.02 ( s, 3H), 1.40–1.36 (m, 1H), 0.82–0.78 (m, 1H). LC/MS (ESI) m/z: 687 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin- 2-yl)-5-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (119):

1H NMR (400 MHz, CD3OD) δ 8.92 (s, 2H), 8.47 (s, 1H), 7.72 (s, 2H), 7.49 (d, J=8.2 Hz, 1H), 7.32 (d, J=8.0 Hz , 1H), 5.74 (d, J=16.7 Hz, 1H), 5.57 (d, J=17.2 Hz, 1H), (dd, J=8.9, 4.5 Hz, 1H), 3.80 (d, J=5.2 Hz, 1H), 3.63 (s, 2H), 3.54 (s, 2H), 3.40-3.38 (m, 1H), 3.04-3.03 (m, 1H), 2.80 (s, 3H), 2.66 (s, 4H), 2.62 -2.55 (m, 6H), 2.04 (s, 3H), 1.64 (s, 4H), 1.50 (s, 2H), 1.36-1.31 (m, 1H), 1.21-1.18 (s, 1H). LC/MS (ESI) m/z: 711 (M+H) ⁺ .

(1R,3S,5R)-5-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl )-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (127):

1H NMR (400 MHz, CD3OD) δ 8.98 (s, 2H), 8.41 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J=8.0 Hz , 1H), 5.94-5.99 (m, 1H), 5.76-5.81 (m, 1H), 4.80 (s, 4H), 4.63-4.65 (m, 1H), 4.08-4.15 (m, 4H), 3.813.83 (m, 1H), 3.13 (s, 2H), 2.74 (s, 6H), 2.65 (s, 3H), 2.49-2.59 (m, 2H), 2.12 (s, 3H), 1.30-1.33 (m, 1H ), 0.950.98 (m, 1H). LC/MS (ESI) m/z: 713 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (128) :

1H NMR (400 MHz, CD3OD) δ 8.98 (s, 2H), 8.41 (s, 1H), 7.53-7.58 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 5.966.01 (m, 2H), 5.77-5.81 (m, 1H), 4.66-4.70 (m, 1H), 3.86-3.89 (m, 3H), 2.63-2.89 (m, 17H), 2.12 (s, 3H), 1.59-291 041794

1.76 (m, 6H), 1.43-1.46 (m, 1H), 1.27-1.30 (m, 1H). LC/MS (ESI) m/z: 725 (M+H)+.

(1R,3S,5R)-5-(2-Azaspiro[3.4]octan-2-ylmethyl)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)1H -indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (129):

¹ H NMR (400 MHz, CD ₃ OD) δ 8.98 (s, 2H), 8.41 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J =8.0 Hz, 1H), 5.97 (m, 1H), 5.79 (m, 1H), 4.67 (m, 1H), 4.07-4.04 (m, 1H), 4.03-3.90 (m, 1H), 3.44 (q, J=13.6 Hz, 2H), 2.74 (m, 6H), 2.67 (s, 3H), 2.61-2.55 (m, 1H), 2.12 (s, 3H), 1.94 (m, 4H), 1.66 (m, 5H ), 1.45 (m, 1H), 1.29–1.20 (m, 1H). LC/MS (ESI) m/z: 725 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-((ethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (132):

¹ H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.44 (s, 1H), 7.60-7.44 (m, 2H), 7.43 (d, J=7.9 Hz, 1H), 5.98 (d, J =17.6Hz, 1H), 5.83 (d, J=17.6Hz, 1H), 4.74 (dd, J=8.3, 4.4Hz, 1H), 3.91 (dd, J=5.8, 2.8Hz, 1H), 3.28-3.07 (m, 3H), 2.77 (s, 6H), 2.70 (s, 3H), 2.68-2.59 (m, 2H), 2.14 (s, 3H), 1.50 (d, J=5.9 Hz, 1H), 1.39 ( t, J=7.3 Hz, 3H), 1.35 (dd, J=5.9, 2.8 Hz, 1H). LC/MS (ESI) m/z: 658 (M+H) ⁺ .

(1R,3S,5R)-5-(2-Azaspiro[3.4]octan-2-ylmethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1 - yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (142):

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.53 (s, 1H), 7.77 (s, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz , 1H), 5.77-5.81 (m, 1H), 5.62-5.66 (m, 1H), 4.65-4.68 (m, 1H), 3.99-4.07 (m, 4H), 3.88-3.90 (m, 1H), 3.36 (s, 2H), 2.75 (s, 3H), 2.68 (s, 3H), 2.57-2.60 (m, 2H), 2.12 (s, 3H), 1.91-1.95 (m, 4H), 1.63-1.67 (m , 4H), 1.37-1.39 (m, 1H), 1.23-1.25 (m, 1H). LC/MS (ESI) m/z: 711 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5 (azetidine- 1-ylmethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (149):

1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.42 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=8.0 Hz , 1H), 5.96-6.01 (m, 1H), 5.78-5.83 (m, 1H), 4.64-4.68 (m, 1H), 4.04-4.09 (m, 4H), 3.86-3.88 (m, 1H), 3.32 -3.34 (m, 1H), 3.18-3.21 (m, 1H), 2.76 (s, 6H), 2.71 (s, 4H), 2.44-2.53 (m, 3H), 2.13 (s, 3H), 1.39-1.42 (m, 1H), 1.21-1.23 (m, 1H). LC/MS (ESI) m/z: 671 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-((3,3-difluoroazetidin-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (150):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.43 (s, 1H), 7.55-7.57 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 5.976.02 (m, 1H), 5.78-5.83 (m, 1H), 4.59-4.63 (m, 1H), 3.67-3.82 (m, 5H), 2.70-2.81 (m, 11H), 2.58-2.60 (m, 2H), 2.16 ( s, 3H), 1.24-1.27 (m, 1H), 1.03-1.05 (m, 1H). LC/MS (ESI) m/z: 707 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin- 2-yl)-5-((cyclopropylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (151):

1H NMR (400 MHz, CD3OD) δ 9.03 (s, 2H), 8.58 (s, 1H), 7.81 (s, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.9 Hz , 1H), 5.82 (d, J=17.2 Hz, 1H), 5.68 (d, J=17.1 Hz, 1H), 4.68-4.57 (m, 1H), 3.69 (s, 1H), 3.16-3.01 (m, 1H), 2.84 (d, J=12.7 Hz, 1H), 2.77 (s, 3H), 2.72 (s, 3H), 2.66-2.56 (m, 2H), 2.35 (s, 1H), 1.30 (s, 1H ), 1.13 (s, 1H), 0.58 (d, J=5.5 Hz, 2H), 0.47 (s, 2H). LC/MS (ESI) m/z: 657 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-(((2,2,2-trifluoroethyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (160):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.44 (s, 1H), 7.56-7.58 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 5.976.02 (m, 1H), 5.80-5.85 (m, 1H), 4.61-4.64 (m, 1H), 3.66-3.69 (m, 1H), 3.32-3.34 (m, 2H), 2.94-2.96 (m, 2H), 2.78 ( s, 6H), 2.76 (s, 3H), 2.59–2.61 (m, 2H), 2.15 (s, 3H), 1.29–1.32 (m, 1H), 1.05–1.08 (m, 1H). LC/MS (ESI) m/z: 713 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5 ((benzylamino )methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (161):

1H NMR (400 MHz, CD3OD) δ 8.85 (s, 2H), 8.27 (s, 1H), 7.28-7.46 (m, 8H), 5.81-5.86 (m, 1H), 5.64-5.69 (m, 1H), 4.56-4.58 (m, 1H), 4.01-4.11 (m, 2H), 3.71-3.74 (m, 1H), 3.01 (s, 2H), 2.63 (s, 6H), 2.56 (s, 3H), 2.502. 54 (m, 2H), 1.99 (s, 3H), 1.29-1.31 (m, 1H), 1.14-1.17 (m, 1H). LC/MS (ESI) m/z: 721 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-(cyanomethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (162):

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.53-7.56 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 5.966.00 (m, 1H), 5.77-5.82 (m, 1H), 4.62-4.66 (m, 1H), 3.82-3.84 (m, 1H), 3.04-3.08 (m, 1H), 2.87-2.91 (m, 1H), 2.69- 2.78 (m, 10H), 2.46-2.50 (m, 1H), 2.14 (s, 3H), 1.40-1.43 (m, 1H), 1.22-1.25 (m, 1H). LC/MS (ESI) m/z: 641 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-methylpyridin-2-yl)-5-((3-hydroxyazetidin-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (164):

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.44 (s, 1H), 7.63-7.53 (m, 2H), 7.42 (d, J=7.9 Hz, 1H), 6.00 (d, J= 17.7 Hz, 1H), 5.82 (d, J=17.7 Hz, 1H), 4.70-4.48 (m, 2H), 4.15 (d, J=26.0 Hz, 2H), 3.81 (s, 1H), 3.50 (s,

- 292 041794

2H), 3.24-3.12 (m, 1H), 3.03 (d, J=13.0 Hz, 1H), 2.77 (d, J=2.9 Hz, 6H), 2.70 (s, 3H), 2.61 (d, J=8.8 Hz, 1H),

2.53 (dd, J=13.5, 4.8 Hz, 1H), 2.14 (s, 3H), 1.34 (d, J=22.4 Hz, 2H), 1.17 (s, 1H). LC/MS (ESI) m/z: 687 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-III-indazol-1-yl)acetyl)-N-(6bromo- 3-methylpyridin-2-yl)-5-(((2-fluorobenzyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (170):

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.43 (s, 1H), 7.59-7.54 (m, 3H), 7.48-7.41 (m, 2H), 7.29-7.22 (m, 2H), 5.96 (d, J=12.8 Hz, 1H), 5.81 (d, J=9 Hz, 1H), 4.70 (s, 1H), 4.26 (d, J=3 Hz, 2H), 3.86-3.84 (m, 1H ), 3.24 (d, J=2.4 Hz, 2H), 2.76 (d, J=2.8 Hz, 6H), 2.69 (s, 3H), 2.66-2.63 (m, 2), 2.12 (s, 3H), 1.45 (s, 1H), 1.281.26 (m, 1H). LC/MS (ESI) m/z: 739 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo- 3-methylpyridin-2-yl)-5-(((1-(2,2,2-trifluoroethyl)-III-pyrazol-3-yl)amino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide :

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.53 (d, J=7.4 Hz, 2H), 7.42 (d, J=2.5 Hz, 1H), 7.37 (d , J=7.9 Hz, 1H), 5.95 (d, J=17.8 Hz, 1H), 5.80 (d, J=17.7 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 4.71-4.58 (m , 3H), 3.74-3.65 (m, 1H), 3.48 (d, J=13.6 Hz, 1H), 3.34 (s, 1H), 2.75 (d, J=4.4 Hz, 6H), 2.68 (s, 3H) , 2.63-2.49 (m, 2H), 2.11 (s, 3H), 1.38-1.35 (m, 1H), 1.10-1.01 (m, 1H). LC/MS (ESI) m/z: 779 (M+H) ⁺ .

Scheme 25. Synthesis of (1S,3S,5S)-5-(acetamidomethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1 -yl)acetyl)-N -(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (43) and (1R,3S,5R)-5-(acetamidomethyl)-2-(2-(3- acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide ( 44) kuts scho

EtOH, 75°C

Stage 2

HATH, DIFEA, DMF

Stage 15 Vg

44-S5

Step 1. (3S)-tert-Butyl 3-(6-bromopyridin-2-ylcarbamoyl)-5-((1,3-dioxoisoindolin-2yl)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (44-S2): DIPEA (0.43 ml, 2.58 mmol) and EEDQ (319 mg, 1.29 mmol). The reaction mixture was stirred at 90° C. overnight and concentrated in vacuo. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 4:1) to give 44-S2 (300 mg, 85.9% yield) as a white solid. LC/MS (ESI) m/z: 541/543 (M+H) ⁺ .

Step 2. (3S)-tert-Butyl 5-(aminomethyl)-3-(6-bromopyridin-2-ylcarbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (44-S3): to 44-S2 solution (300 mg, 0.55 mmol) in EtOH (6 ml) was added hydrazine hydrate (0.3 ml, 85% wt). The reaction mixture was stirred at 75°C for 2 h and then cooled to room temperature. The mixture was filtered, the filtrate was concentrated to dryness and the remaining crude product was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 44-S3 (210 mg, 92.5% yield) as a light yellow oil. LC/MS (ESI) m/z: 411/413 (M+H) ⁺ .

Step 3. (3S)-tert-Butyl 5-(acetamidomethyl)-3-(6-bromopyridin-2-ylcarbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (44-S4): to mixture 44-S3 (100 mg, 0.24 mmol) in dry DCM (3 ml)

- 293 041794 DIPEA (0.08 ml, 0.48 mmol) and acetyl chloride (0.02 ml, 0.28 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (20 ml) and extracted with DCM (4 ml x 2). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining crude product was purified by silica gel column chromatography (eluting with DCM/MeOH=30:1) to give 44-S4 (94 mg, 85.4% yield) as a white solid. LC/MS (ESI) m/z: 453/455 (M+H)+.

Step 4. (3S)-5-(Acetamidomethyl)-N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (44-S5): to a solution of 44-S4 (90 mg , 0.2 mmol) in DCM (2.5 ml) was added TFA (1 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 44-S5 (80 mg, 100.0% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 353/355 (M+H)+.

Step 5. (1S,3S,5S)-5-(acetamidomethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)acetyl) -N-(6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (43) and (1R,3S,5R)-5(acetamidomethyl)-2-(2-(3 -acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide ( 44): to a solution of 44-S5 (35 mg, 0.078 mmol), 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (44-S6, 29 mg, 0.093 mmol) and HATU (59 mg, 0.155 mmol) in DMF (2 mL) were added DIPEA (0.065 mL, 0.40 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 43 (25 mg, 49.8% yield) and 44 (2 mg, 3.98% yield) as white solids. (1S,3S,5S)-5-(acetamidomethyl)-2(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6 -bromopyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (43):

1H NMR (400 MHz, DMSO-d6) δ 10.91(s, 1H), 9.04 (s, 2H), 8.48 (s, 1H), 8.02-8.05 (m, 2H), 7.83-7.89 (m, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 5.86-5.90 (m, 1H), 5.58-5.63 (m, 1H), 4.92-4.95 (m, 1H) , 3.72-3.74 (m, 1H), 3.37-3.40 (m, 2H), 2.62-2.68 (m, 6H), 2.01-2.05 (m, 1H), 1.86 (s, 3H), 1.40-1.42 (m, 1H), 0.89–1.01 (m, 2H). LC/MS (ESI) m/z: 645/647 (M+H)+.

(1R,3S,5R)-5-(acetamidomethyl)-2-(2-(3-αcetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-X-(6- brompyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (44):

1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.54 (s, 1H), 8.08-8.10 (m, 1H), 7.79 (s, 2H), 7.62 (t, J=8.0 Hz, 1H) , 7.26 (d, J=7.6 Hz, 1H), 5.77-5.82 (m, 1H), 5.63-5.68 (m, 1H), 4.57-4.62 (m, 1H), 3.70-3.72 (m, 1H), 3.46 -3.50 (m, 1H), 3.20-3.23 (m, 1H), 2.73-2.75 (m, 6H), 2.30-2.52 (m, 2H), 1.92 (s, 3H), 1.26-1.29 (m, 1H) , 1.06–1.08 (m, 1H). LC/MS (ESI) m/z: 645/647 (M+H)+.

Scheme 26 (6-bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)methylamino)-3-methyl-1oxobutan-2-ylcarbamate (45)

Step 1. (3S)-tert-Butyl 3-(6-bromopyridin-2-ylcarbamoyl)-5-(((S)-2-(methoxycarbonylamino)-3methylbutanamido)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (45-S2): to a mixture of 45-S1 (100 mg, 0.24 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (51 mg, 0.29 mmol) and HATU (182 mg, 0.48 mmol) in DMF (2 ml) was added DIPEA (0.16 ml, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 30:1) to give 45-S2 (105 mg, 76.0% yield) as a white solid. LC/MS (ESI) m/z:

568/570 (M+H)+.

Step 2. Methyl (2S)-1-(((3S)-3-(6-bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-5yl)methylamino)-3-methyl-1-oxobutane -2-ylcarbamate (S3): TFA (1 ml) was added to a solution of 45-S2 (105 mg, 0.18 mmol) in DCM (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 45-S3 (85 mg, 100.0% yield) as a yellow solid which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 468/470 (M+H) ⁺ .

Step 3. Methyl (2S)-1-(((3S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)3 -(6-bromopyridin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)methylamino)-3-methyl-1-oxobutan-2ylcarbamate (45): to a solution of 45-S3 (35 mg, 0.074 mmol) ) DIPEA (0.05 ml, 0.29 mmol) was added to DMF (2 ml). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 45 (39 mg, 68.6% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.04 (s, 2H), 8.47 (s, 1H), 8.01-8.25 (m, 2H), 7.70-7.89 (m, 3H), 7.30-7.33 (m, 1H), 7.11-7.24 (m, 1H), 5.84-5.91 (m, 1H), 5.57-5.64 (m, 1H), 4.92-4.95 (m, 1H), 3.71-3.79 (m , 2H), 3.49 (s, 4H), 3.29-3.33 (m, 1H), 2.65-2.68 (m, 7H), 1.97-2.02 (m, 2H), 1.05-1.36 (m, 2H), 0.87-0.95 (m, 6H). LC/MS (ESI) m/z: 760/762 (M+H) ⁺ .

Scheme 27. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-ethyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (47)

Stage 1. 4-Bromo-2-ethyl-6-methylaniline (47-S2): Br ₂ (5.1 ml) was added dropwise to a solution of 47-S1 (12 g, 88.7 mmol) in AcOH (250 ml) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake washed with diethyl ether. The solid was suspended in water and neutralized with saturated aqueous K ₂ CO ₃ . The mixture was extracted twice with EtOAc and the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give 47-S2 (12.2 g, 57.0% yield) as a purple oil. LC/MS (ESI) m/z: 214 (M+H) ⁺ .

Stage 2. 5-Bromo-7-ethyl-1H-indazole (47-S3): to a solution of 47-S2 (6 g, 28.2 mmol) and KOAc (3.3 g, 33.8 mmol) in CHCl ₃ (60 ml) were added acetic anhydride (8.6 g, 86.4 mmol) at 0°C under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was heated to 60°C and tert-butyl nitrite (5.8 g, 56.4 mmol). The resulting mixture was stirred at 60° C. overnight. The mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated. The remaining residue was dissolved in MeOH and 6N. aqueous HCl (20 ml), and the mixture was stirred at room temperature for 4 h. The reaction mixture was basified with 2N. aqueous NaOH solution and extracted with DCM

- 295 041794 twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 47-S3 (5.0 g, 79.2% yield) as a light yellow solid.

LC/MS (ESI) m/z: 225 (M+H)+.

Stage 3. 5-Bromo-7-ethyl-3-iodo-1H-indazole (47-S4): to a solution of 47-S3 (4.5 g, 20.1 mmol) in DMF (50 ml) was added KOH (2.53 g, 45.23 mmol ) and iodine (7.65 g, 30.15 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched by adding saturated aqueous Na ₂ S ₂ O ₃ (15 ml). The mixture was diluted with DCM and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give 47-S4 (6.56 g, 93.2% yield) as a white solid. LC/MS (ESI) m/z: 351 (M+H) ⁺ .

Step 4. tert-Butyl 2-(5-bromo-7-ethyl-3-iodo-1H-indazol-1-yl)acetate (47-S5): to a solution of 47-S4 (6.56 g, 18.75 mmol) in DMF (70 ml) was added K ₂ CO ₃ (7.76 g, 56.2 mmol) and tert-butyl 2-bromoacetate (2.73 ml, 18.75 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 10:1) to give 47-S5 (3.5 g, 40.2% yield) as a yellow solid. LC/MS (ESI) m/z: 465 (M+H) ⁺ .

Step 5. tert-Butyl 2-(3-acetyl-5-bromo-7-ethyl-1H-indazol-1-yl)acetate (47-S6): to a solution of 47-S5 (1.5 g, 3.23 mmol) in toluene (15 ml) were added tributyl(1-ethoxyvinyl)stannan (1.75 g, 4.85 mmol) and Pd(PPh ₃ ) ₄ (373 mg, 0.32 mmol). The mixture was stirred at 100° C. under nitrogen overnight. The mixture was cooled to room temperature and 0.5 M aqueous HCl was added. The resulting mixture was stirred for another 10 min, diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 60:1) to give 47-S6 (976 mg, 79.5% yield) as a brown solid. LC/MS (ESI) m/z: 381 (M+H) ⁺ .

Step 6. tert-Butyl 2-(3-acetyl-7-ethyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (47S7): to a solution of 47-S6 (500 mg , 1.32 mmol) and (2-methylpyrimidin-5-yl)boronic acid (182 mg, 1.32 mmol) in dioxane (6 ml) and water (0.6 ml) were added K ₂ CO ₃ (455 mg, 3.3 mmol) and Pd( PPh ₃ ) ₄ . The reaction mixture was stirred at 90° C. under nitrogen overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 47-S7 (210 mg, 40.4% yield) as a white solid. LC/MS (ESI) m/z: 395 (M+H) ⁺ .

Step 7. 2-(3-Acetyl-7-ethyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (47S8): to a solution of 47-S7 (170 mg, 0.43 mmol) in THF (3 mL) was added 1 M NaOH aqueous solution (0.86 mL, 0.86 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness, diluted with water, and washed with diethyl ether twice. The aqueous layer was acidified by adding 1N. aqueous HCl and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give 47-S8 (106 mg, 72.9% yield) as a white solid. LC/MS (ESI) m/z: 339 (M+H) ⁺ .

Step 8. (1 R,3S,5R)-2-(2-(3-Acetyl-7-ethyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (47): to a solution of 47S8 (30 mg, 0.089 mmol), 47-S9 (32 mg, 0.093 mmol) and HATU (50.0 mg, 0.133 mmol) in DMF (3 mL) was added DIPEA (34 mg, 0.267 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The mixture was diluted with EtOAc and washed with 10% LiCl aqueous solution and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 47 (8 mg, 10.7% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 9.04 (s, 2H), 8.35 (d, J=1.5 Hz, 1H), 7.64-7.60 (m, 2H), 7.45 (d , J=8.0 Hz, 1H), 5.96 (d, J=16.0 Hz, 1H), 5.68 (d, J=20.0 Hz, 1H), 4.40 (m, 1H), 3.60 (m, 2H), 3.03-2.97 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 2.58 (m, 2H), 2.04 (s, 4H), 1.33 (d, J=8.0 Hz, 6H), 1.06 (t, J=5.3 Hz, 1H), 0.93 (m, 1H). LC/MS (ESI) m/z: 630 (M+H) ⁺ .

Scheme 28. Synthesis of methyl 5-(3-acetyl-1-(2-((1R,3S,5R)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5methyl-2-azabicyclo[3.1. 0]hexan-2-yl)-2-oxoethyl)-7-methyl-1H-indazol-5-yl)-2-methylpyrimidin-1oxide (50) m-CPBA

CHCI ₃

Stage

Stage 2

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1. 5-(3 - Acetyl-1 - (2-tert-butoxy-2-oxoethyl) -7-methyl-1 H-indazol-5-yl) -2 Methylpyrimidine-1-oxide stage (50-S2): to m-CPBA (67 mg, 0.39 mmol) was added to a mixture of 50-S1 (130 mg, 0.39 mmol) in CHCl ₃ (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH 10 with aqueous NaHCO ₃ . The mixture was partitioned with DCM/MeOH (20:1) and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH=120:1) to give the title product (77 mg, 49.2% yield) as a white solid. LC/MS (ESI) m/z: 397 (M+H)+.

Stage 2. 5-(3-acetyl-1-(carboxymethyl)-7-methyl-1H-indazol-5-yl)-2-methylpyrimidine 1-oxide (50S3): to a solution of 50-S2 (77 mg, 0.18 mmol ) in DCM (2 ml) was added TFA (2 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give the title product (60 mg, 88.4% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 341 (M+H)+.

Step 3. 5-(3-Acetyl-1-(2-((1R,3S,5R)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-methyl-2azabicyclo[3.1.0] hexan-2-yl)-2-oxoethyl)-7-methyl-1H-indazol-5-yl)-2-methylpyrimidine 1-oxide (50): to a solution of 50-S3 (60 mg, 0.145 mmol), (1R ,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (50 mg, 0.145 mmol) and HATU (84 mg, 0.22 mmol) in DMF (3 ml) was added DIPEA (57 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was partitioned with DCM/MeOH (20:1) and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 50 (2.2 mg, 1.6% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.95 (d, J=1.9 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.35 (s, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.9 Hz, 1H), 6.03 (d, J=17.9 Hz, 1H), 5.69 (d, J=17.8 Hz, 1H), 4.41 ( dd, J=9.1, 5.5 Hz, 1H), 3.56-3.61 (m, 1H), 2.67 (s, 3H), 2.65 (s, 3H), 2.61 (s, 3H), 2.53-2.59 (m, 1H) , 2.04 (s, 3H), 1.97–2.03 (m, 1H), 1.33 (s, 3H), 1.00–1.05 (m, 1H), 0.91–0.97 (m, 1H). LC/MS (ESI) m/z: 632/634 (M+H)+.

Scheme 29 3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (51)

- 297 041794

Stage 1. 5-Bromo-7-methyl-1H-indazole (51-S2): to a solution of 4-bromo-2,6-dimethylaniline (51-S1, 10 g, 0.05 mol) and potassium acetate (5.88 g, 0.06 mol) in CHCl ₃ (120 ml) was added acetic anhydride (15.3 g, 0.15 mol) dropwise at 0°C under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was heated to 60°C and tert-butyl nitrite (10.3 g, 0.1 mol) was added dropwise. The resulting mixture was stirred overnight at 60°C. The mixture was cooled to room temperature, diluted with H2O and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was dissolved in MeOH and 6N. aqueous HCl (50 ml, v/v = 1:1), and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was basified with 10N. aqueous NaOH and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 51-S2 (10.1 g, 95.7% yield) as a light yellow solid. LC/MS (ESI) m/z: 212 (M+H)+.

Step 2. 5-Bromo-3-iodo-7-methyl-1H-indazole (51-S3): KOH (6.63 g, 0.18 mol) was added to a solution of 51-S2 (10 g, 0.047 mol) in DMF (50 ml). ) followed by the addition of I2 (18.06 g, 0.071 mol) at 0°C. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with aqueous Na ₂ S ₂ O ₃ and diluted with EtOAc. The mixture was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was washed with PE/EtOAc (50 ml, 5:1) and dried under vacuum to give 51-S3 (15.1 g, 94.6% yield) as a light yellow solid. LC/MS (ESI) m/z: 338 (M+H) ⁺ .

Stage 3. tert-Butyl 2-(5-bromo-3-iodo-7-methyl-1H-indazol-1-yl)acetate (51-S4): to a solution of 51-S3 (6.9 g, 0.02 mol) in DMF (20 ml) was added K2CO3 (8.48 g, 0.06 mol) and tert-butyl 2-bromoacetate (3.97 g, 0.02 mol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining crude product was purified by silica gel column chromatography (eluting with PE/EtOAc = 200:1 to 70:1) to give 51-S4 (5.66 g, 61.3% yield) as a light yellow solid. LC/MS (ESI) m/z: 452 (M+H) ⁺ .

Step 4. tert-Butyl 2-(3-acetyl-5-bromo-7-methyl-1H-indazol-1-yl)acetate (51-S5): to a solution of 51-S4 (4.63 g, 10.27 mmol) in dry toluene (25 ml) was added tributyl(1-ethoxyvinyl)stannan (5.19 g, 14.38 mmol) and Pd(PPh ₃ ) ₄ (0.83 g, 0.72 mmol). The reaction mixture was degassed with nitrogen and stirred at 100° C. under nitrogen overnight. The mixture was cooled to room temperature, 0.5 M aqueous HCl (20 ml) was added and then stirred at room temperature for 20 min. The reaction mixture was diluted with H ₂ O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The remaining crude product was purified by silica gel column chromatography (eluting with PE/EtOAc = 150:1 to 60:1) to give 51-S5 (2.63 g, 70.0% yield) as a milky white solid. LC/MS (ESI) m/z: 367 (M+H) ⁺ .

Step 5. tert-Butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (51S6): 51-S5 ( 2.63 g, 7.18 mmol), 2-methylpyrimidin-5-ylboronic acid (0.99 g, 7.18 mmol), K2CO3 (2.48 g, 17.96 mmol) and dioxane/H ₂ O (20 ml, v/v = 9:1 ) in a nitrogen atmosphere. To this mixture was added tetrakis(triphenylphosphine)palladium (0) (0.42 g, 0.36 mmol) and the resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The mixture was diluted with EtOAc and filtered. The filtrate was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The remaining crude product was purified by silica gel column chromatography (eluting with PE/EtOAc = 100:1 to 3:1) to give 51-S6 (1.93 g, 70.7% yield) as a light yellow solid. LC/MS (ESI) m/z: 381 (M+H)+.

Step 6. 2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (51S7): Compound 51-S6 (1.45 g, 3.81 mmol ) was treated with HCl/dioxane (9 ml) and stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and the remaining residue was washed with ether and dried under vacuum to give 51-S7 (1.23 g, 99.8% yield) as a light yellow solid substances. LC/MS (ESI) m/z: 324 (M+H) ⁺ .

Step 7. (3S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (51): to a mixture of 51-S7 (30 mg, 0.093 mmol) and 51-S8 (33 mg, 0.093 mmol) in DMF (1 ml) was added DIPEA (60 mg, 0.46 mmol) followed by the addition of HATU (77 mg, 0.20 mmol). The reaction mixture was stirred

- 298 041794 at room temperature for 1 h. The mixture was diluted with EtOAc, washed with 10% aqueous solution

LiCl and brine, dried and concentrated to give the crude product, which was purified by preparative HPLC to give 51 (2 mg, 3.28% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.46 (s, 1H), 7.64-7.55 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 6.01 (d, J= 17.6 Hz, 1H), 5.83 (d, J=17.6 Hz, 1H), 4.72 (dd, J=8.8, 4.4 Hz, 1H), 3.95 (dd, J=5.6, 2.8 Hz, 1H), 3.59 (d, J=14.0 Hz, 1H), 3.24 (d, J=13.6 Hz, 1H), 2.98 (s, 6H), 2.78 (s, 3H), 2.77 (s, 3H), 2.75-2.73 (m, 1H), 2.70 (s, 3H), 2.59 (dd, J=13.6, 4.0 Hz, 1H), 2.14 (s, 3H), 1.52 (t, J=5.6 Hz, 1H), 1.42-1.39 (m, 1H). LC/MS (ESI) m/z: 660 (M+H)+.

Scheme 30. Synthesis of (2S,4R)-1-(2-(3-acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo-3 -methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamideα (59)

Step 1. (2S,4R)-1-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridine -2-yl)-4-fluoropyrrolidin-2-carboxamide (59-S3): to a solution of 2-(3-acetyl-5-(2methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (59 -S1, 1 eq.) in DMF (10 vol.) at 0°C under nitrogen atmosphere was added (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidin-2- carboxyamide (59-S2, 1.2 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 59-S3.

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.47 (s, 1H), 8.95 (s, 2H), 8.38 (s, 1H), 7.81 (s, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 5.85 (d, J=17.2 Hz, 1H), 5.62 (d, J=16.8 Hz, 1H), 5.50 (s, 1H), 4.60 (t, J=16.8 Hz, 1H), 4.29-4.21 (m, 1H), 4.08-4.05 (m, 1H), 3.98 (s, 3H), 2.67 (s, 3H), 2.66-2.65 (m, 1H), 2.25 -2.14 (m, 1H), 2.00 (s, 3H).

Step 2. (2S,4R)-1-(2-(3-Acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridine -2-yl)-4-fluoropyrrolidine-2-carboxamide (59): to a solution of compound 59-S3 (1 equiv.) in ACN (10 vol.) at 0°C in a nitrogen atmosphere was added TMSCl (2.5 equiv.) and NaI (2 equiv.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and quenched with water. The resulting solid was filtered off and dried to give compound 59.

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.47 (s, 1H), 8.65 (s, 2H), 8.29 (s, 1H), 7.75 (s, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 5.82 (d, J=17.2 Hz, 1H), 5.62 (d, J=16.8 Hz, 1H), 5.50 (s, 1H), 4.59 (t, J=16.8 Hz, 1H), 4.28-4.20 (m, 1H), 4.07-4.04 (m, 1H), 2.55-2.54 (m, 1H), 2.53 (s, 3H), 2.33-2.21 (m, 1H) , 2.00 (s, 3H).

Scheme 31. Synthesis of (1R,3S,5R)-2-(2-(3-αcetyl-5-(2-methylpyrimidin-5-yl)-1H-indαzol-1-yl)acetyl)5-((allyl( methyl)amino)methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane3-carboxamide (70)

- 299 041794

70-S5 TFA

70-S6

Step 1. 2-(tert-Butyl)-3-ethyl-(1R,3S,5R)-5-((allyl(methyl)amino)methyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate ( 70-S2): K ₂ CO ₃ (1 g) was added to a mixture of 2-(tert-butyl)-3-ethyl(1R,3S,5S)-5-(((methylsulfonyl)oxy)methyl)-2-azabicyclo [3.1.0]hexane-2,3-dicarboxylate (70-S1, 0.77 mmol) and N-methylprop-2-en-1-amine (0.663 ml, 6.93 mmol) in ACN (8 ml) and the reaction mixture was heated at 40° C. under argon for 4 hours. EtOAc was added and the diluted reaction mixture was filtered through celite to remove all solids. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography with MeOH in DCM (010%) as eluent to give 2-(tert-butyl)-3-ethyl-(1R,3S,5R)-5- ((allyl(methyl)amino)methyl)2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate 70-S2 (0.211 g) as a yellow amorphous solid.

Step 2. (1R,3S,5R)-5-((Allyl(methyl)amino)methyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (70-S3): 2-(tert-butyl)-3-ethyl-(1R,3S,5R)-5((allyl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (70- S2, 0.211 g, 0.624 mmol) was dissolved in a mixture of THF-EtOH-water (3 ml-0.75 ml-0.7 ml) and treated with LiOH monohydrate (32 mg, 0.75 mmol). The reaction was stirred at room temperature for 6 h before adding Amberlite (weak acid cation exchanger in H form, 1 g). After stirring for 20 minutes, the reaction mixture was filtered and the resulting resin was washed with MeOH. The combined filtrates were concentrated under reduced pressure and the residue was purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give (1R,3S,5R)-5((allyl(methyl)amino)methyl) -2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid 70-S3 (0.188 g) as a colorless amorphous solid.

Step 3. tert-Butyl (1R,3S,5R)-5-((allyl(methyl)amino)methyl)-3-((3-((allyloxy)methyl)-6bromopyridin-2-yl)carbamoyl)-2 -azabicyclo[3.1.0]hexane-2-carboxylate (70-S5): Pyridine ( 0.246 ml, 3.05 mmol) followed by the addition of POCl ₃ (0.057 ml, 0.61 mmol) at 0°C under argon. The reaction mixture was stirred at room temperature for 2 h before adding an aqueous solution of NaHCO ₃ and the mixture was extracted with DCM. After washing with brine, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solution was filtered and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give t-butyl (1R,3S,5R)-5-((allyl(methyl)amino)methyl)-3- ((3-((allyloxy)methyl)-6bromopyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (70-S5, 173.5 mg).

Step 4. (1 R,3S,5R)-5 -((Allyl(methyl)amino)methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2yl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide, TFA salt (70-S6): tert-butyl (1R,3S,5R)-5((allyl(methyl)amino)methyl)-3-((3-((allyloxy)methyl )-6-bromopyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (70-S5, 29.5 mg) in DCM (2 ml) was treated with TFA (2 ml) at room temperature for 1 h. The volatiles were removed under reduced pressure, and the residue was co-evaporated twice with toluene (5 ml) to obtain (1R,3S,5R)-5-((allyl(methyl)amino)methyl)-N-(3((allyloxy) methyl)-6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt 70-S6. This material was carried on without further purification.

Step 5. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-5((allyl (methyl)amino)methyl)-N-(3-((allyloxy)methyl)-6-bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (70): to mixture (1R,3S ,5R)-5-((allyl(methyl)amino)methyl)-N-(3-((allyloxy)methyl)-6

- 300 041794 bromopyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt 70-S6 and 2-(3-acetyl-5-(2methylnirimidin-5-yl)-1H-indazole -1-yl)acetic acid (70-S7, 17 mg, 0.055 mmol) in DMF (1 mL) was added at room temperature with TBTU (26.5 mg) followed by DIEA (0.096 mL) with stirring. After completion of the reaction, an aqueous solution of NaHCO ₃ (10 ml) was added to form a precipitate, which was collected by filtration and purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give 70 (29 mg) as not off-white solid.

¹ H NMR (400 MHz, chloroform-d) δ 8.89 (s, 3H), 8.56 (dd, J=1.7, 0.9 Hz, 1H), 7.61 (qd, J=8.7, 1.3 Hz, 2H), 7.48 (d , J=8.0 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 5.91-5.76 (m, 2H), 5.50 (d, J=2.7 Hz, 2H), 5.25-5.11 (m, 4H) , 4.95 (s, 1H), 4.41-4.26 (m, 2H), 3.88 (d, J=5.7 Hz, 2H), 3.29 (dd, J=5.5, 2.5 Hz, 1H), 3.06 (dt, J=6.4 , 1.4 Hz, 2H), 2.80 (m, 6H), 2.72 (s, 3H), 1.21 (t, J=5.6 Hz, 1H), 0.99 (dd, J=5.5, 2.5 Hz, 1H). LC (method A): tR = 1.35 min. LC/MS (EI) m/z: [M+H]+ 727.

Scheme 32. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (74) and (1S,3S,5S)-2-( 2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)- 5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (75)

Vg

75

Step 1. (3S)-N-(6-Bromo-3-methyl-pyridin-2-yl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (75-S2): to a solution of 75-S1 (150 mg, 0.33 mmol) in dioxane (1.5 mL) was added with HCl/dioxane (1.5 mL, 2 M). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness, diluted with DCM, washed with aqueous NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (DCM/MeOH = 60:1) to give 75-S2 (100 mg, 86.2% yield) as a yellow oil. LC/MS (ESI) m/z: 352 (M+H) ⁺ .

Step 2. (1R,3S,5R)-2-(2-(3-acetyl-7-(fluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (74) and (1S,3S,5S)-2-(2 -(3-acetyl-7-(fluoromethyl)-5-(2-methylnirimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5 -((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (75): to a solution of 75-S2 (40 mg, 0.105 mmol), 75-S3 (30 mg, 0.087 mmol) and HATU (50.0 mg, 0.13 mmol) DIPEA (34 mg, 0.26 mmol) was added to DMF (3 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 74 (2.0 mg, 3.4% yield) and 75 (2.2 mg, 3.8% yield) as white solids.

Compound 74:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.07 (s, 2H), 8.58 (s, 1H), 8.01 (s, 1H), 7.63 (d, J=8.0 Hz, 1H ), 7.45 (d, J=8.0 Hz, 1H), 5.97-5.93 (m, 1H), 5.85-5.76 (m, 1H), 5.75-5.62 (m, 2H), 4.46 (m, 1H), 3.63 ( m, 1H), 2.69 (d, J=8.0 Hz, 6H), 2.46-2.31 (m, 4H), 2.24 (s, 6H), 2.05 (s, 3H), 1.09-1.02 (m, 2H).

Compound 75:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.46 (s, 1H), 9.05 (s, 2H), 8.56 (s, 1H), 7.98 (s, 1H), 7.60 (d, J=8.0 Hz, 1H ), 7.42(d, J=8.0 Hz, 1H), 6.09 (d, J=20.0 Hz, 1H), 5.96 (m, 1H), 5.78-5.65 (m, 1H), 5.64-5.59 (m, 1H) , 4.92 (d, J=8.0 Hz, 1H), 3.73-3.68 (m, 1H), 2.77 (t, J=12.0 Hz, 1H), 2.68 (d, J=4.0 Hz, 6H), 2.38 (s, 2H), 2.23 (s, 6H), 2.00 (m, 1H), 1.96 (s, 3H), 1.46 (d, J=4.0 Hz, 1H), 0.93 (m, 1H).

Scheme 3 3. Synthesis of (2 S ,4R)-1 -(2-(3-acetyl-5-(2-((1,1-dioxidothietan-3-yl)oxy)pyrimidin-5-yl)-1 Hindazole -1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (84)

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Step 1. (2S,4R)-1-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridine -2-yl)-4-fluoropyrrolidin-2-carboxamide (84-S3): to a solution of 2-(3-acetyl-5-(2methoxypyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (84 -S1, 1 eq.) in DMF (10 vol.) at 0°C under nitrogen atmosphere was added (2S,4R)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidin-2- carboxamide (84-S2, 1.2 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 84-S3.

Step 2. (2S,4R)-1-(2-(3-acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3-methylpyridine -2-yl)-4-fluoropyrrolidine-2-carboxamide (84-S4): to a solution of compound 84-S3 (1 equiv.) in ACN (10 vol.) at 0°C in a nitrogen atmosphere was added TMSCl (2.5 equiv. ) and NaI (2 equiv.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and quenched with water. The resulting solid was filtered and dried to give compound 84-S4.

Step 3. (2S,4R)-1 -(2-(3-Acetyl-5-(2-((1,1-dioxidothietan-3-yl)oxy)pyrimidin-5-yl)-1 Hindazol-1- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (84): to a solution of compound 84-S4 (1 equiv.) in ACN (10 vol.) cesium carbonate (3 eq.) and 3-bromothiethane-1,1 dioxide (84-S5, 2 eq.) were added. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and quenched with water. The resulting solid was filtered, dried and then purified by preparative purification to give compound 84.

¹ H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 9.02 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 7.78-7.72 (m, 2H), 7.61 (d, J=8.0Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 5.83 (d, J=17.2Hz, 1H), 5.62 (d, J=17.2Hz, 1H), 5.58- 5.50 (m, 1H), 5.30-5.28 (m, 1H), 5.02-4.96 (m, 2H), 4.61-4.55 (m, 3H), 4.28-3.88 (m, 2H), 2.63 (s, 3H), 2.30-2.12 (m, 1H), 2.00 (s, 3H), 0.98-0.95 (m, 1H).

Scheme 34 allyloxy)methyl)-N-(6-bromo-3-vinylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (93)

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Step 1. 2-Amino-6-bromonicotinaldehyde (93-S2): (2-amino-6-bromopyridin-3-yl)methanol (93-S1, 1.0 g, 4.93 mmol) was treated with activated MnO ₂ (4.29 g, 49.3 mmol) in DCM (50 ml) at room temperature overnight. The mixture was filtered through celite and the solvent was removed under reduced pressure to give 2-amino-6-bromonicotinaldehyde 93-S2 (0.9 g) as a yellow solid.

Step 2. 6-Bromo-3-vinylpyridin-2-amine (93-S3): To a suspension of methyltriphenylphosphonium bromide (1.28 g, 3.6 mmol) in THF (10 ml) was added n-BuLi (1.6 M in hexane, 2.25 ml, mmol) with stirring at 0°C in an argon atmosphere. After 1 hour, 2-amino-6-bromonicotinaldehyde (93-S2, 0.18 g, 0.9 mmol) in THF (5 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath and saturated aqueous solution of NH ₄ Cl (10 ml). The mixture was extracted with EtOAc and the organic layer was washed with water and brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give 6-bromo-3-vinylpyridin-2-amine 93-S3 (0.13 g) as a white solid substances.

Step 3. tert-Butyl (1R,3S,5S)-5-((allyloxy)methyl)-3-((6-bromo-3-vinylpyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (93-S5): pyridine (0.133 ml) was added to a mixture of 93-S4 (97 mg, 0.33 mmol) and 93S3 (65 mg, 0.33 mmol) in DCM (4 ml) followed by the addition of POCl ₃ (0.031 ml , 0.33 mmol) at 0°C in an argon atmosphere. The reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with AcOEt. After washing with brine, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solution was filtered and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography with EtOAc in hexane (0-50%) as eluent to give t-butyl (1R,3S,5S)-5((allyloxy)methyl)-3-((6-bromo -3-vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2carboxylate 93-S5 (88 mg) as a colorless oil.

Step 4. (1R,3S,5S)-5-((allyloxy)methyl)-N-(6-bromo-3-vinylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt (93-S6): tert-butyl (1R,3S,5S)-5-((allyloxy)methyl)-3((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1. 0]hexane-2-carboxylate (93-S5, 23 mg, 0.048 mmol) was dissolved in DCM (2 ml) and treated with TFA (1 ml) at room temperature. The reaction was stirred for 1 hour and the volatiles were removed under reduced pressure. The residue was coevaporated twice with toluene (5 ml) to give (1R,3S,5S)-5-((allyloxy)methyl)-N-(6-bromo-3vinylpyridin-2-yl)-2-azabicyclo[3.1.0] hexane-3-carboxamide, TFA salts, 93-S6. The crude material was carried on to the next step without further purification.

Step 5. (1 R,3S,5S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-5((allyloxy )methyl)-N-(6-bromo-3-vinylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (93): to a mixture of (1R,3S,5S)-5-( (allyloxy)methyl)-N-(6-bromo-3-vinylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide, TFA salts 93-S6 and 2-(3-acetyl-5-( 2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (S7 15.5 mg, 0.05 mmol) in DMF (1 ml) was added TBTU (32.1 mg, 0.1 mmol) followed by the addition of DIEA (0.0435 ml) at room temperature with stirring. After 1 hour was added an aqueous solution of NaHCO ₃ (10 ml) with the formation of a precipitate. The solid was collected by filtration and purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give 93 (21 mg).

1H NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.75 (s, 1H), 8.58 (dd, J=1.7, 0.9 Hz, 1H), 7.71-7.58 (m, 3H), 7.30 ( d, J=8.1Hz, 1H), 6.45 (dd, J=17.4, 11.0Hz, 1H), 5.89 (ddt, J=17.3, 10.4, 5.7Hz, 1H), 5.65 (dd, J=17.5, 0.8Hz , 1H), 5.52 (s, 2H), 5.32-5.15 (m, 3H), 4.91 (dd, J=8.8, 2.9 Hz, 1H), 4.01 (dq, J=5.7, 1.5 Hz, 2H), 3.73 ( d, J=9.8 Hz, 1H), 3.56 (d, J=9.8 Hz, 1H), 3.42 (dd, J=5.6, 2.6 Hz, 1H), 2.80 (s, 3H), 2.72 (s, 3H), 2.29(dd,

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J=13.8, 8.8 Hz, 1H), 1.46 (t, J=5.5 Hz, 1H), 0.99 (dd, J=5.5, 2.7 Hz, 1H). LC (method A): t _R = 2.01 min. LC/MS (EI) m/z: [M+H]+ 670.

Scheme 35. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((2-fluorocyclopent-1-encarboxamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (95)

Step 1. (1R,3S,5R)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((2-fluorocyclopent1-encarboxamido)methyl)-2-azabicyclo[3.1.0 ]hexane-2-carboxylate (95-S2): to a mixture of 95-S1 (30 mg, 0.07 mmol), 2,2-difluorocyclopentanecarboxylic acid (11 mg, 0.07 mmol) and HATU (40 mg, 0.48 mmol) in DMF ( 2 ml) DIPEA (0.03 ml, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 80:1) to give 95-S2 (15 mg, 40.0% yield) as a white solid. LC/MS (ESI) m/z: 537 (M+H) ⁺ .

Step 2. (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-((2-fluorocyclopent-1encarboxamido)methyl)-2-azabicyclo[3.1.0]hexane- 3-carboxamide (95-S3): HCl/dioxane (2 M, 2 ml) was added to a solution of 95-S2 (15 mg, 0.03 mmol) in dioxane (0.5 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 95-S3 (15 mg, 100% yield) as a white solid, which was taken to the next step of the synthesis without purification. LC/MS (ESI) m/z: 437 (M+H) ⁺ .

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)X-( 6-bromo-3-methylpyridin-2-yl)-5-((2-fluorocyclopent-1-encarboxamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (95): to mixture 95-S3 (15 mg, 0.03 mmol), 2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (19 mg, 0.05 mmol) and HATU (27 mg, 0.07 mmol) in DMF (3 ml) was added DIPEA (0.02 ml, 0.11 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 30:1) and further purified by preparative HPLC to give 95 (4.0 mg, 15.0% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 8.91 (s, 2H), 8.33 (d, J=1.1 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 5.88 (m, 1H), 5.72 (m, 1H), 4.54 (m, 1H), 3.68-3.53 (m, 2H), 2.67 (m, 6H), 2.60 (s, 3H), 2.53-2.34 (m, 6H), 2.03 (s, 3H), 1.80 (dt, J=15.4, 7.9 Hz, 2H), 1.24 (m, 2H), 0.98 (m, 1H). LC/MS (ESI) m/z: 743 (M+H) ⁺ .

Scheme 36. Synthesis of (1R,3S,5R)-5-(acetamidomethyl)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5yl)-1H-indazol-1-yl) acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (96)

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Step 1. (1R,3S,5R))-tert-Butyl 5-(acetamidomethyl)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)2-azabicyclo[3.1.0]hexane-2-carboxylate ( 96-S2): DIPEA (18 mg, 0.14 mmol) was added to a solution of 96-S1 (30 mg, 0.071 mmol) in DCM (2 mL), followed by the addition of acetyl chloride (7 mg, 0.089 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 30:1) to give 96-S2 (31 mg, 93.9% yield) as a white solid. LC/MS (ESI) m/z: 467 (M+H)+.

Step 2. (1R,3S,5R)-5-(Acetamidomethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (96-S3): TFA (1 ml) was added to a solution of 96-S2 (31 mg, 0.067 mmol) in DCM (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 96-S3 (24 mg, 100.0% yield) as a light yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 367 (M+H) ⁺ .

Step 3. (1R,3S,5R)-5-(Acetamidomethyl)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl )-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (96): to a solution of 96-S3 (24 mg, 0.066 mmol), 2- (3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetic acid (23 mg, 0.071 mmol) and HATU (50 mg, 0.13 mmol) in DMF (2 ml ) DIPEA (25 mg, 0.20 mmol) was added at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 96 (5.5 mg, 12.5% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 8.89 (d, J=3.3 Hz, 2H), 8.32 (s, 1H), 7.53-7.57 (m, 2H), 7.29 (d, J=8 Hz, 1H), 5.86 (d, J=17.6Hz, 1H), 5.71 (d, J=17.6Hz, 1H), 4.53 (m, 1H), 3.61 (m, 1H), 3.45 (d, J=14.2Hz, 1H), 3.183.05 (m, 1H), 2.66 (s, 3H), 2.65 (s, 3H), 2.58 (s, 3H), 2.42 (m, 2H), 2.02 (s, 3H), 1.90 (s, 3H) , 1.22 (m, 1H), 0.98 (m, 1H). LC/MS (ESI) m/z: 673 (M+H) ⁺ .

Scheme 37. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((2-fluorobenzamido)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (97)

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97-S1 Sun

97-S2

BUT

Stage 1. (1R,3S,5R)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((2fluorobenzamido)methyl)-2-azabicyclo[3.1.0]hexane-2 -carboxylate (97-S2): DIPEA ( 27 mg, 0.21 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 20:1) to give 97-S2 (31 mg, 80.3% yield) as a white solid. LC/MS (ESI) m/z: 547(M+H)+.

Step 2. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((2-fluorobenzamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide ( 97-S3): to a solution of 97-S2 (31 mg, 0.057 mmol) in dioxane (2 mL) was added HCl/dioxane (2 mL, 2 M) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give 97-S3 (25 mg, 100% yield) as a brown oil, which was taken to the next step of the synthesis without purification. LC/MS (ESI) m/z: 447 (M+H)+.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-((2-fluorobenzamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (97): to a solution of 97-S3 (25 mg, 0.056 mmol), 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl)acetic acid (20 mg, 0.062 mmol) and HATU (32 mg, 0.084 mmol) in DMF (2 ml) was added DIPEA (15 mg, 0.12 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 97 (4.2 mg, 10.0% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.44 (s, 1H), 7.72 (td, J=7.5, 1.7 Hz, 1H), 7.52 (m, 3H), 7.38 (d, J= 7.9 Hz, 1H), 7.27-7.15 (m, 2H), 6.00 (d, J=18 Hz, 1H), 5.84 (d, J=18 Hz, 1H), 4.64 (m, 1H), 3.85-3.75 ( m, 2H), 3.58-3.49 (m, 1H), 2.78 (s, 3H), 2.76 (s, 3H), 2.70 (s, 3H), 2.67-2.54 (m, 2H), 2.09 (s, 3H) , 1.42 (m, 1H), 1.13 (m, 1H). LC/MS (ESI) m/z: 753(M+H)+.

Scheme 38. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-(methylsulfonamidomethyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (101)

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Step 1. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5(methylsulfonamidomethyl)-2-azabicyclo[3.1.0]hexane-2- carboxylate (101-S2): Et ₃ N (0.03 ml, 0.18 mmol) was added to a solution of 101-S1 (40 mg, 0.09 mmol) in dry DCM (3 ml), followed by the addition of methanesulfonyl chloride (0.01 ml, 0.11 mmol) at 0 °C. The reaction mixture was stirred at 0° C. for 1 hour. The mixture was then diluted with water (4 ml) and extracted with DCM (3 ml x 2). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel column chromatography (eluting with DCM/MeOH = 60:1) to give 101-S2 (30 mg, 62.5% yield) as a light yellow oil. LC/MS (ESI) m/z: 503 (M+H)+.

Step 2. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-(methylsulfonamidomethyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (101-S3): TFA (0.2 ml) was added to a solution of 101-S2 (30 mg, 0.06 mmol) in DCM (0.5 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 101-S3 (24 mg, 100.0% yield) as a yellow oil, which was taken to the next step of the synthesis without further purification. LC/MS (ESI) m/z: 403 (M+H)+.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-(methylsulfonamidomethyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (101): to a solution of 101-S3 (24 mg, 0.06 mmol), 2 -(3-acetyl-7-methyl-5-(2-methylpyrimidin-5yl)-1H-indazol-1-yl)acetic acid (101-S4, 23 mg, 0.07 mmol) and HATU (45 mg, 0.12 mmol) DIPEA (0.04 ml, 0.24 mmol) was added to DMF (2 ml). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 101 (5.3 mg, 12.6% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.41 (s, 1H), 7.52-7.56 (m, 2H), 7.38 (d, J=8.0 Hz, 1H), 5.945.99 (m, 1H), 5.78-5.83 (m, 1H), 4.63-4.65 (m, 1H), 3.72-3.75 (m, 1H), 3.35-3.43 (m, 2H), 3.01 (s, 3H), 2.76 (s, 6H), 2.69 (s, 3H), 2.53-2.59 (m, 2H), 2.15 (s, 3H), 1.36-1.39 (m, 1H), 1.11-1.13 (m, 1H). LC/MS (ESI) m/z: 709 (M+H)+.

Scheme 39. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((3,3,3-trifluoropropanamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (102)

102-S1 ^{Stage 1} 102-S2

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102-S3

Step 1. (3S)-tert-Butyl 3-(6-bromopyridin-2-ylcarbamoyl)-5-(((S)-2-(methoxycarbonylamino)-3methylbutanamido)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (102-S2): to a mixture of 102-S1 (70 mg, 0.16 mmol), 3,3,3-trifluoropropanoic acid (25 mg, 0.19 mmol) and HATU (122 mg, 0.32 mmol) in DMF ( 2 ml) DIPEA (0.05 ml, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 80:1) to give 102-S2 (75 mg, 85.2% yield) as a white solid. LC/MS (ESI) m/z: 535 (M+H)+.

Step 2. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((3,3,3-trifluoropropanamido)methyl)-2azabicyclo[3.1.0]hexane- 3-carboxamide (102-S3): TFA (1 ml) was added to a solution of 102-S2 (75 mg, 0.14 mmol) in DCM (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 102-S3 (61 mg, 100.0% yield) as a yellow oil, which was taken to the next step of the synthesis without further purification. LC/MS (ESI) m/z: 435 (M+H) ⁺ .

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-( 6-bromo-3-methylpyridin-2-yl)-5-((3,3,3-trifluoropropanamido)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (102): to a solution of 102-S3 (30 mg, 0.07 mmol), 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5yl)-1H-indazol-1-yl)acetic acid (102-S4, 27 mg, 0.08 mmol) and HATU (53 mg, 0.14 mmol) DIPEA (0.06 ml, 0.35 mmol) was added to DMF (2 mL). The reaction mixture was stirred at room temperature for 2 h.

The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 102 (4.5 mg, 12.8% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.36 (s, 1H), 7.45-7.47 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 5.855.89 (m , 1H), 5.69-5.73 (m, 1H), 4.75-4.79 (m, 1H), 3.62-3.64 (m, 1H), 3.24-3.46 (m, 4H), 2.69 (s, 3H), 2.63 (s , 3H), 2.58 (s, 3H), 2.39–2.47 (m, 2H), 1.23–1.25 (m, 1H), 1.00–1.02 (m, 1H). LC/MS (ESI) m/z: 741 (M+H) ⁺ .

Scheme 40. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-((dimethylamino)methyl)pyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (103)

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Stage 1. tert-Butyl 2-(3-acetyl-5-(2-(hydroxymethyl)pyrimidin-5-yl)-1H-indazol-1-yl)acetate (103-S3): to a solution of (5-bromopyrimidin- 2-yl)methanol (103-S2, 1 equiv.) in DMF/H2O (9:1, 10 vol.) was added compound 103-S1 (1 equiv.), K2CO3 (2 equiv.) and tetrakis(triphenylphosphine)palladium (0.1 equiv.). The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography to give compound 103S3.

Step 2 tert-Butyl 2-(3-acetyl-5-(2-((dimethylamino)methyl)pyrimidin-5-yl)-1H-indazol-1yl)acetate (103-S4): to a mixture of compound 103-S3 (1 eq.) in dry DCM (10 vol.) was added Et ₃ N (1 eq.) followed by dropwise addition of MsCl (1.5 eq.) at 0°C, and the reaction mixture was stirred for 2 h at the same temperature . Dimethylamine hydrochloride (1.1 eq.) was added at 0°C and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic layers were separated, dried and concentrated to give the crude product, which was purified with a silica gel column (eluting with DCM/EtOAc) to give compound 103-S4.

Step 3. 2-(3-Acetyl-5-(2-((dimethylamino)methyl)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (103-S5): to a solution of compound 103-S4 (1 equiv.) in an argon atmosphere was added 4n. dioxane/HCl (10 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was immediately used in the next stage of the synthesis.

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-((dimethylamino)methyl)pyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (103): to a solution of compound 103-S5 (1 eq.) in DMF (10 vol.) at 0°C in an argon atmosphere was added (1R,3S,5R)-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3- carboxamide (1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 103.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.05-1.13 (m, 2H), 1.39 (s, 3H), 2.07-2.16 (m, 4H), 2.54-2.60 (m, 1H), 2.73 (s , 3H), 3.01 (s, 6H), 3.64-3.74 (m, 1H), 4.47 (dd, J=5.2, 9.3 Hz, 1H), 4.78 (s, 2H), 5.66 (d, J=17.2 Hz, 1H), 6.02 (d, J=17.3Hz, 1H), 7.52 (d, J=7.9Hz, 1H), 7.69 (d, J=7.9Hz, 1H), 7.99 (q, J=8.8Hz, 2H) , 8.60 (s, 1H), 9.36 (s, 2H), 10.36 (s, 1H).

Scheme 41. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-1-yl)acetyl) -N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azαbicyclo[3.1.0]hexane-3carboxamide (104)

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Step 1. tert-Butyl 2-(5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (104-S2): to a solution of 5-bromo-3-iodo- 1H-pyrazolo[3,4-с]pyridine (1 equiv.) in CH3CN (10 vol.) was added tert-butyl 2-bromoacetate (1.1 equiv.) and potassium carbonate (1.1 equiv.). The mixture was heated at reflux overnight under argon. After the reaction mixture was cooled to room temperature, the mixture was filtered through celite and washed with CH3CN. The filtrate was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 104-S2.

Step 2. tert-Butyl 2-(3-acetyl-5-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (104-S3): to a solution of tert-butyl 2-(5- bromo-3-iodo-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (1 equiv.) in dry DMF (10 vol.) was added tributyl(1-ethoxyvinyl)stannan (1.5 equiv.) and PdCl ₂ (PPh ₃ ) ₂ (0.05 eq.), and the resulting mixture was stirred at 80°C in an argon atmosphere overnight and concentrated to dryness. The remaining residue was diluted with DCM and washed with 2N. aqueous HCl. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 104S3.

Step 3. tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl)acetate (104-S5): to a solution of 2- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (104S4, 1 eq) in dioxane/H ₂ O (9:1, 10 vol) compound 104-S3 (1 equiv.), Cs ₂ CO ₃ (2 equiv.) and tetrakis(triphenylphosphine)palladium (0.1 equiv.) were added. The reaction mixture was stirred at 90°C for 5 h and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 104-S5.

Step 4. 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid (104-S6): to a solution of compound 104 -S5 (1 equiv.) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was carried on without additional purification and was immediately used in the next stage of the synthesis.

Step 5. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-e]pyridin-1 yl) acetyl)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (104): to a solution of compound 104-S6 (1 eq.) in DMF (10 vol.) at 0°C in an argon atmosphere was added (1R,3S,5R)-N-(6-bromo-5-fluoro-3-methylpyridin-2-yl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (S7, 1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 104.

1H NMR (400 MHz, DMSO-d6) δ 0.90-0.97 (m, 1H), 1.00-1.05 (m, 1H), 1.26 (s, 3H), 2.00 (s, 4H), 2.452.52 (m, 1H ), 2.62 (d, J=4.3 Hz, 6H), 3.47-3.56 (m, 1H), 4.27-4.39 (m, 1H), 5.66 (d, J=17.2 Hz, 1H), 5.97 (d, J= 17.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.51-8.57 (m, 1H), 9.23 (d, J=1.4 Hz, 1H), 9.27 (s, 2H), 10.20 (s, 1H).

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Scheme 42. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-((1,1-dioxidothietan-3-yl)oxi)pyrimidin-5-yl)1H-indazole -1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (107)

Step 1. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methokCipyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (107-S3): to a solution of 2-(3acetyl-5-(2-methoxypyrimidin-5-yl)- 1H-indazol-1-yl)acetic acid (107-S1, 1 eq.) in DMF (10 vol.) at 0°C under nitrogen was added (1R,3S,5R)-N-(6-bromo-3 -methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (107-S2, 1.2 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 107-S3.

Step 2. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-hydroxypyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (107-S4): to a solution of compound 107-S3 (1 eq.) in ACN (10 vol.) at TMSCl (2.5 equiv.) and NaI (2 equiv.) were added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and quenched with water. The resulting solid was filtered and dried to give compound 107-S4.

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-((1,1-dioxidothietan-3-yl)oxy)pyrimidin-5-yl)-1 Hindazol- 1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicylo[3.1.0]hexane-3carboxamide (107): to a solution of compound 107-S4 (1 equiv.) in ACN (10 vol.) were added cesium carbonate (3 equiv.) and 3-bromothiethane-1,1-dioxide (107-S5, 2 equiv.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and quenched with water. The resulting solid was filtered, dried and purified by preparative purification to give compound 107.

1H NMR (400 MHz, DMSO-d ₆ ) δ: 10.29 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 7.82-7.14 (m, 2H), 7.63 (d, J=8.0Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 5.91 (d, J=17.6Hz, 1H), 5.56 (d, J=17.6Hz, 1H), 5.29- 5.27 (m, 1H), 5.02-4.97 (m, 2H), 4.62-4.56 (m, 2H), 4.42-4.38 (m, 1H), 2.67 (s, 3H), 2.05 (s, 3H), 1.32 ( s, 3H), 1.04–1.00 (m, 2H), 0.99–0.85 (m, 2H).

Scheme 43. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-cyclopropylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (112)

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Step 1. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-cyclopropylpyridin-2-yl)carbamoyl)-5-((1,3dioxoisoindolin-2-yl)methyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (112-S2): to a mixture of 112-S1 (100 mg, 0.26 mmol) and 6-bromo-3-cyclopropylpyridine-2-amine (55.1 mg, 0.26 mmol) in dry DCM (3 ml) was added pyridine (0.1 ml, 1.30 mmol) followed by the addition of POCl ₃ (39.8 mg, 0.26 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted twice with DCM. The organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (PE/EtOAc = 6:1 to 2:1) to give 112-S2 (127 mg, 84.2% yield) as a white solid. LC/MS (ESI) m/z: 581 (M+H)+.

Stage 2. (1R,3S,5R)-tert-Butyl 5-(aminomethyl)-3-((6-bromo-3-cyclopropylpyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (112-S3): Hydrazine hydrate (21.9 mg, 0.44 mmol) was added to a solution of 112-S2 (127 mg, 0.22 mmol) in EtOH (3 mL). The reaction mixture was stirred at 75°C for 2 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 5:1) to give 112-S3 (79 mg, 79.8% yield) as a white solid. LC/MS (ESI) m/z: 451 (M+H) ⁺ .

Step 3. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-cyclopropylpyridin-2-yl)carbamoyl)-5((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (112-S4): to a solution of 112-S3 (79 mg, 0.18 mmol) in MeOH (3 mL) was added an aqueous solution of HCHO (42.6 mg, 0.53 mmol, ~37% wt.) and NaBH ₃ CN ( 22 mg, 0.35 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1

h. The mixture was then diluted with water (20 ml) and was extracted with DCM (5 ml x 2). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining crude product was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 112-S4 (55 mg, 63.9% yield) as a clear oil. LC/MS (ESI) m/z: 479 (M+H) ⁺ .

Step 4. (1 R,3S,5R)-N-(6-Bromo-3-cyclopropylpyridin-2-yl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (112 -S5): TFA (1 ml) was added to a solution of 112-S4 (55 mg, 0.12 mmol) in DCM (2 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 112-S5 (43 mg) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 379 (M+H)+.

Step 5. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methyl-pyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-cyclopropylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (112): to a mixture of 112-S5 (43 mg, 0.113 mmol), 2 -(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetic acid (112-S6, 36.6 mg, 0.118 mmol) and HATU (64.6 mg, 0.17 mmol) in DMF (2 ml) DIPEA (0.06 ml, 0.339 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 112 (6.5 mg, 8.57% yield) as a white solid.

'H NMR (400 MHz, CD3OD) δ 9.02 (s, 2H), 8.56 (s, 1H), 7.80 (d, J=1.2 Hz, 2H), 7.38 (d, J=8.1 Hz, 1H),

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7.30 (d, J=8.1Hz, 1H), 5.82 (d, J=17.2Hz, 1H), 5.67 (d, J=17.1Hz, 1H), 4.71 (t, J=7.0Hz, 1H), 3.68- 3.66(m,

1H), 2.95-2.90 (m, 1H), 2.77 (s, 3H), 2.71 (s, 3H), 2.66-2.60 (m, 2H), 2.40 (s, 6H), 2.35-2.30 (m, 1H) , 1.87-1.84 (m, 1H), 1.28-1.25 (m, 1H), 1.22-1.20 (m, 1H), 0.87-0.84 (m, 2H), 0.60-0.568 (m, 2H). LC/MS (ESI) m/z: 671 (m+h) ⁺ .

Scheme 44. Synthesis of (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-H6-bromo -4-fluoropyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (116)

1. 2-Bromo-4-fluoro-1-oxidanylpyridine (116-S2): to

Step A stirred solution of 2-bromo-4-fluoropyridine (116-S1, 2 g, 1 eq.) in CHCl ₃ (130 ml) was added 3-chlorobenzooperoxoic acid (5 g, 2 eq.). The reaction mixture was heated to 50°C. The reaction mixture was cooled and neutralized with saturated aqueous NaHCO ₃ (100 ml). The organic layer was washed with saturated aqueous NaHCO ₃ (50 ml x 2) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% CH3OH in DCM, gradient) to give 116-S2 (622 mg, 31%).

Step 2. 6-Bromo-N-(tert-butyl)-4-fluoropyridine-2-amine (116-S3): to a stirred solution of 116S2 (622 mg, 1 eq.), 2-methylpropan-2-amine (1.7 ml, 5 equiv.) in DCM (100 ml) was added a solution of trifluoroacetic anhydride (1.1 ml, 1.1 equiv.) in DCM (10 ml) dropwise at 0-5°C in an argon atmosphere. The reaction mixture was stirred at 0-5°C for 1 h before adding a solution of TFA (1 ml, 1 eq.) in DCM (10 ml) followed by the addition of 2-methylpropan-2-amine (0.4 ml, 1.1 eq.). The reaction mixture was neutralized with aqueous saturated NaHCO3 (20 ml) and the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 30% EtOAc in hexanes) to give 116-S3 (81 mg, 10%).

Step 3 6-Bromo-4-fluoropyridin-2-amine (116-S4): TFA (6 ml) was added to solid 116-S3 and the reaction mixture was heated at 70° C. until the reaction was complete. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (15 ml) and washed with aqueous saturated NaHCO ₃ solution (10 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 116-S4 (63 mg).

Step 4. tert-Butyl (1R,3S,5R)-3-((6-bromo-4-fluoropyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (116 -S5): POCl ₃ (0.04 ml, 2 equiv.) was added dropwise at 0-5°C under argon atmosphere to a stirred solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxylic acid (79 mg, 1 eq.), 116-S4 (63 mg, 1 eq.) in DCM (15 ml) and pyridine (0.13 ml, 5 eq.). The reaction mixture was stirred at room temperature for 2 h, then the reaction was diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO3 (10 ml). The aqueous layer was extracted with DCM (1 x 10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 116-S5 (97 mg, 71%).

Step 5. (1 R,3S,5R)-N-(6-Bromo-4-fluoro-pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 carboxamide hydrochloride (116-S6) : to a solution of 116-S5 (97 mg) was added 4n. HCl in dioxane (10 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness to give 116-S6 (75 mg).

Step 6. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-( 6-bromo-4-fluoro-pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (116): HATU (109 mg, 1.2 equiv.) was added at 0°C under atmospheric argon to a solution of 116-S6 (75 mg, 1 equiv.), 2-(3-acetyl-7-methyl-5

- 313 041794 (2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (78 mg, 1.1 eq.) and DIPEA (0.21 ml, 5 eq.) in DMF (8 ml). The reaction mixture was stirred at room temperature for 3 h, then diluted with EtOAc (35 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 116 (87 mg, 53%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.02 (s, 2H), 8.31 (s, 1H), 7.86 (d, 1H, J=10.6 Hz), 7.63 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=17.6 Hz), 5.67 (d, 1H, J=17.6 Hz), 4.39-4.45 (m, 1H), 3.62- 3.66 (m, 1H), 2.70 (s, 3H), 2.69 (s, 3H), 2.65 (s, 3H), 2.08 (s, 3H), 1.98-2.03 (m, 1H), 1.31 (s, 3H) , 1.17-1.21 (m, 1H), 0.86-1.03 (m, 2H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -98.11 (s, 1F).

Scheme 45 fluoropyrrolidine-2-carboxamido)-6-bromopyridin-3-yl)acetate (61) and 2-(2-(((2S,4R)-1-(2(3-acetyl-5-(2-methylpyrimidin-5 -yl)-1 H-indazol-1 -yl)acetyl)-4-fluoropyrrolidin-2-carboxamido)-6bromopyridin-3-yl)acetic acid (62) and (2S,4R)-1-(2-(3 -acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N-(6-bromo-3-(2-(dimethylamino)-2-oxoethyl)pyridin-2-yl) -4-fluoropyrrolidine-2carboxamide(117)

Step 1. Methyl 2-(6-bromo-1-oxidanyl)pyridin-3-yl)acetate (117-S2): to a stirred solution of methyl 2-(6-bromopyridin-3-yl)acetate (117-S1, 1 g, 1 equiv.) in CHCl ₃ (100 ml) was added 3chlorobenzooperoxoic acid (1.93 g, 2 equiv.). The reaction mixture was heated to 50°C to complete the reaction. The reaction mixture was cooled and neutralized with saturated aqueous NaHCO ₃ (50 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (5% CH3OH in DCM, gradient) to give 117-S2 (848 mg, 80%).

Step 2. Methyl 2-(6-bromo-2-(tert-butylamino)pyridin-3-yl)acetate (117-S3): to a stirred solution of 117-S2 (848 mg, 1 eq.) and 2-methylpropan- 2-amine (1.8 ml, 5 equiv.) in DCM (90 ml) was added a solution of trifluoroacetic anhydride (0.87 ml, 1.5 equiv.) in DCM (10 ml) at 0-5°C dropwise in an argon atmosphere. The reaction mixture was stirred at 0-5°C for 2 h, then neutralized with a solution of aqueous saturated NaHCO ₃ (20 ml). The organic layer was washed with aqueous saturated NaHCO ₃ (40 ml) and brine (40 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 30% EtOAc in hexanes, gradient) to give 117-S3 (104 mg, 10%).

Step 3 Methyl 2-(2-amino-6-bromopyridin-3-yl)acetate (117-S4): TFA (10 ml) was added to solid 117-S3 (104 mg) and the reaction mixture was heated at 70°C . The reaction was concentrated to dryness and the residue was dissolved in DCM (25 ml) and neutralized with aqueous saturated NaHCO ₃ solution (20 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give

117-S4 (96 mg).

Step 4. tert-Butyl (2S,4R)-2-((6-bromo-3-(2-methoxy-2-oxoethyl)pyridin-2-yl)carbamoyl)-4fluoropyrrolidine-1-carboxylate (117-S5) : POCl ₃ (0.08 ml, 2 equiv.) was added dropwise at 0-5°C in an argon atmosphere to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (91 mg , 1 equiv.) and 117-S4 (96 mg, 1 equiv.) in DCM (10 ml) and pyridine (0.16 ml, 5 equiv.). The reaction mixture was warmed to room temperature and stirred until the reaction was complete. The reaction mixture was diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (1 x 10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 117-S5 (146 mg, 82%).

Step 5. Methyl 2-(6-bromo-2-((2S,4R)-4-fluoropyrrolidine-2-carboxamido)pyridin-3-yl)acetate hydrochloride (117-S6): to a solution of 117-S5 (146 mg ) were added 4n. HCl in dioxane (10 ml). The resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness to give 117-S6 (117 mg).

Step 6. Methyl 2-(2-(((2S,4R)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-4- fluoropyrrolidine-2-carboxamido)-6-bromopyridin-3-yl)acetate (61): to a solution of 117-S6 (117 mg, 1 equiv.), 2-(3-acetyl-5-(2-methylpyrimidin-5- yl)-III-indazol-1-yl)acetic acid (92 mg, 1 equiv.) and DIPEA (0.25 ml, 5 equiv.) HATU (137 mg, 1.2 equiv.) was added to DMF (15 ml) at 0° C under argon The reaction mixture was stirred at room temperature for 3 h, then the reaction mixture was diluted with EtOAc (35 ml) and water (15 ml) The aqueous layer was extracted with EtOAc (15 ml) The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 61 (99 mg, 50%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 9.04 (s, 2H), 8.40 (s, 1H), 7.79-7.90 (m, 2H), 7.68 (d, 1H, J= 8.1 Hz), 7.52 (d, 1H, J=8.1 Hz), 5.49-5.88 (m, 3H), 4.56-4.62 (m, 1H), 4.19-4.29 (m, 1H), 3.94-4.30 (m, 1H ), 3.55 (s, 2H), 3.44 (s, 3H), 2.70 (s, 3H), 2.65 (s, 3H), 2.07–2.34 (m, 1H), 0.85–0.92 (m, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -176.07 (s, 1F).

Step 7. 2-(2-((2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4fluoropyrrolidine- 2-carboxamido)-6-bromopyridin-3-yl)acetic acid (62): to a solution of 61 (45 mg, 1 equiv.) in methanol (6 ml) was added an aqueous solution of LiOH in water (3 ml, 1 M, 1.2 eq.), and the reaction mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was acidified with HCl (1N) and was extracted with DCM (10 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness to give 62 (15 mg, 34%).

1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.98 (s, 2H), 8.36 (s, 1H), 7.69-7.82 (m, 2H), 7.60 (d, 1H, J=8.2 Hz), 7.44 (d, 1H, J=8.2 Hz), 5.42-5.77 (m, 3H), 4.52-4.58 (m, 1H), 4.11-4.23 (m, 1H), 3.86-4.01 (m, 1H) , 3.41 (s, 2H), 2.62 (s, 3H), 2.58 (s, 3H), 2.46-2.56 (m, 1H), 2.01-2.21 (m, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ - 176.12 (s, 1F).

Step 8. (2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo3-( 2-(dimethylamino)-2-oxoethyl)pyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (117): to a solution of 62 (44 mg, 1.2 eq.), dimethylamine hydrochloride (33 mg, 1.0 eq.) and DIPEA (0.08 ml, 5 equiv.) in DMF (10 ml) was added HATU (32 mg, 1.2 equiv.) at 0°C under argon. The reaction mixture was stirred at room temperature for 3 h, then the reaction mixture was diluted with EtOAc (20 ml) and water (10 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 117 (32 mg, 50%).

1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.98 (s, 2H), 8.38 (s, 1H), 7.70-7.84 (m, 1H), 7.78 (s, 1H), 7.48 ( d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 5.42-5.81 (m, 3H), 4.46-4.52 (m, 1H), 4.11-4.21 (m, 1H), 3.894 .04 (m, 1H), 2.57 (s, 2H), 2.61 (s, 3H), 2.58 (s, 3H), 2.51 (s, 3H), 2.36 (s, 3H), 1.96-2.15 (m, 2H ); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -175.89 (s, 1F).

Scheme 46. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-(methylamino)pyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6 -bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (120)

- 315 041794

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with a substituted pyrimidine at the R ³² position by a Suzuki cross-coupling reaction wherein the A-ring is functionalized with a boronic acid ester. One skilled in the art will appreciate that the 5-bromo-N-methylpyrimidin-2-amine aryl halide shown above can be substituted with other aryl halides to provide additional compounds of the present invention. Non-limiting examples of aryl halides that the skilled artisan may use include 5-bromo-2-methylpyrimide.

Stage 1. tert-Butyl 2-(3-αcetyl-5-(2-(methylamino)πyrimidin-5-yl)-1H-indazol-1-yl)acetate (120S3): to a solution of 5-bromo-N-methylpyrimidine -2-amineα (120-S2, 1 eq.) in DMF/H2O (9:1, 10 vol.) was added compound 120-S1 (1 eq.), K ₂ CO ₃ (2 eq.) and tetrakis(triphenylphosphine )palladium (0.1 equiv.). The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 120-S3.

Step 2. 2-(3-Acetyl-5-(2-(methylamino)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (120S4): to a solution of compound 120-S3 (1 eq.) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was immediately used in the next stage of the synthesis.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-(methylamino)pyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (120): to a solution of compound 120-S4 (1 eq.) in DMF (10 vol.) at 0°C in an argon atmosphere was added (1R,3S,5R)-N-(6-6pom3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 120.

1H NMR (400 MHz, DMSO-d6) δ 0.97-1.06 (m, 2H), 1.33 (s, 3H), 2.05 (s, 4H), 2.53-2.58 (m, 1H), 2.65 (s, 3H), 2.87 (d, J=4.5 Hz, 3H), 3.55-3.64 (m, 1H), 4.33-4.47 (m, 1H), 5.55 (d, J=17.2 Hz, 1H), 5.88 (d, J=17.3 Hz , 1H), 7.26 (q, J=4.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.69-7.80 (m, 2H), 8.29 (s, 1H), 8.64 (s, 2H), 10.26 (s, 1H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indol-1-yl)αcetyl)-N-(6-bromo- 3methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CDCl3): δ 0.86-0.88 (m, 1H), 1.16 (t, J=5.2 Hz, 1H), 1.41 (s, 3H), 2.08 (s, 3H), 2.33 (t,

J=8.8Hz, 1H) 2.55(s, 3H), 2.67(d, J=13.2Hz, 1H), 2.81(s, 3H), 3.14(d, J=2.8Hz, 1H), 4.83(d, J =6.4Hz, 1H), 5.18(s, 2H), 7.23(d, J=8Hz, 1H), 7.35(d, J=8Hz, 1H), 7.39(d, J=8.4Hz, 1H), 7.49 (dd, J=8.4, 1.2 Hz, 1H), 7.88 (s, 1H), 8.57 (brs, 1H), 8.65 (s, 1H), 8.94 (s, 2H).

- 316 041794 (1 R,3S,5R)-2-(2-(3-Acetyl-5-(pyridin-4-yl)-1 H-indazol-1-yl)acetyl)-N-(6-bromo -3-methylpyridin2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.66 (dd, J=4.5, 1.6 Hz, 2H), 8.52 (d, J=0.8 Hz, 1H), 7.91 (dd, J =8.9, 1.7 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.76 (dd, J=4.5, 1.6 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.45 (d , J=7.9 Hz, 1H), 5.92 (d, J=17.3 Hz, 1H), 5.58 (d, J=17.2 Hz, 1H), 4.41 (m, 1H), 3.59 (m, 1H), 2.66 (s , 3H), 2.602.52 (m, 1H), 2.11-1.99 (m, 4H), 1.32 (s, 3H), 1.07-0.96 (m, 2H). LC/MS (ESI) m/z: 587/589 (M+H)+.

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(5-methylpyridin-2-yl)-1 H-indazol-1 -yl)acetyl)-N-(6-bromo- 3methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.19 (dd, J=8.9, 1.6 Hz, 1H), 7.92 ( d, J=8.2 Hz, 1H), 7.75 (dd, J=16.9, 8.5 Hz, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 5.89 ( d, J=17.3Hz, 1H), 5.55 (d, J=17.1Hz, 1H), 4.41 (dd, J=9.3, 5.1Hz, 1H), 3.59 (dd, J=5.3, 2.4Hz, 1H), 2.64 (d, J=6.6 Hz, 3H), 2.58-2.51 (m, 1H), 2.35 (s, 3H), 2.04 (s, 3H), 1.32 (s, 3H), 1.18-1.14 (m, 1H) , 1.04–1.00 (m, 1H). LC/MS (ESI) m/z: 601/603 (M+H)+.

Scheme 47. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylnirimidin-5-yl)-1H-undazol-1-yl)acetyl)N-(6-bromo -3-vinylpyridin-2-yl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide(123)

Stage 1. 2-(tert-Butyl)-3 -ethyl-( 1R,3 S,5R)-5 -((hex-5 -en-1 -yl(methyl)amino)methyl)-2azabicyclo[3.1.0 ]hexane-2,3-dicarboxylate (123-S2): Cs ₂ CO ₃ (0.8 g) was added to a mixture of 2-(tert-butyl)-3ethyl-(1R,3S,5S)-5-(((methylsulfonyl) hydroxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (123S1, 0.807 mmol) and N-methylhex-5-en-1-amine, HCl salt (0.145 g, 0.968 mmol) in ACN (10 ml). The reaction was heated and stirred at 50° C. under argon overnight. EtOAc was added and the diluted reaction mixture was filtered through celite to remove solids. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give 2-(tert-butyl)-3-ethyl-(1R,3S,5R)- 5-((hex-5-en1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate 123-S2 (0.193 g) as a yellowish oil.

Step 2. (1 R,3S,5R)-5-((Gex-5-en-1-yl(methyl)amino)methyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane- 3-carboxylic acid (123-S3): 2-(tert-butyl)-3-ethyl-(1R,3S,5R)-5-((hex-5-en-1yl(methyl)amino)methyl)-2 -azabicyclo[3.1.0]hexane-2,3-dicarboxylate (123-S2, 0.193 g, 0.508 mmol) was dissolved in THF-EtOH-water (3 ml-0.5 ml-0.5 ml) and treated with LiOH monohydrate (25.6 mg , 0.609 mmol). The reaction was stirred at room temperature for 24 hours, then amberlite (weakly acid cation exchanger in H-form, 1 g) was added. After stirring for 5 minutes, the reaction was filtered and the resulting resin was washed with MeOH. The combined filtrates were concentrated under reduced pressure to give (1R,3S,5R)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0 ]hexane-3-carboxylic acid 123-S3 (0.171 g) as a colorless amorphous solid.

Step 3. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((hex-5-en-1yl(methyl)amino)methyl )-2-azabicyclo[3.1.0]hexane-2-carboxylate (123-S5): to a mixture of 123-S3 (171 mg, 0.486

- 317 041794 mmol) and 123-S4 (77 mg, 0.389 mmol) in DCM (10 ml) was added pyridine (0.196 ml, 2.43 mmol) followed by the addition of POCl ₃ (0.045 ml, 0.486 mmol) at 0°C in an argon atmosphere . The reaction mixture was stirred at room temperature for 2 hours. An aqueous solution of NaHCO ₃ was added and the mixture was extracted with DCM. After washing with brine, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solution was filtered and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography with MeOH in DCM (0-10%) as eluent to give t-butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl )carbamoyl)-5-((hex-5-en-1yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate 123-S5 (99 mg).

Step 4. (1R,3S,5R)-N-(6-Bromo-3-vinylpyridin-2-yl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2azabicyclo[ 3.1.0]hexane-3-carboxamide, TFA salt (123-S6): tert-butyl (1R,3S,5R)-3-((6-6pom-3vinylpyridin-2-yl)carbamoyl)-5-(( hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-2carboxylate (123-S5, 5.7 mg) in DCM (1 ml) was treated with TFA (1 ml) at room temperature temperature. The reaction was stirred for 1 h, then the volatiles were removed under reduced pressure and the residue was co-evaporated with toluene (5 ml) twice to give (1R,3S,5R)-N-(6-bromo-3-vinylpyridin-2-yl) 5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt 123-S6. This material was carried on without further purification.

Step 5. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -vinylpyridin-2-yl)-5-((hex-5-en-1-yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (123): to mixture (1R,3S ,5R)-N-(6-bromo-3-vinylpyridin-2-yl)-5-((hex-5-en-1yl(methyl)amino)methyl)-2-azabicyclo[3.1.0]hexane-3 -carboxamide, TFA salt of 123-S6 and 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (123-S7, 3.4 mg, 0.011 mmol) in DMF ( 0.5 ml) was added TBTU (7.1 mg) followed by the addition of DIEA (0.0096 ml) with stirring. After completion of the reaction, an aqueous solution of NaHCO ₃ (10 ml) was added to form a precipitate, which was collected by filtration and purified by silica gel column chromatography with MeOH in DCM (010%) as eluent to give (1R,3S,5R)-2- (2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N-(6-bromo-3-vinylpyridin-2-yl)-5-((hex -5-en-1-yl(methyl)amino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (123) (6.2 mg) as an off-white solid.

1H NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.67 (s, 1H), 8.58 (dd, J=0.9, 1.6 Hz, 1H), 7.69-7.59 (m, 4H), 7.30 ( d, J=8.1Hz, 1H), 6.46 (dd, J=11.0, 17.4Hz, 1H), 5.80 (ddt, J=6.7, 10.2, 16.9Hz, 1H), 5.66 (dd, J=0.8, 17.4Hz , 1H), 5.51 (d, J=1.1 Hz, 2H), 5.27 (d, J=11.1 Hz, 1H), 5.05-4.91 (m, 2H), 4.88 (d, J=8.6 Hz, 1H), 3.25 (dd, J=2.5, 5.8 Hz, 1H), 2.91 (t, J=14.1 Hz, 2H), 2.80 (s, 3H), 2.72 (s, 3H), 2.41 (tt, J=5.7, 13.0 Hz, 1H), 2.28 (s, 4H), 2.11-2.01 (m, 2H), 1.54-1.34 (m, 4H), 1.30 (s, 0H), 1.02 (dt, J=2.1, 4.1 Hz, 1H), 0.93 -0.76 (m, 1H). LC (method A): tR = 1.48 min. LC/MS (EI) m/z: [M+H]+ 725.

Scheme 48. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (124)

- 318 041794

Step 1. 5-Bromo-1H-indazole-7-carboxamide (124-S2): 5-bromo-1H-indazole-7-carboxylic acid (1 g) was dissolved in DMF (10 ml) and iPr ₂ NEt (3.42 ml, 5 eq.) followed by the addition of NH ₄ Cl (1.2 g) at 5°C. HATU (1.8 g, 1.2 eq.) was added slowly at 5°C and the reaction mixture was stirred overnight at room temperature. Then the reaction mixture was poured into water, and the precipitate was separated by filtration. The white solid was dried and carried on without further purification to the next step.

Step 2. 5-Bromo-1H-indazole-7-carbonitrile (124-S3): To a heterogeneous mixture of 5-bromo-1H-indazole-7carboxamide (0.6 g) in CH ₂ Cl ₂ (6 ml) and pyridine (6 ml ) was added dropwise with TFAA (0.87 ml). The resulting homogeneous solution was stirred for 10 minutes at room temperature. The volatiles were removed and the residue was poured into water (60 ml). The precipitated white product was isolated by filtration, washed with water and dried under vacuum. The solid was carried on without further purification to the next stage.

Step 3. 5-(2-Methylpyrimidin-5-yl)-1H-indazole-7-carbonitrile (124-S4): mixture of 5-bromo-Shindazole-7-carbonitrile (0.32 g, equiv.), 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidine (0.708 g), cesium carbonate (1.4 g) in dioxane (12 ml) and water (3.0 ml) was purged with argon in pressure vessel for 5 minutes. Added PdCl ₂ (dppf) (0.4 g) in an argon atmosphere, and the pressure vessel was sealed and heated at 90°C overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 0-30% MeOH in CH ₂ Cl ₂ ) to give 0.24 g of 124-S4 as a white solid.

Step 4. 3-Bromo-5-(2-methylpyrimidin-5-yl)-1H-indazole-7-carbonitrile (124-S5): to a stirred solution of 5-(2-methylpyrimidin-5-yl)-1H-indazole -7-carbonitrile (0.24 g) in DMF (4 ml) was added NBS (0.2 g). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into water and the precipitate was filtered off, washed with water and dried. The solid was carried on to the next step without further purification.

Step 5 tert-Butyl 2-(3-bromo-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (124S6): 3-bromo-5-( 2-methylpyrimidin-5-yl)-1H-indazole-7-carbonitrile (0.3 g), tert-butyl bromoacetate (148 μl) and potassium carbonate (0.264 g) in anhydrous acetonitrile (5 ml) was heated at reflux for 2 h. the mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 0-1.5% MeOH in CH2Cl2) to give 124-S6 as a white foam.

Step 6. tert-Butyl 2-(3-acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (124-S7): tert-butyl 2- (3-bromo-7-cyano-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetate (0.06 g, 1 eq.), tributyl(1-ethoxyvinyl)tin ( 0.101 g, 2 equiv.) and PdCl ₂ (PPh ₃ ) ₂ (10 mg, 0.1 equiv.) in DMF (5 ml) were heated at 80°C overnight in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with CH ₂ Cl ₂ and washed with cold aqueous HCl (1N). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0-1.5% MeOH in CH ₂ Cl ₂ ) to give the title compound.

Step 7 2-(3-Acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (124-S8): tert-butyl 2-(3- acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (124-S7, 45 mg) was stirred in CH ₂ Cl ₂ (0.5 ml) and TFA (1 ml ). After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure, and the remaining residue was carried on to the next stage of the synthesis without further purification.

Step 8. (1 R,3S,5R)-2-(2-(3-Acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (124): compound 124-S8 was dissolved in DMF (1 ml) and iPr was added ₂ NEt (60 µl, 3 eq.) followed by TFA salt (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide (124-S9, obtained by stirring 47 mg of tert-butyl (1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl2-azabicyclo[3.1.0]hexane-2 -carboxylate in 0.5 ml TFA and 0.5 ml CH ₂ Cl ₂ for 15 min at room temperature and evaporation of volatiles at 5° C. Then HATU (48 mg, 1.2 equiv.) was slowly added at the same temperature, and the reaction mixture was stirred for 30 min at room temperature.The reaction mixture was poured into water and the precipitate was separated by filtration.The solid was dried and purified by silica gel flash column chromatography (eluent: 0-2.0% MeOH in

CH ₂ Cl ₂ ) to give 124 as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.01-1.06 (m, 2H), 1.32 (s, 3H), 2.05 (s, 3H), 2.07 (t, J=5.6 Hz, 1H), 2.51- 2.56 (m, 1H), 2.69 (s, 3H), 2.70 (s, 3H), 3.59(t, J=3.8 Hz, 1H), 4.41 (dd, J=5.3, 9.1 Hz, 1H), 5.88 (d , J=17.9 Hz, 1H), 6.09 (d, J=17.9 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 8.52 (s, 1H ), 8.78 (s, 1H), 9.12 (s, 2H), 10.26 (s, 1H).

Scheme 49. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6 -bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (125)

Step 1. tert-Butyl 2-(3-acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indazol-1-yl)acetate (125-S3): to 5-bromo-N solution ,N-dimethylpyrimidin-2-amine (125-S2, 1 eq.) in DMF/H2O (9:1, 10 vol.) was added compound (125-S1, 1 eq.), K ₂ CO ₃ (2 eq. ) and tetrakis(triphenylphosphine)palladium (0.1 eq.). The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 125-S3.

Step 2. 2-(3-Acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (125-S4): to a solution of compound 125-S3 (1 eq. .) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was carried on without additional purification and was immediately used in the next stage of the synthesis.

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-(dimethylamino)pyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6- bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (125): to a solution of compound 125-S4 (1 eq.) in DMF (10 vol.) (1R,3S,5R)-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (1 equiv.), HATU (2.1 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 3 h and then quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 125.

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.97-1.05 (m, 2H), 1.33 (s, 3H), 2.05 (s, 4H), 2.53-2.58 (m, 1H), 2.65 (s, 3H) , 3.19 (s, 6H), 3.54-3.62 (m, 1H), 4.41 (dd, J=5.1, 9.3 Hz, 1H), 5.55 (d, J=17.2 Hz, 1H), 5.88 (d, J=17.3 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.71-7.81 (m, 2H), 8.30 (s, 1H), 8.71 (s, 2H ), 10.26 (s, 1H).

Scheme 50. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1Hindazol-1-yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-carboxamide (133)

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Stage 1. 4-Bromo-2-methyl-6-(trifluoromethyl)aniline (133-S2): to a solution of 133-S1 (1.0 g, 5.7 mmol) in

MeCN (15 ml) was added N-bromosuccinimide (1.0 g, 5.7 mmol) in portions at 0°C. The reaction mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was poured into water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel chromatography (eluting with PE) to give 133-S2 (1.3 g, 90.3% yield) as a brown oil. LC/MS (ESI) m/z: 254 (M+H)+.

Stage 2. 5-Bromo-7-(trifluoromethyl)-1H-indazole (133-S3): to a mixture of 133-S2 (700 mg, 2.77 mmol) and potassium acetate (325.8 mg, 3.32 mmol) in CHCl ₃ (20 ml ) was added dropwise with acetic anhydride (846.6 mg, 8.30 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was heated to 60° C. and t-butyl nitrite (570.6 mg, 5.54 mmol) was added. After stirring overnight at 60°C, the mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was dissolved in MeOH (5 ml) and 6N. HCl (5 ml). The mixture was stirred at room temperature for 4 h, basified with 10N. aqueous NaOH solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (PE/EtOAc = 10:1 to 3:1) to give 133S3 (420 mg, 57.5% yield) as a yellow oil. LC/MS (ESI) m/z: 265 (M+H)+.

Step 3. 5-Bromo-3-iodo-7-(trifluoromethyl)-1H-indazole (133-S4): KOH (201.6 mg, 3.6 mmol) followed by the addition of I2 (605.7 mg, 2.4 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with 5% aqueous Na ₂ S ₂ O ₃ solution and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 133-S4 (610 mg, 97.7% yield) as a yellow solid which was carried on without additional cleaning. LC/MS (ESI) m/z: 391 (M+H) ⁺ .

Step 4. tert-Butyl 2-(5-bromo-3-iodo-7-(trifluoromethyl)-1H-indazol-1-yl)acetate (133-S5a) and tert-butyl 2-(5-bromo-3-iodo- 7-(trifluoromethyl)-2H-indazol-2-yl)acetate (133-S5b): K2CO3 (541.7 mg, 3.93 mmol) was added to a solution of 133-S4 (610 mg, 1.57 mmol) in DMF (8 mL), followed by by adding tert-butyl 2-bromoacetate (399.8 mg, 2.05 mmol). The resulting mixture was stirred at room temperature overnight, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (PE/EtOAc = 1:0 to 50:1 to 30:1) to give 133-S5a (173 mg, 21.8% yield) and 133-S5b (433 mg, 54.7% yield) as light yellow solids. LC/MS (ESI) m/z: 505 (M+H)+.

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Stage 5. tert-Butyl 2-(3-acetyl-5-bromo-7-(trifluoromethyl)-1H-indazol-1-yl)acetate (133-S6): to a solution of 133-S5a (144 mg, 0.28 mmol) tributyl(1-ethoxyvinyl)stannan (155 mg, 0.43 mmol) and Pd(PPh ₃ ) ₄ (33 mg, 0.028 mmol) were added in dry toluene (9 mL). The resulting mixture was stirred at 100° C. under nitrogen overnight. The cooled reaction mixture was diluted with H ₂ O and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The remaining crude product was dissolved in THF (0.5 ml) and 0.5 M HCl (5 ml) and stirred for 1.5 h at room temperature. The reaction mixture was alkalized with 2N. aqueous NaOH solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (PE/EtOAc = 50:1 to 30:1) to give 133-S6 (86 mg, 71.4% yield) as a brown solid. LC/MS (ESI) m/z: 421 (M+H)+.

Step 6. tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1H-indazol-1yl)acetate (133-S7): to mixture 133-S6 ( 86 mg, 0.2 mmol), (2-methylpyrimidin-5-yl)boronic acid (42 mg, 0.31 mmol) and K ₂ CO ₃ (70 mg, 0.51 mmol) in 1,4-dioxane (5 ml) and H ₂ O (1 ml) was added Pd(PPh ₃ ) ₄ (23 mg, 0.02 mmol). The reaction mixture was stirred at 90° C. under nitrogen overnight. The mixture was filtered and the filtrate was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (PE/EtOAc = 3:1 to 1:1) to give 133-S7 (67 mg, 75.5% yield) as a yellow solid. LC/MS (ESI) m/z: 435 (M+H) ⁺ .

Step 7. 2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1H-indazol-1-yl)acetic acid (133-S8): to a solution of 133-S7 ( 35 mg, 0.08 mmol) in DCM (2 ml) was added TFA (1 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 133-S8 (31 mg, 100% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 335 (M+H) ⁺ .

Step 8. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-7-(trifluoromethyl)-1 H-indazol-1 yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (133): to mixture 133-S8 (26 mg, 0.07 mmol) and 133-S9 (23 mg, 0.07 mmol) in DMF (2 mL), DIPEA (0.04 mL, 0.22 mmol) was added followed by HATU (41.8 mg, 0.11 mmol), and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by prep HPLC to give 133 (11.0 mg, 3.28% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.13 (s, 2H), 8.82 (s, 1H), 8.28 (s, 1H), 7.63 (d, J=8.0 Hz, 1H) , 7.44 (d, J=7.9 Hz, 1H), 5.99 (d, J=18.1 Hz, 1H), 5.59 (d, J=17.9 Hz, 1H), 4.34-4.31 (m, 1H), 3.59-3.55 ( m, 1H), 2.71 (d, J=2.1 Hz, 6H), 2.59-2.53 (m, 1H), 2.09-2.07 (m, 1H), 2.05 (s, 3H), 1.33 (s, 3H), 1.09 -1.06 (m, 1H), 0.85-0.83 (m, 1H). LC/MS (ESI) m/z: 670 (M+H) ⁺ .

Scheme 51. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methyl-pyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(3-( (allyloxy)methyl)-6-bromopyridin-2-yl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (134)

Step 1. 2-(tert-Butyl)-3-ethyl-(1R,3S,5S)-5-formyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (134-S2): to solution 2-(tert-butyl)-3-ethyl-( 1 R,3S,5S)-5-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (134-S1, 67 mg, 0.23 mmol ) in DCM (4 ml), Dess-Martin reagent (0.31

- 322 041794 mmol) at 0°C in an argon atmosphere. The mixture was stirred for an additional 3 h, the reaction was diluted with DCM (20 ml) and quenched with aqueous NaHCO ₃ (10%, 15 ml). The DCM layer was removed and the aqueous phase was extracted with DCM (15 ml x 2). The DCM phase was combined, washed with brine and dried over magnesium sulfate. The solution was filtered and concentrated to give crude product 134-S2 (62 mg) which was carried on without further purification.

Step 2 2-(tert-Butyl)-3-ethyl-(1R,3S,5R)-5-vinyl-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (134-S3): To suspension methyltriphenylphosphonium bromide (111 mg, 0.31 mmol) in 5 mL of dry THF was added dropwise with BuLi (0.31 mmol) at 0°C under argon. The mixture was stirred for 1 h and a solution of aldehyde 134-S2 (62 mg) in THF (2 ml) was added dropwise. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water (10 ml) and extracted with EtOAc (15 ml x 3). The organic phases were combined, washed with brine and dried over magnesium sulfate. The solution was filtered, concentrated and purified to give 134-S3 (31 mg).

1H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.94 (m, 1H), 1.04-1.08 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 1.44 (s, 9H), 2.32 (dd , J=13.2, 7.0 Hz, 1H), 2.43 (dd, J=13.1, 8.8 Hz, 1H), 3.43 (s, 1H), 3.97-4.09 (m, 1H), 4.16-4.26 (m, 2H), 4.99 (d, J=7.8 Hz, 1H), 5.02 (s, 1H), 5.70 (dd, J=17.0, 10.7 Hz, 1H) ppm.

Step 3. (1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (134-S4): Compound 134-S3 (31 mg , 0.11 mmol) was dissolved in a mixture of CH ₃ OH-THF-H ₂ O (2 ml-2 ml-2 ml) and treated with LiOH (24 mg). The reaction mixture was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure and the remaining residue was acidified with 10% citric acid (10 ml). The mixture was extracted with EtOAc (15 ml x 3) and the combined organic layers were washed with water and brine and dried over MgSO ₄ . The solution was concentrated and the residue (134-S4, 26 mg) was dried and carried on without further purification.

Step 4. tert-Butyl (1R,3S,5R)-3-((3-((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5vinyl-2-azabicyclo[3.1.0]hexane- 2-carboxylate (134-S5): (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-vinyl2-azabicyclo[3.1.0]hexane-3-carboxylic acid (134-S4, 26 mg, 0.10 mmol) and 3-((allyloxy)methyl)-6-bromopyridine-2-amine (27 mg, 0.11 mmol) were dissolved in anhydrous DCM (5 ml) in a pre-dried flask. The flask was cooled in an ice bath and dry pyridine (0.25 ml, 3.0 mmol) was added in one portion, followed by POCl ₃ (100 μl, 1.0 mmol). After completion of the addition, the mixture was stirred for 4 h at 0°C, and the reaction was quenched with water (15 ml). The DCM layer was removed and the aqueous phase was extracted with DCM (15 ml x 2). The combined DCM solutions were washed with brine and dried over MgSO4. The solution was filtered and concentrated and the resulting residue was purified to give 134-S5 (35 mg).

Step 5. (1R,3S,5R)-N-(3-((Allyloxy)methyl)-6-bromopyridin-2-yl)-5-vinyl-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (134 -S6): tert-butyl (1R,3S,5R)-3-((3((allyloxy)methyl)-6-bromopyridin-2-yl)carbamoyl)-5-vinyl-2-azabicyclo[3.1.0] hexane-2-carboxylate (134-S5, 28 mg, 0.058 mmol) was transferred into 4N. HCl dioxane (2.0 ml), and the resulting reaction mixture was stirred at room temperature for 2 hours After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure. The remaining residue 134-S6 was carried on without further purification.

Step 6. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(3(( allyloxy)methyl)-6-bromopyridin-2-yl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (134): to a solution of (1R,3S,5R)-N-(3- ((allyloxy)methyl)-6-bromopyridin-2-yl)-5-vinyl-2-azabicyclo[3.1.0]hexane-3carboxamide hydrochloride (134-S6, 0.058 mmol) and 2-(3-acetyl-5- (2-methylpyrimidin-5-yl)-1Hpyrazolo[3,4-c]pyridin-1-yl)acetic acid (134-S7, 18 mg, 0.058 mmol) in DMF (2.0 ml) mmol) followed by dropwise addition of DIEA (5.0 eq.) at room temperature. The mixture was stirred for 1 hour at room temperature and then the volatiles were evaporated. The residue was diluted with 10% sodium carbonate (50 ml) and extracted with ethyl acetate. The combined organic solutions were washed successively with water and brine and dried over MgSO ₄ . The solution was filtered and the solvent was removed. The residue was purified to give 134 (8.1 mg).

1H NMR (400 MHz, DMSO-d6): (main rotamer) δ 1.21-1.25 (m, 1H), 1.35-1.41 (m, 1H), 2.37-2.44 (m, 1H), 2.52-2.57 (m, 1H ), 2.65 (s, 3H), 2.69 (s, 3H), 3.62-3.79 (m, 2H), 3.87-3.93 (m, 1H), 4.20 (d, J=3.2 Hz, 2H), 4.42-4.46 ( m, 1H), 4.96-5.23 (m, 4H), 5.60 (d, J=17.3 Hz, 1H), 5.65-5.79 (m, 1H), 5.84 (dd, J=17.3, 10.6 Hz, 1H), 5.95 (d, J=17.3Hz, 1H), 7.54 (d, J=8.1Hz, 1H), 7.78 (d, J=8.1Hz, 1H), 7.86 (s, 2H), 8.44 (s, 1H), 9.03 (s, 2H), 10.48 (s, 1H) ppm. LC (method A): tR = 2.15 min. LC/MS (EI) m/z: [M+H]+ 670.20, 672.16.

Scheme 52. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(3-bromoisoquinoline -1-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (91) and (1R,3S,5R)-2-(2-(3acetyl-5-(2-methylpyrimidine- 5-yl)-1H-indazol-1-yl)acetyl)-N-(6-chloro-3((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane -3-carboxamide (135)

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Step 1. 6-Bromo-3-((dimethylamino)methyl)pyridine-2-amine (135-S2): To a stirred solution of 6bromo-3-(chloromethyl)pyridine-2-amine (133 mg, 1 eq.) in acetonitrile (10 ml) was added triethylamine (0.3 ml, 3 equiv.) and dimethylamine hydrochloride (84 mg, 2 equiv.) at 0-5°C in an argon atmosphere. The reaction mixture was stirred at room temperature, then the reaction was diluted with DCM (10 ml) and basified with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (2 x 10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give 135-S2 (100 mg, 99%).

Stage 2. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-((dimethylamino)methyl)pyridin-2-yl)carbamoyl)-5methyl-2-azabicyclo[3.1.0]hexane -2-carboxylate (135-S3): POCl ₃ was added dropwise (0.08 ml, 2 equiv.) at 0-5°C in an argon atmosphere to a stirred solution of (1R,3S,5R)-2-(tert-butoxycarbonyl) -5-methyl2-azabicyclo[3.1.0]hexane-3-carboxylic acid (106 mg, 1 equiv.) and 135-S2 (100 mg, 1 equiv.) in DCM (20 ml) and pyridine (0.18 ml, 5 equiv.). The reaction mixture was stirred at room temperature until the reaction was complete, then diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO3 (10 ml). The aqueous layer was extracted with DCM (1 x 10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 135-S3 (169 mg, 85%).

Step 3. (1 R,3S,5R)-N-(6-6pom-3-((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (135-S4) and (1R,3S,5R)-N-(6-chloro-3((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxamide hydrochloride (136-S5): to a solution of 135-S3 (169 mg) was added 4N. HCl in dioxane (15 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness to give 135-S4 (133 mg).

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(3-bromoisoquinoline-1 -yl)-5 -methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (91) and (1 R,3S,5R)-2-(2-(3 Acetyl-5-(2-methylpyrimidine- 5-yl)-1H-indazol-1-yl)acetyl)-N-(6-chloro-3((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane -3-carboxamide (135): HATU (233 mg, 1.2 equiv.) was added at 0°C under argon to a solution of 135-S4 and 135-S5 (133 mg, 1 equiv.), 2-(3acetyl-5- (2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (158 mg, 1.2 eq.) and DIPEA (0.53 ml, 5 eq.) in DMF (10 ml). The reaction mixture was stirred at room temperature for 3 h, then diluted with EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (20 ml) and the combined organic layers were washed with brine (3 x 25 ml), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by C18 reverse phase chromatography (YMC, eluting with acetonitrile and water) to give 91 (60 mg, 24%) and 135 (15 mg).

Compound 91:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 9.07 (s, 2H), 8.46 (s, 1H), 7.86-7.91 (m, 3H), 7.72 (d, 1H, J= 8.3 Hz), 6.01 (d, 1H, J=17.1 Hz), 5.65 (d, 1H, J=17.1 Hz), 4.27 (t, 1H, J=8.5 Hz), 3.92-4.02 (m, 2H), 3.70 -3.74 (m 1H), 2.71 (s, 3H), 2.66 (s, 3H), 2.54-2.61 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.98-2.05 (m, 1H), 1.35 (s, 3H), 0.96–1.07 (m, 2H).

- 324 041794

Compound 135:

1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.09 (s, 2H), 8.48 (s, 1H), 8.00 (d, 1H, J=8.4 Hz), 7.877.95 (m, 2H), 7.60 (d, 1H, J=8.4Hz), 6.02 (d, 1H, J=16.8Hz), 5.65 (d, 1H, J=16.8Hz), 4.27 (t, 1H, J=8.2Hz) , 3.94-4.04 (m, 2H), 3.69-3.74 (m, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.54-2.61 (m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.98–2.05 (m, 1H), 1.35 (s, 3H), 0.95–1.07 (m, 2H).

Scheme 53. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (136) and (1R,3S,5R)-2-(2 -(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6-chloro-3-((dimethylamino)methyl)pyridine-2- yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide(137)

Step 1. (1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-((dimethylamino)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (136) and (1 R,3S,5R) -2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6chloro-3-((dimethylamino) methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (137): HATU (100 mg, 1.2 equiv.) was added at 0°C under argon to a solution of 136 -S1 and 137-S2 (84 mg, 1 eq.), 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (71 mg, 1 equiv.), DIPEA (0.2 ml, 5 equiv.) in DMF (10 ml). The reaction mixture was stirred at room temperature for 3 h, then the reaction mixture was diluted with EtOAc (30 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (15 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by C18 HPLC column (eluting with ACN/water/TFA=20:80:0.1) to give 136 (48 mg) and 137 (32 mg).

Compound 136:

¹ H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.06 (s, 2H), 8.33 (s, 1H), 7.95 (d, 1H, J=8.5 Hz), 7.72 (d, 1H , J=8.5 Hz), 7.65 (s, 1H), 6.13 (d, 1H, J=18.1 Hz), 5.73 (d, 1H, J=18.1 Hz), 4.26-4.31 (m, 1H), 3.91-4.03 (m, 3H), 2.73 (s, 3H), 2.70 (s, 3H), 2.65 (s, 3H), 2.54-2.61 (m, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 1.97-2.00 (m, 1H), 1.35 (s, 3H), 0.96-1.00 (m, 2H).

Compound 137:

1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.05 (s, 2H), 8.34 (s, 1H), 7.99 (d, 1H, J=8.0 Hz), 7.65 (s, 1H ), 7.59 (d, 1H, J=8.0 Hz), 6.13 (d, 1H, J=17.9 Hz), 5.72 (d, 1H, J=17.9 Hz), 4.25-4.31 (m, 1H), 3.94-4.03 (m, 3H), 2.73 (s, 3H), 2.70 (s, 3H), 2.66 (s, 3H), 2.55-2.60 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 1.96-2.06 (m, 1H), 1.35 (s, 3H), 0.97-1.03 (m, 2H).

Scheme 54. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-(morpholinomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (138) and (1 R,3S,5R)-2-(2-(3 -acetyl-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-(6-chloro-3(morpholinomethyl)pyridin-2-yl)-5 -methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide (139)

139-S1 ₁₃₉ . _S2

- 325 041794

Stage 1. 6-Bromo-3-(morpholinomethyl)pyridine-2-amine (139-S2): to a stirred solution of 6bromo-3-(chloromethyl)pyridine-2-amine (241 mg, 1 eq.) and triethylamine (0.48 ml, 3 eq.) in acetonitrile (20 ml) was added morpholine (162 mg, 2 eq.) at 0-5°C in an argon atmosphere. The reaction mixture was stirred at room temperature until completion of the reaction. The reaction was diluted with DCM (25 ml) and basified with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (2 x 10 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 139-S2 (215 mg, 85%).

Step 2. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-(morpholinomethyl)pyridin-2-yl)carbamoyl)-5-methyl2-azabicyclo[3.1.0]hexane-2- carboxylate (139-S3): POCl ₃ was added dropwise (0.03 ml, 2 equiv.) at 0-5°C in an argon atmosphere to a stirred solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5- methyl-2azabicyclo[3.1.0]hexane-3-carboxylic acid (69 mg, 1 eq.) and 139-S2 (78 mg, 1 eq.) in DCM (10 ml) and pyridine (0.12 ml, 5 eq.) . The reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (1 x 10 ml) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 139-S3 (87 mg, 70%).

Step 3. (1R,3S,5R)-N-(6-Bromo-3-(morpholinomethyl)pyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (138-S4 ) and (1R,3S,5R)-N-(6-chloro-3(morpholinomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (139S5): to a solution of 139-S3 (87 mg) was added 4N. HCl in dioxane (10 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness to give 138-S4 and 139-S5.

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -(morpholinomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (138) and (1 R,3S,5R)-2-(2-(3-Acetyl -5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6-chloro-3 (morpholinomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo [3.1.0]hexane-3-carboxamide (139): HATU (68 mg, 1.2 equiv.) was added at 0°C under argon to a solution of 138-S4 and 139-S5 (65 mg, 1 equiv.), 2 -(3-acetyl-5(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (47 mg, 1.05 eq.) and DIPEA (0.13 ml, 5 eq.) in DMF (10 ml ). The reaction mixture was stirred at room temperature for 3 h, then the reaction mixture was diluted with EtOAc (35 ml) and water (15 ml). The aqueous layer was extracted with EtOAc (20 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by C18 HPLC column (eluting with ACN/water/TFA=20/80/0.1) to give 138 (30 mg) and 139 (12 mg).

Compound 138:

1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.97 (s, 2H), 8.39 (s, 1H), 7.70-7.89 (m, 3H), 7.57 (s, 1H), 5.98 (d, 1H, J= 17.5 Hz), 5.55 (d, 1H, J=17.5 Hz), 4.13-4.27 (m, 1H), 3.86-4.02 (m, 4H), 3.63-3.73 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 2.46-2.52 (m, 1H), 2.33 (s, 2H), 2.11-2.24 (m, 4H), 1.89-2.09 (m, 1H), 1.26 ( s, 3H), 0.870.99 (m, 2H).

Compound 139:

1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 8.98 (s, 2H), 9.33 (s, 1H), 8.38 (s, 1H), 7.79-7.93 (m, 3H), 7.46 (s, 1H), 5.96 (d, 1H, J=17.2 Hz), 5.55 (d, 1H, J=17.2 Hz), 4.14-4.32 (m, 1H), 3.80-4.02 (m 1H), 3.57-3.69 (m, 4H), 3.06 (s, 2H), 2.62 (s, 3H), 2.59 (s, 3H), 2.47-2.52 (m, 1H), 1.92-2.13 (m, 5H), 1.28 (s, 3H ), 0.89-0.99

- 326 041794 (m, 2H).

Scheme 55 -bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (143) and (1S,3S)-2-(2-(3- acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-^(6-bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl) -2-azabicyclo[3.1.0]hexane-3carboxamide (144)

Zn(CN)2 PdiPPh^ toluene

Stage 1

Step 1. tert-Butyl 2-(3-acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (144-S2): 144 was loaded into a sealed vial. -S1 (50 mg, 0.112 mmol), Zn(CN) ₂ (53 mg, 0.449 mmol), Pd(PPh ₃ ) ₄ (7 mg, 0.056 mmol) and toluene (3 ml) under nitrogen atmosphere. The vial was sealed and microwaved in a reactor at 150° C. for 2 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the remaining residue was purified by preparative TLC to give 144-S2 (42 mg, 95.9% yield) as a white solid. LC/MS (ESI) m/z: 392 (M+H)+.

Step 2. 2-(3-Acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (144-S3): to a solution of 144-S2 (42 mg , 0.102 mmol) in DCM (1 ml) was added TFA (1 ml). The resulting mixture was stirred at room temperature for 2 hours and concentrated to give 144-S3 (36 mg, 100% yield) as a white solid, which was taken to the next step of the synthesis without purification. LC/MS (ESI) m/z: 336 (M+H)+.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (143) and (1S,3S)-2-( 2-(3-acetyl-7-cyano-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-N-(6-bromo3-methylpyridin-2-yl)-5 -((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (144): to a solution of 144-S3 (35 mg, 0.093 mmol), 144-S4 (37 mg, 0.093 mmol) and DIPEA (40 mg, 0.279 mmol) HATU (79 mg, 0.186 mmol) was added to DMF (1 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 5% aqueous LiCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by preparative HPLC to give 143 (3 mg, 4.8% yield) and 144 (1 mg, 1.6% yield) as white solids.

Compound 143:

1H NMR (400 MHz, CD3OD) δ 9.06 (s, 2H), 8.89 (d, J=1.6 Hz, 1H), 8.32 (d, J=1.6 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H ), 7.43 (d, J=7.9 Hz, 1H), 6.08 (d, J=17.8 Hz, 1H), 6.00 (d, J=17.8 Hz, 1H), 4.73 (m, 1H), 3.89-3.84 (m , 1H), 3.50 (m, 2H), 3.13 (d, J=14.0 Hz, 1H), 2.90 (s, 6H), 2.79 (s, 3H), 2.73 (s, 3H), 2.62 (m, 1H) , 2.15 (s, 3H), 1.58 (d, J=3.1 Hz, 1H), 1.50 (m, 1H). LC/MS (ESI) m/z: 670 (M+H)+.

Compound 144:

¹ H NMR (400 MHz, CD3OD) δ 9.07 (s, 2H), 8.90 (d, J=1.6 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 6.18 (d, J=17.7 Hz, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.19 (m, 1H), 4.00 (m, 1H), 3.70 m, 1H), 3.50 (m, 1H), 3.21-3.15 (m, 1H), 2.98 (s, 6H), 2.79 (s, 3H), 2.73 (s, 3H), 2.62 (m, 1H), 2.19-2.08 (m, 3H), 1.90 (s, 1H), 1.42 (m, 1H). LC/MS (ESI) m/z: 670 (M+H)+.

Scheme 56. Synthesis of 1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2 -yl)-2-oxoethyl)-4-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazole-3carboxamide (145) n Η V n

Pd ₂ (dba) ₃ , DMA Y'y^Br MeOH, NaOH ¹ F Stage 1 ^NC F Stage 2 NH ₂ ^F 145-S3

145-S1 145-S2

- 327 041794

Stage 1. 5-Bromo-4-fluoro-1Н-indazole-3-carbonitrile (145-S2): powdered Zn (18 mg, 0.282 00 mmol), Zn(CN) ₂ (138 mg, 1.173 mmol), dppf (52 mg, 0.094 mmol), Pd ₂ (dba) ₃ (43 mg, 0.0469 mmol), and the mixture was purged with nitrogen. The reaction mixture was heated at 100° C. overnight under a nitrogen atmosphere. The solution was cooled to room temperature and partitioned between EtOAc and 0.5N. aqueous HCl. The organic phase was washed twice with 0.5N. aqueous HCl and brine, and dried over Na ₂ SO ₄ . The mixture was filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 5:1) to give 145-S2 (469 mg, 83.3% yield) as a white solid. LC/MS (ESI) m/z: 240 (M+H)+.

Stage 2. 5-Bromo-4-fluoro-1H-indazole-3-carboxamide (145-S3): to a solution of 145-S2 (469 mg, 1.95 mmol) in MeOH (25 ml) at 0°C was added an ice-cold solution of urea with hydrogen peroxide (1.8 g, 19.54 mmol) in 1N. aqueous NaOH solution (25 ml, 19.54 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to half volume and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give 145-S3 (270 mg, 54% yield) as a white solid. LC/MS (ESI) m/z: 258 (M+H) ⁺ .

Step 3. tert-Butyl 2-(5-bromo-3-carbamoyl-4-fluoro-1H-indazol-1-yl)acetate (145-S4): to a solution of 145-S3 (270 mg, 1.05 mmol) in DMF (2 ml) was added tert-butyl 2-bromoacetate (0.18 ml, 1.26 mmol) and K ₂ CO ₃ (363 mg, 2.625 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc, washed with 10% aqueous LiCl and brine, and dried over Na ₂ SO ₄ . The mixture was filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 1:1) to give 145-S4 (210 mg, 53.7% yield) as a white solid. LC/MS (ESI) m/z: 372 (M+H) ⁺ .

Step 4. tert-Butyl 2-(3-carbamoyl-4-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (145-S5): to a solution of 145-S4 ( 41 mg, 0.11 mmol) and 2-methylpyrimidin-5-ylboronic acid (18 mg, 0.13 mmol) in DMF (2 mL) were added K ₃ PO ₄ (0.17 mL, 2N, 0.33 mmol) and Pd(dppf)Cl ₂ (4 mg, 0.005 mmol) under nitrogen atmosphere. The reaction mixture was further purged with nitrogen and stirred at 100° C. for 3 h. The mixture was poured into ice water and extracted with EtOAc, washed with 10% aqueous LiCl and brine, and dried over Na ₂ SO ₄ . The mixture was filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 50:1) to give 145-S5 (32 mg, 76% yield) as a white solid. LC/MS (ESI) m/z: 386 (M+H) ⁺ .

Step 5. 2-(3-Carbamoyl-4-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (145-S6): to a solution of 145-S5 in DCM ( 2 ml) was added TFA (1 ml) at 0°C, and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness under reduced pressure to obtain 145-S6 (32 mg, 100% yield), which was transferred to the next synthesis step without further purification LC/MS (ESI) m/z: 330 (M+H) ⁺ .

Step 6. 1-(2-((1R,3S,5R)-3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2- yl)-2-oxoethyl)-4-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazole-3carboxamide (145): to a mixture of 145-S6 (32 mg, 0.097 mmol), 145-S7 ( 52 mg, 0.126 mmol) and HATU (74 mg, 0.194 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.582 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with 10% aqueous solution of LiCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give 145 (7 mg, 12% yield) as a light yellow solid.

¹ H NMR (400 MHz, CD3OD) δ 8.93 (s, 2H), 7.64-7.53 (m, 3H), 7.38 (d, J=8 Hz, 1H), 5.76-5.59 (m, 2H), 4.54-4.50 (m, 1H), 3.53-5.50 (m, 1H), 2.73 (s, 3H), 2.65-2.58 (m, 1H), 2.32-2.27 (m, 1H), 2.12 (s, 3H), 1.40 (s ,

- 328 041794

3H), 1.07 (t, J=5.6 Hz, 1H), 0.97-0.95 (m, 1H). LC/MS (ESI) m/z: 621 (M+H)+.

Scheme 57. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (146) he

Step 1 Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylate.

(146-S2): NaH (144 mg, 3.6 mmol, 60% dispersion in mineral oil) was added to a solution of 146-S1 (765 mg, 3 mmol) in dry THF (2 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min, SEMCl (648 mg, 3.9 mmol) was added to the above mixture, and the resulting mixture was stirred at room temperature for 2 h. The mixture was then quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to give crude product which was purified by silica gel column chromatography (eluting with PE/EtOAc=100:0 to 7:1) to give 146-S2 (750 mg, 65.1% yield) as a white solid. LC/MS (ESI) m/z: 385 (M+H) ⁺ .

Stage 2. (5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methanol (146-S3): to a solution of 146-S2 (750 mg, 1.95 mmol) in dry THF (20 ml) was added LiAlH4 (148 mg, 3.5 mmol) at 0°C in small portions. The reaction mixture was stirred at 0°C for 30 min and then warmed to room temperature for 1 h. The mixture was then slowly quenched with water (0.75 ml), 10% aqueous NaOH solution (1.5 ml) and water (2.25 ml). The resulting mixture was filtered and the filtrate was diluted with EtOAc, dried over Na ₂ SO ₄ and concentrated to give a crude product which was purified by silica gel column chromatography (eluting with PE/EA=100:1 to 5:1) to give 146- S3 (494 mg, 71.1% yield) as a colorless oil. LC/MS (ESI) m/z: 357 (M+H) ⁺ .

Step 3. (5-(2-Methylpyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7yl)methanol (146-S4): to 146-S3 solution (494 mg, 1.384 mol) in 1,4-dioxane/H ₂ O (28 ml, 6:1) was added 2-methylpyrimidin-5-ylboronic acid (210 mg, 1.52 mmol), K ₂ CO ₃ (573 mg, 4.152 mmol ) and Pd(PPh ₃ ) ₄ (128 mg, 0.111 mmol). The reaction mixture was stirred at 95° C. for 16 hours under nitrogen. After cooling, the mixture was diluted with water and extracted with DCM/MeOH (20:1). The organic layer was separated, dried and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluting with DCM/MeOH = 100:0 to 50:1) to give 146-S4 (288 mg, 56.2% yield ) as a colorless oil. LC/MS (ESI) m/z: 371 (M+H)+.

Stage 4. 5-(2-Methylpyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7carbaldehyde (146-S5): to a solution of 146-S4 (240 mg, 0.65 mmol) in CHCl ₃ (12 ml) was added MnO ₂ (565 mg, 6.5 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with DCM/EtOAc = 100:1 to 8:1) to give 146-S5 (150 mg, 62.7% yield) as a colorless oil. LC/MS (ESI) m/z: 369 (M+H) ⁺ .

Step 5. 7-(Difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hindazole (146-S6): to a solution of 146-S5 (150 mg , 0.41 mmol) in dry DCM (10 ml) DAST (198 mg, 1.23 mmol) was slowly added at 0°C under nitrogen atmosphere. The resulting mixture was stirred from 0° C. to room temperature over 1 h and then heated to 40° C. for 24 h. The mixture was then quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to dryness. The remaining residue was purified by preparative TLC (eluting with DCM/MeOH = 20:1) to give 146-S6 (92 mg, 58.2% yield) as a colorless oil. LC/MS (ESI) m/z: 391 (M+H) ⁺ .

Step 6. 7-(Difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazole (146-S7): To a solution of 146-S6 (92 mg, 0.24 mmol) in dry DCM (2 ml) was added TFA (2 ml) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to give 146-S7 (62 mg, 68.8% yield) as a colorless oil. LC/MS (ESI) m/z: 261 (M+H) ⁺ .

Step 7. 7-(Difluoromethyl)-3-iodo-5-(2-methylpyrimidin-5-yl)-1H-indazole (146-S8): to a solution of 146-S7 (62 mg, 0.24 mmol) in DMF (5 ml) KOH (41 mg, 0.72 mmol) and I ₂ (92 mg, 0.36 mmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was then quenched with 5% aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc. The organic layer was separated, dried and concentrated to give 146-S8 (85 mg, 91.7% yield) as a colorless oil. LC/MS (ESI) m/z: 387 (M+H) ⁺ .

Step 8. tert-Butyl 2-(7-(difluoromethyl)-3-iodo-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (146-S9): to a solution of 146-S8 ( 85 mg, 0.22 mmol) in DMF (6 mL) were added K2CO3 (61 mg, 0.44 mmol) and tert-butyl 2-bromoacetate (65 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed with 10% LiCl aqueous solution, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with PE/EtOAc=100:0 to 4: 1) to give 146-S9 (66 mg, 60.0% yield) as a colorless oil. LC/MS (ESI) m/z: 501 (M+H) ⁺ .

Step 9 tert-Butyl 2-(3-acetyl-7-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (146-S10): to mixture 146-S9 ( 66 mg, 0.132 mmol) in dry toluene (8 mL) were added tributyl(1ethoxyvinyl)stannan (67 mg, 0.185 mmol) and Pd(PPh3)4 (13 mg, 0.01 mmol). The reaction mixture was stirred at 100° C. for 16 hours under nitrogen. After cooling, the mixture was quenched with 1N. aqueous HCl solution and stirred at room temperature for 15 min. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product which was purified by silica gel column chromatography (eluting with DCM/MeOH=100:0 to 50:1) to give 146 -S10 (52 mg, 92.8% yield) as a colorless oil. LC/MS (ESI) m/z: 417 (M+H) ⁺ .

Step 10 2-(3-Acetyl-7-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (146-S11): to mixture 146-S10 (52 mg, 0.13 mmol) in THF/H2O (8 ml, 3:1, v/v) was added LiOH-H ₂ O (12 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with water, washed with ether, and the aqueous layer was acidified with aqueous HCl (1N) to pH 5. The resulting mixture was extracted with DCM/MeOH (5 ml x 2, 10:1 vol. / vol.). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 146-S11 (36 mg, 76.9% yield) as a white solid. LC/MS (ESI) m/z: 361 (M+H) ⁺ .

Step 11. (1R,3S,5R)-2-(2-(3-Acetyl-7-(difluoromethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicylo[3.1.0]hexane-3-carboxamide (146): to a solution of 146-S11 (36 mg, 0.1 mmol), 146- S12 (45 mg, 0.13 mmol) and HATU (57 mg, 0.15 mmol) in DMF (2 mL) were added DIPEA (40 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by preparative HPLC to give 146 (15 mg, 23.0% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 9.10 (s, 2H), 8.72 (s, 1H), 8.17 (s, 1H), 7.63 (d, J=7.9 Hz, 1H ), 7.27-7.55 (m, 2H), 5.95 (d, J=18.0 Hz, 1H), 5.72 (d, J=17.7 Hz, 1H), 4.35 (dd, J=9.1, 5.2 Hz, 1H), 3.53 -3.58 (m, 1H), 2.71 (s, 3H), 2.69 (s, 3H), 2.53-2.59 (m, 1H), 2.05 (s, 3H), 1.96-2.03 (m, 1H), 1.33 (s , 3H), 1.02-1.07

- 330 041794 (m, 1H), 0.87-0.94 (m, 1H). LC/MS (ESI) m/z: 652 (M+H)+.

Scheme 58. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (147)

Stage 1. 7-Fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazole (147-S2): mixture of 5-bromo-7-fluoro-Sindazole (0.32 g eq.), 2-methyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.384 g), cesium carbonate (1.14 g) in dioxane (8 ml) and water (2.0 ml) was purged with argon in a pressure vessel for 5 min. PdCl ₂ (dppf) (0.190 g) was added under argon atmosphere and the pressure vessel was sealed and heated at 90° C. overnight. The reaction mixture was cooled to room temperature and poured into water. The precipitated product was isolated by filtration, washed with water and dried. This material was carried on without further purification and was immediately used in the next step.

Step 2. 3-Bromo-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazole (147-S3): to a stirred solution of 7-fluoro-5-(2-methylpyrimidin-5-yl) -1H-indazole (0.39 g) in DMF (5 ml) was added NBS (0.335 g). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the precipitate was filtered off, washed with water and dried. This material was carried on without further purification and was immediately used in the next step.

Step 3. tert-Butyl 2-(3-bromo-7-fluoro-5-(2-methylpyrimidin-5-yl)-III-indazol-1-yl)acetate (147S4): 3-bromo-7-fluoro mixture -5-(2-methylpyrimidin-5-yl)-1H-indazole (0.36 g), tert-butyl bromoacetate (181 μm) and potassium carbonate (0.323 g) in anhydrous acetonitrile (5 ml) and DMF (2 ml) were heated refluxed for 1 hour. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 0-1.5% MeOH in CH ₂ Cl ₂ ) to give 147-S4 as a white solid.

Step 4. tert-Butyl 2-(3-acetyl-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (147S5): tert-butyl 2-(3 -bromo-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (0.25 g, 1 eq.), tri-butyl (1-ethoxyvinyl)tin 0.429 g, 2 equiv.) and PdCl ₂ (PPh ₃ ) ₂ (42 mg, 0.1 equiv.) in DMF (3 ml) were heated at 80°C overnight in an argon atmosphere, then concentrated under reduced pressure and diluted with CH ₂ Cl ₂ and washed cold aqueous HCl (1N). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0-1.5% MeOH in CH ₂ Cl ₂ ) to give 147-S5.

Step 6. (1R,3S,5R)-2-(2-(3-Acetyl-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-( 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (147): tert-butyl 2

- 331 041794 (3-acetyl-7-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (70 mg) was stirred in CH ₂ Cl ₂ (0.5 ml) and TFA ( 1.5 ml). After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure. The remaining residue was dissolved in DMF (1 ml) and iPr ₂ NEt (95 μl, 3 eq.) was added, followed by the addition of (1R,3S,5R)-N-(6-bromopyridin-2-yl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxamide, TFA salt (prepared by stirring 74 mg tert-butyl (1R,3S,5R)-3-((6-bromopyridin-2-yl)carbamoyl)-5-methyl-2 -azabicyclo[3.1.0]hexane-2-carboxylate in 1 ml TFA and 1 ml CH ₂ Cl ₂ for 15 min at room temperature and devolatilization) at 5°C. HATU (76 mg, 1.2 equiv.) was added slowly at the same temperature and the reaction mixture was stirred for 30 min at room temperature, then the reaction mixture was poured into water and the precipitate was separated by filtration. The solid was dried and purified by silica gel flash column chromatography (eluent: 0-2.5% MeOH in CH ₂ Cl ₂ ) to give 147 as a light yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 0.84-0.91 (m, 1H), 1.05 (t, J=5.4 Hz, 1H), 1.32 (s, 3H), 2.05 (s, 3H), 2.03-2.07 (m, 1H), 2.52-2.58 (m, 1H), 2.67 (s, 3H), 2.69 (s, 3H), 3.56 (d, J=4 Hz, 1H), 4.41 (dd, J=5.2, 9.2 Hz, 1H), 5.65 (d, J=17.4Hz, 1H), 5.90 (d, J=17.4Hz, 1H), 7.44 (d, J=7.9Hz, 1H), 7.62 (d, J=7.9Hz, 1H), 7.79 (d, J=12.7 Hz, 1H), 8.28 (s, 1H), 9.06 (s, 2H), 10.26 (s, 1H). ¹⁹ F NMR (DMSO4): δ -131.6.

Scheme 59 yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (148)

Stage 1. tert-Butyl 2-(3-acetyl-5-(2-(2-methoxy-2-oxoethyl)pyrimidin-5-yl)-1H-indazol-1yl)acetate (148-S3): to a solution of methyl 2-(5-bromopyrimidin-2-yl)acetate (148-S2, 1 eq.) in DMF/H2O (9:1, 10 vol.) compound 148-S1 (1 eq.), K ₂ CO ₃ ( 2 eq.) and tetrakis(triphenylphosphine)palladium (0.1 eq.). The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 148-S3.

Step 2. 2-(3-Acetyl-5-(2-(2-methoxy-2-oxoethyl)pyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (148-S4): to compound solution 148-S3 (1 equiv.) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was carried on without additional purification and was immediately used in the next stage of the synthesis.

Step 3. Methyl 2-(5-(3-acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5methyl-2 -azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)acetate (148-S6): to a solution of compound 148-S4 (1 eq. ) (1R,3S,5R)-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0 ]hexane-3-carboxamide (148-S5.1 eq.), HATU

- 332 041794 (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 148-S6.

Step 4. 2-(5-(3-Acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl- 2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)acetic acid (148-S7): to a solution of methyl 2-(5-(3 -acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl2-azabicyclo[3.1.0]hexane-2- yl)-2-oxoethyl)-III-indazol-5-yl)pyrimidin-2-yl)acetate (148-S6, 1 equiv.) in THF/H2O (3:1, 10 vol.) was added LiOH (2.1 equiv. .). The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. The remaining residue was neutralized with 2n. HCl, and the precipitated solid was filtered off, dried and immediately used in the next stage of the synthesis.

Step 5. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-(2-(dimethylamino)-2-oxoethyl)pyrimidin-5-yl)-1Hindazol-1-yl )acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (148): to a solution of compound 148-S7 (1 eq.) dimethylamine hydrochloride (1.2 equiv.), HATU (2.1 equiv.), and DIPEA (5 equiv.) were added to DMF (10 vol.) at 0°C under argon. The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 148.

1H NMR (400 MHz, DMSO-d6) δ 0.98-1.06 (m, 2H), 1.33 (s, 3H), 2.05 (s, 4H), 2.53-2.59 (m, 1H), 2.67 (s, 3H), 2.88 (s, 3H), 3.07 (s, 3H), 3.55-3.68 (m, 1H), 4.08 (s, 2H), 4.37-4.47 (m, 1H), 5.59 (d, J=17.2 Hz, 1H) , 5.92 (d, J=17.2Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.87 (t, J=6.5Hz, 2H), 8.47 (s, 1H), 9.10 (s, 2H), 10.26 (s, 1H).

Scheme 60. Synthesis of methyl ((S)-1-((((1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl )acetyl)-3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5yl)methyl)amino)-3-methyl-1-oxobutane -2-yl)carbamate (153)

Step 1. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-5-((1,3dioxoisoindolin-2-yl)methyl) -2-azabicyclo[3.1.0]hexane-2-carboxylate (153-S2): to a mixture of 153-S1 (290 mg, 0.75 mmol) and 6-bromo-3-(methoxymethyl)pyridine-2-amine (162 mg , 0.75 mmol) in dry DCM (3 mL), pyridine (0.3 mL, 3.75 mmol) was added followed by the addition of POCl ₃ (114.7 mg, 0.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and extracted with DCM twice. The organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (PE/EtOAc = 6:1 to 2:1) to give 153-S2 (180 mg, 41.0% yield) as

- 333 041794 white solid. LC/MS (ESI) m/z: 585 (M+H)+.

Step 2. (1R,3S,5R)-tert-Butyl 5-(aminomethyl)-3-((6-bromo-3-(methoxymethyl)pyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (153-S3): Hydrazine hydrate (72.5 mg, 1.24 mmol) was added to a solution of 153-S2 (180 mg, 0.31 mmol) in EtOH (3 mL). The reaction mixture was stirred at 75°C for 2 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 5:1) to give 153-S3 (130 mg, 92.2% yield) as a white solid. LC/MS (ESI) m/z: 455/(M+H)+.

Step 3. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-5-(((S)-2((methoxycarbonyl)amino )-3-methylbutanamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (153S4): to a mixture of 153-S3 (30 mg, 0.066 mmol), (S)-2-(methoxycarbonylamino)-3 -methylbutanoic acid (13.9 mg, 0.079 mmol) and HATU (37.6 mg, 0.099 mmol) in DMF (2 mL) was added DIPEA (0.04 mL, 0.198 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (PE/EtOAc = 2:1 to 0:1) to give 153-S4 (29 mg, 72.0% yield) as a clear oil. LC/MS (ESI) m/z: 612 (M+H) ⁺ .

Step 4. Methyl ((S)-1-((((1R,3S,5R)-3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0] hexan-5-yl)methyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (153-S5): TFA (1 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 153-S5 (25.6 mg, 100% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 512 (M+H) ⁺ .

Step 5. Methyl ((S)-1-((((1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl) acetyl)-3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5yl)methyl)amino)-3-methyl-1-oxobutan- 2-yl)carbamate (153): to a mixture of 153-S5 (25.6 mg, 0.05 mmol), 2-(3acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid ( 153-S6, 16.1 mg, 0.05 mmol) and HATU (29.6 mg, 0.08 mmol) in DMF (2 mL) were added DIPEA (0.03 mL, 0.14 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 153 (5.2 mg, 12.9% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.43 (s, 1H), 9.04 (s, 2H), 8.44 (s, 1H), 8.16 (s, 1H), 7.87 (d, J=1.1 Hz, 2H ), 7.77 (d, J=8.1Hz, 1H), 7.55 (d, J=8.0Hz, 1H), 7.12 (d, J=9.1Hz, 1H), 5.88 (d, J=17.2Hz, 1H), 5.61 (d, J=17.1 Hz, 1H), 4.44-4.39 (m, 1H), 4.17 (s, 1H), 3.85-3.79 (m, 1H), 3.76-3.73 (m, 1H), 3.65-3.63 ( m, 1H), 3.54 (s, 3H), 3.08 (s, 3H), 3.07-3.05 (m, 1H), 2.69 (s, 3H), 2.68-2.67 (m, 1H), 2.66 (s, 3H) , 2.20-2.17 (m, 1H), 1.971.94 (m, 1H), 1.24 (s, 1H), 1.17 (t, J=5.6 Hz, 1H), 1.08 (s, 1H), 0.94-0.81 (m , 6H). LC/MS (ESI) m/z: 804 (M+H) ⁺ .

Scheme 61. Synthesis of (1R,3S,5S)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((2-(dimethylamino)ethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (157)

- 334 041794 '2

-S3 about

O

Vos

157-S1

BnBr ^Boc 157-S6

Boc

_{K2CO3 ,} MeCN

Stage 3

NaH, DMF

MeOH/THF

Stage 5

TFA, DCM

157-S9

Br

157-S8

-S5

HATU, DIPEA DMF

Stage 8

Stage 1. (1R,3S,5S)-2-tert-Butyl 3-ethyl

H ₂ , Pd/C

ROS1 ₃ ru DCM

Stage 6

5-((2-(dimethylamino)-2-oxoethoxy)methyl)-2 azabicyclo[3.1.0]hexane-2,3-dicarboxylate (157-S2): to a solution of 157-S1 (200 mg, 0.70 mmol) in DMF (3 mL) NaH (56 mg, 60% dispersion in mineral oil, 1.40 mmol) was added at 0°C and 2-bromo-N,N-dimethylacetamide (232 mg, 1.40 mmol) was added after 5 min. The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ice water and EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 157-S2 (110 mg, 42.5% yield) as a yellow oil. LC/MS (ESI) m/z: 371 (M+H)+.

Step 2. (1R,3S,5S)-2-(tert-Butoxycarbonyl)-5-((2-(dimethylamino)-2-oxoethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (157 -S3): NaOH (36 mg, 0.90 mmol) was added to a solution of 157-S2 (110 mg, 0.30 mmol) in THF (3 mL) and water (3 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to half volume and washed twice with EtOAc. The mixture was acidified with 2N. aqueous HCl to pH 4 and extracted three times with DCM. The combined organic layers were concentrated to dryness to give 157-S3 (85 mg, 83.3% yield) as a colorless oil. LC/MS (ESI) m/z: 343 (M+H) ⁺ .

Step 3. (1R,3S,5S)-3-Benzyl 2-tert-butyl 5-((2-(dimethylamino)-2-oxoethoxy)methyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate ( 157-S4): K2CO3 (69 mg, 0.50 mmol) and BnBr (58 mg, 0.34 mmol) were added to a solution of 157-S3 (85 mg, 0.25 mmol) in MeCN (2 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 2:1) to give 157-S4 (95 mg, 88.0% yield) as a colorless oil. LC/MS (ESI) m/z: 433 (M+H) ⁺ .

Step 4. (1R,3S,5S)-3-Benzyl 2-tert-butyl 5-((2-(dimethylamino)ethoxy)methyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate (157-S5 ): BH3-THF (0.66 ml, 0.66 mmol, 1 M) was added to a solution of 157-S4 (95 mg, 0.22 mmol) in THF (5 mL). The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was quenched with MeOH and concentrated to dryness. The remaining residue was diluted with EtOH (8 ml) and H2O (1 ml) and the mixture was stirred at reflux for 4 h. The mixture was concentrated to dryness and the remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 30: 1) to give 157-S5 (90 mg, 97.8% yield) as a white solid. LC/MS (ESI) m/z: 419 (M+H) ⁺ .

Step 5. (1R,3S,5S)-2-(tert-Butoxycarbonyl)-5-((2-(dimethylamino)ethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (157-S6 ): to a solution of 157-S5 (90 mg, 0.21 mmol) in MeOH (5 mL) was added Pd/C (10 mg, 10% wt). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated to dryness to give 157-S6 (65 mg, 94.3% yield) in

- 335 041794 as a white solid. LC/MS (ESI) m/z: 329 (M+H)+.

Step 6. (1R,3S,5S)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((2(dimethylamino)ethoxy)methyl)-2-azabicyclo[3.1.0 ]hexane-2-carboxylate (157-S7): to a solution of 157-S6 (65 mg, 0.20 mmol) and 6-bromo-3-methylpyridine-2-amine (23 mg, 0.24 mmol) in DCM (5 ml) was added pyridine (24 mg, 1.22 mmol) at 0°C followed by dropwise addition of POCl ₃ (0.02 ml, 0.20 mmol). The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with ice water and extracted with DCM twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 50:1) to give 157-S7 (80 mg, 67.2% yield) as a white solid. LC/MS (ESI) m/z: 497 (M+H)+.

Step 7. (1R,3S,5S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((2-(dimethylamino)ethoxy)methyl)-2azabicyclo[3.1.0]hexane-3 -carboxamide (157-S8): TFA (1 ml) was added to a solution of 157-S7 (80 mg, 0.14 mmol) in DCM (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 157-S8 (80 mg, 100.0% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 397 (M+H)+.

Step 8. (1 R,3S,5S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-((2-(dimethylamino)ethoxy)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (157): to a solution of 157-S8 ( 30 mg, 0.08 mmol), 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Nindazol-1-yl)acetic acid (157-S9, 28 mg, 0.089 mmol) and HATU (46 mg , 0.12 mmol) DIPEA (0.04 ml, 0.24 mmol) was added to DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give 157 (2.9 mg, 5.3% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 9.04 (s, 2H), 8.59 (s, 1H), 7.85-7.77 (m, 2H), 7.61 (d, J=7.5 Hz, 1H), 7.44 (d, J =7.9 Hz, 1H), 5.82 (m, 1H), 5.71 (m, 1H), 5.36 (m, 1H), 4.72 (m, 1H), 3.98-3.89 (m, 2H), 3.87-3.76 (m, 2H), 3.41 (m, 2H), 2.94 (s, 6H), 2.78 (s, 3H), 2.67 (m, 1H), 2.59 (m, 1H), 2.14 (s, 3H), 1.20 (m, 1H ), 0.91 (m, 1H). LC/MS (ESI) m/z: 689 (M+H)+.

Scheme 62. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((2,2-difluorocyclopentanecarboxamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (158)

Step 1. (1R,3S,5R)-tert-Butyl 3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-((2,2difluorocyclopentanecarboxamido)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (158-S2): DCC (36 mg, 0.18 mmol) was added to a solution of 158-S1 (50 mg, 0.12 mmol) and 2,2-difluorocyclopentanecarboxylic acid (18 mg, 0.12 mmol) in DCM ) at 0°C followed by the addition of DMAP (2 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the remaining residue was purified by silica gel chromatography (DCM/MeOH = 80:1) to give 158-S2 (60 mg, 89.8% yield) as white solid. LC/MS (ESI) m/z: 557 (M+H)+.

Step 2. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((2,2difluorocyclopentanecarboxamido)methyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide (158-S3): HCl/dioxane (2 M, 0.4 ml) was added to a solution of 158-S2 (60 mg, 0.11 mmol) in dioxane (1.5 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 158-S3 (60 mg, 100% yield) as a white solid which was taken to the next step of the synthesis without purification. LC/MS (ESI) m/z: 457 (M+H)+.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-((2,2-difluorocyclopentanecarboxamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (158): to a solution of 158-S3 (30 mg, 0.08 mmol) and 2-(3-acetyl-7methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (27 mg, 0.08 mmol) in DCM (3 ml) DCC (25 mg, 0.12 mmol) was added at 0°C followed by DMAP (2 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness and the remaining residue was purified by preparative HPLC to give 158 (10.1 mg, 16.6% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.40 (s, 1H), 7.61-7.48 (m, 2H), 7.39 (d, J=8.1 Hz, 1H), 5.96 (m, 1H) , 5.80 (m, 1H), 4.65 (m, 1H), 3.58 (m, 3H), 3.13-3.00 (m, 1H), 2.76 (s, 6H), 2.69 (s, 3H), 2.62-2.41 (m , 2H), 2.21-2.06 (m, 6H), 1.99-1.86 (m, 2H), 1.73 (m, 1H), 1.34 (m, 1H), 1.10 (m, 1H). LC/MS (ESI) m/z: 763 (M+H)+.

Scheme 63. Synthesis of (1R,3S,5S)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-X-( 6-bromo-3-methylpyridin-2-yl)-5-(fluoromethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (163)

163-S1

A solution of 163-S1 (40 mg, 0.056 mmol) in TBAF/THF (3 ml, 1 M) was stirred at 60°C for 1 h. The mixture was separated with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give 163 (5 mg, 13.8% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.98 (s, 2H), 8.40 (s, 1H), 7.52-7.55 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 5.945.99 (m, 1H), 5.78-5.83 (m, 1H), 4.64-4.68 (m, 1H), 4.59 (s, 1H), 4.47 (s, 1H), 3.81-3.83 (m, 1H), 2.74 (s, 6H) , 2.69 (s, 4H), 2.56-2.59 (m, 1H), 2.12 (s, 3H), 1.38-1.42 (m, 1H), 1.18-1.20 (m, 1H). LC/MS (ESI) m/z: 634 (M+H)+.

Scheme 64. Synthesis of (1R,3S,5R)-5-(acetamidomethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N -(6-bromo-3-(methoxymethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (165)

But

Step 1. (1R,3S,5R)-tert-Butyl 5-(acetamidomethyl)-3-((6-bromo-3-(methoxymethyl)pyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (165-S2): DIPEA (0.03 ml, 0.176 mmol) was added to a mixture of 165-S1 (40 mg, 0.088 mmol) in dry DCM (3 mL), followed by the addition of a solution of acetyl chloride (8.3 mg, 0.106 mmol) in DCM (0.5 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (20 ml) and extracted with DCM (4 ml x 2). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by silica gel column chromatography (eluting with DCM/MeOH = 240:1) to give 165-S2 (40 mg, 91.7% yield) as a white solid. LC/MS (ESI) m/z: 497 (M+H)+.

Step 2. (1R,3S,5R)-5-(Acetamidomethyl)-N-(6-bromo-3-(methoxymethyl)pyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (165- S3): TFA (1 ml) was added to a solution of 165-S2 (40 mg, 0.08 mmol) in DCM (2 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 165-S3 (35.6 mg, 100% yield) as a yellow solid which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 397 (M+H) ⁺ .

Step 3. (1R,3S,5R)-5-(Acetamidomethyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl)acetyl)-N- (6-bromo-3-(methoxymethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (165): to a mixture of 165-S3 (35.6 mg, 0.09 mmol), 2-( 3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (26.9 mg, 0.09 mmol) and HATU (49.6 mg, 0.13 mmol) in DMF (2 ml) DIPEA was added (0.04 ml, 0.26 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 165 (15.5 mg, 25.0% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 9.04 (s, 2H), 8.44 (s, 1H), 8.03 (t, J=5.9 Hz, 1H), 7.87 (d, J=1.6Hz, 2H), 7.77(d, J=8.1Hz, 1H), 7.55(d, J=8.0Hz, 1H), 5.88(d, J=17.3Hz, 1H), 5.61(d, J= 17.2 Hz, 1H), 4.44-4.41 (m, 1H), 4.21-4.12 (m, 2H), 3.71-3.69 (m, 1H), 3.34-3.32 (m, 1H), 3.25-3.23 (m, 1H) , 3.10 (s, 3H), 2.69 (s, 3H), 2.65 (s, 3H), 2.47-2.43 (m, 1H), 2.24-2.21 (m, 1H), 1.86 (s, 3H), 1.16-1.14 (m, 1H), 1.09–1.07 (m, 1H). LC/MS (ESI) m/z: 689 (M+H) ⁺ .

Scheme 65. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-(methoxymethyl)pyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide(166)

Step 1. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-(methoxymethyl)pyridin-2-yl)carbamoyl)-5((dimethylamino)methyl)-2-azabicyclo[3.1. 0]hexane-2-carboxylate (166-S2): an aqueous solution of HCHO (13.3 mg, 0.443 mmol) and NaBH ₃ CN (18.5 mg, 0.294 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with water (20 ml) and extracted with DCM (5 ml x 2). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 20:1) to give 166-S2 (60 mg, 84.6% yield) as a white solid. LC/MS (ESI) m/z: 483 (M+H) ⁺ .

Step 2. (1R,3S,5R)-N-(6-Bromo-3-(methoxymethyl)pyridin-2-yl)-5-((dimethylamino)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (166-S3): TFA (1 ml) was added to a solution of 166-S2 (38.5 mg, 0.08 mmol) in DCM (2 ml). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give 166-S3 (38 mg, 100% yield) as a yellow solid, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 383 (M+H) ⁺ .

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -(methoxymethyl)pyridin-2-yl)-5-((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (166): to a mixture of 166-S3 (30.5 mg, 0.08 mmol), 2- (3-acetyl-5-(2-methylpyrimidin-5-yl)-1H- 338 041794 indazol-1-yl)acetic acid (25.3 mg, 0.08 mmol) and HATU (44.3 mg, 0.12 mmol) in DMF (2 ml ) DIPEA (0.04 ml, 0.24 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 166 (6.5 mg, 12.1% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.53 (s, 1H), 7.78 (s, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.0 Hz , 1H), 5.82 (d, J=17.2 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 4.67 (d, J=4.0 Hz, 1H), 4.30-4.22 (m, 2H), 3.87 (d, J=2.9Hz, 1H), 3.46 (d, J=13.2Hz, 1H), 3.14 (s, 3H), 3.03 (d, J=13.3Hz, 1H), 2.83 (s, 6H), 2.76 (s, 3H), 2.70 (s, 3H), 2.67 (s, 1H), 2.59-2.55 (m, 1H), 1.46-1.43 (m, 1H), 1.37-1.35 (m, 1H). LC/MS (ESI) m/z: 675 (M+H)+.

Scheme 66. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)1H-indazol-1-yl) acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide(167)

Step 1. tert-Butyl 2-(3-acetyl-7-(hydroxymethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (167-S2): to a solution of 167-S1 ( 1.19 g, 3.1 mmol) in dioxane/H ₂ O (20 ml) were added Pd(PPh ₃ ) ₄ (358 mg, 0.31 mmol), K ₂ CO ₃ (1.28 g, 9.3 mmol) and 2-methylpyrimidin-5-ylboronic acid (470 mg, 3.4 mmol). The reaction mixture was purged with nitrogen and stirred at 90° C. for 16 h under nitrogen. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by silica gel chromatography (DCM/EtOAc = 5:1) to give 167-S2 (400 mg, 32.5% yield) as a white solid. LC/MS (ESI) m/z: 397 (M+H) ⁺ .

Stage 2. tert-Butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-7-((methylsulfonyloxy)methyl)-1Hindazol-1-yl)acetate (167-S3): to solution 167 -S2 (200 mg, 0.51 mmol) in dry DCM (8 ml) was added Et ₃ N (128 mg, 1.26 mmol) followed by dropwise addition of MsCl (88 mg, 0.77 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. The mixture was diluted with DCM, washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 167-S3 (220 mg, 90.8% yield) as a white solid, which was used in the next step of the synthesis without additional cleaning. LC/MS (ESI) m/z: 475 (M+H) ⁺ .

Stage 3. tert-Butyl 2-(3-acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetate (167-S4): to solution 167 -S3 (110 mg, 0.3 mmol) in dry DCM (8 ml) Et3N (90 mg, 0.9 mmol) and dimethylamine hydrochloride (60 mg, 0.54 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. The mixture was separated by DCM and NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 5:1) to give 167-S4 (62 mg, 48.7% yield) as a white solid. LC/MS (ESI) m/z: 424 (M+H) ⁺ .

- 339 041794

Step 4. 2-(3-Acetyl-7-(methoxycarbonyl)-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetic acid (167-S5): to 167-S4 solution (62 mg, 0.15 mmol) in MeOH/THF/H ₂ O (2:1:1, 4 ml) was added NaOH (18 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and washed with diethyl ether twice. The aqueous layer was adjusted to pH 5 with 10% aqueous HCl and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 167-S5 (50 mg, 90.6% yield) as a white solid, which was taken to the next synthesis step without further purification. LC/MS (ESI) m/z: 368 (M+H)+.

Step 5. (1 R,3S,5R)-2-(2-(3-Acetyl-7-((dimethylamino)methyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl )-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (167): to a solution of 167-S5 (30 mg, 0.08 mmol) and (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (28 mg, 0.08 mmol) in DMF (3 ml) DIPEA (42 mg, 0.32 mmol) and HATU (61 mg, 0.16 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, washed successively with 10% aqueous LiCl and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by preparative HPLC (eluting with MeCN/water) to give 167 (10 mg, 18.9% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.05 (s, 2H), 8.46 (d, J=1.6 Hz, 1H), 7.72 (s, 1H), 7.62(d, J =8.0 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 6.49 (d, J=17.3 Hz, 1H), 5.82 (d, J=17.1 Hz, 1H), 4.43 (dd, J=9.0 , 5.5 Hz, 1H), 3.79 (d, J=12.8 Hz, 1H), 3.46-3.54 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 2.54-2.58 (m, 1H) , 2.23 (s, 6H), 2.04 (s, 3H), 1.97–2.02 (m, 1H), 1.32 (s, 3H), 0.96–1.04 (m, 2H). LC/MS (ESI) m/z: 661 (M+H) ⁺ .

Scheme 67. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-( 6-bromo-3-methylpyridin-2-yl)-5-((2,2,2-trifluoroacetamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (168)

168-S2

Step 1. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-((2,2,2trifluoroacetamido)methyl)-2-azabicyclo[ 3.1.0]hexane-2-carboxylate (168-S2): to a mixture of 168-S1 (40 mg, 0.094 mmol), Et ₃ N (23 mg, 0.24 mmol) and DMAP (1 mg, catalytic amount) in dry DCM (2 ml) was added 2,2,2-trifluoroacetic anhydride (40 mg, 0.19 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 hours. The mixture was diluted with DCM, washed with brine, dried and concentrated to give the crude product, which was purified by silica gel chromatography (PE/EtOAc=10:1 to 5:1 to 4:1 ) to give 168-S2 (35 mg, 71.5% yield) as a light oil. LC/MS (ESI) m/z: 521 (M+H) ⁺ .

Stage 2. 3-(6-Bromo-3-methylpyridin-2-ylcarbamoyl)-5-[(2,2,2-trifluoroacetylamino)-methyl]-2azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ether (168-S3): to a solution of 168-S2 (35 mg, 0.067 mmol) in DCM (2 ml) was added TFA (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give 168-S3 (28 mg, 99.5% yield) as a clear oil, which was taken to the next synthesis step without further purification. LC/MS (ESI) m/z: 421 (M+H)+.

Step 3 2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-indazol-1-yl]acetyl}-5-[(2,2,2trifluoroacetylamino)methyl] -2-azabicyclo[3.1.0]hexane-3-carboxylic acid (6-bromo-3-methylpyridin2-yl)amide (168): to a mixture of 168-S3 (28 mg, 0.067 mmol), 168-S4 (22 mg , 0.067 mmol) and HATU (38 mg, 0.10 mmol) in DMF (3 mL) were added DIPEA (26 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by preparative HPLC to give 168 (5.5 mg, 11.3% yield) in form of a white solid.

- 340 041794

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.68 (s, 1H), 9.03 (s, 2H), 8.32 (s, 1H), 7.63 (d, J=8.0 Hz,

2H), 7.44 (d, J=8.0 Hz, 1H), 6.00 (d, J=20.0 Hz, 1H), 5.71 (d, J=20.0 Hz, 1H), 4.47 (m, 1H), 3.79 (m, 1H), 3.51 (m, 1H), 2.68 (s, 6H), 2.64 (d, J=8.0 Hz, 3H), 2.54 (d, J=8.0 Hz, 1H), 2.24 (m, 1H), 2.07 ( d, J=12.0 Hz, 3H),

1.27-1.04 (m, 3H). LC/MS (ESI) m/z: 727 (M+H)+.

Scheme 68. Synthesis of 2-{2-[3-acetyl-7-methoxymethyl-5-(2-methylpyrimidin-5-yl)indazol-1yl]acetyl}5-methyl-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid (6-bromo-3-methoxymethyl-pyridin2-yl)-amide (169)

169-S1 Step>1 toluene>DCM

Stage c

HATU, DIPEA

Stage ί I

Vos

ROS1 ₃ , Ru

Stage 1. 2-Bromo-5-bromomethylpyridine (169-S2): NBS (5.22 g, 29.1 mmol) and BPO (350 mg, 1.4 mmol). The reaction mixture was stirred at 80° C. under nitrogen for 2 hours. The mixture was diluted with DCM, washed with water and brine, dried and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc = 120:1) to give 169-S2 (3.81 g, 52.6% yield) as a yellow oil. LC/MS (ESI) m/z: 250 (M+H)+.

Stage 2. 2-Bromo-5-methoxymethylpyridine (169-S3): to a solution of 169-S2 (3.81 g, 15.3 mmol) in MeOH (38 ml) was added MeONa (4.1 ml, 30% wt. in MeOH) at 0° C. The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting material was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=100:1) to give 169-S3 (2.7 g, 87.8% yield) as a yellow oil. LC/MS (ESI) m/z: 202 (M+H)+.

Step 3. 2-Bromo-5-methoxymethylpyridine-1-oxide (169-S4): m-CPBA (3.47 g, 20.1 mmol) was added to a solution of 169-S3 (2.7 g, 13.4 mmol) in DCM (23 ml). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with DCM, washed with 1N. aqueous NaOH solution and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH = 40:1) to give 169-S4 (2.5 g, 86.2% yield) as a yellow oil. LC/MS (ESI) m/z: 218 (M+H)+.

Step 4. (6-Bromo-3-methoxymethylpyridin-2-yl)-tert-butylamine (169-S5): to a solution of 169-S4 (1.0 g, 4.6 mmol) in DCM/toluene (20 mL, v/v . = 5/2) was added tert-butylamine (2.42 g, 33.2 mmol) followed by dropwise addition of a solution of p-toluenesulfonic anhydride (4.96 g, 15.2 mmol) in DCM/toluene (240 ml, v/v = 5/ 2) for 4 hours at -15°C. The reaction mixture was stirred at room temperature overnight, washed with aqueous NaHCO ₃ and brine, dried and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=400:1) to give 169-S5 (425 mg, 34.0% yield) as a yellow oil.

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LC/MS (ESI) m/z: 273 (M+H)+.

Step 5. 6-Bromo-3-methoxymethylpyridin-2-ylamine (169-S6): TFA (3 ml) was added to a solution of 169-S5 (214 mg, 0.78 mmol) in chloroform (3 ml). The mixture was stirred at 90°C for 20 min in a microwave reactor. The mixture was concentrated to dryness and diluted with DCM. The mixture was washed with aqueous NaHCO ₃ and brine, dried and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=6:1) to give 169-S6 (65 mg, 38.4% yield) as a white solid. LC/MS (ESI) m/z: 217 (M+H) ⁺ .

Step 6. 3-(6-Bromo-3-methoxymethylpyridin-2-ylcarbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexane-2carboxylic acid tert-butyl ester (169-S8): to mixture 169-S6 (40 mg, 0.18 mmol) and 169-S7 (45 mg, 0.186 mmol) in DCM (3 mL) were added pyridine (0.08 mL, 0.93 mmol) and POCl ₃ (0.02 mL, 0.186 mmol) under nitrogen at 0°C . The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with DCM, washed with aqueous NaHCO3 and brine, dried and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with PE/EtOAc=3:1) to give 169-S8 (38 mg, 46.9% yield) as a white solid. LC/MS (ESI) m/z: 440 (M+H) ⁺ .

Stage 7. 5-Methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (6-bromo-3methoxymethylpyridin-2-yl)amide (169-S9): to a solution of 169-S8 (38 mg, 0.086 mmol ) in DCM (2 ml) was added TFA (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 169-S9 (29 mg, 99.5% yield) as a clear oil, which was taken to the next synthetic step without further purification. LC/MS (ESI) m/z: 340 (M+H) ⁺ .

Step 8. 2-{2-[3-Acetyl-7-methoxymethyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5methyl-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid (6-bromo-3-methoxymethylpyridin-2-yl)amide (169): to a mixture of 169-S9 (29 mg, 0.086 mmol), 169-S10 (40 mg, 0.11 mmol) and HATU (49 mg, 0.13 mmol) in DMF (3 ml) was added DIPEA (33 mg, 0.26 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product which was purified by prep HPLC to give 169 (5.3 mg, 9.1% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.05 (s, 2H), 8.49 (d, J=2.0 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.54 (d, J=12.0 Hz, 1H), 6.00 (d, J=16.0 Hz, 1H), 5.73 (d, J=20.0 Hz, 1H), 4.84 ( d, J=12.0 Hz, 1H), 4.66 (d, J=12.0 Hz, 1H), 4.39 (m, 1H), 4.15 (d, J=4.0 Hz, 2H), 3.56 (m, 1H), 3.34- 3.33 (m, 3H), 3.08 (s, 3H), 2.69 (s, 3H), 2.66 (s, 3H), 2.58-2.53 (m, 1H), 2.04 (m, 1H), 1.34 (s, 3H) , 1.04-0.99 (m, 2H). LC/MS (ESI) m/z: 676 (M+H) ⁺ .

Scheme 69: (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -vinylpyridin-2-yl)-5-((but-3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (171)

Stage I

171-S1 171-S3

Stage 1. tert-Butyl (1R,3S,5R)-5-(azidomethyl)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-2- 342 041794 azabicyclo[3.1.0]hexane -2-carboxylate (171-S3): Pyridine (0.193 ml, 2.4 mmol) was added to a mixture of 171-S1 (135 mg, 0.479 mmol) and 171-S2 (95.3 mg, 0.479 mmol) in DCM (5 mL), followed by by adding POCl ₃ (0.045 mL, 0.48 mmol) at 0°C under argon. The reaction mixture was stirred at room temperature for 2 hours. An aqueous solution of NaHCO ₃ was added and the mixture was extracted with DCM. After washing with brine, the organic layer was dried over anhydrous Na ₂ SO ₄ . The solution was filtered and the solvent was removed under reduced pressure to give tert-butyl (1R,3S,5R)-5-(azidomethyl)3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[ 3.1.0]hexane-2-carboxylate 171-S3 (0.23 g) as a foam. This material was carried on without further purification.

Stage 2. tert-Butyl (1R,3S,5R)-5-(aminomethyl)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (171-S4): tert-butyl (1R,3S,5R)-5-(azidomethyl)-3-((6-bromo-3vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane- 2-carboxylate (171-S3, 0.23 g) was treated with trimethyl phosphate (1.0 M in THF, 0.958 ml, 0.958 mmol) in THF (10 ml) in the presence of water (0.017 ml, 0.958 mmol) at room temperature overnight. The mixture was extracted with EtOAc and the organic layer was washed with aqueous NaHCO ₃ and brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl (1R,3S,5R)-5-(aminomethyl)-3-((6-bromo-3vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate 171-S4 (0.221 g) as a pale yellow syrup. The material was carried to the next step without further purification.

Step 3. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((but-3-en-1ylsulfonamido)methyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate (171-S5): tert-butyl (1R,3S,5R)-5(aminomethyl)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl )-2-azabicyclo[3.1.0]hexane-2-carboxylate (171-S4, 0.221 g) was treated with but-3-ene-1-sulfonyl chloride (46.5 mg, 0.30 mmol) in DCM (5 ml) in the presence of DIEA (0.066 ml, 0.378 mmol). The reaction was stirred at room temperature for 30 min, then aqueous NaHCO3 was added and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give tert-butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((but-3-en-1- ylsulfonamido)methyl)-2azabicyclo[3.1.0]hexane-2-carboxylate 171-S5 (0.158 g) as a pale yellow syrup. The material was carried to the next step without further purification.

Step 4. (1R,3S,5R)-N-(6-Bromo-3-vinylpyridin-2-yl)-5-((but-3-en-1-ylsulfonamido)methyl)-2azabicyclo[3.1.0] hexane-3-carboxamide, TFA salt (171-S6): tert-butyl (1R,3S,5R)-3-((6-6pom-3vinylpyridin-2-yl)carbamoyl)-5-((but-3- en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-2carboxylate (171-S5, 19.8 mg) in DCM (1 ml) was treated with TFA (1 ml). The reaction was stirred at room temperature for 1 h, then the volatiles were removed under reduced pressure, and the residue was coevaporated twice with toluene (5 ml) to give (1R,3S,5R)-N-(6-bromo-3-vinylpyridine-2 -yl)5-((but-3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt 171-S6. The material was carried to the next step without further purification.

Step 5. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -vinylpyridin-2-yl)-5-((but-3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (171): to a mixture of (1R,3S,5R)- N-(6-bromo-3-vinylpyridin-2-yl)-5-((but-3-en-1ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salts (171- S6, 0.0356 mmol) and 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (171-S7, 11 mg) in DMF (1.0 ml) were added TBTU (23 mg) followed by the addition of DIEA (0.031 ml) with stirring. After completion of the reaction, an aqueous solution of NaHCO ₃ (10 ml) was added to form a precipitate, which was collected by filtration and purified by silica gel column chromatography with MeOH in DCM (010%) as eluent to give (1R,3S,5R)-2- (2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-N-(6-bromo-3-vinylpyridin-2-yl)-5-((but -3-en-1-ylsulfonamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (171) (17 mg) as a pale yellow solid.

1H NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.83 (s, 1H), 8.58 (t, J=1.2 Hz, 1H), 7.69-7.58 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 6.44 (dd, J=11.0, 17.4 Hz, 1H), 5.81 (ddt, J=6.5, 10.2, 16.8 Hz, 1H), 5.74 (s, 1H), 5.64 (d, J =17.4 Hz, 1H), 5.51 (d, J=3.1 Hz, 2H), 5.28 (d, J=11.1 Hz, 1H), 5.18-5.06 (m, 2H), 4.94 (d, J=8.3 Hz, 1H ), 3.58 (dd, J=4.6, 13.7 Hz, 1H), 3.52 (dd, J=2.8, 5.7 Hz, 1H), 3.16-3.08 (m, 3H), 2.80 (s, 4H), 2.72 (s, 3H), 2.56 (q, J=7.0 Hz, 2H), 2.27 (dd, J=8.4, 13.9 Hz, 1H), 1.44 (t, J=5.8 Hz, 1H), 1.12 (dd, J=2.8, 5.9 Hz, 1H). LC (method A): t _R = 1.85 min. LC/MS (Ei) m/z: [M+H]+ 747.

Scheme 70. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-yl)-5-methyl-2-azabityclo[3.1.0]hexane-3carboxamide (177)

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Step 1. 6-Bromo-3-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-amine (177-S2): to a stirred solution of 6-bromo-3-(chloromethyl)pyridine-2- amine (204 mg, 1 equiv.) and triethylamine (0.4 mg, 3 equiv.) in acetonitrile (20 ml) was added 3,3-difluoroazetidine hydrochloride (230 mg, 2 equiv.) at 0-5°C in an argon atmosphere. The reaction mixture was stirred at room temperature until completion of the reaction. The reaction was diluted with DCM (25 ml) and basified with aqueous saturated NaHCO ₃ solution (20 ml). The aqueous layer was extracted with DCM (2x10 ml) and the combined organic layers were washed with brine (25 ml), dried over Na ₂ SO ₄ and concentrated to dryness to give 177-S2 (96 mg, 40%).

Stage 2. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2yl)carbamoyl)-5-methyl-2 -azabicyclo[3.1.0]hexane-2-carboxylate (177-S3): POCl ₃ (0.04 ml, 2 equiv.) was added dropwise at 0-5°C under argon to a stirred solution of (1R,3S,5R) -2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (83 mg, 1 eq.) and 177-S2 (96 mg, 1 eq.) in DCM (10 ml ) and pyridine (0.1 ml, 5 equiv.). The reaction mixture was stirred at room temperature until completion of the reaction. The reaction was diluted with DCM (15 ml) and basified with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (1 x 15 ml) and the combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 177-S3 (147 mg, 85%).

Step 3. (1R,3S,5R)-N-(6-bromo-3-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-yl)-5-methyl-2azabicyclo[3.1.0 ]hexane-3-carboxamide (TFA salt) (177-S4): TFA (5 ml) was added to a solution of 177-S3 (147 mg) in DCM (5 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give 177-S4.

Step 4. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -3-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (177): to a solution of 177-S4 (135 mg, 1 eq.), 2-(3-acetyl-5-(2-methylpyrimudin-5-yl)-1Hindazol-1-yl)acetic acid (100 mg, 1.05 eq.) and DIPEA (0.26, 5 eq. ) in DMF (10 mL) was added HATU (146 mg, 1.2 equiv.) at 0°C under argon. The reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with EtOAc (40 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (25 ml) and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 177 (25 mg, 12%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.96 (s, 2H), 8.37 (s, 1H), 7.80 (m, 2H), 7.67 (d, 1H, J=8.2 Hz ), 7.42 (d, 1H, J=8.2 Hz), 5.87 (d, 1H, J=17.5 Hz), 5.52 (d, 1H, J=17.5 Hz), 4.29-4.36 (m, 1H), 3.22-3.56 (m, 1H), 3.37-3.45 (m, 2H), 3.25-3.33 (m, 3H), 2.62 (s, 3H), 2.58 (s, 3H), 2.26 (s, 1H), 1.99-2.04 (m , 1H), 1.27 (s, 3H), 0.91–0.99 (m, 3H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -97.89 (2F).

Scheme 71. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabiclo[3.1.0]hexane-3-carboxamide (178)

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Step 1. 2-Bromo-3-fluoro-5-methyl-(1-oxidanyl)pyridine (178-S2): to a stirred solution of 2bromo-3-fluoro-5-methylpyridine (178-S1, 10 g, 1 eq. ) in CHCl ₃ (200 ml) was added 3-chlorobenzoic acid (24 g, 2 eq.). The reaction mixture was heated to 50°C. The reaction mixture was cooled and neutralized with saturated aqueous NaHCO ₃ ((100 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified using silica gel column chromatography (5% CH3OH in DCM, gradient) to obtain 178-S2 (9.4 g, 87%).

Stage 2. 6-Bromo-N-(tert-butyl)-5-fluoro-3-methylpyridin-2-amine (178-S3): to a stirred solution of 178-S2 (3.2 g, 1 eq.) and 2-methylpropane -2-amine (8.1 ml, 5 equiv.) in DCM (100 ml) at 0-5 °C, a solution of trifluoroacetic anhydride (TFAA, 2.7 ml, 1.1 equiv.) in DCM (20 ml) was slowly added dropwise using a drip funnel, for 40 min in an argon atmosphere at 0-5°C. The reaction mixture was stirred at 0-5° C. for 1 h and monitored by LC/MS. (If the reaction was not complete after 1 h, a solution of TFAA (2.5 ml, 1 eq.) in DCM (20 ml) was added over 15 to 20 min and 2-methylpropan-2-amine (1.6 ml, 1 eq., added once. The reaction was diluted with DCM (60 ml) and neutralized with aqueous saturated NaHCO ₃ solution (80 ml). The organic layer was washed with brine (80 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with hexanes/EtOAc=3:1) to give 178S3.

Step 3 6-Bromo-5-fluoro-3-methylpyridin-2-amine (178-S4): TFA (20 ml) was added to solid 178S3 and the reaction mixture was heated at 70°C until the reaction was complete. The reaction was concentrated to dryness and the residue was dissolved in DCM (35 ml), washed with aqueous saturated NaHCO ₃ (15 ml x 2) and brine, dried over Na ₂ SO ₄ and concentrated to give 178-S4 (838 mg, 26%).

Step 4. (1R,3S,5R)-N-(6-Bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane3-carboxamide hydrochloride (178- S5): POCl ₃ (0.1 ml, 2 equiv.) was added dropwise to a solution of (1R,3S,5R)2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acids (121 mg, 1 equiv.) and 178-S4 (101 mg, 1 equiv.) in DCM (8 ml) and pyridine (0.2 ml, 5 equiv.) and cooled at 0-5°C in an argon atmosphere. The reaction mixture was stirred at room temperature until completion of the reaction. The reaction was diluted with DCM (10 ml) and neutralized with aqueous saturated NaHCO ₃ solution (10 ml). The aqueous layer was extracted with DCM (1 x ml) and the combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 178-S5 (131 mg, 62%).

Step 5. (1R,3S,5R)-N-(6-Bromo-5-fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane3-carboxamide hydrochloride (178- S6): to a solution of 178-S5 (131 mg) was added 4N. HCl in dioxane (8 ml). The resulting solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness to give 178-S6.

Step 6. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-5 -fluoro-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (178): to a solution of 178-S6 (137 mg, 1 equiv.), 2-( 3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (115 mg, 1.2 eq.) and DIPEA (0.3 ml, 5 eq.) in DMF (10 ml) HATU (141 mg, 1.2 equiv.) was added at 0°C under argon. The reaction mixture was stirred at room temperature for 3 h, then diluted with EtOAc (30 ml) and water (15 ml). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM/MeOH=10:1) to give 178 (79 mg, 41%).

¹ H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.06 (s, 2H), 8.46 (s, 1H), 7.87 (s, 1H), 7.81-7.87 (m, 2H), 5.92 (d, 1H, J=17.4 Hz), 5.59 (d, 1H, J=17.4 Hz), 4.37-4.42 (m, 1H), 3.58 (d, 1H, J=5.4 Hz), 2.70 (s, 3H) , 2.67 (s, 3H), 2.54-2.59 (m, 1H), 2.08 (s, 3H), 2.02-2.07 (m, 1H), 1.33 (s, 3H), 0.99-1.06 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -118.95 (s, 1F).

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Scheme 72. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1Hindazol-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide(180)

Stage 1. tert-butyl 2-(3-acetyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indazol-1yl)acetate (180-S3): to a solution of 6- bromo-2-methylpyrazolo[1,5-a]pyrimidine (180-S2, 1 eq.) in DMF/H2O (9:1, 10 vol.) compound 180-S1 (1 eq.), K2CO3 (2 eq. .) and tetrakis(triphenylphosphine)palladium (0.1 eq.). The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 180-S3.

Stage 2. 2-(3-Acetyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indazol-1-yl)acetic acid (180-S4): to a solution of compound 180 -S3 (1 equiv.) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was immediately used in the next stage of the synthesis.

Step 3. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1 H-indazol-1 yl) acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (180): to a solution of compound 180-S4 (1 equiv. ) (1R,3S,5R)-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0 ]hexane-3-carboxamide (1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 180.

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.98-1.09 (m, 2H), 1.33 (s, 3H), 2.06 (s, 4H), 2.47 (s, 3H), 2.52-2.59 (m, 1H) , 2.67 (s, 3H), 3.56-3.63 (m, 1H), 4.42 (dd, J=5.1, 9.3 Hz, 1H), 5.58 (d, J=17.2 Hz, 1H), 5.92 (d, J=17.3 Hz, 1H), 6.58 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.90 ( d, J=8.8 Hz, 1H), 8.48 (s, 1H), 8.86 (d, J=2.2 Hz, 1H), 9.35 (d, J=2.2 Hz, 1H), 10.26 (s, 1H).

Scheme 73. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-(difluoromethyl)-4-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (187)

- 346 041794

Step 1. 2-Bromo-5-(difluoromethyl)-4-methyl-1-oxidanyl)pyridine (187-S2): to a stirred solution of 2-bromo-5-(difluoromethyl)-4-methylpyridine (187-S1, 1 g, 1 equiv.) in CHCl3 (150 ml) was added 3-chlorobenzooperoxoic acid (2.1 g, 2 equiv.). The reaction mixture was heated to 50°C to complete the reaction. The reaction mixture was cooled and neutralized with saturated aqueous NaHCO ₃ (60 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% CH3OH in DCM, gradient) to give 187-S2 (851 mg, 80%).

Step 2. 6-Bromo-N-(tert-butyl)-3-(difluoromethyl)-4-methylpyridin-2-amine (187-S3): to a stirred solution of 187-S2 (222 mg, 1 eq.) and 2 -methylpropan-2-amine (0.49 ml, 5 equiv.) in DCM (100 ml) was added a solution of trifluoroacetic anhydride (0.3 ml, 2 equiv.) in DCM (5 ml) at 0-5°C dropwise in an argon atmosphere. The reaction mixture was stirred at 0-5°C for 2 h, then the reaction was neutralized with aqueous saturated NaHCO3 solution (15 ml). The organic layer was washed with brine (15 ml), dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography (eluting with 30% EtOAc in hexanes) to give 187-S3 (130 mg, 48%).

Step 3 6-Bromo-3-(difluoromethyl)-4-methylpyridin-2-amine (187-S4): TFA (8 ml) was added to solid 187-S3 (130 mg) and the reaction mixture was heated at 70°C until the completion of the reaction. The reaction mixture was concentrated to dryness and the residue was dissolved in DCM (15 ml) and neutralized with aqueous saturated NaHCO3 (15 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give 187-S4 (92 mg, 87%).

Step 4. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-(difluoromethyl)-4-methylpyridin-2-yl)carbamoyl)-5methyl-2-azabicyclo[3.1.0]hexane -2-carboxylate (187-S5): POCl ₃ was added dropwise (0.05 ml, 2 equiv.) at 0-5°C in an argon atmosphere to a stirred solution of (1R,3S,5R)-2-(tert-butoxycarbonyl) -5-methyl2-azabicyclo[3.1.0]hexane-3-carboxylic acid (94 mg, 1 equiv.) and 187-S4 (92 mg, 1 equiv.) in DCM (10 ml) and pyridine (0.1 ml, 5 equiv.). The reaction mixture was stirred at room temperature until completion of the reaction. The reaction was diluted with DCM (20 ml) and neutralized with aqueous saturated NaHCO ₃ solution (15 ml). The aqueous layer was extracted with DCM (1 x 10 ml) and the combined organic layers were washed with brine (10 ml), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with 5% MeOH in DCM, gradient) to give 187-S5 (109 mg, 61%).

Step 5. (1R,3S,5R)-N-(6-Bromo-3-(difluoromethyl)-4-methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (TFA salt) (187-S6): TFA (5 ml) was added to a solution of S5 (109 mg) in DCM (5 ml). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to give 187-S6 (65 mg).

Step 6. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -(difluoromethyl)-4-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (187): to a solution of 187-S6 (65 mg, 1 eq), 2- (3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (44 mg, 1.05 eq.) and DIPEA (0.12 ml, 5 eq.) in DMF (8 ml ) was added HATU (64 mg, 1.2 equiv.) at 0°C in an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (40 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (20 ml) and the combined organic layers were washed with brine (3 x 20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica

- 347 041794 l (eluting with DCM/MeOH=10:1) to give 187 (67 mg, 27%).

¹ H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.04 (s, 2H), 8.46 (s, 1H), 7.87 (S, br, 2H), 7.64 (s, 1H), 6.66 (m, 1H), 5.93 (d, 1H, J=18.2 Hz), 5.61 (d, 1H, J=18.2 Hz), 4.28-4.34 (m, 1H), 3.62-3.66 (m, 1H), 2.69 ( s, 3H), 2.66 (s, 3H), 2.46 (s, 3H), 2.53-2.58 (m, 1H), 1.99-2.06 (M, 1H), 1.33 (s, 3H), 0.93-1.05 (m, 2H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -112.35 (1F), -113.24 (1F).

Scheme 74. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-vinylpyridin-2-yl)-5-((N-methylbut-3-en-1-ylsulfonamido)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (188)

Step 1. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5((methylamino)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (188-S2): tert-butyl (1R,3S,5R)-5(aminomethyl)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1 .0]hexane-2-carboxylate (188-S1, 0.104 g, 0.238 mmol) was treated with methyl triflate (0.032 ml, 0.286 mmol) in 1,1,1,3,3,3hexafluoro-2-propanol at room temperature. The reaction was stirred at room temperature for 3 h, then EtOAc was added to dilute the reaction. The mixture was washed with NaHCO ₃ and brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed to give tert-butyl (1R,3S,5R)-3-((6bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((methylamino)methyl)-2-azabicyclo[3.1.0]hexane -2 carboxylate 188-S2. The material was carried to the next step without further purification.

Step 2. tert-Butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((N-methylbut-3-en1-ylsulfonamido)methyl)- 2-azabicyclo[3.1.0]hexane-2-carboxylate (188-S3): tert-butyl (1R,3S,5R)-5((methylamino)aminomethyl)-3-((6-bromo-3-vinylpyridine- 2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2carboxylate 188-S2 was treated with but-3-en-1-sulfonyl chloride (44 mg, 0.286 mmol) in DCM (5 ml) in the presence of DIEA (0.062 ml, 0.357 mmol). The reaction was stirred at room temperature for 30 minutes, then aqueous NaHCO ₃ was added. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure to give a mixture containing tert-butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-((N-methylbut-3- en-1ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate 188-S3. The material was carried to the next step without further purification.

Step 3. (1R,3S,5R)-N-(6-Bromo-3-vinylpyridin-2-yl)-5-((N-methylbut-3-en-1ylsulfonamido)methyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide, TFA salt (188-S4): tert-butyl (1R,3S,5R)-3-((6-bromo-3-vinylpyridin-2-yl)carbamoyl)-5-(( N-methylbut-3-en-1-ylsulfonamido)methyl)2-azabicyclo[3.1.0]hexane-2-carboxylate 188-S3 in DCM (3 ml) was treated with TFA (3 ml) at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was co-evaporated with toluene (5 ml) twice to give a mixture of (1R,3S,5R)-N-(6-bromo-3-vinylpyridin-2-yl)-5-((Nmethylbut- 3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt 188-S4. The material was carried to the next step without further purification.

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -vinylpyridin-2-yl)-5-((N-methylbut-3-en-1-ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane3-carboxamide (188): to mixture (1R,3S,5R )-N-(6-bromo-3-vinylpyridin-2-yl)-5-((N-methylbut-3-en-1ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt of 188-S4 and 2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (188-S5, 74 mg) in DMF (3.0 ml), TBTU was added ( 115 mg) followed by the addition of DIEA (0.414 ml) with stirring. After completion of the reaction, the mixture was purified by HPLC to give (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin5-yl)-1 H-indazol-1 -yl)acetyl)- N-(6-bromo-3-vinylpyridin-2-yl)-5-((N-methylbut-3-en-1 ylsulfonamido)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (188, 25.5 mg) as a white powder.

- 348 041794

Ή NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.74 (s, 1H), 8.58 (s, 1H), 7.71-7.55 (m, 3H), 7.30 (d,

J=8.1 Hz, 1H), 6.44 (dd, J=11.0, 17.4 Hz, 1H), 5.91-5.70 (m, 1H), 5.65 (d, J=17.4 Hz, 1H), 5.51 (s, 2H), 5.27(d,

J=11.0 Hz, 1H), 5.19-5.02 (m, 2H), 4.93 (d, J=8.4 Hz, 1H), 3.48 (dd, J=6.8, 13.0 Hz, 3H), 3.01 (d, J=18.8 Hz,

5H), 2.80 (s, 4H), 2.72 (s, 3H), 2.54 (q, J=7.3 Hz, 2H), 2.31 (t, J=11.4 Hz, 1H), 1.48 (t, J=5.9 Hz, 1H), 1.06 (dd,

J=2.7, 6.0 Hz, 1H). LC (method A): tR = 2.01 min. LC/MS (EI) m/z: [M+H]+ 761.

Scheme 75. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-αzabicyclo[3.1.0]hexan-3carboxamide (193)

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with a substituted pyrimidine at the R ³² position using a boronic acid ester in a Suzuki cross-coupling reaction. One skilled in the art will appreciate that the above boronic acid ester may be replaced with other boronic acid esters or boronic acids to provide additional compounds of the present invention. One of skill in the art will also appreciate that the A-ring shown may be substituted with other A-rings to provide additional compounds of the present invention. Non-limiting examples of boronic acid esters that can be used by one skilled in the art include 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrimidin-2-amine and 2-methyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine.

Stage 1. tert-Butyl 2-(3-αcetyl-5-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl)acetate (193-S3): to a solution of 2- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (193-S2, 1 eq.) in dioxane/H ₂ O (9:1, 10 vol .) compound 193-S1 (1 equiv.), Cs ₂ CO ₃ (2 equiv.) and tetrakis(triphenylphosphine)palladium (0.1 equiv.) were added. The reaction mixture was stirred at 90°C for 5 h and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 193-S3.

Step 2. 2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-p-pyrazolo[3,4-c]-pyridin-1-yl)acetic acid (193-S4): to a solution of compound 193 -S3 (1 equiv.) in DCM (10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance was carried on without additional purification and was immediately used in the next stage of the synthesis.

Step 3. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methoxypyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl) acetyl)-N-(6-bromo-3-methyl-pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (193): to a solution of compound 193-S4 (1 equiv. ) (1R,3S,5R)-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0 ]hexane-3-carboxamide (193-S5, 1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and then concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 193.

1H NMR (400 MHz, DMSO-d ₆ ) δ 1.02 (t, J=5.5 Hz, 1H), 1.10 (dd, J=2.4, 5.3 Hz, 1H), 1.34 (s, 3H), 2.012.10 (m , 4H), 2.56 (dd, J=9.3, 13.3 Hz, 1H), 2.69 (s, 3H), 3.58-3.65 (m, 1H), 4.01 (s, 3H), 4.35-4.52 (m, 1H), 5.72 (d, J=17.2Hz, 1H), 6.04 (d, J=17.3Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 8.55 ( d, J=1.3 Hz, 1H), 9.22-9.30 (m, 3H), 10.27 (s, 1H).

- 349 041794 (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-aminopyrimidin-5-yl)-III-pyrazolo[3,4-c]pyridin-1-yl)acetyl )-N(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (194):

1H NMR (400 MHz, DMSO-d6) δ 0.98-1.04 (m, 1H), 1.06-1.11 (m, 1H), 1.33 (s, 3H), 1.98-2.09 (m, 4H), 2.54-2.61 (m , 1H), 2.67 (s, 3H), 3.55-3.65 (m, 1H), 4.38-4.46 (m, 1H), 5.69 (d, J=17.2 Hz, 1H), 6.01 (d, J=17.3 Hz, 1H), 6.90 (s, 2H), 7.45 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 8.37 (s, 1H), 8.93 (s, 2H), 9.20 ( s, 1H), 10.27 (s, 1H).

1-(2-((1R,3S,5R)-3-((6-Bromo-5-fluoro-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2 -yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-Dpyridine-3carboxamide (199):

¹ H NMR (400 MHz, DMSO-d6) δ 0.89-0.98 (m, 2H), 1.26 (s, 3H), 1.93-2.02 (m, 4H), 2.47-2.51 (m, 1H), 2.62 (s, 3H), 3.47-3.54 (m, 1H), 4.27-4.40 (m, 1H), 5.57 (d, J=17.3 Hz, 1H), 5.87 (d, J=17.3 Hz, 1H), 7.55 (s, 1H ), 7.75 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 8.53 (s, 1H), 9.18 (s, 1H), 9.26 (s, 2H), 10.19 (s, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-N (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CDCl ₃ ): δ 0.91-0.93 (m, 1H), 1.20 (t, J=5.6 Hz, 1H), 1.43 (s, 3H), 2.11 (s, 3H), 2.39 (t, J=8.4Hz, 1H), 2.58(s, 3H), 2.66(d, J=11.6Hz, 1H), 2.81(s, 3H), 3.18(d, J=4Hz, 1H), 4.84(d, J=7.6Hz, 1H), 5.21(d, J=16.8Hz, 1H), 5.32(d, J=17.2Hz, 1H), 7.23(d, J=8Hz, 1H), 7.36(d, J= 7.6 Hz, 1H), 7.98 (s, 1H), 8.41 (brs, 1H), 8.71 (s, 1H), 8.81 (s, 1H), 9.29 (s, 2H).

((2S,4R)-N-(6-Bromopyridin-2-yl)-4-fluoro-1-(2-(5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)pyrrolidine -2-carboxamide:

1H NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.58 (s, 2H), 8.14 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.84 (s, 1H), 7.54-7.43 (m, 3H), 7.14 (d, J=8Hz, 1H), 5.29-5.16 (dd, J=16Hz, 2H), 4.81 (t, J=8Hz, 1H), 4.03-3.95 (q, J=12 Hz, 1H), 3.52-3.39 (m, 1H), 2.8 (s, 3H), 2.51-2.45 (m, 3H). LC/MS (ESI) m/z: 537 (M+H)+.

(1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(5-(2-methylpyrimidin-5-yl)-3-(2 ,2,2trifluoroacetyl)-1H-indol-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.02 (s, 2H), 8.66 (s, 1H), 8.45 (s, 1H), 7.73-7.79 (m, 2H), 7.61- 7.63 (d, J=8Hz, 1H), 7.43-7.45 (d, J=7.2Hz, 1H), 5.67-5.71 (d, J=16.8Hz, 1H), 5.44-5.48 (d, J=17.2Hz , 1H), 4.37-4.41 (m, 1H), 3.57-3.58 (m, 1H), 2.68 (s, 3H), 2.02 (s, 3H), 1.95-2.07 (m, 2H), 1.33 (s, 3H ), 0.98–1.05 (m, 2H). LC/MS (ESI) m/z: 657 (m+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetyl)-N-(6-bromo-5- fluoro-3methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.55 (s, 1H), 8.25 (s, 1H), 7.55-7.58 (m, 3H), 5.45-5.48 (d, J=17.2 Hz, 1H), 5.34-5.39 (d, J=17.2 Hz, 1H), 4.48-4.51 (m, 1H), 3.51-3.53 (m, 1H), 2.73 (s, 3H), 2.60-2.64 (m, 1H) , 2.54 (s, 3H), 2.28-2.29 (m, 1H), 2.14 (s, 3H), 1.40 (s, 3H), 1.08-1.11 (m, 1H), 0.97-.099 (m, 2H). LC/MS (ESI) m/z: 619/621 (M+H) ⁺ .

(1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(5-(2-methylpyrimidin-5-yl)-3-(2 ,2,2trifluoroacetyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)acetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.32 (s, 2H), 9.09 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.62 (s, 1H) , 7.63 (d, J=8.0Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 5.81 (d, J=17.2Hz, 1H), 5.57 (d, J=17.1Hz, 1H), 4.41 -4.42 (m, 1H), 3.55 (t, J=3.9 Hz, 1H), 2.69 (s, 3H), 2.52-2.54 (m, 1H), 2.03-2.04 (m, 1H), 2.02 (s, 3H ), 1.33 (s, 3H), 1.04 (m, 2H). LC/MS (ESI) m/z: 656 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-2-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indol-1-yl)acetyl)-N-(6 -bromo3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.03 (s, 2H), 8.28 (s, 1H), 7.67-7.41 (m, 4H), 5.54 (d, J=17.8 Hz , 1H), 5.23 (d, J=17.8 Hz, 1H), 4.39 (m, 1H), 3.66 (m, 1H), 2.67 (s, 3H), 2.65 (s, 3H), 2.64 (s, 3H) , 2.33 (m, 1H), 2.04–2.05 (m, 1H), 2.02 (s, 3H), 1.33 (s, 3H), 1.02 (m, 2H). LC/MS (ESI) m/z: 615/617 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)-N (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.27 (s, 1H), 9.07 (s, 2H), 8.73 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.56 (s, 1H), 7.62 (d, J=8.1Hz, 1H), 7.44 (d, J=7.9Hz, 1H), 5.56 (d, J=17.1Hz, 1H), 5.36 (d, J=16.9 Hz, 1H), 4.41 (m, 1H), 3.59-3.55 (m, 1H), 2.67 (s, 3H), 2.53-2.55 (m, 1H), 2.51 (s, 3H), 2.07 (s, 3H) , 2.02–2.05 (m, 1H), 1.32 (s, 3H), 1.06 (m, 1H), 0.95 (m, 1H). LC/MS (ESI) m/z: 602/604 (M+H) ⁺ .

(1R,3S,5R)-2-(2-(3-Acetyl-6-fluoro-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetyl)-N-(6- bromo-3methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.87 (s, 2H), 8.39 (s, 1H), 8.25-8.27 (d, J=7.8 Hz, 1H), 7.61 (dd, J=17.8, 9.7 Hz, 2H), 7.45 (d, J=7.9 Hz, 1H), 5.55 (d, J=17.2 Hz, 1H), 5.27 (d, J=17.2 Hz, 1H), 4.39 (m, 1H), 3.56-3.57 (m, 1H), 2.69 (s, 3H), 2.51 (s, 3H), 2.33-2.35 (m, 1H), 2.07-2.10 (m, 1H), 2.03 (s, 3H) , 1.33 (s, 3H), 1.05–0.95 (m, 2H). LC/MS (ESI) m/z: 619/621 (M+H) ⁺ .

(1R,3S,5R)-2-{2-[1-Acetyl-6-(2-methylpyrimidin-5-yl)indazol-3-yl]acetyl}-N-(6-bromo-3methylpyridin-2-yl )-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.99 (d, J=4.9 Hz, 2H), 8.61 (s, 1H), 7.97-7.92 (m, 1H), 7.69-7.64 (m, 1H),

- 350 041794

7.54 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 4.54-4.48 (m, 1H), 4.42-4.27 (m, 2H), 3.56-3.51 (m, 1H) , 2.75(s,

3H), 2.74 (s, 3H), 2.63-2.55 (m, 1H), 2.32-2.25 (m, 1H), 2.14 (s, 3H), 1.36 (s, 3H), 1.02-0.97 (m, 1H) , 0.88-0.83 (m, 1H). LC/MS (ESI) m/z: 602/604 (M+H)+. (1R,3S,5R)-2-{2-[3-Acetyl-5-({2-oxo-[1,2'-bunyridine]-3yl}amino)indazol-1-yl]acetyl}-N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide:

Ή NMR (400 MHz, CD3OD) δ 8.64-8.60 (m, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.05-8.01 (m, 1H), 7.80 (d, J=8.1 Hz, 1H) , 7.59-7.50 (m, 3H), 7.39-7.33 (m, 2H), 7.28-7.25 (m, 1H), 7.24-7.21 (m, 1H), 6.44-6.40 (m, 1H), 5.71 (d, J=17.2 Hz, 1H), 5.58 (d, J=17.1 Hz, 1H), 4.60-4.51 (m, 2H), 3.52-3.49 (m, 1H), 2.66 (s, 3H), 2.64-2.58 (m , 1H), 2.33-2.28 (m, 1H), 2.12 (s, 3H), 1.39 (s, 3H), 1.08-1.04 (m, 1H), 0.98-0.95 (m, 1H). LC/MS (ESI) m/z: 695 (M+H) ⁺ .

Scheme 76. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-undazol-1-yl)acetyl)5-methyl-N- (3-methyl-6-(trifluoromethoxy)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (196)

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with a trifluoromethyl group on the B-ring using the Togni reagent to prepare a synthetic B-ring intermediate. One skilled in the art will appreciate that other B-rings with trifluoromethyl functionality can be used to make additional compounds of the present invention. One of skill in the art will also appreciate that other A-rings may be linked to the C- and B-rings shown above to give the compounds of the present invention.

Step 1 5-Methyl-2-(trifluoromethoxy)pyridine (196-S2): A dried beaker was charged with 5-methylpyridin-2-ol (0.518 g) and Togni reagent (0.5 g) in nitromethane (10 ml). The reaction mixture was stirred at 100°C for 5 h in the presence of air. After the reaction mixture was cooled to room temperature, the reaction was diluted with water and extracted several times with CH ₂ Cl ₂ . The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated to give 196-S2, which was carried on without further purification to the next stage of the synthesis.

Step 2 2-Trifluoromethoxy-2-methyl-pyridine-N-oxide (196-S3): Crude 5-methyl-2(trifluoromethoxy)pyridine (196-S2) in CH ₂ Cl ₂ was cooled in an ice bath and solid complex of hydrogen peroxide with urea (0.688 g) followed by dropwise addition of TFAA (1.7 ml). After the addition was complete, the cooling bath was removed and the reaction mixture was stirred overnight at room temperature. Additional hydrogen peroxide urea complex (0.688 g) and TFAA (1.7 ml) was added and the reaction mixture was stirred for 24 h. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water, saturated aqueous sodium metabisulphite and dried (Na2SO4). The organic layer was filtered and concentrated to give 196-S3, which was taken on without further purification and used as is in the next step.

Stage 3. N-(tert-Butyl)-3-methyl-6-(trifluoromethoxy)pyridine-2-amine (196-S4): to a solution of 196-S3 (0.46 g) at -20°C in CH ₂ Cl ₂ (10 ml) was added tert-butylamine (1.25 ml) followed by the addition of

- 351 041794 drops of trifluoromethanesulfonic anhydride (1.2 ml). After stirring for 1 h at -20°C, the reaction mixture was quenched by adding water. The layers were separated and the organic layer was washed with a saturated solution of K ₂ CO ₃ , dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexanes) to give 196-S4 as a colorless liquid.

Step 4. 3-Methyl-6-(trifluoromethoxy)pyridine-2-amine, TFA salt (196-S5): a solution of 196-S4 (50 mg) in TFA (1.0 ml) was stirred at room temperature for 24 h. Then the volatiles were removed under reduced pressure and the residue was carried on without further purification to the next step (196-S5).

Step 5. tert-Butyl (1R,3S,5R)-5-methyl-3-((3-methyl-6-(trifluoromethoxy)pyridin-2-yl)carbamoyl)2-azabicyclo[3.1.0]hexane-2 -carboxylate (196-S7): to an ice-cold solution of 196-S5 (50 mg) and (1R,2S,5S)-3(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (196 -S6, 53 mg) in CH ₂ Cl ₂ (1.5 ml) was added pyridine (82 μl) followed by the addition of POCl ₃ (20 μl) slowly dropwise at 5°C, and the reaction mixture was stirred for 3 h, then saturated an aqueous solution of NaHCO ₃ and stirred for 1 h at room temperature. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (10 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0-2% EtOAc in hexanes) to give 196-S7.

Step 6. (1R,3S,5R)-5-Methyl-N-(3-methyl-6-(trifluoromethoxy)pyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt (196 -S8): compound 196-S7 (11 mg) was stirred in TFA (0.25 ml) and CH ₂ Cl ₂ (0.25 ml) for 30 min at room temperature. The reaction mixture was evaporated to dryness under reduced pressure, and the remaining residue was carried on without further purification to the next stage of the synthesis.

Step 7. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-methylN-(3 -methyl-6-(trifluoromethoxy)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (196): to a solution of 2-(3-acetyl-5-(2-methylpyrimidine-5- yl)-1H-indazol-1-yl)acetic acid (12 mg) in DMF (0.5 ml) was added iPr ₂ NEt (35 μl, 5 eq.) followed by addition of 196-S7 (from the previous step) at 5°C . HATU (16 mg, 1.1 equiv.) was added slowly at the same temperature and the reaction mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated to dryness and the residue was dissolved in CH ₂ Cl ₂ . The organic layer was washed with 1% LiOH aqueous solution and water and dried (Na ₂ SO ₄ ). After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: 0-2.5% MeOH in CH ₂ Cl ₂ ) to give 196 as a white solid.

1H NMR (400 MHz, chloroform-d) δ 0.77-0.96 (m, 2H), 1.42 (s, 3H), 2.09 (s, 3H), 2.29 (dd, J=8.8, 13.6 Hz, 1H), 2.71 ( s, 3H), 2.66-2.77 (m, 1H), 2.81 (s, 3H), 3.20 (dd, J=2.4, 5.4 Hz, 1H), 4.88 (d, J=7.7 Hz, 1H), 5.50 (s , 2H), 6.80 (d, J=8.1 Hz, 1H), 7.53-7.66 (m, 3H), 8.58 (s, 1H), 8.68 (s, 1H), 8.90 (s, 2H). ¹⁹ F-NMR (Chloroform-d): δ -56.6.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetyl)-5-methyl-N (3-methyl-6-(trifluoromethoxy)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CDCl ₃ ): δ 0.84-0.90 (m, 1H), 1.16 (t, J=5.4 Hz, 1H), 1.43 (s, 3H), 2.12 (s, 3H), 2.35 (t, J=8.4 Hz, 1H), 2.53 (s, 3H), 2.66 (brs, 1H), 2.69 (s, 3H), 2.79 (s, 3H), 3.11 (d, J=4.4 Hz, 1H), 4.93 ( s, 1H), 5.35 (d, J=17.6 Hz, 1H), 5.42 (d, J=17.7 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.57 ( d, J=8.1 Hz, 1H), 7.69 (s, 1H), 8.49 (brs, 1H), 8.55 (s, 1H), 8.89 (s, 2H). ¹⁹ F (CDCl ₃ ): δ -56.5.

(1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetyl)-5-methyl-N (3-methyl-6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 0.88 (dd, J=2.4, 5.5 Hz, 1H), 1.16 (t, J=5.4 Hz, 1H), 1.43 (s, 3H), 2.22 (s, 3H) , 2.36-2.42 (m, 1H), 2.53 (s, 3H), 2.67 (d, J=14 Hz, 1H), 2.72 (s, 3H), 2.79 (s, 3H), 3.13 (d, J=4.0 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 5.31 (d, J=17.6 Hz, 1H), 5.48 (d, J=17.5 Hz, 1H), 7.19 (s, 1H), 7.42 ( d, J=7.7 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.69 (s, 1H), 8.55 (s, 1H), 8.57 (brs, 1H), 8.89 (s, 2H). ¹⁹ F: δ -67.6.

Scheme 77. Synthesis of (1R,3S,5S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-methylpyridin-2-yl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (197)

- 352 041794

Step 1. (1R,3S,5S)-2-(tert-Butoxycarbonyl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0]hexane-3carboxylic acid (197-S2): to solution 2 -(tert-butyl)-3-ethyl-(1R,3S,5S)-5-formyl-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate (197-S1, 142 mg, 0.50 mmol) and p- toluenesulfonylmethyl isocyanide (146.4 mg, 0.75 mmol) in MeOH (15 ml) was added solid K ₂ CO ₃ (1.50 mmol). The mixture was heated at reflux overnight under argon. The reaction mixture was cooled to room temperature and the volatiles were evaporated. The residue was loaded onto a pad of silica gel and purified to give 197-S2 (72 mg).

Stage 2. tert-Butyl (1R,3S,5S)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-(oxazol-5-yl)-2azabicyclo[3.1.0]hexane -2-carboxylate (197-S3): (1R,3S,5S)-2-(tert-Butoxycarbonyl)-5-(oxazol-5-yl)2-azabicyclo[3.1.0]hexane-3-carboxylic acid ( 197-S1, 72 mg, 0.24 mmol) and 6-bromo-3-methylpyridine2-amine (197-S2, 46 mg, 0.24 mmol) were dissolved in anhydrous DCM (6.0 mL) in a pre-dried flask. The flask was cooled in an ice bath and dry pyridine (0.25 mL, 3.0 mmol) was added in one portion followed by POCl ₃ (100 μL, 1.0 mmol). After completion of the addition, the mixture was stirred for 4 h at 0°C, and then the reaction was quenched with water (15 ml). The DCM layer was removed and the aqueous phase was extracted with DCM (15 ml x 2). The combined DCM solution was washed with brine and dried over MgSO ₄ . The solution was filtered and concentrated and the resulting residue was purified to give 197-S3 (59.3 mg).

Step 3. (1R,3S,5S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0]hexane3-carboxamide hydrochloride ( 197-S4): tert-butyl (1R,3S,5S)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0 ]hexane-2-carboxylate (197-S3, 59.3 mg, 0.13 mmol) was taken up in 4N. HCl dioxane (2.0 ml), and the resulting reaction mixture was stirred at room temperature for 2 hours After completion of the reaction (monitored by HPLC), the solvent was removed under reduced pressure. The remaining residue 197-S4 was carried on without further purification.

Step 4. (1R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (197): to a solution of (1R,3S,5S)-N-(6- bromo-3-methylpyridin-2-yl)-5-(oxazol-5-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (197-S4, 0.13 mmol) and 2-(3-acetyl -5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-1-yl)acetic acid (197-S5, 40 mg, 0.13 mmol) in DMF (2.0 ml) was added HATU ( 1.5 equiv., 0.20 mmol) followed by dropwise addition of DIEA (5.0 equiv.) at room temperature. The mixture was stirred for 1 hour at room temperature and then the volatiles were evaporated. The residue was diluted with 10% sodium carbonate (50 ml) and extracted with ethyl acetate. The combined organic solutions were washed successively with water and brine and dried over MgSO ₄ . The solution was filtered and the solvent was removed. The residue was purified to give 197 (29.2 mg).

1H NMR (400 MHz, DMSO-d ₆ ): (main rotamer) δ 1.71 (d, J=4.6 Hz, 2H), 2.03 (s, 3H), 2.59 (dd, J=13.5, 4.8 Hz, 1H), 2.66 (s, 3H), 2.69 (s, 3H), 2.82 (dd, J=13.5, 9.2 Hz, 1H), 4.20 (t, J=4.6 Hz, 1H), 4.60 (dd, J=9.2, 4.7 Hz , 1H), 5.65 (d, J=17.3 Hz, 1H), 5.97 (d, J=17.3 Hz, 1H), 7.15 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.62 (d , J=7.9 Hz, 1H), 7.87 (s, 2H), 8.31 (s, 1H), 8.45 (s, 1H), 9.04 (s, 2H), 10.38 (s, 1H) ppm. LC (method A): tR = 1.55 min. LC/MS (EI) m/z: [M+H]+ 655.07, 657.16.

Scheme 78. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-(oxetan-3-yloxy)pyrimidin-5-yl)-1Hindazol-1-yl )acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (208)

- 353 041794

Br Br

To a solution of 121 (1 equiv.) in DMF (10 vol.) was added potassium carbonate (3 equiv.) and oxetan-3-yl 4-methylbenzenesulfonate (2 equiv.). The reaction mixture was heated to 100° C. for 12 hours. The reaction mixture was quenched with water and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give 208.

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.94 (d, J=2.6 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J=8.0Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 6.02 (d, J=17.3Hz, 1H), 5.65 (d, J=18.0Hz , 1H), 5.41-5.38 (m, 1H), 4.93-4.84 (m, 4H), 4.34-4.32 (m, 1H), 3.59-3.58 (m, 1H), 2.65 (s, 3H), 2.64-2.63 (m, 1H), 2.58 (s, 3H), 2.04 (s, 3H), 2.01–1.98 (m, 1H), 1.32 (s, 3H), 1.01–0.94 (m, 2H).

Scheme 79 yl)-1H-pyrazole-3-carboxamide (211)

211

Stage 1. tert-Butyl 2-(3-carbamoyl-5-(pyridin-3-yl)-1H-pyrazol-1-yl)acetate (211-S3): to a solution of 5-(pyridin-3-yl)- 1H-pyrazole-3-carboxamide (211-S1, 1 equiv.) in CH ₃ CN (10 vol.) was added tert-butyl 2bromoacetate (211-S2, 1.1 equiv.) and potassium carbonate (1.1 equiv.). The mixture was heated at reflux overnight under argon. After the reaction mixture was cooled to room temperature, the mixture was filtered through celite and washed with CH3CN. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with DCM/EtOAc) to give compound 211-S3.

Step 2. 2-(3-Carbamoyl-5-(pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid (211-S4): to a solution of compound 211-S3 (1 eq.) in DCM ( 10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting substance (211-S4) was transferred further to the next stage of the synthesis without further purification.

Step 3. 1-(2-((2S,4R)-2-((6-Bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)5-(pyridin-3- yl)-1H-pyrazole-3-carboxamide (211): ((2S,4R)-N-( 6-bromopyridin-2-yl)-4-fluoropyrrolidine-2carboxamide hydrochloride (1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.) The reaction mixture was stirred at room temperature for 3 h and then quenched with water ( 30 vol.) The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 211.

1H NMR (400 MHz, DMSO-d6) δ 2.02-2.24 (m, 1H), 2.54-2.61 (m, 1H), 3.73-3.89 (m, 1H), 4.00-4.17 (dd, J=12.9, 21.3 Hz , 1H), 4.62-4.71 (t, J=8.3 Hz, 1H), 5.03-5.13 (d, J=17.4 Hz, 1H), 5.34-5.58 (m, 2H), 6.81-6.92 (d, J=2.7 Hz, 1H), 7.26-7.31 (s, 1H), 7.33-7.37 (d, J=7.7 Hz, 1H), 7.46-7.57 (m, 2H), 7.71-7.78 (t, J=8.0 Hz, 1H) , 7.84-7.89 (m, 1H), 8.03-8.12 (d, J=8.2 Hz, 1H), 8.57-8.75 (m, 2H), 10.18-11.70 (s, 1H).

Scheme 80. Synthesis of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-2-(2-(3-carbamoyl-5-(furan-2-yl)- 354 041794

1H-pyrazol-1-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (212) and (1R,3S,5R)-N-(6bromo-3-methylpyridine-2 -yl)-2-(2-(5-carbamoyl-3-(furan-2-yl)-III-pyrazol-1-yl)acetyl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (213)

212 213

Stage 1. tert-Butyl 2-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)acetate and tert-butyl 2-(5carbamoyl-3-(furan-2-yl) -1H-pyrazol-1-yl)acetate (212-S3 and 213-S4): to a solution of 5-(furan-2-yl)-1Hpyrazol-3-carboxamide (213-S1, 1 eq.) in CH3CN (10 vol.) was added tert-butyl 2-bromoacetate (213-S2, 1.1 eq.) and potassium carbonate (1.1 eq.). The mixture was heated at reflux overnight under argon. After the reaction mixture was cooled to room temperature, the mixture was filtered through celite and washed with CH3CN. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with EtOAc/DCM) to give a mixture of compounds 212-S3 and 213-S4. This mixture was carried on as a mixture without further purification.

Step 2. 2-(3-Carbamoyl-5-(furan-2-yl)-1H-pyrazol-1-yl)acetic acid and 2-(5-carbamoyl-3(furan-2-yl)-1H-pyrazole -1-yl)acetic acid (212-S5 and 213-S6): TFA (5 about.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting material (a mixture of 212-S5 and 213-S6) was carried on as a mixture without further purification.

Step 3. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-2-(2-(3-carbamoyl-5-(furan-2-yl)-1Hpyrazol-1 -yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (212) and (1R,3S,5R)-N-(6-Bromo-3methylpyridin-2-yl)-2 -(2-(5-carbamoyl-3-(furan-2-yl)-1H-pyrazol-1-yl)acetyl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (213): to (1R,3S,5R)-N-(6-bromo-3-methylpyridine-2- yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (213-S7, 1 eq.), HATU (2.1 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compounds 212 and 213.

(1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-2-(2-(3-carbamoyl-5-(furan-2-yl)-1H-pyrazol-1yl) acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (212):

'11 NMR (400 MHz, DMSO-d ₆ ) δ 0.87 (dd, J=2.4, 5.4 Hz, 1H), 0.99 (t, J=5.5 Hz, 1H), 1.21-1.34 (m, 4H), 1.94- 2.08 (m, 4H), 3.51 (dd, J=2.4, 5.6 Hz, 1H), 4.36 (dd, J=5.5, 9.2 Hz, 1H), 5.38 (d, J=17.4 Hz, 1H), 5.52 (d , J=17.3 Hz, 1H), 6.60 (dd, J=1.8, 3.5 Hz, 1H), 6.79 (d, J=3.4 Hz, 1H), 6.96 (s, 1H), 7.28 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 10.28 (s, 1H).

(1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-2-(2-(5-carbamoyl-3-(furan-2-yl)-1H-pyrazol-1

- 355 041794 yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (213):

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.83-0.93 (m, 1H), 0.99 (t, J=5.4 Hz, 1H), 1.20-1.32 (m, 4H), 1.98-2.10 (m, 4H) , 3.37-3.43 (m, 1H), 4.35 (dd, J=5.0, 9.2 Hz, 1H), 5.51 (d, J=16.4 Hz, 1H), 5.69 (d, J=16.3 Hz, 1H), 6.58 ( dd, J=1.7, 3.4 Hz, 1H), 6.69 (t, J=3.9 Hz, 1H), 7.19 (s, 1H), 7.42-7.50 (m, 2H), 7.63 (d, J=7.9 Hz, 1H ), 7.73 (d, J=1.7 Hz, 1H), 8.02 (s, 1H), 10.18 (s, 1H).

Scheme 81. Synthesis of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-2-(2-(3-carbamoyl-5-(thiophen-2-yl)1H-pyrazole -1-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (214)

Stage 1. tert-Butyl 2-(3-carbamoyl-5-(thiophen-2-yl)-1H-pyrazol-1-yl)acetate (214-S3): to a solution of 5-(thiophen-2-yl)- 1H-pyrazole-3-carboxamide (214-S1, 1 equiv.) in CH ₃ CN (10 vol.) was added tert-butyl 2bromoacetate (214-S2, 1.1 equiv.) and potassium carbonate (1.1 equiv.). The mixture was heated at reflux overnight under argon. After the reaction mixture was cooled to room temperature, the mixture was filtered through celite and washed with CH3CN. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with DCM/EtOAc) to give compound 214-S3.

Step 2. 2-(3-Carbamoyl-5-(thiophen-2-yl)-1H-pyrazol-1-yl)acetic acid (214-S4): to a solution of compound 214-S3 (1 eq.) in DCM ( 10 vol.) at 0°C in an argon atmosphere was added TFA (5 vol.). The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The obtained substance (214-S4) was used immediately at the next stage of the synthesis without additional purification.

Step 3. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-2-(2-(3-carbamoyl-5-(thiophen-2-yl)-1Hpyrazol-1 -yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (214): to a solution of compound 214-S4 (1 equiv.) in DMF (10 vol.) at 0°C in (1R,3S,5R)-N-(6-6pom-3methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (214-S5, 1 eq. ), HATU (2.1 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 214.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.77 (dd, J=2.3, 5.3 Hz, 1H), 0.93 (t, J=5.4 Hz, 1H), 1.09-1.32 (m, 4H), 1.98- 2.05 (m, 1H), 2.07 (s, 3H), 3.47 (dd, J=2.3, 5.6 Hz, 1H), 4.38 (dd, J=5.5, 9.2 Hz, 1H), 5.24 (d, J=17.4 Hz , 1H), 5.44 (d, J=17.4 Hz, 1H), 6.86 (s, 1H), 7.13 (dd, J=3.7, 5.1 Hz, 1H), 7.24-7.33 (m, 2H), 7.46 (d, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.70 (dd, J=1.1, 5.1 Hz, 1H), 10.30 (s, 1H).

Scheme 82 5-yl)-1H-pyrazole-3-carboxamide (215)

- 356 041794

Step 1. Ethyl 5-(2-methylpyrimidin-5-yl)-1H-pyrazol-3-carboxylate (215-S3): to a solution of ethyl 5-iodo-1H-pyrazole-3-carboxylate (215-S1, 1 eq.) in dioxane/H ₂ O (9:1, 10 vol.) compound 215S2 (1 equiv.), Cs ₂ CO ₃ (3 equiv.) and tetrakis(triphenylphosphine)palladium (0.1 equiv.) were added. The reaction mixture was stirred at 90°C for 5 h and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 215-S3.

Stage 2. tert-Butyl 2-(3-carbamoyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazol-1-yl)acetate and ethyl 1(2-(tert-Butoxy)-2-oxoethyl) -3-(2-methylpyrimidin-5-yl)-1H-pyrazol-5-carboxylate (215-S5 and 215-S6): to a solution of ethyl 5-(2-methylpyrimidin-5-yl)-1H-pyrazol-3 -carboxylate (215-S3, 1 equiv.) in CH3CN (10 vol.) were added tert-butyl 2-bromoacetate (215-S2, 1.1 equiv.) and potassium carbonate (1.1 equiv.). The mixture was heated at reflux overnight under argon. After the reaction mixture was cooled to room temperature, the mixture was filtered through celite and washed with CH3CN. The filtrate was concentrated under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluting with DCM/EtOAc) to give a mixture of compounds 215-S5 and 215-S6. The mixture was carried on without further purification.

Step 3. 2-(3-(Ethoxycarbonyl)-5-(2-methylpyrimidin-5-yl)-1H-pyrazol-1-yl)acetic acid and 2-(5-(ethoxycarbonyl)-3-(2-methylpyrimidine) -5-yl)-1H-pyrazol-1-yl)acetic acid (215-S7 and 215-S8): to a solution of compounds 215-S5 and 215-S6 (1 eq., mixture) in DCM (10 vol.) at 0°C in an argon atmosphere, TFA (5 vol.) was added. The reaction mixture was stirred at room temperature for 3 hours and concentrated to dryness. The resulting material (a mixture of 215-S7 and 215-S8) was carried on without further purification.

Step 4 Ethyl 1-(2-((2S,4R)-2-((6-bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2oxoethyl)-5-(2-methylpyrimidin- 5-yl)-1H-pyrazol-3-carboxylate (215-S10) and Ethyl 1-(2-((2S,4R)-2-((6bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidine-1 - yl)-2-oxoethyl)-3-(2-methylpyrimidin-5-yl)-1Hpyrazol-4-carboxylate (215-S11): to a solution of compounds 215-S7 and 215-S8 (1 eq.) in DMF (10 vol.) at 0°C in an argon atmosphere was added (2S,4R)-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide hydrochloride (215-S9, 1 eq.), HATU (2.1 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give separate pure compounds 215-S10 and 215-S11.

Step 5. 1-(2-((2S,4R)-2-((6-Bromopyridin-2-yl)carbαmoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)5-(2-methylpyrimidin- 5-yl)-1H-pyrazol-3-carboxylic acid (215-S12): to a solution of ethyl 1-(2-(((2S,4R)2-((6-bromopyridin-2-yl)carbamoyl)-4 -fluoropyrrolidin-1-yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)1H-pyrazole-3-carboxylate (215-S10, 1 eq.) in THF/H2O (3:1, 10 v.) LiOH (2.1 eq.) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure to remove volatiles. The remaining water was neutralized using 2N HCl, then the solid was filtered and purified using column chromatography on silica gel (eluting with DCM/MeOH) to give compound 215-S12.

Step 6 5-yl)-1H-nirazol-3-carboxamide (215): NH4Cl (3 equiv.), HATU (2.1 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 215.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.03-2.23 (m, 1H), 2.52-2.58 (m, 1H), 2.66 (s, 3H), 3.81-3.98 (m, 1H), 4.10 (dd , J=12.5, 21.9 Hz, 1H), 4.66 (t, J=8.4 Hz, 1H), 5.36 (d, J=16.5 Hz, 1H), 5.41-5.57 (m, 1H), 5.73 (d, J= 16.5 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 7.43 (s, 1H), 7.54 (s, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.97-8.06 (m, 2H), 9.00 (d, J=3.7 Hz, 2H), 10.98 (s, 1H).

Scheme 83 5-yl)-1 H-pyrazole-4-carboxamide (216)

Step 1. 1-(2-((2S,4R)-2-((6-Bromopyridin-2-yl)carbαmoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)3-(2-methylpyrimidin- 5-yl)-1H-n-pyrazole-4-carboxylic acid (216-S2): to a solution of ethyl 1-(2-(((2S,4R)-2((6-bromopyridin-2-yl)carbamoyl)-4 -fluoropyrrolidin-1-yl)-2-oxoethyl)-3-(2-methylpyrimidin-5-yl)-1Hpyrazol-4-carboxylate (216-S1, 1 eq.) in THF/H2O (3:1, 10 vol .) LiOH (2.1 eq.) was added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure to remove volatiles. The remaining water was neutralized using 2N HCl, then the solid was filtered and purified by column chromatography on silica gel (eluting with DCM/MeOH) to give compound 216-S2.

- 358 041794

Step 2. 1-(2-((2S,4R)-2-((6-Bromopyridin-2-yl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)3-(2-methylpyrimidin- 5-yl)-1H-pyrazole-4-carboxamide (216): NH ₄ Cl (3 equiv.) , HATU (2.1 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 3 h and quenched with water (30 vol.). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The remaining residue was purified by silica gel column chromatography (eluting with DCM/MeOH) to give compound 216.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.92-2.12 (m, 1H), 2.45-2.50 (m, 1H), 2.61 (d, J=3.1 Hz, 3H), 3.64-3.83 (m, 1H ), 3.94-4.08 (m, 1H), 4.57 (t, J=8.5 Hz, 1H), 5.10 (d, J=17.5 Hz, 1H), 5.31-5.50 (m, 2H), 6.89 (s, 1H) , 7.19-7.29 (m, 2H), 7.44 (s, 1H), 7.62-7.71 (m, 1H), 7.95 (d, J=8.2 Hz, 1H), 8.69 (s, 2H), 10.94 (s, 1H ).

Scheme 84. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-(1-fluoroethyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (220)

220-S1 220-S2

Stage 1. 4-Bromo-2-iodo-6-methylaniline (220-S2): I ₂ (6.828 g, 26.88 mmol) was added to a solution of compound 220-S1 (5 g, 26.88 mmol) in EtOH (100 ml) and Ag ₂ SO ₄ (8.382 g, 26.88 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether to give compound 220-S2 (6.31 g, 75.5%) as a light brown solid. LC/MS (ESI) m/z: 312 (M+H)+.

Stage 2. 5-Bromo-7-iodo-1H-indazole (220-3): to a solution of compound 220-S2 (6.31 g, 20.29 mmol) and potassium acetate (2.386 g, 24.35 mmol) in CHCl ₃ (100 ml) acetic anhydride (6.209 g, 60.87 mmol) was added dropwise at 0°C under N2 and the mixture was stirred at room temperature for 1 h. The reaction mixture was heated to 60°C and tert-butyl nitrite (10.3 g, 0.1 mol ), and the reaction was stirred at 60°C overnight. The mixture was diluted with water and extracted with DCM (2x). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was dissolved in MeOH and 6N. HCl (v/v = 1:1) and the mixture was stirred at room temperature

- 359 041794 for 5 hours. The mixture was made alkaline with 10N. aqueous NaOH solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100:1 to 8:1) to give compound 220-S3 (3.73 g, 57.1%) as a light yellow solid. LC/MS (ESI) m/z: 323 (M+H)+.

Step 3. 5-Bromo-7-vinyl-1H-indazole (220-S4): to a solution of compound 220-S3 (1.9 g, 5.92 mmol) in DME/H2O (40 ml, v/v=3/1 ) potassium trifluoro(vinyl)borate (0.793 g, 5.92 mmol), K2CO3 (0.980 g, 7.10 mmol) and Pd(PPh ₃ ) ₄ (0.684 g, 0.59 mmol) were added. The mixture was degassed under N ₂ three times and stirred at 85° C. under N 2 overnight. The mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100:1 to 8:1) to give compound 220-S4 (0.78 g, 59.4%) as a light yellow solid. LC/MS (ESI) m/z: 223 (M+H) ⁺ .

Step 4. 1-(5-Bromo-1H-indazol-7-yl)ethanol (220-S5): BH3-THF ( 1.13 ml, 1 M in THF) dropwise at 0°C under N ₂ and the mixture was stirred at the boil under reflux overnight. The mixture was cooled to 0°C and was added 3n. an aqueous solution of NaOH followed by the addition of 30% H ₂ O ₂ . The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in DCM. The mixture was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100:1 to 6:1) to give compound 220-S5 (170 mg, 20.1%) as a light brown solid. LC/MS (ESI) m/z: 242 (M+H) ⁺ .

Step 5. 5-Bromo-7-(1-fluoroethyl)-1H-indazole (220-S6): to a solution of compound 220-S5 (0.16 g, 0.66 mmol) in anhydrous DCM (5 ml) was added DAST (0.22 g 1.33 mmol) dropwise at -70°C under N2 atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with an aqueous solution of NaHCO ₃ at 0°C and diluted with DCM. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100:1 to 6:1) to give compound 220-S6 (70 mg, 43.5% yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) ⁺ .

Step 6. 5-Bromo-7-(1-fluoroethyl)-3-iodo-1H-indazole (220-S7): KOH ( 40 mg, 0.72 mmol) followed by the addition of I ₂ (110 mg, 0.43 mmol) at 0°C, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with aqueous Na2S2O3, diluted with water, and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (80:1 to 6:1) to give compound 220-S7 (80 mg, 75.5% yield) as a light yellow solid. LC/MS (ESI) m/z: 370 (M+H) ⁺ .

Step 7. tert-Butyl 2-(5-bromo-7-(1-fluoroethyl)-3-iodo-1H-indazol-1-yl)acetate (220-S8): to a solution of compound 220-S7 (80 mg, 0.22 mmol) in DMF (2 ml) was added K2CO3 (75 mg, 0.54 mmol) and tert-butyl 2bromoacetate (46 mg, 0.24 mmol). The mixture was stirred at room temperature overnight and then diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (100:1 to 20:1) to give compound 220-S8 (50 mg, 47.7% yield) as a light yellow solid. LC/MS (ESI) m/z: 485 (M+H) ⁺ .

Step 8. tert-Butyl 2-(3-acetyl-5-bromo-7-(1-fluoroethyl)-1H-indazol-1-yl)acetate (220-S9): to a solution of compound 220-S8 (50 mg, 0.10 mmol) in dry toluene (3 ml) were added tributyl(1ethoxyvinyl)stannan (45 mg, 0.12 mmol) and Pd(PPh ₃ ) ₄ (12 mg, 0.01 mmol). The mixture was stirred at 100° C. under N ₂ overnight. The mixture was cooled to room temperature, 0.5 M aqueous HCl was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting crude product was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (80:1 to 8:1) to give compound 220-S9 (30 mg, 73.2% yield) as a milky white solid. LC/MS (ESI) m/z: 399 (M+H) ⁺ .

Step 9. tert-Butyl 2-(3-acetyl-7-(1-fluoroethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (220-S10): Loaded into a round bottom flask compound 220-S9 (30 mg, 0.075 mmol), 2methylpyrimidin-5-ylboronic acid (11 mg, 0.083 mmol), K2CO3 (26 mg, 0.19 mmol) in dioxane/H ₂ O (2 ml, v/v = 5:1). Tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) was added to the mixture under N2, and the reaction was stirred at 90°C overnight under N2. The mixture was diluted with EtOAc and washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether/EtOAc (50:1 to 3:1) to give compound 220-S10 (18 mg, 58.1% yield) as light

- 360 041794 yellow solid. LC/MS (ESI) m/z: 413 (M+H)+.

Step 10. 2-(3-Acetyl-7-(1-fluoroethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (220-S11): to a solution of compound 220 -S10 (18 mg, 0.044 mol) in DCM (1 ml) was added TFA (0.5 ml) and the mixture was stirred at room temperature for 1.5 h. The solvent was removed and the residue was washed with ether and dried under vacuum to obtain compound 220-S11 (10 mg, 64.3% yield) as a light yellow solid. LC/MS (ESI) m/z: 357 (M+H)+.

Step 11. (1R,3S,5R)-2-(2-(3-Acetyl-7-(1-fluoroethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)- N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (220): to a mixture of compound 220-S11 (9 mg, 0.025 mmol) and compound 220-S12 (10 mg, 0.032 mmol) in DMF (1 ml) was added DIPEA (15 mg, 0.12 mmol) followed by the addition of HATU (24 mg, 0.064 mmol). The reaction was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by prep HPLC to give 220 (2 mg, 12.5%) as white solid.

1H NMR (400 MHz, CD3OD) δ 9.03 (s, 2H), 8.68-8.62 (m, 1H), 7.83 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 6.44-6.05 (m, 1H), 6.03-5.78 (m, 2H), 4.58-4.46 (m, 1H), 3.52 (dd, J=5.6, 2.4 Hz, 1H), 2.76 (s , 3H), 2.70 (d, J=1.6 Hz, 3H), 2.63 (dd, J=13.2, 9.2 Hz, 1H), 2.35-2.26 (m, 1H), 2.11 (s, 3H), 1.96-1.82 ( m, 3H), 1.42 (s, 3H), 1.16–1.10 (m, 1H), 1.03–0.97 (m, 1H). LC/MS (ESI) m/z: 648 (M+H) ⁺ .

Scheme 85. Synthesis of (1R,3S,5S)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N3-( 6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3,5-dicarboxamide (221) and (1R,3S,5S)-2-(2-(3-acetyl- 7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin-2-yl)-5-cyano-2-azabicyclo[3.1 .0]hexane-3-carboxamide (222)

Step 1. (1R,3S,5S)-3-((6-Bromo-3-methylpyridin-2-yl)carbamoyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane-5-carboxylic acid (222-S2): to a mixture of compound 222-S1 (380 mg, 0.89 mmol) in t-BuOH (10 ml) was added aqueous NaOH (3.12 ml, 1 M, 3.12 mmol) followed by the addition of potassium permanganate (281 mg, 1.78 mmol) dissolved in water (20 ml) at 0°C. The reaction was stirred at 30°C overnight, and the solvent was removed under vacuum. The residue was acidified with 2N. aqueous HCl and extracted with DCM/i-PrOH (3/1, v/v) twice. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified with a silica gel column (eluting with DCM/MeOH=50/1) to give compound 222-S2 (220 mg, 57.8% yield) as a white solid. LC/MS (ESI) m/z: 440/442 (M+H)+.

Step 2. (1R,3S,5S)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-carbamoyl-2azabicyclo[3.1.0]hexane-2-carboxylate (222 -S3): HBTU (379 mg, 1.0 mmol) and DIPEA (0.16 ml, 1.0 mmol ) at 0°C. The reaction was stirred at room temperature for 16 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified with a silica gel column (eluting with DCM/MeOH = 60/1) to give compound 222-S3 (200 mg, 90.1% yield) as a white solid. LC/MS (ESI) m/z: 439/441 (M+H)+.

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Step 3. (1 R,3S,5S)-N ³ -(6-Bromo-3-methylpyridin-2-yl)-2-azabicyclo [3.1.0]hexane-3,5dicarboxamide (222-4): to solution compound 222-S3 (80 mg, 0.18 mmol) in dioxane (1 ml) was added HCl/dioxane (4 M, 1 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give compound 222-S4 (80 mg, 100% yield) as a white solid, which was immediately used in the next reaction without further purification. LC/MS (ESI) m/z: 339/341 (M+H)+

Step 4. (1 R,3S,5S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N ³ -(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3,5-dicarboxamide (221): to a solution of compound 222-S4 (80 mg, 0.18 mmol), 2 -(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetic acid (59 mg, 0.18 mmol) and HATU (138 mg, 0.36 mmol) in DMF (2 ml) DIPEA (0.12 ml, 0.73 mmol) was added. The reaction was stirred at room temperature for 2 hours. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified with a silica gel column (eluting with DCM/MeOH = 60/1) to give 221 (30 mg, 25.6% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 9.04 (s, 2H), 8.43 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J=7.4 Hz , 1H), 5.82 (m, 1H), 5.71 (m, 1H), 5.36 (m, 1H), 4.72 (m, 1H), 3.29-3.31 (m, 2H), 2.67-2.80 (m, 10H), 2.26 (s, 3H), 0.85-0.89 (m, 2H). LC/MS (ESI) m/z: 645/647 (M+H)+.

Step 5. (1 R,3S,5S)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)N -(6-bromo-3-methylpyridin-2-yl)-5-cyano-2-azabicyclo[3.1.0]hexane-3-carboxamide (222): to a solution of 221 (20 mg, 0.03 mmol) and pyridine (4.9 mg, 0.06 mmol) in dry THF (3 ml) was added TFAA (31.5 mg, 0.25 mmol). The reaction was stirred at 60°C for 12 h and then concentrated under reduced pressure. The residue was purified by preparative TLC to give 222 (3.5 mg, 17.5% yield) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 9.04 (s, 2H), 8.43 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J =7.4 Hz, 1H), 5.82 (m, 1H), 5.71 (m, 1H), 5.36 (m, 1H), 4.72 (m, 1H), 3.46-3.51 (m, 1H), 2.67-2.80 (m, 9H), 2.01-2.11 (m, 1H), 2.24 (s, 3H), 0.85-0.89 (m, 2H). LC/MS (ESI) m/z: 627/629 (M+H)+.

Scheme 86 brom-3-methylpyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (223) but ₆ he

BUT, oO o—

N O

Vos

223-S1

Mel

_{K2CO3 ,} DMF

Stage )1

N O Sun

223-S2

TCCA, TEMPO DCM

Stage )2

N O

Vos 223-S3

H.O.

TMSCF ₃

TBAF, THF

Stage >3

CF ₃ o—

HE

N O

Vos 223-S4

N

Vos

223-S5

TBSCI

TEA, DMAP

Stage >5

Stage )6 223-S7 Stage j7

NaBH ₄ , LiCI EtOH/THF

Stage )4

TosCI

NaH,THF

t-BuOK

THF

223-S8

H2

EtOAc

Stage)8

Vos

Stage )9

223-S9

NMOJPAP THF

Stage )10

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Step 1. (2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (223-S2): to a solution of compound 223-S1 (10 g, 43.7 mmol) in DMF (100 ml ) was added K ₂ CO ₃ (18.1 g, 131.3 mmol) followed by the addition of MeI (9.31 g, 65.6 mmol) at 0°C, and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 5:1 to 2:1) to give compound 223-S2 (10.1 g, 94.4% yield) as a white solid. LC/MS (ESI) m/z: 246 (M+H)+.

Step 2. (S)-1-tert-Butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (223-S3): To a solution of compound 223-S2 (10 g, 41.2 mmol) in DCM (100 ml) was added TCCA (10.04 g, 43.2 mmol) followed by the addition of TEMPO (64.3 mg, 0.41 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, the filtrate was washed with saturated potassium carbonate solution and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 223-S3 (8 g, 80.7% yield) as a white solid. LC/MS (ESI) m/z: 244 (M+H) ⁺ .

Stage 3. (2S)-1-tert-Butyl 2-methyl 4-hydroxy-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylate (223-S4): to a solution of compound 223-S3 (6 g, 24.7 mmol) TMSCF3 (5.26 g, 37.0 mmol) was added in THF (100 mL) followed by TBAF (0.15 mL, 0.15 mmol, 1 mol/L in THF) at 0°C, and the reaction was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 223-S4 (4.4 g, 56.8% yield) as a yellow oil. LC/MS (ESI) m/z: 314 (M+H) ⁺ .

Step 4. (2S)-tert-Butyl 4-hydroxy-2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate (223-S5): to a solution of compound 223-S4 (4.4 g, 14.1 mmol) in THF ( 56 ml) were added LiCl (1.31 g, 30.91 mmol) and NaBH ₄ (1.33 g, 35.1 mmol) followed by dropwise addition of EtOH (112 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 h and left to warm to room temperature and stirred overnight. The mixture was cooled at 0°C and acidified to pH 4 with 10% aqueous citric acid. The mixture was extracted with DCM and washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 15:1) to give compound 223-S5 (3.4 g, 85.0% yield) as a yellow oil. LC/MS (ESI) m/z: 286 (M+H) ⁺ .

Step 5. (2S)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxy-4(trifluoromethyl)pyrrolidine-1-carboxylate (223-S6): to a solution of compound 223-S5 ( 3.4 g, 11.9 mmol) in DCM (50 ml) were added TEA (1.2 g, 11.9 mmol) and TBDMSCl (2.15 g, 14.28 mmol) at 0°C and the reaction was stirred at room temperature overnight under N ₂ atmosphere. The reaction mixture was diluted with DCM, washed with saturated aqueous NH4Cl and brine, dried over Na2SO4 and concentrated under reduced pressure to remove volatiles. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 60:1) to give compound 223S6 (4.2 g, 88.3% yield) as a yellow oil. LC/MS (ESI) m/z: 400 (M+H) ⁺ .

Step 6. (2S)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(tosyloxy)-4(trifluoromethyl)pyrrolidine-1-carboxylate (223-S7): to a solution of compound 223- S6 (4 g, 10.0 mmol) in THF (40 mL) was added NaH (802 mg, 20.0 mmol) at 0°C. The mixture was stirred at room temperature for 30 min and tosyl chloride (3.82 g, 20.0 mmol) was added in portions at 0°C. The reaction mixture was stirred at room temperature overnight under N ₂ . The reaction was quenched with saturated aqueous NH4Cl and the mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 80:1) to give compound 223-S7 (4.9 g,

88.5%) as a yellow oil. LC/MS (ESI) m/z: 554 (M+H)+.

Step 7. (S)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(trifluoromethyl)-2,3-dihydro1H-pyrrole-1-carboxylate (223-S8): to compound solution 223-S7 (4.2 g, 7.59 mmol) in THF (40 mL) was added t-BuOK (1.70 g, 15.19 mmol) at –78°C, and the reaction was stirred at room temperature for 2 h under N2 atmosphere. The reaction was quenched with cold water and the mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 80:1) to give compound 223-S8 (1.6 g, 55.3% yield) as a yellow oil. LC/MS (ESI) m/z: 382 (M+H) ⁺ .

Step 8. (2S,4S)-tert-Butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4(trifluoromethyl)pyrrolidine-1-carboxylate (223-S9): to a solution of compound 223-S8 (300 mg , 0.78 mmol) in EtOAc (5 mL) was added Pd/C (15 mg, 10% wt). The reaction mixture was stirred under H2 balloon at room temperature for 2 h. The mixture was filtered and concentrated to dryness to give compound 223-S9 (280 mg, 93.3%) as a brown oil. LC/MS (ESI) m/z: 384 (M+H) ⁺ .

Step 9. (2S,4S)-tert-Butyl 2-(hydroxymethyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate (223S10): to a solution of compound 223-S9 (280 mg, 0.73 mmol) in THF (5 ml ) was added TBAF (1 mol/l in THF) (3.65 ml, 3.65 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was diluted with EtOAc, washed with saturated NH ₄ Cl solution and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 223-S10 (200 mg, 96.6% yield) as a yellow oil. LC/MS (ESI) m/z: 270 (M+H) ⁺ .

Step 10. (2S,4S)-1-(tert-Butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (223-S11): to a solution of compound 223-S10 (200 mg, 0.72 mmol) in THF ( 5 ml) NMO (842 mg, 7.20 mmol) and TPAP (25.2 mg, 0.073 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours under nitrogen. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:CH+OH = 50:1) to give compound 223-S11 (150 mg, 71.4%) as a yellow oil. LC/MS (ESI) m/z: 284 (M+H) ⁺ .

Step 11. (2S,4S)-tert-Butyl 2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4(trifluoromethyl)pyrrolidine-1-carboxylate (223-S12): to a solution of compound 223 -S11 (50 mg, 0.18 mmol) and 6-bromo-3-methylpyridin-2-amine (33.3 mg, 0.18 mmol) in DCM (3 mL) were added pyridine (71.1 mg, 0.90 mmol) at 0°C followed by dropwise POCl ₃ (27.54 mg, 0.18 mmol). The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with ice water and extracted with DCM twice. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO 4 , filtered and concentrated to dryness. The residue was purified with a silica gel column (eluting with DCM/MeOH = 50/1) to give compound 223-S12 (45 mg, 57.0%) as a white solid. LC/MS (ESI) m/z: 452/454 (M+H) ⁺ .

Step 12: (2S,4S)-N-(6-Bromo-3-methylpyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, TFA salt (223-S13): to a solution of compound 223-S12 (45 mg, 0.10 mmol) in DCM (2.5 ml) was added TFA (1 ml). The reaction was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to give compound 223-S13 (50 mg, 100.0% yield) as a yellow solid, which was immediately taken to the next step without further purification. LC/MS (ESI) m/z: 352/354 (M+H) ⁺ .

Step 13: (2S,4S)-1-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N(6- bromo-3-methylpyridin-2-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (223): to a solution of compound 223-S13 (50 mg, 0.10 mmol), compound 223-S14 (32.4 mg, 0.10 mmol) and HATU (76.0 mg, 0.20 mmol) in DMF (2 mL) DIPEA (0.07 mL, 0.40 mmol) was added at 0°C. The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative HPLC to give 233 (5.2 mg, 7.9% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 8.99 (d, J=3.4 Hz, 2H), 8.41 (s, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.37 (d, J=7.9 Hz, 1H), 5.78 (s, 2H), 4.72 (t, J=8.3 Hz, 1H), 4.37-4.29 (m, 1H), 3.87 (t, J=10.4 Hz, 1H), 3.48 (s, 1H), 2.74 (s, 7H), 2.67 (s, 3H), 2.28 (d, J=5.8 Hz, 1H), 2.08 (s, 3H). LC/MS (ESI) m/z:658/660 (M+H) ⁺ .

Scheme 87. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-5-( (bis(2-fluoroethyl)amino)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (227)

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Boc ₂ O/Na ₂ CO ₃ H ^ ^NH 2 HCI ------------ N ------THF/H ₂ O ^{f Boc} NaH/DMF

227-S1 227-S2

Stage 1. tert-Butyl 2-fluoroethylcarbamate (227-S2): NaHCO ₃ (1.69 g, 20.1 mmol) was added to a solution of 227-S1 (500 mg, 5.03 mmol) in THF (5 ml)/H ₂ O (5 ml ) and Boc ₂ O (1.31 g, 6.03 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with H2O solution and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified with a silica gel column (eluting with PE:EtOAc=20:1 to 10:1) to give compound 227S2 (400 mg, 48.8%) as a white solid. LC/MS (ESI) m/z: 108(M-56+H)+.

Stage 2. tert-Butyl bis(2-fluoroethyl)carbamate (227-S3): NaH (59 mg, 1.47 mmol) was added to a solution of 227-S2 (200 mg, 1.23 mmol) in DMF (5 ml) at 0°C . After stirring at room temperature for 30 min, 1-fluoro-2-iodoethane (235 mg, 1.35 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with H ₂ O at 0° C., extracted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified with a silica gel column (eluting with PE:EtOAc=30:1 to 20:1) to give compound 227-S3 (130 mg, 50.6%) as a white solid. LC/MS (ESI) m/z: 154(M-56+H) ⁺ .

Step 3. Bis(2-fluoroethyl)amine (227-S4): HCl/dioxane (1 ml, 4 M) was added to a solution of compound 227-S3 (130 mg, 0.62 mmol) in dioxane (1 ml) and the reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give compound 227-S4 (120 mg, 100%) as a white solid, which was used immediately in the next step without further purification. LC/MS (ESI) m/z: 110 (M+H) ⁺ .

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)5-( (bis(2-fluoroethyl)amino)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (227): to a solution of compound 227-S5 ( 30 mg, 0.05 mmol) in MeCN (3 mL) was added DIPEA (0.03 mL, 0.21 mmol), NaI (8 mg, 0.05 mmol), and compound 227-S4 (120 mg, 0.62 mmol). The reaction mixture was stirred at 60°C overnight. The mixture was partitioned with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by a silica gel column (eluting with DCM/MeOH = 20/1) and further purified by preparative HPLC to give 227 (1.3 mg, 3.6%) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.39 (d, J=1.0 Hz, 1H), 7.58-7.46 (m, 2H), 7.36 (d, J=7.9 Hz, 1H), 5.95 (m, 1H), 5.77 (m, 1H), 4.62 (m, 3H), 4.50 (m, 2H), 3.61 (m, 1H), 3.10-2.87 (m, 5H), 2.74 (s, 7H), 2.67 (s, 3H), 2.64-2.48 (m, 2H), 2.12 (s, 3H), 1.06 (m, 1H), 0.90 (m, 1H). LC/MS (ESI) m/z: 723/725 (M+H) ⁺ .

Scheme 88. Synthesis of 5-(3-acetyl-1-(2-((1R,3S,5R)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-methyl2-azabicyclo[3.1.0 ]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methylpyrimidine 1 oxide (228)

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Step 1. 4-Methyl-6-(2-methylpyrimidin-5-yl)pyridin-3-amine (228-S3): to a mixture of compound 228S1 (1.6 g, 8.6 mmol), (2-methylpyrimidin-5- yl)boronic acid (2.14 g, 15.5 mmol) and potassium carbonate (3.0 g, 21.5 mmol) in dioxane (18 ml) and water (2 ml) was added Pd(PPh ₃ ) ₄ (0.99 g, 0.86 mmol), and the mixture stirred at 80°C for 16 h in an atmosphere of N ₂ . The mixture was cooled and filtered and the filtrate was diluted with water (20 ml) and extracted with EtOAc (50 ml x 3). The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude product, which was recrystallized from EtOAc to give compound 228-S3 (750 mg, 43.6%) as a white solid. LC/MS (ESI) m/z: 201 (M+H)+.

Stage 2. 5-(2-Methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine (228-S4): to a mixture of compound 228-S3 (750 mg, 3.55 mmol) and potassium acetate (107 mg, 1.09 mmol) in CHCl ₃ (15 mL) was added acetic anhydride (869 mg, 8.51 mmol) at 0°C. The mixture was stirred at 25°C for 1 h and then heated to 60°C. tert-Butyl nitrite (831 mg, 8.05 mmol) was added dropwise and the mixture was stirred at 60° C. for 16 h. The mixture was cooled and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the crude product, which was recrystallized from EtOAc to give compound 228-S4 (300 mg, 40.1%) as a white solid. LC/MS (ESI) m/z: 212 (M+H) ⁺ .

Step 3. 3-Iodo-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine (228-S5): to a mixture of compound 228-S4 (300 mg, 1.42 mmol) in DMF was added KOH (179 mg, 3.20 mmol) and I ₂ (541 mg, 2.13 mmol) at 0°C. The mixture was stirred at room temperature for 1.5 h. The mixture was quenched with 5% aqueous Na ₂ S ₂ O ₃ (10 ml) and extracted with EtOAc (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give compound 228-S5 (350 mg, 73.1%) as a yellow solid. LC/MS (ESI) m/z: 338 (M+H) ⁺ .

Step 4 tert-Butyl 2-(3-iodo-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (228-S6): to mixture compound 228-S5 (350 mg, 1.04 mmol), tert-butyl 2-bromoacetate (304 mg, 1.56 mmol) in DMF (6 ml) was added K ₂ CO ₃ (287 mg, 2.08 mmol) and the mixture was stirred at room temperature during the night. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified with a silica gel column (eluting with petroleum ether:ethyl acetate = 5:1 to 1:1) to give compound 228-S6 (350 mg, 82.2%) as a white solid. LC/MS (ESI) m/z: 452 (M+H) ⁺ .

Step 5 tert-Butyl 2-(3-iodo-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (228-S8): to mixture compound 228-S6 (350 mg, 0.78 mmol) in toluene (15 mL), Pd(PPh ₃ ) ₄ (72 mg, 0.062 mmol) and tributyl(1-ethoxyvinyl)stannan (336 mg, 0.93 mmol) were added. The mixture was stirred at 100° C. for 16 hours under nitrogen. The reaction mixture was quenched with 0.5N. hydrochloride (10 ml) and stirred at room temperature for 1 h. The mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with brine, dried with Na ₂ SO ₄ and concentrated to dryness. The residue was purified with a silica gel column (eluting with petroleum ether:ethyl acetate = 5:1 to 1:1) to give compound 228-S8 (270 mg, 94.3%) as a white solid. LC/MS (ESI) m/z: 368 (M+H) ⁺ .

Step 6. 5-(3-Acetyl-1-(2-tert-butoxy-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2methylpyrimidine 1-oxide (228-S9) : m-366 041794 was added to a solution of compound 228-S8 (270 mg, 0.73 mmol).

CPBA (165 mg, 0.96 mmol). The mixture was stirred at room temperature for 16 h and then quenched with 5% Na2S2O ₃ solution and extracted with DCM. The organic layer was separated, dried and concentrated to give the crude product, which was purified with a silica gel column (eluting with DCM:MeOH=100:0 to 80:1) to give compound 228-S9 (110 mg, 39.3%) as a white solid substances. LC/MS (ESI) m/z: 384(M+H)+.

Step 7. 5-(3-Acetyl-1-(carboxymethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-methylpyrimidine 1 oxide (228-S10): NaOH solution (34 mg, 0.86 mmol) in 1 mL of water was added to a solution of compound 228-S9 (110 mg, 0.29 mmol) in methanol (1 mL) and THF (1 mL). The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue taken up in ether (20 ml) and more water (10 ml). The organic phase was separated and the aqueous phase was diluted with EtOAc and then acidified with 1N. HCl to approximately pH 5. The organic phase was washed with brine and dried, concentrated to give compound 228-S10 (80 mg, 84.2%) as a white solid. LC/MS (ESI) m/z: 328 (M+H)+.

Step 8. 5-(3-Acetyl-1-(2-((1R,3S,5R)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-5-methyl-2azabicyclo[3.1.0] hexan-2-yl)-2-oxoethyl)-1H-n-pyrazolo[3,4-c]pyridin-5-yl)-2-methylpyrimidine 1-oxide (228): to a solution of compound 228-S10 (80 mg, 0.244 mmol), compound 228-S11 (75 mg, 0.244 mmol) and HATU (139 mg, 0.366 mmol) in DMF (3 ml) were added DIPEA (127 mg, 0.976 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by preparative HPLC to give compound 228 (14 mg, 9.3%) as white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 9.32 (d, J=1.2 Hz, 1H), 9.17 (d, J=1.8 Hz, 1H), 8.91 (d, J= 1.9Hz, 1H), 8.69 (d, J=1.2Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 6.07 (d, J=17.3Hz , 1H), 5.75 (d, J=17.2 Hz, 1H), 4.43 (dd, J=9.2, 5.1 Hz, 1H), 3.60 (dd, J=5.5, 2.3 Hz, 1H), 2.69 (s, 3H) , 2.63 (s, 3H), 2.53-2.57 (m, 1H), 2.05-2.11 (m, 1H), 2.04 (s, 3H), 1.33 (s, 3H), 1.07-1.13 (m, 1H), 0.98 -1.04 (m, 1H). LC/MS (ESI) m/z: 619/621(M+H)+.

Scheme 89 α-lyloxymethyl)-N-(6-bromo-3-methyl-pyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (229)

Step 1. tert-Butyl 2-(3-acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (2293): to a mixture of compound 229-S1 (267 mg, 0.6 mmol) and compound 229-S2 (222 mg, 1.32 mmol) in toluene (10 mL) and H2O (2 mL) were added K ₃ PO ₄ (382 mg, 1.8 mmol) followed by the addition of Pd(dppf)Cl ₂ (44 mg,

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0.06 mmol). The reaction was stirred at 100°C for 16 h under N2. The mixture was cooled, diluted with EtOAc and washed with water and brine. The organic layer was separated, dried and concentrated to give the crude product, which was purified with a silica gel column (eluting

PE:EtOAc=20:1 to 2:1) to give compound 229-S3 (194 mg, 79.5%) as a white solid. LC/MS (ESI) m/z: 407(M+H)+.

Step 2. 2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (229S4): to a mixture of compound 229-S3 (130 mg, 0.32 mmol) in MeOH/THF (4 ml, 1:1) was added an aqueous solution of NaOH (39 mg, 0.96 mmol in 2 ml of water). The mixture was stirred at room temperature for 4 hours and then diluted with water (3 ml) and extracted with ether. The aqueous layer was taken and acidified with aqueous HCl (1N) to approximately pH 5. The resulting mixture was extracted with DCM/MeOH (20 ml x 2, 10:1, v/v) and the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 229-S4 (73 mg, 65.2%) as a white solid. LC/MS (ESI) m/z: 351(M+H)+.

Step 3. (1R,3S,5S)-2-tert-Butyl 3-ethyl 5-(allyloxymethyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (229-S7): to a mixture of compound 229-S5 (1.37 g, 4.8 mmol) in dry DMF (20 mL) was added NaH (384 mg, 9.6 mmol) at 0°C under N2 atmosphere and the mixture was stirred at room temperature for 40 min, then compound 229-S6 (3.24 g, 19.2 mmol) at 0°C in portions. The mixture was stirred at room temperature for 2 hours and the mixture was quenched with saturated aqueous NH ₄ Cl. The reaction was extracted with DCM and the organic layer was dried and concentrated to give crude compound 229-S7 (1.56 g, 99.9% yield) as a colorless oil which was taken on without further purification. LC/MS (ESI) m/z: 348(M+Na)+.

Step 4. (1R,3S,5S)-5-(Allyloxymethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3carboxylic acid (229-S8): to a mixture of compound 229-S7 ( 1.56 g, 4.8 mmol) in MeOH/THF (20 ml, 1:1) was added an aqueous solution of NaOH (384 mg, 9.6 mmol in 10 ml water). The mixture was stirred at room temperature for 4 hours and then diluted with water (20 ml). The reaction was extracted with ether and the aqueous layer was taken and acidified with aqueous HCl (1N) to pH approximately 5. The mixture was extracted with DCM/MeOH (20 ml x 2.10:1, v/v) and the combined organic phases were washed with brine , dried over anhydrous Na2SO4, filtered and concentrated to give compound 229-S8 (630 mg, 44.0%) as a colorless oil. LC/MS (ESI) m/z: 320(M+Na)+.

Step 5. (1R,3S,5S)-tert-Butyl 5-(allyloxymethyl)-3-(6-bromo-3-methylpyridin-2-ylcarbamoyl)-2azabicyclo[3.1.0]hexane-2-carboxylate (229- S10): to a solution of compound 229-S8 (210 mg, 0.71 mmol) and 6bromo-3-methylpyridin-2-amine (133 mg, 0.71 mmol) in dry DCM (6 mL) was added pyridine (280 mg, 3.55 mmol) at 0°C followed by dropwise addition of POCl ₃ (120 mg, 0.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then quenched with ice water and extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified with a silica gel column (eluting with PE:EtOAc = 12:1) to give compound 229-S10 (150 mg, 67.2%) as a colorless oil. LC/MS (ESI) m/z: 466/468 (M+H) ⁺ .

Step 6. (1R,3S,5S)-5-(Allyloxymethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (229-S11): TFA (2 ml) was added to a solution of compound 229-S10 (150 mg, 0.32 mmol) in DCM (2 ml) at room temperature under N ₂ atmosphere. The resulting mixture was stirred at room temperature for 2 h, and the mixture was concentrated to give compound 229-S11 (100 mg, 85.5%) as a colorless oil, which was immediately used in the next reaction without further purification. LC/MS (ESI) m/z: 366(M+H)+.

Step 7. (1 R,3S,5S)-2-(2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)5 -(allyloxymethyl)-M-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (229): to a solution of compound 229-S11 (100 mg, 0.21 mmol ), compound 229-S4 (73 mg, 0.21 mmol) and HATU (160 mg, 0.42 mmol) in DMF (2 mL) were added DIPEA (110 mg, 0.84 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with DCM:MeOH=100:0 to 80 :1) to give compound 229 (130 mg, 88.4%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.03 (s, 2H), 8.40 (d, J=1.7 Hz, 1H), 7.56-7.66 (m, 2H), 7.45 (d, J=7.9 Hz, 1H), 6.17-6.26 (m, 1H), 5.86-5.97 (m, 2H), 5.65 (d, J=17.5 Hz, 1H), 5.29 (dd, J=17.3, 1.9 Hz, 1H ), 5.18 (t, J=9.9Hz, 2H), 4.91 (d, J=17.1Hz, 1H), 4.48 (dd, J=9.4, 5.1Hz, 1H), 4.07 (dd, J=13.2, 5.4Hz , 1H), 3.99 (dd, J=13.2, 5.3 Hz, 1H), 3.78-3.86 (m, 1H), 3.67-3.75 (m, 2H), 3.58 (d, J=10.6 Hz, 1H), 3.47 ( d, J=10.7 Hz, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 2.24-2.35 (m, 2H), 2.05 (s, 3H), 1.17-1.21 (m, 1H), 1.03 -1.08 (m, 1H). LC/MS (ESI) m/z: 698/700 (M+H) ⁺ .

Scheme 90. Synthesis of (2S,4R)-1-(2-(3-acetyl-5-(2-((3-methyloxetan-3-yl)methylsulfonyl)ethoxy)-1Hindazol-1-yl)acetyl)-N -(6-bromo-3-methylpyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide (230)

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Stage 1. tert-Butyl 2-(3-acetyl-7-(but-3-enyl)-5-(2-methylpyrimidin-5-yl)-III-indazol-1yl)acetate (230-3): to the mixture compound 230-S1 (444 mg, 1 mmol) and compound 230-S2 (200 mg, 2 mmol) in toluene (15 ml) and H ₂ O (3 ml) was added K ₃ PO ₄ (637 mg, 3 mmol) with followed by the addition of Pd(dppf)Cl ₂ (74 mg, 0.1 mmol). The reaction was stirred at 100°C for 16 h under N ₂ atmosphere, then the mixture was cooled, diluted with EtOAc and washed with water and brine. The organic layer was separated, dried and concentrated to give the crude product, which was purified with a silica gel column (eluting with PE:acetone = 20:1 to 12:1) to give compound 230-S3 (354 mg, 84.1%) as a white solid substances. LC/MS (ESI) m/z: 421(M+H)+.

Step 2. 2-(3-Acetyl-7-allyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (230S4): to a mixture of compound 230-S3 (354 mg, 0.843 mmol) in MeOH/THF (12 ml, 1:1) was added 3 ml of an aqueous solution of NaOH (101 mg, 2.53 mmol). The mixture was stirred at room temperature for 4 hours, then the mixture was diluted with water (15 ml) and extracted with ether. The aqueous layer was taken and acidified with aqueous HCl (1N) to pH approximately 5. The resulting mixture was extracted with DCM/MeOH (20 ml x 2, 10:1, v/v). The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 230-S4 (280 mg, 90.9%) as a white solid. LC/MS (ESI) m/z: 365(M+H) ⁺ .

Step 3. (1R,3 S,5S)-2-(2-(3-Acetyl-7-(but-3-enyl)-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)acetyl)-5-(allyloxymethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (230): to a solution of compound 230-S4 (210 mg, 0.44 mmol), compound 230-S5 (160 mg, 0.44 mmol) and HATU (334 mg, 0.88 mmol) in DMF (4 mL) were added DIPEA (286 mg, 2.2 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried and concentrated to give the crude product, which was purified using a silica gel column (eluting with DCM:MeOH=100:0 to 80: 1) to give compound 230 (250 mg, 79.9%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (d, J=8.1 Hz, 1H), 8.95-9.10 (m, 2H), 8.36-8.40 (m, 1H), 7.56-7.64 (m, 2H ), 7.45 (d, J=7.9 Hz, 1H), 6.19-6.32 (m, 1H), 5.84-6.00 (m, 2H), 5.63-5.75 (m, 1H), 5.26-5.35 (m, 1H), 5.06-5.18 (m, 2H), 4.87-4.98 (m, 1H), 4.44-4.51 (m, 1H), 3.93-4.06 (m, 3H), 3.72-3.81 (m, 2H), 3.59 (d, J =10.5 Hz, 1H), 3.46-3.51 (m, 1H), 2.71 (s, 3H), 2.65 (s, 3H), 2.19-2.36 (m, 2H), 2.05 (s, 3H), 1.63-1.70 ( m, 1H), 1.411.50 (m, 1H), 1.16–1.25 (m, 1H), 0.92–1.06 (m, 1H). LC/MS (ESI) m/z: 712/714 (M+H) ⁺ .

Scheme 91 2-yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazol-3-carboxylate (467), 1{2-[(1R,3S,5R)-3-[(6-bromo -3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl]-2oxoethyl}-5-(2-methylpyrimidin-5-yl)indazol-3-carboxylic acids (469), and methyl 1-{2-[(1R,3S,5R)-3[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0 ]hexan-2-yl]-2-oxoethyl}-5-(2methylpyrimidin-5-yl)indazole-3-carboxylate (474)

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The above scheme and the following detailed description depict one non-limiting method for synthesizing compounds where the carboxylic acid at the R ⁶ position is functionalized by coupling with an amine using HATU. One skilled in the art will appreciate that ethylamine can be replaced with other amines to provide additional compounds of the present invention. Non-limiting examples of amine include methylamine, 2,2,2-trifluoroethylamine, isobutylamine, propylamine, butylamine, pentylamine, cyclopropylmethanamine, cyclobutylmethanamine, 2,2dimethyl-1-propylamine, ethylenediamine, N ¹ -methylethane-1,2-diamine, (2- aminoethyl)dimethylamine, aminocyclopropane, isopropylamine, allylamine, propargylamine, 1-cyclopropylethanamine, 2-cyclopropylpropan-2-amine, 2-methylpent-3-yn-2-amine and but-3-yn-2-amine.

Step 1. Methyl 5-bromo-1H-indazole-3-carboxylate (2): to a stirred suspension of 5-bromo-Shindazole-3-carboxylic acid (5.0 g, 21 mmol, 1 eq.) in methanol (84 ml, 2.0 mol, 100 eq.) was added sulfuric acid (10 g, 100 mmol, 5 eq.). The mixture was heated to 60° C. and stirred overnight at which point LC-MS showed quantitative conversion to the desired product. The mixture was then concentrated to a residue which was taken up in EtOAc (20 ml) and washed with water (20 ml). The aqueous layer was neutralized with saturated sodium bicarbonate and then extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with saturated aqueous bicarbonate, brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product 2 as a tan solid, which was used in the next step without purification.

Stage 2. Methyl 5-bromo-1-[2-(tert-butoxy)-2-oxoethyl]indazole-3-carboxylate (4): to a solution of methyl 5-bromo-1H-indazole-3-carboxylate (0.60 g, 2.4 mmol, 1 equiv.) in dimethylformamide (23 ml, 0.1 M, 39 vol.) at room temperature was added tert-butyl 2-bromoacetate (0.51 g, 0.38 ml, 2.6 mmol, 1.1 equiv.) and potassium carbonate ( 0.36 g, 2.6 mmol, 1.1 equiv.). The mixture was stirred overnight at room temperature under argon. The mixture was then concentrated, diluted with DCM, filtered through a pad of celite and then purified by silica gel column chromatography (eluting with 0-100% EtOAc in hexanes, gradient) to give 4.

Step 3 Methyl 1-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylate (6): 5-bromo-2-methylpyrimidine (250 mg , 1.44 mmol, 1 eq.), bis(pinacolato)diborone (0.385 g, 1.52 mmol, 1.05 eq.), potassium acetate (0.425 g, 4.34 mmol, 3 eq.) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (1:1) (0.106 g, 0.144 mmol, 0.1 equiv.) were combined in a sealed reaction vessel which was evacuated and filled with argon gas. The mixture was then diluted with 1,4-dioxane (5.0 ml,

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0.29 M, 20 vol) and heated to 90°C for 3 h, at which point LC-MS showed conversion to the target boronate. To this mixture was added potassium carbonate (0.665 g, 4.81 mmol, 3 eq.) mmol, 1 equiv.) and water (0.3 ml). The orange mixture was allowed to stir at 100° C. for 2 hours, at which point LC-MS showed a conversion peaking at a mass corresponding to the desired product. The mixture was diluted with EtOAc (20 ml) and washed with water. The aqueous layer was extracted once with EtOAc (20 ml). The organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an orange solid. This solid was then purified by silica gel chromatography eluting with a 15 CV gradient of 0-100% EtOAc in hexanes to give 6 as a colorless solid.

Step 4 [3-(Methoxycarbonyl)-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (7): to a stirred solution of methyl 1-[2-(tert-butoxy)-2- oxoethyl]-5-(2-methylpyrimidin-5-yl)indazole3-carboxylate (250 mg, 0.654 mmol, 1 equiv.) in 1,2-dichloroethane (6.54 ml, 0.1 M, 26 vol.) acid (1.00 ml, 13.1 mmol, 20 equiv.). The solution was stirred at room temperature for 24 hours. The mixture was concentrated under vacuum azeotropically with toluene (2x15 ml) and DCM (2x15 ml) to give 7 as a yellow solid. This material was transferred without further purification.

Alternatively, [3-(methoxycarbonyl)-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (7) was prepared as follows: molecular iodine (14 g, 56 mmol, 3.5 eq.) was taken up in methanol (160 ml, 0.1 M, 32 vol.) and [3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (5.0 g, 16 mmol, 1 equiv.) was added. ). Next, sodium methoxide (5.0 g, 97 mmol, 6 equiv.) was added as a solution in MeOH (30 ml). The resulting slurry was stirred vigorously at room temperature for 1 hour. The mixture was concentrated and then taken up in a 3:1 mixture of acetonitrile and 2-propanol (100 ml). The mixture was acidified with 1M HCl and the layers were separated. The aqueous layer was extracted with a 3:1 mixture of acetonitrile and 2-propanol (2x30 ml). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to give the desired product 7 as a tan solid. This material was transferred without further purification.

Step 5. Methyl 1-{2-[(1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2 -yl]-2-oxoethyl} -5-(2-methylpyrimidin-5-yl)indazol-3-carboxylate (467): to a stirred solution of [3-(methoxycarbonyl)-5-(2-methylpyrimidin-5-yl) indazol-1-yl]acetic acid (0.019 g, 0.058 mmol, 1 equiv.) and (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2azabicyclo[ 3.1.0]hexane-3-carboxamide (0.022 g, 0.070 mmol, 1.2 equiv.) in dimethylformamide (0.58 ml, 0.1 M, 30 vol.) )-1,1,3,3-tetramethyluronium hexafluorophosphate) (0.055 g, 0.15 mmol, 2.5 eq.) followed by the addition of diisopropylethylamine (0.023 g, 0.18 mmol, 3 eq.). The mixture was stirred at room temperature for 30 minutes at which point LC-MS showed quantitative conversion with a peak corresponding to the desired product. The reaction solution was immediately purified by reverse phase HPLC and concentrated to give methyl 1-{2-[(1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5- methyl 2-azabicyclo[3.1.0]hexan2-yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylate (467) as a white film.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.06 (s, 2H), 8.35 (s, 1H), 7.86 (s, 2H), 7.62 (d, J=7.9 Hz, 1H ), 7.44 (d, J=7.9Hz, 1H), 5.89 (d, J=17.2Hz, 1H), 5.57 (d, J=17.2Hz, 1H), 4.40 (dd, J=9.3, 5.1Hz, 1H ), 3.96 (s, 3H), 3.56 (t, J=4.0 Hz, 1H), 2.69 (s, 3H), 2.09-1.99 (m, 1H), 2.04 (s, 3H), 1.32 (s, 3H) , 1.30-1.22 (m, 1H), 1.00 (d, J=4.6 Hz, 2H).

Step 6. 1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2- yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylic acid (469): sodium hydroxide (0.23 ml, 0.23 mmol, 10 eq.) (1 M aq.) was added to a stirred suspension of methyl 1-{2-[(1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2- yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylate (15 mg, 0.023 mmol, 1 equiv.) in methanol (1.0 ml, 0.023 M, 69 vol.) at room temperature temperature. The mixture was stirred at room temperature for 2 hours, after which the mixture turned into a solution, and LC-MS showed the absence of starting material. The solution was immediately purified by reverse phase HPLC to give 1-{2-[(1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[ 3.1.0]hexan-2-yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylic acid (469) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 10.26 (s, 1H), 9.05 (s, 2H), 8.34 (d, J=1.2 Hz, 1H), 7.84 (s, 2H) , 7.63 (d, J=8.0Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 5.88 (d, J=17.2Hz, 1H), 5.55 (d, J=17.2Hz, 1H), 4.41 (dd, J=9.2, 5.1 Hz, 1H), 3.57 (t, J=4.0 Hz, 1H), 2.69 (s, 3H), 2.60-2.51 (m, 1H), 2.05 (dd, J=17.6, 4.2 Hz, 1H), 2.05 (s, 3H), 1.33 (s, 3H), 1.01 (d, J=4.1 Hz, 2H).

Step 7. 1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2- yl]-2-oxoethyl}-N-ethyl-5-(2-methylpyrimidin-5-yl)indazol-3-carboxamide (474): to a stirred solution of l-{2-[(1R,3S,5R)-3 -[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5

- 371 041794 methyl-2-azabicyclo[3.1.0]hexan-2-yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxylic acid (21 mg, 0.035 mmol) in dimethylformamide (1.5 ml) was added 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate N-oxide (0.026 g, 0.069 mmol) and diisopropylethylamine (0.024 ml, 0.139 mmol). The mixture was stirred at room temperature for 15 min and then ethylamine (0.17 mL, 0.35 mmol) was added. The mixture was stirred at room temperature for an additional 2 hours, at which point LC-MS showed conversion with a peak at the desired mass. The solution was filtered and immediately purified by reverse phase HPLC to give l-{2[(1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2 -azabicyclo[3.1.0]hexan-2-yl]-2oxoethyl}-N-ethyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide (10 mg, 0.016 mmol, 46% yield) as white solid.

1H NMR (400 MHz, methanol-^) δ 9.04 (s, 2H), 8.56 (s, 1H), 7.84-7.73 (m, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 5.73 (d, J=17.2 Hz, 1H), 5.63 (d, J=17.1 Hz, 1H), 4.55 (dd, J=9.3, 5.3 Hz, 1H), 3.51 (dt, J=14.4, 6.3 Hz, 3H), 2.77 (s, 3H), 2.67 (s, 1H), 2.67-2.57 (m, 1H), 2.33 (dd, J=13.4, 5.1 Hz, 1H), 2.16 (d , J=13.7 Hz, 3H), 1.42 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.07 (t, J=5.5 Hz, 1H), 0.95 (dd, J=5.5, 2.5 Hz , 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-methyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.57 (s, 1H), 8.47 (s, 3H), 7.79 (q, J=8.7 Hz, 2H), 7.57 (d, J=8.0Hz, 1H), 7.41(d, J=7.9Hz, 1H), 5.72(d, J=17.1Hz, 1H), 5.63(d, J=17.1Hz, 1H), 4.55(s, 1H) , 3.53 (s, 1H), 3.00 (s, 3H), 2.77 (s, 3H), 2.37-2.29 (m, 1H), 2.14 (s, 3H), 1.41 (s, 3H), 1.25 (m, 1H ), 1.07 (s, 1H), 0.94 (s, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-methyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.56 (s, 1H), 7.86-7.75 (m, 2H), 7.56 (d, J=7.9 Hz, 1H), 7.40 (d , J=8.0 Hz, 1H), 5.76 (d, J=17.0 Hz, 1H), 5.66 (d, J=17.1 Hz, 1H), 4.55 (t, J=7.2 Hz, 1H), 4.14 (dd, J =13.7.6.1 Hz, 2H), 3.54 (s, 1H), 2.77 (s, 3H), 2.70-2.54 (m, 2H), 2.38-2.28 (m, 1H), 2.14 (s, 3H), 1.42 ( s, 3H), 1.07 (d, J=5.7 Hz, 1H), 0.96 (s, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(2-methylpropyl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.03 (s, 2H), 8.55 (d, J=1.4 Hz, 1H), 8.41 (t, J=6.3 Hz, 1H), 7.82-7.72 (m, 2H ), 7.56 (d, J=7.9Hz, 1H), 7.39 (d, J=7.9Hz, 1H), 5.73 (d, J=17.1Hz, 1H), 5.62 (d, J=17.2Hz, 1H), 4.55 (dd, J=9.3, 5.2Hz, 1H), 3.53 (dd, J=5.6, 2.4Hz, 1H), 3.29 (t, J=6.4Hz, 2H), 2.77 (s, 3H), 2.70-2.57 (m, 1H), 2.32 (dd, J=13.5, 5.2 Hz, 1H), 2.13 (s, 3H), 1.97 (hept, J=6.7 Hz, 1H), 1.41 (s, 3H), 1.11-0.98 ( m, 7H), 0.95 (dd, J=5.5, 2.4 Hz, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl} -5-(2-methylpyrimidin-5-yl)-N-propylindazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.56 (s, 1H), 8.45 (d, J=5.9 Hz, 1H), 8.30 (s, 1H), 7.847.73 (m , 2H), 7.57 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.73 (d, J=17.1 Hz, 1H), 5.63 (d, J=17.1 Hz, 1H ), 4.55 (dd, J=9.2, 5.3 Hz, 1H), 3.57-3.50 (m, 1H), 3.48-3.34 (m, 2H), 2.77 (s, 3H), 2.70-2.57 (m, 2H), 2.33 (dd, J=13.7, 5.1 Hz, 1H), 2.14 (s, 3H), 1.70 (h, J=7.3 Hz, 2H), 1.41 (s, 3H), 1.11-0.92 (m, 5H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-butyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.56 (s, 1H), 8.41 (t, J=5.9 Hz, 1H), 8.24 (s, 1H), 7.847.73 (m , 2H), 7.57 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.73 (d, J=17.1 Hz, 1H), 5.63 (d, J=17.1 Hz, 1H ), 4.55 (dd, J=9.3, 5.2 Hz, 1H), 3.57-3.42 (m, 3H), 3.23 (dt, J=34.7, 6.7 Hz, 1H), 2.77 (s, 3H), 2.74-2.57 ( m, 2H), 2.38-2.28 (m, 1H), 2.14 (s, 3H), 1.66 (p, J=7.3 Hz, 2H), 1.60-1.49 (m, 1H), 1.41 (m, 3H), 1.11 -0.90 (m, 6H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl} -5-(2-methylpyrimidin-5-yl)-N-pentylindazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.56 (s, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 7.84-7.73 (m, 2H), 7.57 (d, J=8.0Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 5.73 (d, J=17.1Hz, 1H), 5.63 (d, J=17.1Hz, 1H), 4.55 (dd , J=9.3, 5.2 Hz, 1H), 3.56-3.50 (m, 1H), 3.46 (q, J=6.5 Hz, 2H), 2.77 (s, 3H), 2.70-2.57 (m, 2H), 2.33 ( dd, J=13.8, 5.2 Hz, 1H), 2.14 (s, 3H), 1.68 (s, 2H), 1.42 (d, J=5.2 Hz, 2H), 1.41 (s, 3H), 1.35 (s, 1H ), 1.07 (t, J=5.6 Hz, 1H), 1.000.92 (m, 4H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(cyclopropylmethyl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.56 (s, 1H), 8.46 (t, J=6.0 Hz, 1H), 8.23 (s, 1H), 7.847.73 (m , 2H), 7.56 (d, J=8.0 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.74 (d, J=17.2 Hz, 1H), 5.63 (d, J=17.1 Hz, 1H ), 4.56 (dd, J=9.4, 5.2 Hz, 1H), 3.54 (dd, J=5.7, 2.4 Hz, 1H), 3.36 (d, J=5.7 Hz, 1H), 2.77 (s, 3H), 2.70 -2.57 (m, 2H), 2.33 (dd, J=13.6, 5.2 Hz, 1H), 2.14 (s, 3H), 1.42 (s, 3H), 1.15 (q, J=6.4, 5.4 Hz, 1H), 1.08 (t, J=5.6 Hz, 1H), 0.96 (dd, J=5.6, 2.4 Hz, 1H), 0.61-0.51 (m, 2H), 0.34 (q, J=5.1 Hz, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(cyclobutylmethyl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

- 372 041794 ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.55 (d, J=1.5 Hz, 1H), 8.37 (dd, J=12.1, 6.1 Hz, 1H),

7.83-7.72 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 5.73 (d, J=17.1 Hz, 1H), 5.62 (d, J =17.1 Hz,

1H), 4.55 (dd, J=9.2, 5.2 Hz, 1H), 3.57-3.45 (m, 3H), 2.77 (s, 3H), 2.74-2.57 (m, 2H), 2.32 (dd, J=13.6, 5.2 Hz

1H), 2.13 (s, 3H), 2.19-2.06 (m, 2H), 2.02-1.78 (m, 4H), 1.41 (s, 3H), 1.07 (t, J=5.7 Hz, 1H), 0.95 (dd , J=5.6, 2.4

Hz, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(2,2-dimethylpropyl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.58-8.48 (m, 1H), 8.23 (t, J=6.6 Hz, 1H), 7.84-7.73 (m, 2H), 7.56 (d, J=8.0Hz, 1H), 7.40 (d, J=7.9Hz, 1H), 5.75 (d, J=17.2Hz, 1H), 5.64 (d, J=17.2Hz, 1H), 4.56 ( dd, J=9.3, 5.3 Hz, 1H), 3.54 (dd, J=5.6, 2.4 Hz, 1H), 3.30 (d, J=5.5 Hz, 2H), 2.77 (s, 3H), 2.70-2.57 (m , 1H), 2.33 (dd, J=13.7, 5.3 Hz, 1H), 2.13 (s, 3H), 1.41 (s, 3H), 1.38 (s, 1H), 1.02 (s, 8H), 1.00-0.90 ( m, 2H).

N-(2-aminoethyl)-1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0 ]hexan-2-yl]-2-oxoethyl}-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.04 (s, 2H), 8.58 (s, 1H), 8.49 (s, 2H), 7.88-7.76 (m, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.77 (d, J=17.3 Hz, 1H), 5.64 (d, J=17.2 Hz, 1H), 4.60-4.51 (m, 1H), 3.74 (t, J=5.6 Hz, 2H), 3.59-3.52 (m, 1H), 3.22 (t, J=5.8 Hz, 2H), 2.78 (s, 3H), 2.74-2.59 (m, 4H), 2.32 (dd, J=13.4, 5.4 Hz, 1H), 2.15 (s, 3H), 1.43 (s, 3H), 1.12 (t, J=5.5 Hz, 1H), 1.00-0.91 (m, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-K-[2-(methylamino)ethyl]-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.03 (s, 2H), 8.57 (s, 1H), 8.43 (s, 2H), 7.87-7.76 (m, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 5.77 (d, J=17.2 Hz, 1H), 5.64 (d, J=17.2 Hz, 1H), 4.55 (dd, J=9.1, 5.3 Hz, 1H), 3.77 (t, J=5.5 Hz, 2H), 3.59-3.52 (m, 1H), 3.29 (t, J=5.5 Hz, 2H), 2.78 (d, J=4.1 Hz, 6H), 2.74-2.57 (m, 2H), 2.32 (dd, J=13.5, 5.4 Hz, 1H), 2.15 (s, 3H), 1.42 (s, 3H), 1.12 (t, J=5.6 Hz, 1H), 0.97 (dd, J=5.6, 2.4Hz, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-K-[2-(dimethylamino)ethyl]-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, methanol-d4) δ 9.04 (s, 2H), 8.57 (s, 1H), 8.44 (s, 2H), 7.86-7.75 (m, 2H), 7.57 (d, J=7.9 Hz , 1H), 7.40 (d, J=8.0 Hz, 1H), 5.77 (d, J=17.2 Hz, 1H), 5.64 (d, J=17.2 Hz, 1H), 4.55 (dd, J=9.1, 5.2 Hz , 1H), 3.81 (t, J=5.9 Hz, 2H), 3.55 (dd, J=5.8, 2.3 Hz, 1H), 3.30 (d, J=5.7 Hz, 2H), 2.92 (s, 6H), 2.78 (s, 3H), 2.742.59 (m, 2H), 2.32 (dd, J=13.6, 5.2 Hz, 1H), 2.15 (s, 3H), 1.42 (s, 3H), 1.11 (t, J=5.5 Hz, 1H), 0.97 (dd, J=5.5, 2.4 Hz, 1H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-cyclopropyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 9.03 (s, 2H), 8.45 (d, J=4.6 Hz, 2H), 7.86-7.73 (m, 2H), 7.62 ( d, J=7.9Hz, 1H), 7.44 (d, J=7.9Hz, 1H), 5.80 (d, J=9.2, 5.3Hz, 1H), 5.75 (s, 1H), 5.47 (d, J=17.4 Hz, 1H), 4.38 (dd, J=9.2, 5.3 Hz, 1H), 3.55 (dd, J=5.5, 2.4 Hz, 1H), 2.91 (td, J=11.2, 4.4 Hz, 1H), 2.69 (s , 3H), 2.54 (dd, J=9.6, 3.7 Hz, 1H), 2.05 (d, J=13.6 Hz, 4H), 1.32 (s, 3H), 1.04-0.91 (m, 2H), 0.68 (tt, J=7.1, 2.2 Hz, 4H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-isopropyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.04 (s, 2H), 8.46 (d, J=1.5 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.89-7.75 (m, 2H), 7.63 (d, J=7.9Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 5.83 (d, J=17.4Hz, 1H), 5.76 (s, 0H ), 5.50 (d, J=17.3 Hz, 1H), 4.40 (dd, J=9.3, 5.2 Hz, 1H), 4.19 (dt, J=13.5, 6.7 Hz, 1H), 3.56 (dd, J=5.6, 2.4 Hz, 1H), 2.69 (s, 3H), 2.60-2.51 (m, 1H), 2.06 (d, J=12.4 Hz, 4H), 1.33 (s, 3H), 1.22 (dd, J=6.6, 1.4 Hz, 6H), 1.06-0.94 (m, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-5-(2-methylpyrimidin-5-yl)-N-(prop-2-en-1-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.04 (s, 2H), 8.56 (t, J=6.0 Hz, 1H), 8.46 (d, J=1.5 Hz, 1H) , 7.89-7.76 (m, 2H), 7.63 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 6.00-5.73 (m, 2H), 5.51 (d, J=17.3 Hz, 1H), 5.19 (dt, J=17.2, 1.8 Hz, 1H), 5.09 (dd, J=10.2, 1.7 Hz, 1H), 4.41 (dd, J=9.2, 5.1 Hz, 1H), 3.99-3.91 (m, 2H), 3.57 (dd, J=5.5, 2.4 Hz, 1H), 2.69 (s, 3H), 2.55 (dd, J=9.2, 4.3 Hz, 1H), 2.05 (s, 3H), 1.33 ( s, 3H), 1.05–0.93 (m, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-5-(2-methylpyrimidin-5-yl)-N-(prop-2-yn-1-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.05 (s, 2H), 8.81 (t, J=6.0 Hz, 1H), 8.46 (d, J=1.5 Hz, 1H), 7.89-7.77 (m, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 5.84 (d, J=17.3 Hz, 1H), 5.51 (d, J =17.2 Hz, 1H), 4.41 (dd, J=9.2, 5.2 Hz, 1H), 4.08 (dt, J=5.5, 2.5 Hz, 2H), 3.58 (dd, J=5.5, 2.4 Hz, 1H), 3.08 (t, J=2.5 Hz, 1H), 2.69 (s, 3H), 2.60-2.51 (m, 1H), 2.05 (s, 3H), 2.10-1.96 (m, 1H), 1.33 (s, 3H), 1.05-0.93 (m, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(1-cyclopropylethyl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.05 (s, 2H), 8.47 (d, J=1.4 Hz, 1H), 8.23 (dd, J=8.7, 2.0 Hz, 1H), 7.88-7.75 (m, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 5.86 (dd, J=17.5, 3.7 Hz, 1H), 5.77 (s, OH), 5.52 (dd, J=17.3, 3.9 Hz, 1H), 4.42 (dd, J=9.3, 5.2 Hz, 1H), 3.58 (dd, J=5.6, 2.4 Hz, 1H), 3.50 (q, J=8.1

- 373 041794

Hz, 1H), 2.70 (s, 3H), 2.61-2.53 (m, 1H), 2.08 (s, 3H), 2.01 (m, 1H), 1.31, (s, 3H), 1.32-1.25 (m, 3H ), 1.26-1.08 (m, 1H), 1.08-0.96 (m, 2H), 0.49 (m, 1H), 0.41 (m, 1H), 0.29 (ddt, J=29.4, 9.4, 4.5 Hz, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-Ni(2-methylbut-3-yn-2-yl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.06 (s, 2H), 8.46 (d, J=1.5 Hz, 1H), 7.92 (s, 1H), 7.897.75 (m , 2H), 7.63 (d, J=8.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 5.85 (d, J=17.3 Hz, 1H), 5.51 (d, J=17.2 Hz, 1H ), 4.40 (dd, J=9.2, 5.1 Hz, 1H), 3.57 (dd, J=5.3, 2.6 Hz, 1H), 3.19 (s, 1H), 2.70 (s, 3H), 2.60-2.51 (m, 1H), 2.05 (s, 3H), 2.00 (m, 1H), 1.68 (s, 6H), 1.33 (s, 3H), 1.06-0.96 (m, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-(2-cyclopropylpropan-2-yl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.05 (s, 2H), 8.46 (d, J=1.5 Hz, 1H), 7.87-7.76 (m, 2H), 7.63 (d , J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.25 (s, 1H), 5.84 (d, J=17.3 Hz, 1H), 5.51 (d, J=17.3 Hz, 1H ), 4.40 (dd, J=9.2, 5.1 Hz, 1H), 3.58 (t, J=4.0 Hz, 1H), 3.18 (d, J=4.7 Hz, 1H), 2.69 (s, 3H), 2.60-2.51 (m, 1H), 2.06 (m, 1H), 2.05 (s, 3H), 1.46 (dq, J=10.8, 6.2 Hz, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 1.02 ( d, J=4.0 Hz, 2H), 0.45-0.37 (m, 4H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-5-(2-methylpyrimidin-5-yl)-N-(sec-butyl)indazole-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.04 (s, 2H), 8.46 (t, J=1.2 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.87-7.75 (m, 2H), 7.63 (d, J=8.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 5.84 (d, J=17.4 Hz, 1H), 5.50 (d, J =17.3 Hz, 1H), 4.40 (dd, J=9.3, 5.2 Hz, 1H), 4.01 (p, J=7.1 Hz, 1H), 3.57 (d, J=5.0 Hz, 1H), 2.69 (s, 3H ), 2.60-2.51 (m, 1H), 2.06 (m, 1H), 2.05 (s, 3H), 1.33 (s, 3H), 1.32-1.21 (m, 1H), 1.19 (dd, J=6.7, 1.7 Hz, 3H), 1.06-0.95 (m, 2H), 0.89 (td, J=7.4, 2.2 Hz, 3H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-N-tert-butyl-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.05 (s, 2H), 8.46 (t, J=1.2 Hz, 1H), 7.87-7.75 (m, 2H), 7.63 (d , J=8.0 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.39 (s, 1H), 5.83 (d, J=17.4 Hz, 1H), 5.50 (d, J=17.3 Hz, 1H ), 4.40 (dd, J=9.3, 5.1 Hz, 1H), 3.61-3.54 (m, 1H), 2.69 (s, 3H), 2.60-2.51 (m, 1H), 2.06 (m, 1H), 2.05 ( s, 3H), 1.45 (s, 9H), 1.33 (s, 3H), 1.05–0.98 (m, 2H).

1-{2-[(1R,3S,5R)-3-[(6-Bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2-azabicyclo[3.1.0]hexan-2yl]- 2-oxoethyl}-Na(but-3-yn-2-yl)-5-(2-methylpyrimidin-5-yl)indazole-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.04 (s, 2H), 8.73 (d, J=8.3 Hz, 1H), 8.45 (s, 1H), 7.897.77 (m , 2H), 7.63 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 5.85 (d, J=17.7 Hz, 1H), 5.52 (d, J=17.7 Hz, 1H ), 4.92 (t, J=7.6 Hz, 1H), 4.45-4.36 (m, 1H), 3.57 (dd, J=5.4, 2.4 Hz, 1H), 3.21-3.13 (m, 1H), 2.69 (s, 3H), 2.602.51 (m, 1H), 2.06 (m, 1H), 2.05 (s, 3H), 1.46 (dd, J=7.0, 2.4 Hz, 3H), 1.33 (s, 3H), 1.06-0.95 (m, 2H).

Scheme 92. Synthesis of (1R,3S,5R)-2-{2-[3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1yl]acetyl}-N-ethyl-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (506)

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds where the carboxylic acid on the C-ring is functionalized by coupling to an amine using propanephosphonic anhydride (T3P). One skilled in the art will appreciate that ethylamine can be replaced with other amines to provide additional compounds of the present invention. Non-limiting examples of amines include propylamine, butylamine, arylamine, cyclopropylmethanamine, 2,2-dimethyl-1-propylamine, isobutylamine, methylamine, 1,3-propanediamine, dimethylaminopropylamine, amylamine, benzylamine, hexylamine, heptylamine, octylamine, and 2-phenylethylamine.

To a stirred solution of 1 (1 equiv.) in DCM (10 vol.) at 0°C under nitrogen atmosphere were added N,Ndiisopropylethylamine (DIEA) (3 equiv.) and propanephosphonic acid anhydride (T3P) (1.5 equiv.). The reaction mixture was stirred at 0°C for 10 min. Ethylamine was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated and immediately purified by reverse phase HPLC to give compound 506.

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.33 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.67 (d, J=17.8Hz, 1H), 4.16 (dd, J=9.1, 5.0Hz, 1H), 3.51 (dd, J=5.7, 2.3Hz, 1H) , 3.11-2.99 (m, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.38 (dd, J=13.1, 9.1 Hz, 1H), 1.90 (dd, J =13.1, 5.0

- 374 041794

Hz, 1H), 1.28 (s, 3H), 1.01 (m, 1H), 0.98 (t, J=7.2 Hz, 3H), 0.85 (dd, J=5.4, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-Npropyl-2- azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.33 (d, J=1.6 Hz, 1H), 7.79 (t, J=5.8 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.67 (d, J=17.8Hz, 1H), 4.18 (dd, J=9.1, 5.0Hz, 1H), 3.51 (dd, J=5.6, 2.4Hz, 1H ), 3.00 (q, J=6.6 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.40 (dd, J=13.1, 9.1 Hz, 1H), 1.90 (dd, J=13.0, 5.0Hz, 1H), 1.38 (h, J=7.2Hz, 2H), 1.28 (s, 3H), 1.01 (t, J=5.4Hz, 1H), 0.86 (m, 1H) , 0.81 (t, J=7.2 Hz, 3H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-butyl-5methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.33 (d, J=1.6 Hz, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.67 (d, J=17.7Hz, 1H), 4.17 (dd, J=9.1, 4.9Hz, 1H), 3.50 (dd, J=5.6, 2.4Hz, 1H ), 3.03 (q, J=6.7 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.2, 9.1 Hz, 1H), 1.90 (dd, J=13.2, 4.9 Hz, 1H), 1.41-1.29 (m, 2H), 1.28 (s, 3H), 1.27-1.17 (m, 2H), 1.01 (t, J=5.4 Hz, 1H), 0.84 (t, J=7.2 Hz, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N pentyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.77 (t, J=5.7 Hz, 1H), 7.63 (s, 1H) , 5.97 (d, J=17.8Hz, 1H), 5.67 (d, J=17.7Hz, 1H), 4.17 (dd, J=9.1, 4.9Hz, 1H), 3.50 (dd, J=5.6, 2.4Hz, 1H), 3.02 (q, J=6.6 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.1, 9.1 Hz, 1H), 1.90 (dd, J=13.2, 4.9 Hz, 1H), 1.37 (p, J=6.9 Hz, 2H), 1.31-1.14 (m, 7H), 1.01 (t, J=5.3 Hz, 1H), 0.89-0.78 (m, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N(cyclopropylmethyl)-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 8.35 (d, J=1.6 Hz, 1H), 7.87 (t, J=5.8 Hz, 1H), 7.66 (s, 1H), 6.01 (d, J=17.8Hz, 1H), 5.70 (d, J=17.7Hz, 1H), 4.23 (dd, J=9.1, 4.9Hz, 1H), 3.54 (dd, J=5.6, 2.3Hz, 1H ), 2.98 (t, J=6.1 Hz, 2H), 2.74-2.63 (m, 9H), 2.43 (dd, J=13.1, 9.1 Hz, 1H), 1.94 (dd, J=13.3, 4.9 Hz, 1H) , 1.32 (s, 3H), 1.04 (t, J=5.5 Hz, 1H), 0.89 (dq, J=6.2, 3.7 Hz, 2H), 0.38 (dt, J=8.6, 2.8 Hz, 2H), 0.16 ( p, J=3.9, 3.3 Hz, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-(2,2dimethylpropyl) -5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.71 (t, J=6.4 Hz, 1H), 7.63 (s, 1H) , 6.00 (d, J=17.8Hz, 1H), 5.66 (d, J=17.7Hz, 1H), 4.27 (dd, J=9.1, 5.0Hz, 1H), 3.53 (dd, J=5.6, 2.3Hz, 1H), 2.93 (dd, J=13.1, 6.7 Hz, 1H), 2.79 (dd, J=13.0, 6.0 Hz, 1H), 2.72-2.59 (m, 9H), 2.42 (dd, J=13.1, 9.1 Hz , 1H), 1.92 (dd, J=13.1, 4.9 Hz, 1H), 1.29 (s, 3H), 1.01 (t, J=5.4 Hz, 1H), 0.94-0.72 (m, 2H), 0.80 (s, 8H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (2 -methylpropyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.33 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.9 Hz, 1H), 7.63 (s, 1H), 5.98 (d, J=17.8Hz, 1H), 5.67 (d, J=17.7Hz, 1H), 4.21 (dd, J=9.1, 4.9Hz, 1H), 3.51 (dd, J=5.6, 2.3Hz, 1H ), 2.86 (h, J=6.6 Hz, 2H), 2.72-2.60 (m, 9H), 2.41 (dd, J=13.2, 9.1 Hz, 1H), 1.91 (dd, J=13.1, 5.0 Hz, 1H) , 1.66 (hept, J=6.7 Hz, 1H), 1.28 (s, 3H), 1.01 (t, J=5.4 Hz, 1H), 0.94-0.77 (m, 7H). (1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N,5-dimethyl-2- azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, methanol-d4) δ 8.97 (s, 2H), 8.41-8.35 (m, 1H), 7.52 (s, 1H), 5.89 (d, J=17.7 Hz, 1H), 5.78 (d , J=17.7 Hz, 1H), 4.30 (dd, J=9.2, 5.3 Hz, 1H), 3.46 (dd, J=5.6, 2.4 Hz, 1H), 2.78-2.65 (m, 12H), 2.51 (dd, J=13.4, 9.2Hz, 1H), 2.09 (dd, J=13.3, 5.4Hz, 1H), 1.38 (s, 3H), 1.10 (t, J=5.5Hz, 1H), 0.91 (dd, J=5.5 , 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(3-aminopropyl)-5methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 2H), 8.45 (s, 1H), 8.39 (s, 1H), 8.12 (t, J=5.9 Hz, 1H), 7.88 (d, J=7.6 Hz, 2H), 5.88 (dd, J=17.2, 12.1 Hz, 1H), 5.54 (d, J=17.2 Hz, 1H), 4.17 (dd, J=9.3, 4.8 Hz, 1H), 3.51 ( m, 1H), 3.31 (m, 1H) 3.11 (m, 2H), 2.91 (d, J=6.6 Hz, 1H), 2.68 (d, J=14.6 Hz, 7H), 2.40 (dt, J=16.3, 8.3 Hz, 1H), 1.91 (dd, J=12.8, 5.2 Hz, 1H), 1.62 (t, J=6.9 Hz, 1H), 1.53-1.45 (m, 1H), 1.28 (s, 3H), 0.99 ( p, J=5.1 Hz, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-N-[3(methylamino)propyl ]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.35 (s, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.88 (s, 2H), 5.89 (d, J =17.2 Hz, 1H), 5.54 (d, J=17.2 Hz, 1H), 4.16 (dd, J=9.2, 4.9 Hz, 1H), 3.51 (t, J=3.9 Hz, 1H), 3.11 (q, J =6.6 Hz, 2H), 2.70 (s, 3H), 2.66 (s, 3H), 2.58-2.61 (m, 3H), 2.28 (s, 3H), 1.92 (dd, J=13.1, 4.9 Hz, 1H) , 1.60 (p, J=6.9 Hz, 2H), 1.28 (s, 3H), 0.98 (s, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-[3(dimethylamino)propyl]-5- methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 2H), 8.23 (s, 1H), 7.87 (s, 2H), 5.87 (d, J=17.2 Hz, 1H), 5.54 (d, J=17.2 Hz, 1H), 4.17 (dd, J=9.2, 4.7 Hz, 1H), 3.49 (dd, J=5.4, 2.7 Hz, 1H), 3.07 (q, J=6.5 Hz, 2H), 2.70 ( d, J=15.4Hz, 3H), 2.66 (d, J=15.4Hz, 3H), 2.38 (dd, J=13.2, 9.1Hz, 1H), 2.20 (t, J=7.2Hz, 2H), 2.09 ( s, 6H), 1.92 (dd, J=13.1, 4.7 Hz, 1H), 1.51 (p, J=7.0 Hz, 2H), 1.28 (s, 3H), 1.03-0.94 (m, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-N-propyl-2- 375 041794 azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (m, 2H), 7.82 (m, 1H), 5.87 (d, J=17.2

Hz, 1H), 5.53 (d, J=17.2 Hz, 1H), 4.18 (dd, J=9.2, 4.6 Hz, 1H), 3.48 (dd, J=5.5, 2.5 Hz, 1H), 3.01 (q, J =6.5 Hz,

2H), 2.70 (s, 3H), 2.66 (s, 3H), 2.38 (dd, J=13.2, 9.1 Hz, 1H), 1.92 (dd, J=13.2, 4.6 Hz, 1H), 1.39 (h, J =7.2 Hz,

2H), 1.28 (s, 3H), 1.03-0.85 (m, 2H), 0.81 (t, J=7.4 Hz, 3H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-butyl-5-methyl-2azabicyclo[3.1. 0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.80 (t, J=5.8 Hz, 1H), 5.87 (d, J =17.2 Hz, 1H), 5.53 (d, J=17.2 Hz, 1H), 4.18 (dd, J=9.2, 4.5 Hz, 1H), 3.48 (dd, J=5.5, 2.5 Hz, 1H), 3.05 (q , J=6.7 Hz, 2H), 2.68 (d, J=14.0 Hz, 6H), 2.38 (dd, J=13.2, 9.2 Hz, 1H), 1.91 (dd, J=13.2, 4.6 Hz, 1H), 1.36 (p, J=7.0 Hz, 2H), 1.30-1.18 (m, 5H), 0.98 (dt, J=7.6, 5.0 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-N-pentyl-2azabicyclo[3.1. 0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.80 (t, J=5.8 Hz, 1H), 5.87 (d, J =17.2 Hz, 1H), 5.53 (d, J=17.2 Hz, 1H), 4.18 (dd, J=9.2, 4.5 Hz, 1H), 3.48 (dd, J=5.5, 2.5 Hz, 1H), 3.04 (q , J=6.6 Hz, 2H), 2.70 (s, 3H), 2.66 (s, 3H), 2.38 (dd, J=13.2, 9.2 Hz, 1H), 1.91 (dd, J=13.1, 4.5 Hz, 1H) , 1.37 (td, J=13.0, 11.7, 6.0 Hz, 2H), 1.33-1.16 (m, 7H), 1.06-0.93 (m, 2H), 0.81 (t, J=6.8 Hz, 3H).

(1R,3S,5R)-2- {2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(2,2dimethylpropyl)-5-methyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.44 (d, J=6.1 Hz, 1H), 7.86 (s, 2H), 7.69 (t, J=6.4 Hz, 1H), 5.90 (d, J=17.2Hz, 1H), 5.54 (d, J=17.1Hz, 1H), 4.27 (dd, J=9.2, 4.6Hz, 1H), 3.51 (dd, J=5.6, 2.4Hz, 1H) , 2.94 (dd, J=13.0, 6.8 Hz, 1H), 2.81 (dd, J=13.0, 6.0 Hz, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.40 (dd, J=13.2 , 9.2 Hz, 1H), 1.95 (dd, J=13.2, 4.6 Hz, 1H), 1.28 (s, 2H), 1.03-0.88 (m, 2H), 0.80 (s, 9H).

(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-benzyl-5-methyl-2azabicyclo[3.1. 0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 2H), 8.48-8.39 (m, 2H), 7.86 (s, 2H), 7.39-7.16 (m, 5H), 5.88 (d, J=17.2 Hz, 1H), 5.56 (d, J=17.2 Hz, 1H), 4.29 (m, 3H), 3.51 (t, J=4.1 Hz, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.44 (dd, J=13.2, 9.2 Hz, 1H), 1.97 (dd, J=13.2, 4.5 Hz, 1H), 1.28 (s, 3H), 1.01 (d, J=3.9 Hz, 2H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-hexyl-5methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.67 (d, J=17.8Hz, 1H), 4.17 (dd, J=9.1, 4.9Hz, 1H), 3.50 (dd, J=5.6, 2.3Hz, 1H ), 3.02 (q, J=6.5 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.1, 9.1 Hz, 1H), 1.89 (dd, J=13.1, 4.9 Hz, 1H), 1.36 (m, 2H), 1.28 (s, 3H), 1.29-1.21 (m, 6H), 1.01 (t, J=5.4 Hz, 1H), 0.88- 0.77 (m, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-heptyl-5methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.63 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.66 (d, J=17.7Hz, 1H), 4.17 (dd, J=9.0, 4.9Hz, 1H), 3.50 (dd, J=5.7, 2.3Hz, 1H) , 3.02 (q, J=6.5 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.2, 9.1 Hz, 1H), 1.89 ( dd, J=13.2, 5.0 Hz, 1H), 1.36 (q, J=7.0 Hz, 2H), 1.28 (s, 3H), 1.21 (m, 8H), 1.01 (t, J=5.4 Hz, 1H), 0.88-0.77 (m, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N octyl- 2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.33 (s, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.62 (s, 1H), 5.97 (d, J =17.8 Hz, 1H), 5.66 (d, J=17.8 Hz, 1H), 4.17 (dd, J=9.2, 5.0 Hz, 1H), 3.50 (dd, J=5.9, 2.3 Hz, 1H), 3.02 (q , J=6.6 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H) 2.39 (dd, J=13.1, 9.1 Hz, 1H), 1.89 (dd, J=13.0 , 4.9 Hz, 1H), 1.35 (s, 2H), 1.28 (s, 3H), 1.20 (m, 10H), 1.01 (t, J=5.5 Hz, 1H), 0.83 (dt, J=13.1, 5.9 Hz , 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-Nnonyl-2- azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.76 (t, J=5.8 Hz, 1H), 7.62 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.66 (d, J=17.8Hz, 1H), 4.17 (dd, J=9.1, 4.9Hz, 1H), 3.50 (dd, J=5.7, 2.3Hz, 1H ), 3.02 (q, J=6.6 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.1, 9.1 Hz, 1H), 1.89 (dd, J=13.2, 4.9 Hz, 1H), 1.35 (t, J=6.9 Hz, 2H), 1.28 (s, 3H), 1.28-1.16 (m, 12H), 1.01 (t, J=5.4 Hz, 1H), 0.83 (q, J=7.8, 7.0 Hz, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-decyl-5methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.76 (t, J=5.8 Hz, 1H), 7.62 (s, 1H), 5.97 (d, J=17.8Hz, 1H), 5.66 (d, J=17.8Hz, 1H), 4.17 (dd, J=9.1, 4.9Hz, 1H), 3.50 (dd, J=5.7, 2.3Hz, 1H) , 3.02 (q, J=6.6 Hz, 2H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.39 (dd, J=13.1, 9.1 Hz, 1H), 1.89 ( dd, J=13.2, 4.9 Hz, 1H), 1.35 (t, J=6.9 Hz, 2H), 1.28 (s, 3H), 1.28-1.16 (m, 14H), 1.01 (t, J=5.4 Hz, 1H ), 0.83 (q, J=7.8, 7.0 Hz, 4H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N - 376 041794 (2-phenylethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.33 (s, 1H), 7.89 (t, J=5.8 Hz, 1H), 7.63 (s, 1H), 7.22 (dd,

J=25.8, 7.1 Hz, 5H), 5.96 (d, J=17.7 Hz, 1H), 5.67 (d, J=17.7 Hz, 1H), 4.17 (dd, J=9.2, 4.9 Hz, 1H), 3.48 ( dd,

J=5.6, 2.3Hz, 1H), 3.24(m, 2H), 2.73-2.63(m, 11H), 2.35(dd, J=13.2,9.1Hz, 1H), 1.81(dd, J=13.2, 4.9Hz) ,

1H), 1.24 (s, 3H), 0.99 (t, J=5.4 Hz, 1H), 0.84 (dd, J=5.1, 2.3 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (3 -phenylpropyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.32 (s, 1H), 7.86 (t, J=5.5 Hz, 1H), 7.60 (s, 1H), 7.16 (m, 5H) , 5.98 (d, J=17.8Hz, 1H), 5.68 (d, J=17.7Hz, 1H), 4.18 (dd, J=9.2, 5.1Hz, 1H), 3.52 (dd, J=5.6, 2.3Hz, 1H), 3.05 (q, J=6.5 Hz, 2H), 2.74-2.57 (m, 11H), 2.41 (dd, J=13.2, 9.1 Hz, 1H), 1.92 (dd, J=13.2, 5.2 Hz, 1H ), 1.64 (dt, J=13.6, 6.7 Hz, 2H), 1.29 (s, 3H), 1.00 (t, J=5.5 Hz, 1H), 0.86 (dd, J=5.3,2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (4 -phenylbutyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.32 (d, J=1.6 Hz, 1H), 7.79 (t, J=5.8 Hz, 1H), 7.61 (s, 1H), 7.23 -7.09 (m, 5H), 5.97 (d, J=17.8Hz, 1H), 5.66 (d, J=17.7Hz, 1H), 4.16 (dd, J=9.1, 5.0Hz, 1H), 3.50 (dd, J=5.6, 2.3 Hz, 1H), 3.06 (q, J=6.5 Hz, 2H), 2.71-2.57 (m, 11H), 2.38 (dd, J=13.2, 9.1 Hz, 1H), 1.88 (dd, J =13.1, 5.0 Hz, 1H), 1.52 (tt, J=8.4, 4.7 Hz, 2H), 1.39 (p, J=7.2 Hz, 2H), 1.27 (s, 3H), 1.00 (t, J=5.4 Hz , 1H), 0.85 (dd, J=5.2, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (5 -phenylpentyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.32 (s, 1H), 7.77 (t, J=5.9 Hz, 1H), 7.61 (s, 1H), 7.30-7.09 (m, 5H), 5.97 (d, J=17.8 Hz, 1H), 5.66 (d, J=17.8 Hz, 1H), 4.16 (dd, J=9.1, 5.0 Hz, 1H), 3.50 (dd, J=5.6, 2.3 Hz, 1H), 3.02 (q, J=6.5 Hz, 2H), 2.71-2.53 (m, 11H), 2.37 (dd, J=13.2, 9.2 Hz, 1H), 1.87 (dd, J=13.1, 5.0 Hz , 1H), 1.52 (p, J=7.7 Hz, 2H), 1.40 (p, J=7.1 Hz, 2H), 1.26 (m, 5H), 1.00 (t, J=5.4 Hz, 1H), 0.85 (dd , J=5.5, 2.3 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (6 -phenylhexyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 8.32 (s, 1H), 7.76 (t, J=5.7 Hz, 1H), 7.61 (s, 1H), 7.31-7.19 (m , 2H), 7.13 (m, 3H), 5.97 (d, J=17.8 Hz, 1H), 5.66 (d, J=17.7 Hz, 1H), 4.17 (dd, J=9.1, 4.9 Hz, 1H), 3.533 .46(m, 1H), 3.01 (q, J=6.5 Hz, 2H), 2.71-2.54 (m, 11H), 2.38 (dd, J=13.2, 9.1 Hz, 1H), 1.89 (dd, J=13.2 , 4.9 Hz, 1H), 1.50 (t, J=7.5 Hz, 2H), 1.35 (s, 2H), 1.36-1.18 (m, 7H), 1.00 (t, J=5.5 Hz, 1H), 0.85 (dd , J=5.0, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-benzyl-5methyl-2 -azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (d, J=1.7 Hz, 2H), 8.42-8.31 (m, 2H), 7.63 (s, 1H), 7.32-7.19 (m, 5H), 5.98 (d, J=17.7 Hz, 1H), 5.78-5.65 (m, 1H), 4.28 (m, 3H), 3.55-3.49 (m, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.50-2.42 (m, 1H), 1.94 (dd, J=13.3, 4.8 Hz, 1H), 1.29 (s, 3H), 1.02 (d, J=5.5 Hz, 1H), 0.91 -0.85 (m, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-[(2methoxyphenyl)methyl ]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.34 (d, J=1.6 Hz, 1H), 8.19 (t, J=6.0 Hz, 1H), 7.63 (s, 1H), 7.30 -6.86 (m, 4H), 6.81 (t, J=1.4Hz, 1H), 5.99 (d, J=17.8Hz, 1H), 5.70 (d, J=17.8Hz, 1H), 4.31 (dd, J= 9.2, 4.9 Hz, 1H), 4.29-4.15 (m, 2H), 3.78 (s, 3H), 3.56-3.49 (m, 1H), 3.18 (s, 1H), 2.72-2.61 (m, 9H), 2.44 (dd, J=13.2, 9.1 Hz, 1H), 2.08 (s, 1H), 1.97 (dd, J=13.3, 4.8 Hz, 1H), 1.30 (s, 3H), 1.03(t, J=5.4 Hz, 1H), 0.88 (dd, J=5.2, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-[(3methoxyphenyl)methyl ]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.43-8.31 (m, 2H), 7.62 (s, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.81-6.70 (m, 3H), 5.99 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.39-4.17 (m, 3H), 3.54 (dd, J=5.6, 2.3 Hz, 1H), 3.52 (s, 3H), 3.18 (s, 1H), 2.69 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.45 (dd, J=13.1, 9.1 Hz, 1H ), 1.94 (dd, J=13.2, 5.2 Hz, 1H), 1.29 (s, 3H), 1.02 (t, J=5.3 Hz, 1H), 0.88 (dd, J=5.4, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-]4-[(4methoxyphenyl) methyl]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.36-8.25 (m, 2H), 7.63 (s, 1H), 7.13 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5Hz, 2H), 5.98(d, J=17.9Hz, 1H), 5.68(d, J=17.7Hz, 1H), 4.83(s, 6H), 4.23(dd, J=22.3, 5.1Hz, 3H), 3.69 (s, 3H), 3.52 (dd, J=5.7, 2.5 Hz, 1H), 3.18 (s, 1H), 2.72-2.61 (m, 9H), 2.43 (dd, J=13.2, 9.2 Hz , 1H), 2.08 (s, 2H), 1.93 (dd, J=13.1, 4.9 Hz, 1H), 1.28 (s, 3H), 1.22 (d, J=18.3 Hz, 0H), 1.01 (t, J= 5.4 Hz, 1H), 0.87 (dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N[( 1S)-1-phenylethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.33 (d, J=1.7 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.64 (t, J=1.5 Hz, 1H), 7.41-7.17 (m, 5H), 6.02 (d, J=17.9 Hz, 1H), 5.65 (d, J=17.8 Hz, 1H), 4.87 (p, J=7.1 Hz, 1H), 4.25 (dd, J=9.0, 5.4Hz, 1H), 3.53 (dd, J=5.6, 2.3Hz, 1H), 2.69 (s, 3H), 2.69 (s, 3H), 2.65 (s, 3H), 2.41 (dd, J=13.1,

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9.0 Hz, 1H), 1.83 (dd, J=13.0, 5.4 Hz, 1H), 1.30 (d, J=7.0 Hz, 3H), 1.23 (s, 3H), 0.99 (t, J=5.4 Hz, 1H) , 0.86 (dd,

J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K [( 1Н)-1-phenylethyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.33 (d, J=1.7 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.62 (d, J=1.7 Hz , 1H), 7.32-7.18 (m, 4H), 7.22-7.13 (m, 1H), 5.99 (d, J=17.8 Hz, 1H), 5.66 (d, J=17.8 Hz, 1H), 4.91 (p, J=7.0 Hz, 1H), 4.29 (dd, J=9.1, 4.9 Hz, 1H), 3.54 (dd, J=5.5, 2.4 Hz, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 2.65 (s, 3H), 2.42 (dd, J=13.2, 9.2 Hz, 1H), 1.92 (dd, J=13.2, 4.8 Hz, 1H), 1.40-1.14 (m, 6H), 1.02 (t, J= 5.4 Hz, 1H), 0.87 (dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-[(2fluorophenyl)methyl ]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.42-8.31 (m, 2H), 7.63 (s, 1H), 7.27 (q, J=7.2 Hz, 2H), 7.24-7.12 (m, 1H), 7.15-7.02 (m, 1H), 5.98 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H) 4.39-4.24 (m, 3H), 3.53 (dd , J=5.5, 2.3 Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.45 (dd, J=13.2, 9.1 Hz, 1H), 1.93 (dd, J=13.3, 5.0 Hz, 1H), 1.28 (s, 3H), 1.02 (t, J=5.4 Hz, 1H), 0.89 (dd, J=5.4, 2.3 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-[(3fluorophenyl)methyl ]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.46 (t, J=6.0 Hz, 1H), 8.33 (d, J=1.7 Hz, 1H), 7.63 (s, 1H), 7.31 (td, J=8.5, 6.3 Hz, 1H), 7.10-6.98 (m, 3H), 5.98 (d, J=17.8 Hz, 1H), 5.71 (d, J=17.8 Hz, 1H), 4.33-4.24 ( m, 3H), 3.53 (dd, J=5.7, 2.4 Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.49-2.41 (m, 1H), 1.94 (dd, J=13.2, 5.0 Hz, 1H), 1.29 (s, 3H), 1.03 (t, J=5.4 Hz, 1H), 0.89 (dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-N-[(4fluorophenyl)methyl ]-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.44-8.31 (m, 2H), 7.63 (s, 1H), 7.29-7.20 (m, 2H), 7.127.02 (m, 2H ), 5.98 (d, J=17.8Hz, 1H), 5.68 (d, J=17.8Hz, 1H), 4.26 (dd, J=7.9, 5.4Hz, 3H), 3.52 (dd, J=5.5, 2.4Hz , 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.65 (s, 3H), 2.44 (dd, J=13.2, 9.1 Hz, 1H), 1.93 (dd, J=13.2, 4.9 Hz, 1H), 1.28 (s, 3H), 1.02 (t, J=5.3 Hz, 1H), 0.88 (dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl-N[(2 -methylphenyl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.34 (d, J=1.7 Hz, 1H), 8.24 (t, J=5.8 Hz, 1H), 7.63 (s, 1H), 7.19-7.02(m, 4H), 5.99 (d, J=17.8 Hz, 1H), 5.69 (d, J=17.8 Hz, 1H), 4.34-4.16 (m, 3H), 3.53 (dd, J=5.7, 2.4 Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.45 (dd, J=13.1, 9.2 Hz, 1H), 2.23 (s, 3H), 1.95 ( dd, J=13.1, 5.0 Hz, 1H), 1.30 (s, 3H), 1.02 (t, J=5.4 Hz, 1H), 0.88 (dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K [( 3-methylphenyl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.39-8.31 (m, 2H), 7.63 (s, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.01 (dd, J=13.2, 7.6 Hz, 3H), 5.98 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.32-4.16 (m, 3H), 3.53 (dd, J=5.6 , 2.4 Hz, 1H), 2.70 (s, 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.45 (dd, J=13.2, 9.1 Hz, 1H), 2.18 (s, 3H), 1.95 (dd, J=13.2, 4.9 Hz, 1H), 1.30 (s, 3H), 1.03 (t, J=5.5 Hz, 1H), 0.88 (dd, J=5.2, 2.5 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K [( 4-methylphenyl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.36-8.29 (m, 2H), 7.63 (d, J=1.7 Hz, 1H), 7.08 (q, J=8.0 Hz, 4H ), 5.98 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.25 (m, 3H), 3.52 (dd, J=5.5, 2.5 Hz, 1H), 2.70 (s , 3H), 2.67 (s, 3H), 2.65 (s, 3H), 2.44 (dd, J=13.2, 9.2 Hz, 1H), 2.24 (s, 3H), 1.94 (dd, J=13.2, 4.9 Hz, 1H), 1.29 (s, 3H), 1.02 (t, J=5.4 Hz, 1H), 0.88 (dd, J=5.4, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K (pyrimidine -2-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.79-8.69 (m, 2H), 8.41-8.30 (m, 2H), 7.63 (s, 1H), 7.427.36 (m, 1H ), 5.99 (d, J=17.8 Hz, 1H), 5.69 (d, J=17.7 Hz, 1H), 4.49-4.42 (m, 2H), 4.37 (dd, J=9.1, 4.5 Hz, 1H), 3.51 (dd, J=5.5, 2.4 Hz, 1H), 2.69 (s, 3H), 2.68 (s, 3H), 2.65 (s, 3H), 2.43 (dd, J=13.2, 9.1 Hz, 1H), 2.15- 2.08 (m, 1H), 1.31 (s, 3H), 1.04 (t, J=5.2 Hz, 1H), 0.93-0.82 (m, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K (pyrimidine -4-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.06 (m, 3H), 8.59 (m, 2H), 8.34 (s, 1H), 7.64 (m, 1H), 7.31 (d, J=5.3 Hz, 1H) , 5.99 (d, J=17.8 Hz, 1H), 5.71 (d, J=17.8 Hz, 1H), 4.33 (m, 3H), 3.56-3.50 (m, 1H), 2.77-2.63 (m, 9H), 2.432.39 (m, 1H), 2.04-1.96 (m, 1H), 1.28 (s, 3H), 1.02 (t, J=5.6 Hz, 1H), 0.93-0.91 (m, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K (pyrimidine -5-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (d, J=2.9 Hz, 3H), 8.64 (s, 2H), 8.53 (t, J=5.9 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 7.62 (s, 1H), 5.97 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.32 (d, J=5.9 Hz, 2H), 4.25 ( dd, J=9.1, 5.3 Hz, 1H), 3.53 (dd, J=5.6, 2.3 Hz, 1H), 2.70 (s, 3H), 2.65 (s, 3H), 2.65 (s, 3H), 2.45 (dd , J=13.1, 9.1 Hz,

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1H), 1.92 (dd, J=13.3, 5.4 Hz, 1H), 1.28 (s, 3H), 1.01 (t, J=5.4 Hz, 1H), 0.90(dd, J=5.3, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-K (pyridine -2-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.60-8.51 (m, 2H), 8.34 (d, J=1.7 Hz, 1H), 7.80 (t, J=7.9 Hz, 1H) , 7.63 (s, 1H), 7.41-7.31 (m, 2H), 5.99 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8 Hz, 1H), 4.41 (d, J=5.9 Hz, 2H), 4.31 (dd, J=9.2, 5.2 Hz, 1H), 3.54 (dd, J=5.6, 2.4 Hz, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.65 (s, 3H ), 2.50-2.42 (m, 1H), 1.99 (dd, J=13.2, 5.2 Hz, 1H), 1.30 (s, 3H), 1.02 (t, J=5.5 Hz, 1H), 0.91 (dd, J= 5.2, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (pyridine -3-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.56 (dd, J=6.6, 4.0 Hz, 3H), 8.34 (d, J=1.6 Hz, 1H), 7.93 (d, J= 7.9Hz, 1H), 7.63(s, 1H), 7.55(dd, J=7.9, 5.2Hz, 1H), 5.97(d, J=17.8Hz, 1H), 5.70(d, J=17.8Hz, 1H) , 4.38 (d, J=5.9 Hz, 2H), 4.26 (dd, J=9.1, 5.4 Hz, 1H), 3.53 (dd, J=5.5, 2.4 Hz, 1H), 2.70 (s, 3H), 2.65 ( s, 3H), 2.64 (s, 3H), 2.50-2.41 (m, 1H), 1.93 (dd, J=13.0, 5.4 Hz, 1H), 1.29 (s, 3H), 1.01 (t, J=5.4 Hz , 1H), 0.90 (dd, J=5.2, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (pyridine -4-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 2H), 8.74-8.59 (m, 3H), 8.35 (d, J=1.6 Hz, 1H), 7.65-7.58 (m, 3H), 5.99 (d, J=17.8Hz, 1H), 5.70 (d, J=17.8Hz, 1H), 4.47 (d, J=5.9Hz, 2H), 4.30 (dd, J=9.2, 5.5Hz, 1H), 3.55 (dd, J=5.6, 2.4 Hz, 1H), 3.18 (s, 2H), 2.72-2.62 (m, 9H), 2.48 (s, OH), 1.97 (dd, J=13.2, 5.5 Hz, 1H), 1.31 (s, 3H), 1.02 (t, J=5.4 Hz, 1H), 0.93 (dd, J=5.4, 2.4 Hz, 1H).

(1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]-acetyl}-5-methyl-N (pyridazine -3-ylmethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6) δ 9.10 (dd, J=4.9, 1.6 Hz, 1H), 9.05 (s, 2H), 8.65 (t, J=6.0 Hz, 1H), 8.34 (d, J= 1.7 Hz, 1H), 7.63 (s, 1H), 7.54 (dd, J=8.5, 4.8 Hz, 1H), 7.47 (dd, J=8.6, 1.7 Hz, 1H), 5.98 (d, J=17.8 Hz, 1H), 5.70 (d, J=17.8Hz, 1H), 4.57 (d, J=5.9Hz, 2H), 4.29 (dd, J=9.2, 5.3Hz, 1H), 3.53 (dd, J=5.7, 2.4 Hz, 1H), 2.70 (s, 3H), 2.65 (s, 3H), 2.56 (s, 3H), 2.50-2.42 (m, 1H), 1.97 (dd, J=13.3, 5.2 Hz, 1H), 1.29 (s, 3H), 1.01 (t, J=5.5 Hz, 1H), 0.90 (dd, J=5.2, 2.5 Hz, 1H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-isopentyl-5methyl-2-azabicyclo [3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.06 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.81 (t, J=5.56 Hz, 1H), 5.87 (d, J=17.36 Hz, 1H), 5.53 (d, J=17.08 Hz, 1H), 4.16 (q, J=4.76 Hz, 1H), 3.07-3.05 (m, 2H), 2.68 (s, 3H), 2.66 ( s, 3H), 2.40-2.34 (m, 2H), 1.92-1.87 (m, 1H), 1.55-1.48 (m, 1H), 1.30-1.24 (m, 5H), 0.99-0.98 (m, 2H), 0.88-0.82 (m, 6H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-methyl-N-((S )-3methylbutan-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.51 (d, J=8.04 Hz, 1H), 5.91 (d, J =17.36 Hz, 1H), 5.53 (d, J=17.24 Hz, 1H), 4.19-4.16 (m, 1H), 3.57-3.53 (m, 2H), 2.70 (s, 3H), 2.66 (s, 3H) , 2.41-2.33 (m, 1H), 1.90-1.87 (m, 1H), 1.60-1.57 (m, 1H), 1.27 (s, 3H), 0.97-0.91 (m, 5H), 0.80 (t, J= 3.76Hz, 6H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-((S)-3, 3dimethylbutan-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.38 (d, J=9.60 Hz, 1H), 5.93 (d, J =17.32 Hz, 1H), 5.53 (d, J=17.12 Hz, 1H), 4.23 (q, J=5.20 Hz, 1H), 3.64 (q, J=6.56 Hz, 1H), 3.55-3.54 (m, 1H ), 2.70 (s, 3H), 2.66 (s, 3H), 2.38-2.33 (m, 2H), 1.90 (d, J=4.80 Hz, 1H), 1.27 (s, 3H), 0.93-0.92 (m, 4H), 0.79 (s, 9H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5-methyl-N-((S )pentan-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.52 (d, J=8.44 Hz, 1H), 5.90 (d, J =17.16 Hz, 1H), 5.52 (d, J=17.12 Hz, 1H), 4.13 (q, J=5.00 Hz, 2H), 3.73 (q, J=6.52 Hz, 1H), 3.52-3.51 (m, 1H ), 2.70 (s, 3H), 2.66 (s, 3H), 2.39-2.33 (m, 2H), 1.87 (d, J=4.76 Hz, 1H), 1.50-1.47 (m, 1H), 1.35-1.33 ( m, 1H), 1.27 (s, 3H), 1.27-1.20 (m, 1H), 1.17-0.97 (m, 4H), 0.80 (t, J=7.16 Hz, 3H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-((S)-hexane- 2yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.52 (d, J=8.44 Hz, 1H), 5.90 (d, J =17.20 Hz, 1H), 5.52 (d, J=17.20 Hz, 1H), 4.14 (q, J=4.80 Hz, 1H), 3.73-3.69 (m, 1H), 3.52-3.51 (m, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.41-2.34 (m, 1H), 1.87 (d, J=5.40 Hz, 1H), 1.37-1.32 (m, 3H), 1.27 (s, 3H), 1.25-1.21 (m, 4H), 1.19-0.99 (m, 4H), 0.77 (t, J=7.04 Hz, 3H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-((S)-heptan- 2yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.05 (s, 2H), 8.45 (s, 1H), 7.87 (s, 2H), 7.52 (d, J=8.44 Hz, 1H), 5.90 (d, J=17.36 Hz, 1H), 5.52 (d, J=16.88 Hz, 1H), 4.14 (q, J=4.84 Hz, 1H), 3.73-3.69 (m, 1H), 3.56-3.48 (m, 1H), 2.69

- 379 041794 (s, 3H), 2.66 (s, 3H), 2.41-2.34 (m, 2H), 1.87 (d, J=4.56 Hz, 1H), 1.34-1.33 (m, 2H), 1.27 (s, 3H), 1.24-1.10 (m,

6H), 1.00-0.96 (m, 4H), 0.77 (t, J=6.48 Hz, 3H).

(1R,3 S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-((S)- 1-(4fluorophenyl)ethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.06 (s, 2H), 8.46 (s, 1H), 8.23 (d, J=8.04 Hz, 1H), 7.87 (s, 2H), 7.307.27 (m, 2H), 7.06 (t, J=8.84Hz, 2H), 5.92 (d, J=17.24Hz, 1H), 5.54 (d, J=17.16Hz, 1H), 4.89 (t, J=7.36Hz , 1H), 4.21 (q, J=5.24 Hz, 1H), 3.53 (t, J=3.96 Hz, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.42-2.34 (m, 1H) , 1.84 (d, J=5.32 Hz, 1H), 1.32 (d, J=7.00 Hz, 3H), 1.24 (s, 3H), 0.97-0.96 (m, 2H).

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-((S)-1- (2,3dimethylphenyl)ethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.07 (s, 2H), 8.46 (s, 1H), 8.20 (d, J=7.64 Hz, 1H), 7.87 (s, 2H), 7.127.10 ( m, 1H), 7.01-6.99 (m, 2H), 5.92 (d, J=17.28 Hz, 1H), 5.53 (d, J=17.04 Hz, 1H), 5.07 (t, J=7.16 Hz, 1H), 4.22 (q, J=5.52 Hz, 1H), 3.52-3.52 (m, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.40-2.33 (m, 2H), 2.21 (s, 3H) , 2.14 (s, 3H), 1.82 (d, J=5.00 Hz, 1H), 1.26-1.23 (m, 4H), 1.17-1.14 (m, 1H), 0.97-0.88 (m, 2H).

Scheme 93. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -4-carbamoylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (503)

493 503

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds where the carboxylic acid on the C-ring is functionalized using HATU and ammonium chloride. One skilled in the art will appreciate that the A-ring may be replaced with other A-rings to provide additional compounds of the present invention. One of skill in the art will also appreciate that the C-ring can be functionalized using coupling reagents other than HATU.

To a mixture of compound 493 (20 mg, 0.032 mmol) and NH ₄ Cl (2 mg, 0.041 mmol) in DMF (2 mL) was added HATU (0.016 g, 0.041 mmol) and DIPEA (0.012 g, 0.095 mmol), and the mixture was stirred at 25°C for 12 hours the Mixture was diluted with EtOAc and washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give compound 503 (6.5 mg, 32.5% yield) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 9.52 (s, 1H), 8.93 (s, 2H), 8.42 (s, 1H), 8.31 (s, 1H), 7.52-7.20 (m, 3H), 6.82 (s , 1H), 6.32 (s, 1H), 5.43 (dd, J=38.5, 16.2 Hz, 2H), 4.73 (m, 1H), 3.20 (m, 1H), 2.86 (s, 3H), 2.64 (s, 3H), 2.33 (m, 2H), 1.31 (s, 3H), 1.04 (m, 1H), 0.91 (m, 1H). LC/MS (ESI) m/z: 631/633 (M+H)+.

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(4-(2-amino -2oxoethyl)-6-bromopyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.54 (s, 1H), 8.06 (s, 1H), 7.80 (m, 2H), 7.24 (m, 1H), 5.82 (d, J= 17.4 Hz, 1H), 5.64 (d, J=17.2 Hz, 1H), 4.48 (m, 1H), 3.55 (m, 1H), 3.51 (m, 2H), 2.75 (s, 3H), 2.70 (s, 3H), 2.63-2.49 (m, 1H), 2.20-2.16 (m, 1H), 1.37 (s, 3H), 1.07 (m, 1H), 0.99 (m, 1H). LC/MS (ESI) m/z: 645/647 (M+H) ⁺ .

(1R,3 S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5-methyl-N-( (S)-1 (p-tolyl)ethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD): δ 9.07 (s, 2H), 8.57 (s, 1H), 7.80 (s, 2H), 7.16 (d, J=8.00 Hz, 2H), 7.10 (d, J=8.40 Hz, 2H), 5.78 (d, J=17.20 Hz, 1H), 5.61 (d, J=17.20 Hz, 1H), 4.95-4.94 (m, 1H), 4.37-4.33 (m, 1H), 3.493.47 (m, 1H), 2.79 (s, 3H), 2.71 (s, 3H), 2.51-2.46 (m, 1H), 2.30 (s, 3H), 2.01-1.96 (m, 1H), 1.39 (d, J =6.80 Hz, 3H), 1.31 (s, 3H), 1.05 (t, J=5.60 Hz, 1H), 0.95-0.93 (m, 1H).

(1R,3 S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-((S)- 1 -(3 chlorophenyl)ethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, CD3OD): δ 9.07 (s, 2H), 8.58 (s, 1H), 7.84-7.79 (m, 2H), 7.31-7.27 (m, 2H), 7.25-7.22 (m, 2H) , 5.79 (d, J=17.20 Hz, 1H), 5.64 (d, J=17.20 Hz, 1H), 4.95-4.85 (m, 1H), 4.37-4.34 (m, 1H), 3.50-3.48 (m, 1H ), 2.79 (s, 3H), 2.72 (s, 3H), 2.54-2.49 (m, 1H), 1.99 (d, J=5.60 Hz, 1H), 1.42 (d, J=7.20 Hz, 3H), 1.32 (s, 3H), 1.08–1.05 (m, 1H), 0.97–0.96 (m, 1H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-((S)- 1-(2fluorophenyl)ethyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.07 (s, 2H), 8.46 (s, 1H), 8.31 (d, J=7.52 Hz, 1H), 7.90 (s, 2H), 7.32-380 041794

7.22 (m, 2H), 7.12-7.04 (m, 2H), 5.94 (d, J=17.12 Hz, 1H), 5.54 (d, J=17.20 Hz, 1H), 5.08 (t, J=6.92 Hz, 1H ),

4.22 (q, J=4.72 Hz, 1H), 3.53-3.43 (m, 1H), 2.70 (s, 3H), 2.66 (s, 3H), 2.43-2.33 (m, 1H), 1.85-1.81 (m, 1H),

1.32 (d, J=6.96 Hz, 3H), 1.13 (s, 3H), 0.96 (d, J=3.40 Hz, 2H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5 -(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-5-methyl-N-( (S)-1 phenylethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

¹ H NMR (400 MHz, CD3OD): δ 9.06 (s, 2H), 8.57 (s, 1H), 7.81 (s, 2H), 7.30-7.30 (m, 4H), 7.29-7.18 (m, 1H), 5.79 (d, J=17.20 Hz, 1H), 5.63 (d, J=17.20 Hz, 1H), 5.12-5.06 (m, 1H), 4.38-4.34 (m, 1H), 3.49-3.48 (m, 1H) , 2.79 (s, 3H), 2.72 (s, 3H), 2.50 (q, J=9.20 Hz, 1H), 1.99 (q, J=5.20 Hz, 1H), 1.42 (d, J=6.80 Hz, 3H) , 1.32 (s, 3H), 1.07–1.04 (m, 1H), 0.95–0.93 (m, 1H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-5-methyl-N-( R)-1 phenylethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 2H), 8.45 (s, 1H), 8.20 (d, J=8.24 Hz, 1H), 7.87 (s, 2H), 7.307.19 (m , 5H), 5.90 (d, J=17.24Hz, 1H), 5.54 (d, J=17.20Hz, 1H), 4.92 (t, J=7.88Hz, 1H), 4.27 (q, J=4.76Hz, 1H ), 2.69 (s, 3H), 2.63 (s, 3H), 2.44-2.33 (m, 2H), 1.92 (d, J=4.72 Hz, 1H), 1.36-1.24 (m, 6H), 1.00-0.98 ( m, 2H).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-K-(3,3dimethylbutyl) -5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.06 (s, 2H), 8.45 (d, J=0.92 Hz, 1H), 7.87 (s, 2H), 7.79 (t, J=5.64 Hz, 1H) , 5.87 (d, J=17.32 Hz, 1H), 5.53 (d, J=17.12 Hz, 1H), 4.17-4.13 (m, 1H), 3.47 (s, 1H), 3.05 (q, J=7.92 Hz, 2H), 2.70 (s, 3H), 2.66 (s, 3H), 2.39-2.33 (m, 1H), 2.09-2.08 (m, 1H), 1.31-1.26 (m, 4H), 0.99-0.97 (m, 2H), 0.96 (s, 1H), 0.87 (s, 9H).

Scheme 94. Synthesis of (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5yl)-1H-indazole -1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (310)

sic

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with R ²⁰¹ nucleophilic groups on the C-ring. One skilled in the art will appreciate that the pyrazole may be substituted with other nucleophilic reagents to provide additional compounds of the present invention. Non-limiting examples of groups that a person skilled in the art can use instead of pyrazole include: triazole, imidazole, azetidine, or the like.

Step 1. 2-(tert-butyl)-3-ethyl-(1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane2,3- dicarboxylate (2): sodium hydride (0.02 g, 0.51 mmol) was added to pyrazole (0.035 g, 0.51 mmol) in DMF (0.5 ml) with stirring. After 20 min at room temperature, 2-tert-butyl 3-ethyl (1R,3S,5S)-5-[(methanesulfonyloxy)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate 1 (0.124 g, 0.34 mmol) in DMF (2 ml). The mixture was stirred at 60° C. for 3 hours to give a racemic mixture. The resulting solid was removed by filtration and the filtrate was purified by HPLC to give 2-tert-butyl 3-ethyl (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-2azabicyclo[3.1 .0]hexane-2,3-dicarboxylate 2 (24 mg).

Stage 2. (1 R,3 S,5R)-5-(( 1 H-pyrazol-1 -yl)methyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid ( 3): 2-(tert-butyl)-3-ethyl-(1R,3S,5R)-5-((1H-pyrazol-1yl)methyl)-2-azabicyclo[3.1.0]hexane-2,3- dicarboxylate 2 (24 mg, 0.072 mmol) was treated with lithium hydroxide (1.5N, 0.072 mL, 0.107 mmol) in THF (1 mL) and ethanol (0.1 mL) at room temperature overnight. After completion of the reaction, Amberlite CG-50 (0.1 g) was added and the mixture was stirred for 30 min. The resin was removed by filtration and washed with MeOH. The solvent was removed under reduced pressure to give (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid 3 (25 mg).

- 381 041794

Step 3. tert-Butyl (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-2-azabicyclo[ 3.1.0]hexane-2-carboxylate (4): into a mixture of (1R,3S,5R)-5-((1H-pyrazol-1yl)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1. 0]hexane-3-carboxylic acid 3 (25 mg) and 6bromo-3-methylpyridin-2-amine (15.2 mg) in DCM (1.5 ml) was added pyridine (0.033 ml, 0.407 mmol) followed by the addition of phosphoryl chloride (7.6 μm, 0.081 mmol) with stirring. After 2 h was added an aqueous solution of NaHCO ₃ . The mixture was extracted with DCM. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH in DCM 010%) to give t-butyl (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)- 3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate S4 (23 mg).

Step 4. (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane- 3-carboxamide, TFA salt (5): tert-butyl (1R,3S,5R)-5-((1H-pyrazol-1yl)methyl)-3-((6-bromo-3-methylpyridin-2-yl) carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate 4 (23 mg, 0.048 mmol) was treated with TFA (1.0 ml) in DCM (1 ml) at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene (5 ml x 2) to give (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-N-(6-bromo-3-methylpyridin-2 -yl)-2azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt, 5, for next step.

Step 5. (1R,3S,5R)-5-((1H-Pyrazol-1-yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1Hindazol- 1 -yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (310): to a mixture of (1R,3S,5R)- N-(6-bromo-3-methylpyridin-2-yl)-5-(pyrazol-1-ylmethyl)-2-azabicyclo[3.1.0]hexane-3carboxamide, TFA salt 5 (0.048 mmol) and [3-acetyl -5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid 6 (0.015 g, 0.048 mmol) in DMF (1 ml) was added TBTU (0.023 g, 0.072 mmol) followed by the addition of N,N- diisopropylethylamine (0.062 g, 0.084 ml, 0.48 mmol) with stirring. After completion of the reaction, an aqueous solution of NaHCO ₃ was added. The mixture was extracted with EtOAc and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (MeOH in DCM 0-10%) to give (1R,3S,5R)-5-((1H-pyrazol-1-yl)methyl)-2-(2-(3- acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3 -carboxamide (310) (25 mg).

1H NMR (400 MHz, chloroform-d) δ 8.93-8.86 (m, 2H), 8.74 (s, 1H), 8.59-8.52 (m, 1H), 7.70-7.59 (m, 2H), 7.55-7.51 (m , 1H), 7.45 (q, J=2.1 Hz, 1H), 7.34 (dd, J=3.5, 8.3 Hz, 1H), 7.23 (dd, J=4.0, 7.9 Hz, 1H), 6.27 (p, J= 2.2 Hz, 1H), 5.57-5.42 (m, 2H), 4.88 (s, 1H), 4.53 (dd, J=7.2, 14.1 Hz, 1H), 4.35 (dt, J=2.2, 14.3 Hz, 1H), 3.49 (dd, J=2.8, 5.8Hz, 1H), 2.80 (d, J=2.3Hz, 3H), 2.70 (dd, J=1.5, 2.6Hz, 3H), 2.26 (dd, J=8.7, 13.7Hz , 1H), 1.26 (q, J=6.3 Hz, 1H), 1.03 (dd, J=3.5, 6.0 Hz, 1H). LC (method A): t _R = 1.62 min. LC/MS (EI) m/z: [M+H]+ 668.

(1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin- 2-yl)-5-((3-(tert-butyl)-1H-pyrazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide:

1H NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.70 (d, J=14.2 Hz, 1H), 8.57 (dd, J=0.8, 1.7 Hz, 1H), 7.70-7.56 (m, 2H), 7.39-7.19 (m, 4H), 6.09 (d, J=2.3 Hz, 1H), 5.48 (s, 2H), 4.89 (d, J=7.9 Hz, 1H), 4.53 (d, J=14.4 Hz, 1H), 4.34 (d, J=14.3 Hz, 1H), 4.12 (q, J=7.1 Hz, 1H), 3.39 (dd, J=2.7, 5.8 Hz, 1H), 2.81 (s, 4H), 2.70 (s, 4H), 2.28 (t, J=11.3 Hz, 1H), 2.05 (d, J=3.5 Hz, 4H), 1.99 (s, 2H), 1.28 (s, 9H), 1.20-1.15 (m , 1H), 0.96 (dd, J=2.7, 5.9 Hz, 1H). LC (method A): t _R = 2.22 min. LC/MS (EI) m/z: [M+H]+ 724.

(1R,3S,5R)-5-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl) -1Hindazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide:

1H NMR (400 MHz, chloroform-d) δ 8.90 (d, J=2.6 Hz, 2H), 8.81 (s, 1H), 8.56 (t, J=2.2 Hz, 1H), 8.20 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.67-7.55 (m, 2H), 7.38-7.30 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 5.61-5.41 (m, 2H), 4.91 (d, J=8.2Hz, 1H), 4.62 (d, J=14.0Hz, 1H), 4.30 (d, J=14.4Hz, 1H), 3.58 (dd, J=5.9, 2.8Hz, 1H), 2.80 (d, J=2.0Hz, 3H), 2.71 (d, J=2.1Hz, 3H), 2.21 (q, J=15.8, 13.0Hz, 2H), 2.03 (d, J=2.5Hz, 3H), 1.38 (t, J=5.8 Hz, 1H), 1.12 (dd, J=6.1, 2.9 Hz, 1H). LC (method A): t _R =1.36 min. LC/MS (EI) m/z: [M+H]+ 669.

(1R,3S,5R)-5-((1H-1,2,4-Triazol-1-yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl) -1Hpyrazolo[3,4-c]pyridin-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide:

1H NMR (400 MHz, chloroform-d) δ 9.28 (s, 2H), 9.10 (d, J=1.3 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.34 (dd, J=0.8, 7.9 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H), 5.73-5.50 (m, 2H), 4.92 ( d, J=8.4 Hz, 1H), 4.62 (d, J=14.4 Hz, 1H), 4.34 (d, J=14.4 Hz, 1H), 3.64 (dd, J=2.8, 5.9 Hz, 1H), 2.81 ( s, 3H), 2.76 (s, 1H), 2.72 (s, 3H), 2.32 (s, 1H), 2.04 (s, 3H), 1.43 (t, J=6.0 Hz, 1H), 1.18 (dd, J =2.9, 6.1 Hz, 1H). LC (method a): t _R =1.27 min. LC/MS (EI) m/z: [M+H]+ 670.

Scheme 95. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -3-methylpyridin-2-yl)-5-((4-methyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (314) and (1R,3R,5R )-5-((1H-1,2,4-triazol-1-yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin5-yl)-1H-pyrazolo[3,4 -c]pyridin-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (315)

- 382 041794

Stage 1. 2-tert-Butyl 3-ethyl (1R,5R)-5-[(4-methylimidazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane2,3-dicarboxylate (2): in 4-methyl-1Н-imidazole (0.042 g, 0.51 mmol) in DMF (0.5 ml) was added sodium hydride (0.02 g, 0.51 mmol) at room temperature with stirring. After 15 min, 2tert-butyl 3-ethyl (1R,3S,5S)-5-[(methanesulfonyloxy)methyl]-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate 1 (0.124 g, 0.34 mmol) in DMF was added (2 ml), and the mixture was stirred at 60°C for 3 h to obtain a racemic mixture. The solid was removed by filtration and the filtrate was purified by HPLC to give 2-tert-butyl 3-ethyl (1R,5R)-5-[(4-methylimidazol-1-yl)methyl]-2azabicyclo[3.1.0]hexane- 2,3-dicarboxylate 2 (59 mg).

Step 2. (1R,5R)-2-(tert-butoxycarbonyl)-5-[(4-methylimidazol-1-yl)methyl]-2azabicyclo[3.1.0]hexane-3-carboxylic acid (3): 2- tert-butyl 3-ethyl (1R,5R)-5-[(4-methylimidazol-1yl)methyl]-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate S2 (57.4 mg) was treated with lithium hydroxide (10 mg) in THF (2 ml), ethanol (0.15 ml) and water (0.15 ml) at room temperature for 4 days. Amberlite CG-50 (0.2 g) was added and the mixture was stirred for 30 minutes. The resin was removed by filtration and washed with MeOH. The solvent was removed under reduced pressure to give (1R,5R)-2-(tert-butoxycarbonyl)-5-[(4-methylimidazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid 3 ( 59 mg).

Step 3. tert-butyl (1R,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(4-methylimidazol-1yl)methyl]-2-azabicyclo[3.1. 0]hexane-2-carboxylate (4): into a mixture of (1R,5R)-2-(tert-butoxycarbonyl)-5-[(4methylimidazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane- 3-carboxylic acid S3 (53 mg, 0.164 mmol) and 6-bromo-3-methylpyridine-2-amine (34 mg, 0.18 mmol) in DCM (3.0 ml) was added pyridine (0.066 ml, 0.82 mmol) followed by the addition of phosphoryl chloride (15 µl, 0.16 mmol) at 0°C with stirring. After 2 h at room temperature was added an aqueous solution of NaHCO ₃ . The mixture was extracted with DCM. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (MeOH in DCM 0-10%) to give t-butyl (1R,5R)-3-[(6-6pom-3methylpyridin-2-yl)carbamoyl ]-5-[(4-methylimidazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-2carboxylate 4 (35 mg) as a white solid.

Step 4. (1R,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-methylimidazol-1-yl)methyl]-2azabicyclo[3.1.0]hexane-3- carboxamide, TFA salt (5): tert-butyl (1R,5R)-3-[(6-bromo-3-methylpyridin-2yl)carbamoyl]-5-[(4-methylimidazol-1-yl)methyl]-2 -azabicyclo[3.1.0]hexane-2-carboxylate 4 (35 mg, 0.065 mmol) was treated with TFA (2.0 ml) in DCM (2 ml) at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was co-evaporated with toluene (5 ml x 2) to give (1R,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-methylimidazol-1-yl)methyl]-2-azabicyclo[ 3.1.0]hexane-3carboxamide, TFA salt S5, for the next step.

Step 5. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6bromo-3 -methylpyridin-2-yl)-5-((4-methyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (314) and (1 R,3R,5R) -5-((1H-1,2,4-Triazol-1 -yl)methyl)-2-(2-(3-acetyl-5-(2-methylpyrimidin5-yl)-1H-pyrazolo[3,4- c]pyridin-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (315): to a mixture of (1R,5R)- N-(6-bromo-3-methylpyridin-2-yl)-5-[(4

- 383 041794 methylimidazol-1-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt S5 (0.065 mmol), and [3acetyl-5-(2-methylpyrimidin-5-yl)indazole -1-yl]acetic acid S6 (0.020 g, 0.065 mmol) in DMF (1 mL), TBTU (0.04 g, 0.098 mmol) followed by N,N-diisopropylethylamine (0.091 mL, 0.52 mmol) was added with stirring. After completion of the reaction, the mixture was purified by HPLC to give (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl) -N-(6-bromo3-methylpyridin-2-yl)-5-((4-methyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (314) (17 mg) and (315) (18 mg).

(1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6-bromo- 3 methylpyridin-2-yl)-5-((4-methyl-III-imidazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (314):

¹ H NMR (400 MHz, chloroform-d) δ 8.90 (s, 2H), 8.80 (s, 1H), 8.57 (dt, J=0.8, 1.6 Hz, 1H), 7.71-7.56 (m, 2H), 7.53 -7.33 (m, 2H), 7.28-7.20 (m, 2H), 6.84-6.64 (m, 1H), 5.59-5.38 (m, 2H), 4.96 (d, J=8.1 Hz, 1H), 4.44 (t , J=15.5 Hz, 1H), 4.00 (dd, J=14.5, 37.2 Hz, 1H), 3.41-3.25 (m, 1H), 2.81 (s, 3H), 2.71 (d, J=2.0 Hz, 3H) , 2.22 (dd, J=0.9, 2.1 Hz, 3H), 2.05 (d, J=1.5 Hz, 3H), 2.04-1.97 (m, 4H), 1.28 (dd, J=5.4, 11.4 Hz, 1H), 1.13 (td, J=2.7, 6.0, 6.7 Hz, 1H). LC (method A): tR=1.12 min. LC/MS (EI) m/z: [M+H]+ 682.

(1R,3R,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3methylpyridin- 2-yl)-5-((4-methyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (315):

1H NMR (400 MHz, chloroform-d) δ 8.89 (s, 3H), 8.56 (dd, J=0.9, 1.8 Hz, 1H), 7.69-7.53 (m, 3H), 7.537.37 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.72 (d, J=74.9 Hz, 1H), 5.63-5.37 (m, 3H), 5.14 (t, J =19.5 Hz, 2H), 4.04 (d, J=6.7 Hz, 3H), 3.54 (ddd, J=2.7, 6.4, 16.7 Hz, 1H), 2.80 (s, 4H), 2.72 (d, J=1.3 Hz , 4H), 2.49 (d, J=13.5 Hz, 1H), 2.21 (s, 4H), 2.02 (d, J=6.5 Hz, 9H), 0.95 (t, J=6.4 Hz, 1H), 0.87 (t , J=6.2 Hz, OH). LC (method A): t _R = 1.19 min. LC/MS (EI) m/z: [M+H]+ 682.

Scheme 96. Synthesis of (1R,3S,5R)-2-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6bromo-3-methylpyridine -2-yl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl]-2-azabicyclo[3.1. 0]hexane-3 carboxamide (338)

Stage 1. 2-tert-butyl 3-ethyl (1R,3S,5R)-5-(cyanomethyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (2): to 2-tert-butyl 3-ethyl ( 1R,3S,5S)-5-[(methanesulfonyloxy)methyl]-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate 1 (0.124 g, 0.34 mmol) in DMF (2.5 ml), sodium cyanide (0.083 g , 1.7 mmol) with stirring. The mixture was stirred at 60° C. for 3 hours. The solid was removed by filtration. The filtrate was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc in hexane 0-50%) to give 2-tert-butyl 3-ethyl (1R,3S,5R)-5-(cyanomethyl)-2azabicyclo[ 3.1.0]hexane-2,3-dicarboxylate 2 (81 mg) as a colorless oil.

Stage 2. 2-tert-Butyl 3-ethyl (1R,3S,5R)-5-(carbamothioylmethyl)-2-azabicyclo[3.1.0]hexane-2,3

- 384 041794 dicarboxylate (3): 2-tert-butyl 3-ethyl (1R,3S,5R)-5-(cyanomethyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (40 mg, 0.136 mmol) dissolved in hydrochloric acid 4n. in dioxane (0.34 ml, 1.36 mmol) and treated with diethylphosphorodithioic acid (0.034 ml, 0.204 mmol) at room temperature for 1 day. Water (10 ml) was added followed by the addition of an aqueous solution of 1N. NaOH to adjust the pH to approximately 9. To a mixture of di-tert-butyl dicarbonate (0.297 g, 1.36 mmol) in EtOAc (10 mL) was added with vigorous stirring over 15 min. The EtOAc layer was separated and washed with brine. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc in Hex, 0-50%) to give 2-tert-butyl 3-ethyl (1R,3S,5R)-5(carbamothioylmethyl)-2- azabicyclo[3.1.0]hexane-2,3-dicarboxylate 3 (24 mg).

Step 3. 2-tert-Butyl 3-ethyl (1R,3S,5R)-5-[(4-tert-butyl-1,3-tuαzol-2-ul)methyl]-2azabicyclo[3.1.0]hexane- 2,3-dicarboxylate (4): mixture of 2-tert-butyl 3-ethyl (1R,3S,5R)-5(carbamothioylmethyl)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (24 mg, 0.073 mmol), 1-brompinacolone (0.015 g, 0.08 mmol) and triethylamine (0.011 ml, 0.08 mmol) were refluxed in ethanol (5 ml) under Ar for 1 h. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography to give an intermediate. The intermediate hydrate was refluxed in toluene (5 ml) for an additional 2 h. The solvent was removed under reduced pressure to give 2-t-butyl 3-ethyl (1R,3S,5R)-5-[(4-t- butyl-1,3-thiazol-2-yl)methyl]-2-azabicyclo[3.1.0]hexane2,3-dicarboxylate 4 (23 mg).

Step 4. (1R,3S,5R)-2-(tert-Butoxycarbonyl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl]-2azabicyclo[3.1.0]hexane- 3-carboxylic acid (5): 2-tert-butyl 3-ethyl (1R,3S,5R)-5-[(4-tert-butyl-1,3thiazol-2-yl)methyl]-2-azabicyclo[3.1 .0]hexane-2,3-dicarboxylate (23 mg, 0.056 mmol) in tetrahydrofuran (0.5 mL) and ethanol 0.05 mL) was treated with lithium hydroxide (1.5N, 0.056 mL, 0.084 mmol) at room temperature overnight. After completion of the reaction, amberlite CG-50 (0.1 g, 1 equiv.) was added and stirred for 10 min. The resin was removed by filtration and washed with MeOH. The filtrate was concentrated and the residue coevaporated with toluene to give (1R,3S,5R)-2-(t-butoxycarbonyl)-5[(4-t-butyl-1,3-thiazol-2-yl)methyl]-2- azabicyclo[3.1.0]hexane-3-carboxylic acid 5 (21 mg) for the next step.

Step 5. tert-Butyl (1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(4-tert-butyl-1,3thiazol-2-yl )methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (6): mixture of (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-[(4-tert-butyl-1,3- thiazol-2-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (21 mg, 0.055 mmol) and 6-bromo-3-methylpyridin-2-amine (0.011 g, 0.058 mmol) in dichloromethane (2 ml) was treated with pyridine (0.022 ml, 0.276 mmol) followed by the addition of phosphoryl chloride (0.005 ml, 0.055 mmol) at 0°C. After the reaction was stirred at room temperature for 2 h, aqueous NaHCO ₃ was added. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give t-butyl (1R,3S,5R)-3-[(6bromo-3-methylpyridin-2-yl)carbamoyl]-5-[(4 -tert-butyl-1,3-thiazol-2-yl)methyl]-2azabicyclo[3.1.0]hexane-2-carboxylate 6 (8.5 mg).

Step 6. (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl]- 2azabicyclo[3.1.0]hexane-3-carboxamide (7): tert-butyl (1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2yl)carbamoyl]-5-[(4-tert -butyl-1,3-thiazol-2-yl)methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (8.5 mg, 0.015 mmol) was treated with trifluoroacetic acid (1 ml) in dichloromethane (1 ml) at room temperature for 90 min. The solvent was removed under reduced pressure and the residue was co-evaporated with toluene to give (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-tert-butyl-1,3 -thiazol-2yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide 7 as TFA salt for the next step.

Step 7. (1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6-bromo3-methylpyridin- 2-yl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (338): to mixture (1R, 3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl]-2azabicyclo[3.1.0] hexane-3-carboxamide, TFA salt 7 (0.015 mmol) and [3-acetyl-5-(2-methylpyrimidin-5yl)indazol-1-yl]acetic acid 8 (4.6 mg, 0.015 mmol) in N,N-dimethylformamide (1 ml) was added O(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate (0.007 g, 0.023 mmol) followed by the addition of N,N-diisopropylethylamine (0.019 g, 0.026 ml, 0.15 mmol) with mixing. After completion of the reaction was added an aqueous solution of NaHCO ₃ and the mixture was extracted with EtOAc. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (MeOH in DCM 0-10%) to give (1R,3S,5R)-2-{2-[3-acetyl-5-(2-methylpyrimidine -5yl)indazol-1-yl]acetyl}-N-(6-bromo-3-methylpyridin-2-yl)-5-[(4-tert-butyl-1,3-thiazol-2-yl)methyl] -2azabicyclo[3.1.0]hexane-3-carboxamide (338) (8.2 mg).

1H NMR (400 MHz, chloroform-d) δ 8.91 (s, 2H), 8.65 (s, 1H), 8.58 (dd, J=0.9, 1.7 Hz, 1H), 7.71-7.55 (m, 2H), 7.39- 7.30 (m, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.78 (s, 1H), 5.50 (s, 2H), 4.88 (d, J=8.4 Hz, 1H), 3.64 (d, J =15.2 Hz, 1H), 3.46 (dd, J=2.6, 5.6 Hz, 1H), 3.14 (d, J=15.3 Hz, 1H), 2.88 (d, J=13.7 Hz, 1H), 2.81 (s, 3H ), 2.71 (s, 3H), 2.40 (t, J=11.4 Hz, 1H), 1.33 (s, 10H), 1.00 (dd, J=2.6, 5.8 Hz, 1H), 0.92-0.79 (m, 1H) . LC (method A): t _R =

- 385 041794

2.40 min. LC/MS (EI) m/z: [M+H]+ 741.

Scheme 97: (1 R,3S,5R)-2-(2-(3-acetyl-7-(hydroxymethyl)-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (526)

Stage 1. tert-Butyl 5-bromo-7-methyl-1H-indazole-1-carboxylate (2): solution of 5-bromo-7-methyl-1Hindazole (45 g), Boc ₂ O (55.8 g), potassium carbonate (5.9 g) and DMAP (0.26 g) in dichloromethane (900 ml) and water (90 ml) were stirred overnight at room temperature. The layers were separated, the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound.

Stage 2. tert-Butyl 5-bromo-7-(bromomethyl)-1H-indazole-1-carboxylate (3): a heterogeneous mixture of tert-butyl 5-bromo-7-methylindazole-1-carboxylate (0.2 g, 0.643 mmol, 1 equiv.), NBS (0.114 g, 0.641 mmol, 0.997 equiv.) and AIBN (0.017 g, 0.104 mmol, 0.161 equiv.) in carbon tetrachloride were heated at reflux for 4 h. The starting material remained (15% S2) , and therefore added 0.1 equiv. NBS and an AIBN crystal and the reaction was heated under reflux for 1 h. The reaction mixture was cooled and diluted with water and extracted with EtOAc. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-5% EtOAc in hexanes) to give the desired product as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.72 (s, 9H), 4.88 (s, 2H), 7.48 (s, 1H), 7.77 (d, J=1.2 Hz, 1H), 8.56 (s, 1H).

Stage 3. tert-Butyl 7-(acetoxymethyl)-5-bromo-1H-indazole-1-carboxylate (4): to a solution of tert-butyl 5-bromo-7-(bromomethyl)indazole-1-carboxylate (41.43 g, 106.21 mmol , 1 eq.) in DMF (410 mL) was added potassium acetate (31.27 g) at room temperature and the reaction was stirred at room temperature for 15 min. The reaction mixture was then placed in a 40°C bath and stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-1% EtOAc in dichloromethane) to give the title compound as a yellow solid.

Stage 4. tert-Butyl 7-(acetoxymethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-carboxylate (5): a heterogeneous mixture of 5-bromo-2-methylpyrimidine (23.91 g, 138.198 mmol , 1.501 eq.), bis(pinacolato)diborone (38.47 g, 152.031 mmol, 1.651 eq.), potassium acetate (27.13 g, 276.414 mmol, 3.002 eq.) and dichloro-1,1'-bis(diphenylphosphino)palladium adduct (II) dichloromethane (5.64 g, 6.906 mmol, 0.075 equiv.) in dioxane was degassed with argon and heated at 100°C overnight. The reaction mixture was cooled to room temperature and loaded with tert-butyl 7-[(acetyloxy)methyl]-5-bromomindazole-1-carboxylate (34 g, 92.087 mmol, 1 eq.), potassium carbonate (38.2 g, 276.391 mmol, 3.001 eq.) and water. The reaction mixture was again degassed and heated at 100°C for 1.5 h. The solvent was then removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water. The combined aqueous layer was extracted with dichloromethane. The combined organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluent: 0-5% MeOH in dichloromethane) to give the title compound as an off-white solid.

Step 5. (5-(2-Methylpyrimidin-5-yl)-1H-indazol-7-yl)methyl acetate (6): finely ground tert-butyl 7-[(acetyloxy)methyl]-5-(2-methylpyrimidin- 5-yl)indazole-1-carboxylate (20.8 g, 54.39 mmol, 1 eq.) was suspended in 4N. HCl in dioxane (210 ml, 54.39 mmol, 1 eq) and stirred at room temperature for 1 h with sonication. After completion of the reaction, the solid was separated by filtration. The solid was partitioned between chloroform (1 L) and saturated aqueous sodium bicarbonate. The organic layer was separated, dried and concentrated to give the title compound as an off-white solid.

Step 6. (3-Bromo-5-(2-methylpyrimidin-5-yl)-1H-indazol-7-yl)methyl acetate (7): [5-(2methylpyrimidin-5-yl)-1H-indazol-7- yl]methyl acetate (20 g, 70.846 mmol, 1 eq.) was suspended in DMF (200 ml) and the mixture was heated until the solution became homogeneous. This solution was then allowed to cool to room temperature with stirring. While the solution was cooling to room temperature, NBS (13.88 g) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then poured into 2 L of water with stirring. The solid was isolated by filtration, washed with 100 ml of saturated aqueous sodium bicarbonate and water, and dried to give the title compound as an off-white solid.

¹ H NMR (DMSO-d6): δ 2.10 (s, 3H), 2.68 (s, 3H), 5.38 (s, 2H), 7.89 (s, 1H), 7.95 (s, 1H), 9.09 (s, 2H ), 13.75 (s, 1H).

Step 7. (3-Acetyl-5-(2-methylpyrimidin-5-yl)-III-indazol-7-yl)methyl acetate (8): [3-bromo-5-(2-methylpyrimidin-5-yl)-1H solution -indazol-7-yl]methylacetate (10 g, 27.686 mmol, 1 eq.) and transdichlorobis(triphenylphosphine)palladium (II) (1.94 g, 2.764 mmol, 0.1 eq.) in DMF (200 ml) was purged with argon and tributyl was added (1-ethoxyvinyl)tin (14.99 g, 14.03 ml, 41.506 mmol, 1.499 equiv.) while continuing to purge with argon for 5 min. The reaction mixture was then heated at 80° C. overnight. The solvent was removed under reduced pressure. To the reaction mixture was added chloroform (200 ml) and cold 2n. aqueous HCl (50 ml) and the mixture was stirred for 10 min in an ice bath. The reaction mixture was then made basic by carefully adding saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was concentrated to dryness. The remainder was used as is in the next step.

Step 8. tert-Butyl 2-(7-(acetoxymethyl)-3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetate (9): [3-acetyl-5-( 2-methylpyrimidin-5-yl)-1H-indazol-7-yl]methyl acetate (from the previous step) was taken up in DMF (150 ml) and potassium carbonate (7.65 g, 55.351 mmol, 2 eq.) was added followed by the addition of tert- butyl bromoacetate (6.5 g, 4.921 ml, 33.325 mmol, 1.204 eq.). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a funnel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in dichloromethane) to give the title compound as an off-white solid.

Step 9. (1R,3S,5R)-2-(2-(3-Acetyl-7-(hydroxymethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-N- (6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (526): {3-acetyl-1-[2-(tert-butoxy )-2-oxoethyl]-5-(2-methylpyrimidin-5-yl)indazol-7yl}methyl acetate (S9, 0.05 g, 0.115 mmol, 1 eq.) in dichloromethane (1 ml) and TFA (1 ml) were stirred at room temperature for 3 h, and the volatiles were removed under reduced pressure. Separately, tert-butyl (1R,3S,5R)-3-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (0.047 g, 0.115 mmol, 1 eq) S10, 1 ml TFA and 1 ml dichloromethane in DCM (1 ml) were stirred at room temperature for 30 min. After evaporation of the solvents, the mixture S10 was mixed with S9. The reaction mixture was cooled in an ice bath, and DIPEA (0.1 ml) and HATU (0.048 g, 0.126 mmol, 1.102 equiv.) were added successively, then the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then poured into 10 ml of 1% aqueous LiOH and extracted with chloroform. The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography (eluent: 0-4% MeOH in dichloromethane) to give compound 526 as a white solid.

1H NMR (Chloroform-d) δ 0.97 (d, J=5.2 Hz, 1H), 1.17 (t, J=5.5 Hz, 1H), 1.39 (s, 3H), 2.08-2.15 (m, 1H), 2.15 ( s, 3H), 2.72-2.75 (m, 1H), 2.75 (s, 3H), 2.81 (s, 3H), 3.18 (d, J=3.7 Hz, 1H), 4.86 (d, J=8.1 Hz, 1H ), 5.145.24 (m, 2H), 5.51 (d, J=16.9 Hz, 1H), 6.07 (d, J=17.0 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.43 (d , J=8.0 Hz, 1H), 7.49 (s, 1H), 8.59 (s, 1H), 8.91 (s, 2H), 9.19 (s, 1H).

(3-Acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl-5-methyl-2azabicyclo[3.1.0]hexane-2 -yl)-2-oxoethyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-7-yl)methyl acetate (529): Compound 529 was prepared in a similar manner as Compound 526 except Step 8: solution {3-acetyl-1-[2-(tert-butoxy)-2-oxoethyl]-5-(2-methylpyrimidin-5-yl)indazol-7-387 041794 yl}methyl acetate (S9, 0.05 g, 0.114 mmol, 1 eq.) in TFA (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 3 h. Then the volatiles were removed under reduced pressure. (1R,3S,5R)-N-(6-bromo -3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (0.035 g, 0.114 mmol, 1 equiv.) and DMF (1 ml) The solution was cooled in an ice bath. to this cooled solution was added DIPEA (0.1 ml) followed by TBTU (0.04 g) The reaction mixture was stirred at room temperature for 30 min, then the solvent was removed under reduced pressure, and the residue was separated by me waiting with chloroform and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with water. The organic layer was dried, concentrated and the residue was purified by silica gel column chromatography (02.5% MeOH in dichloromethane) to give compound 529 as a white solid.

Ή NMR (400 MHz, chloroform-d) δ 0.99 (dd, J=2.3, 5.4 Hz, 1H), 1.19 (t, J=5.2 Hz, 1H), 1.44 (s, 3H), 2.08 (s, 3H) , 2.10 (s, 3H), 2.34 (t, J=11.4 Hz, 1H), 2.70-2.72 (m, 1H), 2.72 (s, 3H), 2.81 (s, 3H), 3.21 (d, J=3.6 Hz, 1H), 4.83 (d, J=8.3 Hz, 1H), 5.46-5.60 (m, 2H), 5.70 (d, J=17.4 Hz, 1H), 5.87 (d, J=17.4 Hz, 1H), 7.23 (d, J=8Hz, 1H), 7.35 (d, J=7.9Hz, 1H), 7.69 (s, 1H), 8.63 (s, 1H), 8.69 (s, 1H), 8.91 (s, 2H ).

Scheme 98 yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (472)

Br

Stage 1. 5-Bromo-7-methyl-1H-pyrrolo[2,3-c]pyridine (2): a stirred solution of compound 1 (1.5 g, 6.91 mmol) in THF (30 ml) under N2 atmosphere at -78° C was treated with bromo(ethenyl)magnesium (20.7 ml, 20.7 mmol, 1 M) and the mixture was stirred at -40°C for 2 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc. The layers were separated and the organic phase was dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc=1:0 to 1:1) to give compound 2 (0.45 g, 30.85% yield) as an orange oil. LC/MS (ESI) m/z: 211/213 (M+H)+.

Step 2. 1-(5-Bromo-7-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone (3): to a solution of compound 2 (464 mg, 2.2 mmol) in DCM (20 ml) was added acetyl chloride (0.345 g, 4.4 mmol) and AlCl ₃ (0.59 g, 4.4 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. The mixture was poured into ice water and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc=4:1) to give compound 3 (0.22 g, 39.5% yield) as a yellow oil. LC/MS (ESI) m/z: 253/255 (M+H) ⁺ .

Step 3. tert-Butyl 2-(3-acetyl-5-bromo-7-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)acetate (4): to a solution of compound 3 (220 mg, 0.869 mmol) in DMF (5 mL) was added K2CO3 (0.24 g, 1.74 mmol) followed by addition of tert-butyl 2-bromoacetate (0.203 g, 1.04 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum to obtain compound 4 (0.21 g, 65.8% yield) as a white solid. LC/MS (ESI) m/z: 367/369 (M+H) ⁺ .

Step 4. tert-Butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin1-yl)acetate (5): to a stirred To a solution of compound 4 (210 mg, 0.57 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added 2-methylpyrimidin-5-ylboronic acid (95 mg, 0.69 mmol) and K ₂ CO ₃ (0.158 g , 1.144 mmol). The mixture was degassed three times in an N2 atmosphere, Pd(dppf)Cl ₂ (0.042 g, 0.057 mmol) was added,

- 388 041794 and the reaction was stirred at 100°C in an atmosphere of N ₂ for 16 hours the Reaction mixture was diluted with water and was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting with PE:EtOAc=1:0 to 1:1) to give compound 5 (0.15 g, 68.9% yield) as a white solid. LC/MS (ESI) m/z: 381/383(M+H)+.

Stage

5.

2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-pyrrolo[2,3-c]pyridin-1 yl)acetic acid (6): to a solution of compound 5 ( 150 mg, 0.39 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.019 g, 0.79 mmol) and the reaction mixture was stirred at 25°C for 2 h. The mixture was diluted with water and washed twice with ether. The aqueous layer was acidified with 1N. aqueous HCl to pH approximately 3 and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give compound 6 (75 mg, 58.6% yield) as a white solid. LC/MS (ESI) m/z: 325 (M+H) ⁺ .

Step 6. (1R,3S,5R)-2-(2-(3 - Acetyl-7-methyl-5 -(2-methylpyrimidin-5 -yl) -1 H-pyrrolo[2,3c]pyridin-1- yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (472): to a stirred solution of compound 6 (20 mg, 0.062 mmol) and (1R,3S,5R)-N-(6bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt (25.6 mg, 0.062 mmol) in DMF (3 ml) were added HATU (23 mg, 0.062 mmol) and DIPEA (23.2 mg, 0.18 mmol) and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give 472 (4.5 mg, 11.8% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.26 (s, 2H), 8.48 (t, J=11.9 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.9Hz, 1H), 5.80 (d, J=17.9Hz, 1H), 5.48 (d, J=17.8Hz, 1H), 4.41 (m, 1H), 3.58-3.55 (m, 1H) , 2.55 (m, 1H), 2.49 (s, 3H), 2.09–1.96 (m, 4H), 1.33 (s, 3H), 1.02 (m, 1H), 0.91 (m, 1H). LC/MS (ESI) m/z: 616/618 (M+H) ⁺ .

Scheme 99 2-azabicyclo[3.1.0]hexane-3-carboxamido)-6-bromisonicotinic acid (493)

NMP, 100°С

H ₂ N'

Vg

Stage 3

TFA, DCM

493

POCI ₃ , pyridine DCM

Stage 5

CONC. H ₂ SO _{4 Me0H} heating with reverse _Bg refrigerator j

stage 2 nick

Stage 1. 2-Bromo-6-fluoroisonicotinic acid (2): to a stirred solution of compound 1 (400 mg, 2.105 mmol) in sulfuric acid (3 ml) was added chromium trioxide (0.631 g, 6.315 mmol) in portions on a water bath, in while the temperature was maintained between 20-50°C and the mixture was stirred at room temperature for 16 hours. The reaction mixture was slowly poured into ice water and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was washed water, dried under vacuum to give compound 2 (400 mg, 86.4% yield) as a white solid. LC/MS (ESI) m/z: 220/222 (M+H) ⁺ .

Stage 2. Methyl 2-bromo-6-fluoropyridine-4-carboxylate (3): to a solution of compound 2 (400 mg, 1.82 mmol) in methanol (10 ml) was added sulfuric acid (0.5 ml) at 0°C, and the mixture heated to 60°C overnight. The mixture was then concentrated to dryness and the residue was partitioned between water and EtOAc. The layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 3 (380 mg, 89.2% yield) as a white solid. LC/MS (ESI) m/z:

234/236 (M+H)+.

Step 3 Methyl 2-bromo-6-(tert-butylamino)pyridine-4-carboxylate (4): Compound 3 (200 mg, 0.855 mmol) and erbumine (0.63 g, 8.55 mmol) were dissolved in NMP (3 ml), and the reaction mixture was stirred at 100° C. for 4 hours in a sealed tube. The mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc=5:1) to give compound 4 (150 mg, 61.8% yield) as a white solid. LC/MS (ESI) m/z: 287/289 (M+H) ⁺ .

Step 4. Methyl 2-amino-6-bromopyridine-4-carboxylate (5): a solution of compound 4 (150 mg, 0.522 mmol) in TFA (3 mL) was stirred at 70°C under N2 for 16 h. The mixture was concentrated to dryness, and the residue was poured into saturated aqueous NaHCO ₃ and extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc=9:1 to 5:1) to give compound 5 (81 mg, 67.1% yield) as a white solid. LC/MS (ESI) m/z: 231/233(M+H)+.

Step 5. tert-Butyl (1R,3S,5R)-3-{[6-bromo-4-(methoxycarbonyl)pyridin-2-yl]carbamoyl}-5methyl-2-azabicyclo[3.1.0]hexane-2- carboxylate (6): to a mixture of compound 5 (71 mg, 0.307 mmol), pyridine (0.146 g, 1.844 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid (74 mg, 0.307 mmol) in DCM (5 mL), POCl ₃ (0.061 g, 0.399 mmol) was added dropwise at 0°C, and the mixture was stirred at 20°C for 5 h under N2 atmosphere. The mixture was diluted with DCM and washed with 0.5N. aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc=9:1 to 5:1) to give compound 6 (100 mg, 71.6% yield) as a white solid. LC/MS (ESI) m/z: 454/456(M+H)+.

Step 6. Methyl 2-bromo-6-[(1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-3-amido]pyridine-4carboxylate (7): to a solution of compound 6 (100 mg, 0.22 mmol) in DCM (2 ml) was added with TFA (1 ml) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and the residue was washed with ether and dried under vacuum to give compound 7 (95 mg, yield 100%) as a yellow oil. LC/MS (ESI) m/z: 354/356(M+H)+.

Step 7 Methyl 2-[(1R,3S,5R)-2-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5methyl-2-azabicyclo [3.1.0]hexane-3-amido]-6-bromopyridine-4-carboxylate (8): to a mixture of compound 7 (95 mg, 0.22 mmol) and [3-acetyl-5-(2-methylpyrimidin-5-yl )indazol-1-yl]acetic acid (75 mg, 0.242 mmol) in DMF (4 mL) was added HATU (0.167 g, 0.44 mmol) and DIPEA (0.114 g, 0.881 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc=10:1 to 5:1) to give compound 8 (110 mg, 77.3% yield) as a white solid. LC/MS (ESI) m/z: 646/648(M+H)+.

Step 8 2-[(1R,3S,5R)-2-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5-methyl2-azabicyclo[ 3.1.0]hexane-3-amido]-6-bromopyridine-4-carboxylic acid (493): Lithium (16 mg, 0.68 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was acidified by adding 1N. aqueous HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give compound 493 (80 mg, 74.34% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 9.03 (s, 2H), 8.49 (s, 1H), 8.42 (s, 1H), 7.87 (m, 2H), 7.61 (m , 1H), 5.97 (d, J=17.3 Hz, 1H), 5.57 (d, J=17.2 Hz, 1H), 4.42 (m, 1H), 3.66-3.62 (m, 1H), 2.68 (s, 3H) , 2.65 (s, 3H), 2.48 (m, 1H), 2.01 (m, 1H), 1.30 (s, 3H), 0.98 (m, 2H). LC/MS (ESI) m/z: 632/634 (M+H)+.

Scheme 100 -methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-6-bromopyridin-4-yl)acetic acid (514)

- 390 041794

Step 1. 2-(2-Bromo-6-fluoropyridin-4-yl)acetic acid (2): oxalyl chloride (0.231 g, 1.82 mmol) was added to a solution of compound 1 (200 mg, 0.91 mmol) in DCM (5 ml) followed by the addition of DMF (0.1 ml) at 0°C. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was dissolved in THF (5 ml) and TMSCHN2 (0.114 g, 1 mmol) was added at 0°C. The mixture was stirred at 0° C. for 3 hours and allowed to warm to room temperature. The reaction was quenched with acetic acid at 0°C, diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was dissolved in 1,4-dioxane (3 ml) and water (3 ml) and AgOAc (0.015 g, 0.091 mmol) was added. The reaction mixture was stirred at 100°C for 12 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give compound 2 (150 mg, 70.5% yield) as a white solid. LC/MS (ESI) m/z: 234/236 (M+H)+.

Stage 2. methyl 2-(2-Bromo-6-fluoropyridin-4-yl)acetate (3): H2SO4 (1 ml) was added to a solution of compound 2 (150 mg, 0.64 mmol) in MeOH (4 ml) at 0° C, and the mixture was stirred at 60°C overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 3 (130 mg, 81.8% yield) as a white solid. LC/MS (ESI) m/z: 248/250 (M+H) ⁺ .

Step 3. Methyl 2-(2-bromo-6-(tert-butylamino)pyridin-4-yl)acetate (4): compound 3 (130 mg, 0.524 mmol) and erbumine (0.46 g, 6.29 mmol) were dissolved in NMP (4 ml), and the reaction mixture was stirred at 100°C for 24 h in a sealed tube. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc = 5:1) to give compound 4 (48 mg, 30.4% yield) as a yellow solid. LC/MS (ESI) m/z: 301/303 (M+H) ⁺ .

Step 4. Methyl 2-(2-amino-6-bromopyridin-4-yl)acetate (5): a solution of compound 4 (48 mg, 0.159 mmol) in TFA (3 mL) was heated to 70°C under N ₂ in for 2 hours the Mixture was concentrated to dryness, was added a saturated aqueous solution of NaHCO ₃ and the organic layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with: PE:EtOAc=9:1-5:1) to give compound 5 (30 mg, 76.7% yield) as a white solid. LC/MS (ESI) m/z: 245/247 (M+H) ⁺ .

Step 5. (1R,3S,5R)-tert-Butyl 3-((6-bromo-4-(2-methoxy-2-oxoethyl)pyridin-2-yl)carbamoyl)-5methyl-2-azabicyclo[3.1. 0]hexane-2-carboxylate (6): to a solution of compound 5 (40 mg, 0.163 mmol), pyridine (77 mg, 0.979 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-5- methyl-2-αzabicyclo[3.1.0]hexane-3carboxylic acid (39 mg, 0.163 mmol) in DCM (5 ml) POCl ₃ (38 mg, 0.245 mmol) was added dropwise

- 391 041794 at 0°C. The mixture was stirred at 20° C. for 5 hours. The mixture was diluted with EtOAc and washed with water and brine, dried and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc=3:1) to give compound 6 (26 mg, 34.0% yield) as a white solid. LC/MS (ESI) m/z: 468/470 (M+H)+.

Stage

6.

Methyl

2-(2-bromo-6-((1R,3S,5R)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)pyridin-4-yl)acetate (7): to a solution of compound 6 (26 mg, 0.055 mmol) in DCM (1 ml) was added TFA (0.5 ml) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and the residue was washed with ether and dried under vacuum to obtain compound 7 (25 mg , 100% yield) as a yellow solid. LC/MS (ESI) m/z: 368/370 (M+H)+.

Step 7. Methyl 2-(2-((1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl)acetyl)-5 -methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-6-bromopyridin-4-yl)acetate (8): to a solution of compound 7 (25 mg, 0.055 mmol) and [3-acetyl-5- (2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (21 mg, 0.068 mmol) in DMF (4 ml) was added HATU (0.043 g, 0.114 mmol) and DIPEA (0.029 g, 0.228 mmol), and the reaction mixture was stirred at ambient temperature for 4 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc=3:1 to 1:1) to give compound 8 (25 mg, 66.4% yield) as a white solid. LC/MS (ESI) m/z: 660/662 (M+H) ⁺ .

Step 8 2-(2-(( 1 R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl )-5methyl-2-azabicyclo[3.1.0]hexane-3-carboxamido)-6-bromopyridin-4-yl)acetic acid (514): to a solution of compound 8 (25 mg, 0.038 mmol) in THF (1 ml) and water (0.5 ml) were added lithium (3 mg, 0.114 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was acidified by adding 1N. aqueous HCl, and the organic layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried and concentrated to dryness. The residue was purified by preparative HPLC to give compound 514 (20 mg, 81.7% yield) as a white solid.

¹ H NMR (400 MHz, CD3OD) δ 8.99 (s, 2H), 8.52 (s, 1H), 8.02 (s, 1H), 7.78 (m, 2H), 7.22 (m, 1H), 5.81 (d, J =18.0 Hz, 1H), 5.63 (d, J=16.9 Hz, 1H), 5.33 (m, 1H), 4.47 (m, 1H), 3.54 (m, 1H), 3.47 (m, 2H), 2.74 (s , 3H), 2.69 (s, 3H), 2.55 (m, 1H), 2.17–2.12 (m, 1H), 1.37 (s, 3H), 1.07 (m, 1H), 0.98 (m, 1H). LC/MS (ESI) m/z: 646/648 (M+H) ⁺ .

Scheme 101. Synthesis of (1R,3S,5R)-2-{2-[3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1yl]acetyl}-5-methyl-N- {2-oxo-[1,2'-bipyridine]-3-yl}-2-azabicyclo[3.1.0]hexane-3-carboxamide (460)

NO ^H 1

Water stage _{Na2CO3THF _}

Step > 1 ^NH 2 CbzCl

'2

HATU, DIPEA DMF

Stage )6

K ₂ CO ₃ , dioxane

Stage 2

ROS1 ₃ pyridine

460

Step 1. Benzyl N-(2-hydroxypyridin-3-yl)carbamate (2):

to a solution of 3-amino-1,2dihydropyridin-2-ol (4.97 g, 44.32 mmol) in THF (125 ml) was added a solution of sodium carbonate (5.16 g, 48.75 mmol) in water (60 ml) followed by dropwise addition of CbzCl ( 8.31 g, 48.75 mmol) at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water and the resulting suspension was filtered. The filter cake was washed with water and dried under vacuum to give benzyl N-(2-hydroxypyridin-3-yl)carbamate (6.51 g, 60.13% yield) as a white solid. LC/MS (ESI) m/z: 245(M+H)+.

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Step 2. Benzyl N-{2-oxo-[1,2'-bipyridin]-3-yl}carbamate (3): to a solution of benzyl N-(2hydroxypyridin-3-yl)carbamate (0.51 g, 2.08 mmol) in 1,4-dioxane (10 ml) was added 2-bromopyridine (0.42 g, 2.71 mmol), 1,2-dimethylethylenediamine (0.074 g, 0.83 mmol), copper iodide (0.08 g, 0.41 mmol) and K ₂ CO ₃ (0.57 g, 4.17 mmol), and the mixture was degassed three times under N2. The reaction was stirred at 115°C for 16 h in a sealed tube. The mixture was diluted with EtOAc and filtered. The filtrate was washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 3:1) to give benzyl N-{2-oxo-[1,2'-bipyridine]-3-yl}carbamate (0.19 g, 28.3% yield) as a white solid. LC/MS (ESI) m/z: 322(M+H)+.

Step 3. 3-Amino-[1,2'-bipyridin]-2-one (4): to a solution of benzyl N-{2-oxo-[1,2'-bipyridine]-3yl}carbamate (0.19 g, 0.59 mmol) in methanol (6 ml) and THF (2 ml) was added Pd/C (20 mg, 10% wt) and the mixture was degassed three times under N2 atmosphere. The reaction was stirred under balloon H ₂ at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give 3-amino-[1,2'-bipyridin]-2-one (0.11 g, 99.4% yield) as yellow solid. LC/MS (ESI) m/z: 188 (M+H) ⁺ .

Step 4. tert-Butyl (1R,3S,5R)-5-methyl-3-({2-oxo-[1,2'-bipyridin]-3-yl}carbamoyl)-2azabicyclo[3.1.0]hexane- 2-carboxylate (5): to a mixture of 3-amino-[1,2'-bipyridine]-2-one (0.051 g, 0.27 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-5 -methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (0.066 g, 0.27 mmol) in DCM (3 ml) was added pyridine (0.11 g, 1.36 mmol) followed by the addition of POCl ₃ (0.063 g, 0.41 mmol ) at 0°C. The mixture was stirred at room temperature for 30 min and then diluted with DCM and washed with 0.5N. aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl (1R,3S,5R)-5-methyl-3-({2-oxo-[1,2'-bipyridine]-3yl }carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.11 g, 98.4% yield) as a light yellow solid, which was used immediately in the next step. LC/MS (ESI) m/z: 411(M+H)+.

Step 5. (1R,3S,5R)-5-Methyl-N-{2-oxo-[1,2'-bipyridin]-3-yl}-2-azabicyclo[3.1.0]hexane-3carboxamide, TFA salt (6): to a solution of tert-butyl (1R,3S,5R)-5-methyl-3-({2-oxo-[1,2'-bipyridine]-3yl}carbamoyl)-2-azabicyclo[3.1.0 ]hexane-2-carboxylate (0.11 g, 0.25 mmol) in DCM (3 mL) was added with TFA (1.5 mL) at 0°C and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and co-evaporated with DCM twice and dried under vacuum to give (1R,3S,5R)-5-methyl-N-{2-oxo-[1,2'-bipyridin]-3-yl}-2-azabicyclo[3.1.0]hexane-3 α-carboxamide, TFA salt (105 mg, 100% yield), as a yellow oil, which was used immediately in the next step. LC/MS (ESI) m/z: 311 (M+H) ⁺ .

Step 6. (1R,3S,5R)-2-{2-[3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-5methyl-N-{ 2-oxo-[1,2'-bipyridin]-3-yl}-2-azabicyclo[3.1.0]hexane-3-carboxamide (460): to a mixture of (1R,3S,5R)-5-methyl-N -{2-oxo-[1,2'-bipyridin]-3-yl}-2-azabicyclo[3.1.0]hexane-3-carboxamide (40 mg, 0.12 mmol) and [3-acetyl-7-methyl- 5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (42 mg, 0.12 mmol) in DMF (3 mL) was added HATU (74 mg, 0.19 mmol) and DIPEA (84 mg, 0.64 mmol) , and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH ₄ Cl and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give 460 (31 mg, 38.8% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.95 (s, 2H), 8.59-8.54 (m, 1H), 8.42-8.35 (m, 2H), 7.98-7.93 (m, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.57-7.53 (m, 1H), 7.51-7.44 (m, 2H), 6.47-6.42 (m, 1H), 5.98 (d, J=17.8 Hz, 1H), 5.77 (d, J= 17.7 Hz, 1H), 4.68-4.53 (m, 2H), 3.55-3.51 (m, 1H), 2.73 (d, J=4.9 Hz, 6H), 2.66 (s, 3H), 2.57-2.51 (m, 1H ), 2.30-2.25 (m, 1H), 1.39 (s, 3H), 1.14-1.08 (m, 1H), 1.00-0.96 (m, 1H). LC/MS (ESI) m/z: 617 (M+H) ⁺ .

Scheme 102. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-(6-bromo -4-propylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (516)

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516

Stage 1. 2-Bromo-4-(prop-2-en-1-yl)pyridine (2): to a mixture of compound 1 (2.0 g, 7.05 mmol) and tributyl(prop-2-en-1-yl)stannan (2.33 g, 7.05 mmol) in toluene (20 mL) was added Pd(PPh ₃ ) ₄ (814 mg, 0.70 mmol) and the mixture was stirred at 100°C under N ₂ for 20 h. The mixture was concentrated to dryness and the residue purified by silica gel chromatography (PE:EtOAc = 75:1) to give compound 2 (1.0 g, 71.7% yield) as a yellow oil. LC/MS (ESI) m/z: 198/200 (M+H) ⁺ .

Stage 2. 2-Bromo-4-propylpyridine (3): to a solution of compound 2 (1.0 g, 5.05 mmol) in EtOAc (8 ml) was added PtO ₂ (120 mg) at 0°C, and the mixture was degassed in an atmosphere of N ₂ three times and stirred at room temperature under ballooned H ₂ for 10 min. The mixture was filtered and the filtrate was concentrated to dryness to give compound 3 (990 mg, 98.0% yield) as a white solid, which was used immediately in the next step. LC/MS (ESI) m/z: 200/202(M+H) ⁺ .

Step 3. 2-Bromo-4-propylpyridine 1-oxide (4): m-CPBA (1.37 g, 7.9 mmol) was added to a solution of compound 3 (990 mg, 4.9 mmol) in chloroform (10 ml) and the mixture was stirred at room temperature overnight under N ₂ atmosphere. The mixture was washed with saturated aqueous NaHCO ₃ and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give compound 4 (800 mg, 74.1% yield) as a yellow oil. LC/MS (ESI) m/z: 216/218 (M+H) ⁺ .

Step 4. 6-Bromo-N-tert-butyl-4-propylpyridin-2-amine (5): 2-methylpropan-2-amine ( 1.34 g, 18.3 mmol) followed by dropwise addition of trifluoromethanesulfonic anhydride (1.55 g, 5.5 mmol) at 0°C. The mixture was stirred at 0° C. for 30 min under N ₂ atmosphere. The mixture was washed with aqueous NaHCO ₃ and brine, dried and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to give compound 5 (800 mg, 80.4% yield) as a yellow oil. LC/MS (ESI) m/z: 271/273 (M+H) ⁺ .

Step 5 6-Bromo-4-propylpyridin-2-amine (6): a solution of compound 5 (800 mg, 2.95 mmol) in TFA (8 ml) was stirred at 70°C for 16 h. The mixture was concentrated to dryness and the residue poured into ice-cold saturated aqueous NaHCO ₃ and extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc=10:1) to give compound 6 (144 mg, 22.7% yield) as a light yellow oil. LC/MS (ESI) m/z: 215/217 (M+H) ⁺ .

Step 6. tert-Butyl (1R,3S,5R)-3-[(6-bromo-4-propylpyridin-2-yl)carbamoyl]-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (7 ): to a solution of compound 6 (68 mg, 0.32 mmol) and (1R,3S,5R)-2(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (76 mg , 0.32 mmol) in DCM (5 ml) was added pyridine (125 mg, 1.6 mmol) followed by dropwise addition of POCl ₃ (53 mg, 0.35 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with 0.5N. aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give compound 7 (139 mg, 100.0% yield) as a yellow solid which was used immediately in the next step. LC/MS (ESI) m/z: 438/440 (M+H) ⁺ .

Step 7. (1R,3S,5R)-N-(6-Bromo-4-propylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (8): to a solution of compound 7 (139 mg, 0.32 mmol) in DCM (4 ml) was added TFA (2 ml) at 0°C and the reaction was stirred at room temperature for 2 h. The mixture was concentrated to dryness

- 394 041794 and washed with ether and dried under vacuum to obtain compound 8 (130 mg, 100% yield) as a brown syrup, which was immediately used for the next reaction without purification. LC/MS (ESI) m/z: 338/340 (M+H)+.

Step 8. (1R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6bromo -4-propylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (516): to a mixture of compound 8 (65 mg, 0.15 mmol) and [3-acetyl-5- (2-methylpyrimidin-5-yl)indazol-1-yl]acetic acid (46 mg, 0.15 mmol) in DMF (5 ml) was added DIPEA (96 mg, 0.74 mmol) and HATU (84 mg, 0.22 mmol) at 0 °C and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative HPLC to give compound 516 (12 mg, 12.9% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 9.04 (t, J=2.6 Hz, 2H), 8.43 (d, J=3.2 Hz, 1H), 7.91 (d, J=3.6 Hz, 1H), 7.88 (t, J=2.4 Hz, 2H), 7.21 (t, J=2.4 Hz, 1H), 5.96 (d, J=17.6 Hz, 1H), 5.57 (d, J=17.6 Hz, 1H),

4.40 (d, J=8.8 Hz, 1H), 3.63 (d, J=4.4 Hz, 1H), 2.69 (s, 3H), 2.66 (s, 3H), 2.63-2.52 (m, 2H), 2.46 (d , J=14.4 Hz, 1H), 2.02-1.95 (m, 1H), 1.57 (q, J=8.4 Hz, 2H), 1.30 (t, J=2.7 Hz, 3H), 0.98 (d, J=4.4 Hz , 2H), 0.90–0.84 (m, 3H). LC/MS (ESI) m/z: 630/632(M+H) ⁺ .

Scheme 103. Synthesis of (2S,4R)-1-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6bromo-3-methylpyridin-2 -yl)-4-fluoro-4-methylpyrrolidine-2-carboxamide (430)

Stage

TMS ₃ SiH

VAZO, 1 cat. dioxane

Stage 2

_H2 , Pd/C

MeOH

Stage 3

1. 2-Benzyl 1-tert-butyl (2S,4R)-4-fluoro-4-{[(4 fluorophenoxymethanethioyl)oxy]methyl}pyrrolidine-1,2-dicarboxylate (2): to a mixture of compound 1 (0.41 g , 1.15 mmol) and 4-fluorophenylchloromethanethioate (0.33 g, 1.73 mmol) in DCM (10 ml) were added DMAP (0.42 g, 3.39 mmol) and the mixture was stirred at 25°C for 1 day. The mixture was diluted with DCM and washed with 0.5N.

HCl and brine, dried and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with PE:EtOAc = 30:1 to 20:1) to give compound 2 (0.19 g, 32% yield) as a yellow oil. LC/MS (ESI) m/z: 452 (M+H) ⁺ .

Stage 2. 2-Benzyl 1-tert-butyl (2S,4R)-4-fluoro-4-methylpyrrolidine-1,2-dicarboxylate (3): to a solution of compound 2 (0.19 g, 0.37 mmol) in 1,4- tris(trimethylsilyl)silane (0.14 g, 0.55 mmol) and VAZO (0.03 g, 0.18 mmol) were added in dioxane (5 mL), and the mixture was stirred at 105°C for 1.5 h. The reaction mixture was concentrated to dryness, and the residue was purified with silica gel column chromatography (PE:EtOAc = 100:1) gave compound 3 (84 mg, 94.60% yield) as a light yellow oil, which was used immediately in the next step. LC/MS (ESI) m/z: 338 (M+H) ⁺ .

Stage 3. (2S,4R)-1-(tert-Butoxycarbonyl)-4-fluoro-4-methylpyrrolidine-2-carboxylic acid (4): to a solution of compound 3 (84 mg, 0.25 mmol) in MeOH (3 ml) Pd/C (17 mg, 10 wt%) was added and the mixture was degassed under N ₂ three times and stirred under balloon H ₂ at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated to dryness to give compound 4 (60 mg, 97.46% yield) as a light oil. LC/MS (ESI) m/z: 248(M+H) ⁺ .

Step 4. tert-Butyl (2S,4R)-2-[(6-bromo-3-methylpyridin-2-yl)carbamoyl]-4-fluoro-4methylpyrrolidin-1-carboxylate (5): to a mixture of compound 4 (60 mg, 0.24 mmol) and 6-bromo-3methylpyridin-2-amine (0.045 g, 0.24 mmol) in DCM (3 ml) was added pyridine (0.096 g, 1.21 mmol) followed by the addition of POCl ₃ (0.041 g, 0.27 mmol) at 0°C. The mixture was stirred at room temperature for 30 minutes. The mixture was quenched with ice water and extracted with DCM. The combined organic layers were washed with 0.5N. HCl and brine, dried with anhydrous Na ₂ SO ₄ and concentrated to dryness to give compound 5 (87 mg, 86.13% yield) as a yellow solid. LC/MS (ESI) m/z: 416 (M+H) ⁺ .

Step 5. (2S,4R)-N-(6-Bromo-3-methylpyridin-2-yl)-4-fluoro-4-methylpyrrolidin-2-carboxamide,

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TFA salt (6): to a solution of compound 5 (87 mg, 0.21 mmol) in DCM (2 ml) was added TFA (1 ml) at 0°C, and the mixture was stirred at 25°C for 2 h. The mixture was concentrated to dryness and washed with ether to give compound 6 (90 mg, 100% yield) as a yellow solid, which was used immediately in the next step. LC/MS (ESI) m/z: 316 (M+H)+.

Step 6. (2S,4R)-1-{2-[3-Acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-(6-bromo-3methylpyridin-2- yl)-4-fluoro-4-methylpyrrolidin-2-carboxamide (430): to a mixture of compound 6 (30 mg, 0.07 mmol) and [3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1- yl]acetic acid (25 mg, 0.079 mmol) in DMF (3 mL), HATU (45 mg, 0.12 mmol) and DIPEA (0.031 g, 0.24 mmol) were added at 0°C, and the mixture was stirred at room temperature for 1 h The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give 430 (8 mg, 17.04% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.04 (d, J=2.2 Hz, 2H), 8.43 (s, 1H), 7.87-7.78 (m, 2H), 7.60 (d , J=8.1 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 5.82 (d, J=17.2 Hz, 1H), 5.57 (d, J=17.2 Hz, 1H), 4.64-4.59 (m , 1H), 4.27-4.20 (m, 1H), 3.94-3.86 (m, 1H), 2.68 (s, 3H), 2.64 (s, 3H), 2.20-2.04 (m, 2H), 2.00 (s, 3H ), 1.64 (d, J=21.0 Hz, 3H). LC/MS (ESI) m/z: 607(M+H) ⁺ .

Scheme 104 6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (505)

^{Stage 1} Stage 2

505

Stage 1. 1,3-diphenylpropan-2-amine (2): ammonium acetate (1.83 g, 23.78 mmol) and NaBH ₃ CN (300 mg, 4.76 mmol) at 0°C, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with 1N. aqueous NaOH solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH = 200:1 to 20:1) to give compound 2 (340 mg, 67.7% yield) as a colorless oil. LC/MS (ESI) m/z: 212 (M+H) ⁺ .

Step 2. tert-Butyl(1R,3S,5R)-3-((1,3-diphenylpropan-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (3): to a mixture of 2 (70 mg, 0.33 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (88 mg, 0.36 mmol) DIPEA (86 mg, 0.66 mmol) and HATU (252 mg, 0.66 mmol) were added to DMF (3 mL) at 0°C and the mixture was stirred at 25°C for 2 h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with petroleum ether:EtOAc = 50:1 to 1:1) to give compound 3 (110 mg, 76.4% yield) as a colorless oil. LC/MS (ESI) m/z: 435(M+H) ⁺ .

Stage 3. (1R,3S,5R)-N-(1,3-diphenylpropan-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (4): to a solution of compound 3 (50 mg, 0.115 mmol) in DCM (3 mL) was added TFA (1 mL) at 0°C and the mixture was stirred at 25°C for 4 h. The mixture was concentrated to dryness and the residue was co-evaporated with DCM twice and dried under vacuum to give 4 (55 mg, 100% yield) as a brown oil which was used immediately in the next step without further purification. LC/MS (ESI) m/z: 335(M+H) ⁺ .

Step 4. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1I-indazol-1-yl)acetyl)X-( 1,3-diphenylpropan-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (505): to a mixture of compound 4 (20 mg, 0.06 mmol) and 2-(3-acetyl -7-methyl-5-(2-methylpyrimidin-5-yl)-1N-indazol-1-yl)acetic acid (16.5 mg, 0.05 mmol) in DMF (1 ml) was added DIPEA (23 mg, 0.18 mmol) and HATU (45 mg, 0.12 mmol) at 0°C and the mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give 505 (1.9 mg, 6.44% yield) as a white solid.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.34 (s, 1H), 7.58-7.73 (m, 2H), 7.13-7.30 (m, 10H), 5.925.96 (d, J=17.9 Hz, 1H), 5.63-5.67 (d, J=17.8 Hz, 1H), 4.10-4.17 (m, 2H), 3.10-3.11 (m, 1H), 2.63-2.72 (m, 13H), 21.3 -2.23 (m, 1H), 1.08 (s, 3H), 0.93-0.95 (m, 1H), 0.76-0.78 (m, 1H). LC/MS (ESI) m/z: 641 (M+H)+.

Scheme 105. Synthesis of (2S,4S)-1-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N(6-bromo-3 -methylpyridin-2-yl)-4-fluoro-4-(methoxymethyl)pyrrolidin-2-carboxamide (421)

Stage 1 2 Stage 2 3 Stage 3

1. (2S,4S)-2-Benzyl

-tert-butyl

4-(((tert-butyldimethylsilyl)oxy)methyl)-4Fluoropyrrolidine-1,2-dicarboxylate step (2): DAST (0.78 ml, 5.81 mmol) at -65°C under N2 atmosphere, and the reaction mixture was stirred at room temperature for 2 h. The mixture was then poured into ice-cold saturated NaHCO ₃ solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give compound 2 (1.6 g, crude) as a yellow oil which was used immediately in the next reaction without further purification. LC/MS (ESI) m/z: 468 (M+H) ⁺ .

Stage 2. (2S,4S)-2-Benzyl 1-tert-butyl 4-fluoro-4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3): to a solution of compound 2 (1.6 g, 34.2 mmol) in THF (15 ml) TBAF (4.3 ml, 4.28 mmol, 1 M in THF) was added at 0°C and the reaction mixture was stirred at room temperature for 30 min. The mixture was then poured into ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 6:1 to 2:1) to give compound 3 (700 mg, 57.9% yield) as a light yellow oil. LC/MS: m/z 354 (M+H) ⁺ .

Stage 3. (2S,4S)-2-Benzyl 1-tert-butyl 4-fluoro-4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (4): to a solution of compound 3 (100 mg, 0.283 mmol) in anhydrous DCM (4 ml) was added with AgOTf (116.4 mg, 0.453 mmol) followed by the addition of 2,6-di-tert-butylpyridine (0.13 ml, 0.566 mmol). Then the reaction mixture was cooled to 0°C (external temperature, ice bath) and MeI (0.04 ml, 0.567 mmol) was added dropwise. The resulting slurry was stirred at 0°C for 1.5 h at room temperature overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 15:1 to 5:1) to give compound 4 (30 mg, 28.9% yield) as a clear oil. LC/MS: m/z 368 (M+H) ⁺ .

Stage 5. (2S,4S)-1-(tert-Butoxycarbonyl)-4-fluoro-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (5): to a solution of compound 4 (30 mg, 0.082 mmol) in methanol ( 2 ml) was added Pd/C (5 mg, 10% wt) and the reaction mixture was stirred at room temperature under ballooned H ₂ for 1 h. The mixture was filtered and the filtrate was concentrated to dryness to give compound 5 (22 mg, 97.2 yield %) as a clear oil. LC/MS: m/z 278 (M+H) ⁺ .

Step 6. (2S,4S)-tert-Butyl 2-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-4-fluoro-4(methoxymethyl)pyrrolidine-1-carboxylate (7): to mixture compounds 5 (22 mg, 0.079 mmol) and compound 6 (14.7 mg, 0.079 mmol) in anhydrous DCM (3 mL) pyridine (31.2 mg, 0.395 mmol) was added followed by the addition of POCl ₃ (13.3 mg, 0.087 mmol) at 0° C under N2 and the reaction mixture was stirred at room temperature for 30 min. The mixture was poured into ice water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give compound 7 (30 mg, crude) as a light yellow solid which was used immediately in the next reaction without further purification.

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LC/MS (ESI) m/z: 446 (M+H)+.

Step 7. (2S,4S)-N-(6-Bromo-3-methylpyridin-2-yl)-4-fluoro-4-(methoxymethyl)pyrrolidine-2carboxamide (8): to a solution of compound 7 (30 mg) in DCM (2 ml) was added with TFA (1 ml) at 0°C and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness to give compound 8 (30 mg, crude) as a yellow oil, which was immediately used in next reaction without further purification. LC/MS (ESI) m/z: 346 (M+H) ⁺ .

Step 8. (2S,4R)-1-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo3-methylpyridine -2-yl)-4-fluoro-4-(methoxymethyl)pyrrolidine-2-carboxamide (421): to a mixture of compound 8 (30 mg, 0.09 mmol) and compound 9 (28 mg, 0.09 mmol) in DMF (2 ml ) was added DIPEA (35 mg, 0.27 mmol) followed by HATU (32 mg, 0.135 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with EtOAc twice. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 421 (8 mg, 14.48% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.05 (s, 2H), 8.44 (s, 1H), 7.91-7.86 (m, 2H), 7.63 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 5.73 (d, J=17.3 Hz, 1H), 5.62 (d, J=17.2 Hz, 1H), 4.72 (d, J=10.3 Hz, 1H), 4.15 (d, J=27.8 Hz, 2H), 3.75-3.64 (m, 3H), 3.41 (s, 3H), 2.69 (s, 3H), 2.65 (s, 3H), 2.36-2.31 (m , 1H), 2.02 (s, 3H). LC/MS (ESI) m/z: 638 (M+H) ⁺ .

Scheme 106 5-yl)-1H-indazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (359)

water UN

MeOH/THF

Stage ι3

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with -CH ₂ -oxadiazole at position R ²⁰¹ . One skilled in the art will appreciate that formohydrazide may be substituted with other hydrazide reagents to provide additional compounds of the present invention. For example, acetohydrazine can be used in place of formohydrazide to form a substituted -CH ₂ -oxadiazole at the R ²⁰¹ position.

Step 1. (1R,3S,5R)-3-Benzyl 2-tert-butyl 5-(2-(2-formylhydrazinyl)-2-oxoethyl)-2azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2 ): EDCI (0.124 g, 0.8 mmol) and HOBt (0.108 g, 0.8 mmol) were added to a mixture of compound 1 (0.2 g, 0.53 mmol) and N-formylhydrazine (0.064 g, 1.06 mmol) in 1,4-dioxane (4 mL) followed by the addition of DIPEA (0.37 ml, 2.13 mmol) at 0°C, and the mixture was stirred at 25°C for 16 h. The mixture was diluted with EtOAc and washed with saturated aqueous NH ₄ Cl three times. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM:MeOH=20:1 to 10:1) to give compound 2 (0.12 g, 53.9% yield) as a light yellow solid. LC/MS (ESI) m/z: 440 (M+Na) ⁺ .

Step 2. (1R,3S,5R)-3-Benzyl 2-tert-butyl 5-((1,3,4-oxadiazol-2-yl)methyl)-2azabicyclo[3.1.0]hexane-2,3- dicarboxylate (3): to a solution of compound 2 (0.12 g, 0.29 mmol) in tetrahydrofuran (5 mL) was added (Al) Burgess reagent (0.082 g, 0.34 mmol) in one portion under N2 atmosphere, and the reaction was stirred at 75°C under N ₂ for 4 hours, after which TLC (DCM:MeOH=20:1) showed about 30% conversion. Additional Burgess reagent (0.089 g, 0.37 mmol) was added and the reaction mixture was stirred under N2 for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with DCM:MeOH = 30:1 to 15:1) to give compound 3 (0.089 g, 62% yield) as a light yellow oil. LC/MS (ESI) m/z: 422 (M+Na)+.

Step 3. (1R,3S,5R)-5-((1,3,4-oxadiazol-2-ul)methyl)-2-(tert-butoxycarbonyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (4): lithium (0.012 g, 0.481 mmol) was added to a solution of compound 3 (0.08 g, 0.16 mmol) in THF (2 mL), MeOH (2 mL), and water (1 mL) at 0°C, and the reaction mixture stirred at 0° C. for 3 hours. The mixture was concentrated to dryness and diluted with water. The mixture was washed twice with EtOAc, and the aqueous layer was acidified by adding 0.5N. HCl to pH approximately 3. The mixture was extracted twice with DCM and the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 4 (0.035 g, 70.6% yield) as a yellow solid. LC/MS (ESI) m/z: 332 (M+Na) ⁺ .

Step 4. (1R,3S,5R)-tert-Butyl 5-((1,3,4-oxadiazol-2-yl)methyl)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)- 2-azabicyclo[3.1.0]hexane-2-carboxylate (5): to a mixture of compound 4 (0.035 g, 0.113 mmol) and 6-bromo-3-methylpyridine-2-amine (0.021 g, 0.113 mmol) in DCM ( 2 ml) pyridine (0.054 g, 0.679 mmol) was added and the mixture was cooled to 0°C. POCl ₃ (0.035 g, 0.226 mmol) was added dropwise to the mixture at 0°C, and the reaction mixture was stirred at 0°C for 3 h. aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness to give compound 5 (0.033 g, 61% yield) as a light yellow solid, which was immediately used for the next reaction without purification. LC/MS (ESI) m/z: 480 (M+H) ⁺ .

Step 5. (1 R,3S,5R)-5 -((1,3,4-oxadiazol-2-yl)methyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1 .0]hexane-3-carboxamide, TFA salt (6): to a solution of compound 5 (0.033 g, 0.069 mmol) in DCM (1 ml) was added TFA (0.4 ml) at 0°C, and the mixture was stirred at 0°C over 2 h. The mixture was concentrated to dryness to give compound 6 (0.04 g, 95.6% yield) as a yellow syrup, which was immediately used in the next reaction without purification. LC/MS (ESI) m/z: 380 (M+H) ⁺ .

Step 6. (1R,3S,5R)-5-((1,3,4-Oxadiazol-2-yl)methyl)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidine-5 -ul)-1H-undazol-1-yl)acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-2azabicyclo[3.1.0]hexane-3-carboxamide (359): to a mixture of compound 6 DIPEA ( 0.053 g, 0.41 mmol) at 0°C followed by the addition of HATU (0.046 g, 0.12 mmol) and the mixture was stirred at 25°C for ₄ h. over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative TLC (eluting with DCM:MeOH = 15:1) to give compound 359 (6 mg, 10.8% yield) as a white solid.

1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.93 (s, 1H), 8.39 (s, 1H), 7.51-7.53 (d, J=8.0 Hz, 1H), 7.51 (s, 1H) , 7.35-7.37 (d, J=8.0 Hz, 1H), 5.95-6.00 (d, J=18.0 Hz, 1H), 5.78-5.82 (d, J=18.0 Hz, 1H), 4.59-4.63 (m, 1H ), 3.84-3.86 (m, 1H), 3.37-3.41 (d, J=16.0 Hz, 1H), 3.18-3.22 (d, J=16.0 Hz, 1H), 2.73 (s, 3H), 2.74 (s, 3H), 2.692.72 (m, 1H), 2.67 (s, 3H), 2.44-2.49 (m, 1H), 2.08 (s, 3H), 1.28-1.30 (m, 1H), 1.18-1.20 (m, 1H). LC/MS (ESI) m/z: 684/686 (M+H) ⁺ .

(1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-ul)acetyl)-N-( 6bromo-3-methylpyridin-2-yl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide:

1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.99 (s, 1H), 8.41 (s, 1H), 7.52-7.54 (d, J=8.0 Hz, 1H), 7.53 (s, 1H) , 5.97-6.01 (d, J=17.6 Hz, 1H), 5.79-5.84 (d, J=17.6 Hz, 1H), 4.60-4.62 (m, 1H), 3.83-3.85 (m, 1H), 3.233.27 (d, J=15.6 Hz, 1H), 3.14-3.18 (d, J=15.6 Hz, 1H), 2.76 (s, 3H), 2.74 (s, 3H), 2.70-2.72 (m, 1H), 2.71 ( s, 3H), 2.51 (s, 3H), 2.43-2.48 (m, 1H), 2.08 (s, 3H), 1.28-1.30 (m, 1H), 1.17-1.19 (m, 1H). LC/MS (ESI) m/z: 698/700 (M+H) ⁺ .

Scheme 107. Synthesis of (1R,3S,5R)-N-(3-((2H-tetrazol-5-yl)methyl)-6-bromo-pyridin-2-yl)-2-(2-(3-acetyl5-( 2-methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1-yl)acetyl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (397)

- 399 041794

Stage 1. 6-Bromo-2-fluoronicotinic acid (2): to a solution of compound 1 (5 g, 28.41 mmol) in tetrahydrofuran (80 ml) was added LDA (15.6 ml, 31.2 mmol, 2 M and THF) dropwise at - 78°C under N2 and the mixture was stirred at -78°C for 3 hours. A stream of dry CO2 was purged through the solution and the mixture was stirred at -78°C for an additional 30 minutes. The reaction was quenched with water and washed with EtOAc. The aqueous layer was acidified with 1N. aqueous HCl and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ and concentrated to give compound 2 (2.85 g, 45.60% yield) as a yellow solid, which was used immediately in the next step. LC/MS (ESI) m/z: 221 (M+H)+.

Stage 2. (6-Bromo-2-fluoropyridin-3-yl)methanol (3): to a solution of compound 2 (2.85 g, 12.96 mmol) in tetrahydrofuran (20 ml) was added a borane-tetrahydrofuran complex (32.3 ml, 32.3 mmol, 1 M in THF) dropwise at 0°C and the mixture was stirred at room temperature under N ₂ overnight. After cooling to 0°C, the reaction mixture was made basic with saturated aqueous K ₂ CO ₃ and the solvent was removed. The residue was extracted twice with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 30:1 to 10:1) to give compound 3 (1 g, 37.47% yield) as a white solid. LC/MS (ESI) m/z: 206 (M+H) ⁺ .

Step 3. 6-Bromo-3-(chloromethyl)-2-fluoropyridine (4): to a solution of compound 3 (53 mg, 0.26 mmol) in thionyl chloride (8 mL) was added DMF (0.02 mL) at 0°C under N2 atmosphere , and the mixture was stirred at room temperature for 5 h under N ₂ . The mixture was concentrated to dryness and the residue was taken up in DCM. The mixture was made basic by adding saturated aqueous NaHCO ₃ and the layers were separated. The organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness to give compound 4 (52 mg, 90.07% yield) as a yellow oil, which was used immediately in the next step. LC/MS (ESI) m/z: 224 (M+H) ⁺ .

Step 4 2-(6-Bromo-2-fluoropyridin-3-yl)acetonitrile (5): powdered sodium cyanide (0.22 g, 4.46 mmol) was added to DMSO (5 ml) and the mixture was stirred at room temperature for 20 min. A solution of compound 4 (0.5 g, 2.23 mmol) in DMSO (5 ml) was added dropwise to the above mixture over 10 min. The resulting mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0°C, and water was slowly added to the mixture. The resulting mixture was extracted twice with DCM and the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 50:1 to 40:1) to give compound 5 (0.17 g, 34.66% yield) as a light yellow solid. LC/MS (ESI) m/z: 216 (M+H) ⁺ .

Step 5. 2-(6-Bromo-2-(tert-butylamino)pyridin-3-yl)acetonitrile (6): to a mixture of compound 5 (0.17 g, 0.77 mmol) and DIPEA (0.3 g, 2.32 mmol) in DMSO (4 ml) was added erbumine (0.28 g, 3.86 mmol) and the mixture was stirred at 40°C in a sealed tube overnight. The mixture was diluted with H ₂ O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc=100:1 to 60:1) to give compound 6 (0.11 g, 53.13% yield) as a yellow oil. LC/MS (ESI) m/z: 268 (M+H) ⁺ .

Step 6. 2-(2-Amino-6-bromopyridin-3-yl)acetonitrile (7): Compound 6 (0.11 g, 0.41 mmol) and trifluoroacetic acid (2 ml) were charged into a round bottom flask, and the mixture was stirred at 70°C C for 0.5 hours. The reaction mixture was concentrated to dryness and the residue was made basic with saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 50:1 to 8:1) to give compound 7 (69 mg, 79.31% yield) as a white solid. LC/MS (ESI) m/z: 214 (M+H) ⁺ .

- 400 041794

Step 7. (1R,3S,5R)-tert-butyl 3-(6-bromo-3-(cyanomethyl)pyridin-2-ylcarbamoyl)-5-methyl-2azabicyclo[3.1.0]hexane-2-carboxylate (8 ): to a mixture of compound 7 (65 mg, 0.31 mmol) and (1R,3S,5R)-2(tert-butoxycarbonyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (81 mg , 0.34 mmol) in dichloromethane (5 mL), pyridine (121 mg, 1.53 mmol) was added followed by phosphoryl chloride (52 mg, 0.34 mmol) at 0°C, and the mixture was stirred at room temperature for 0.5 h under N2 atmosphere. The mixture was poured into ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 30:1 to 8:1) to give compound 8 (45 mg, 33.72% yield) as a yellow solid. LC/MS (ESI) m/z: 436 (M+H)+.

Step 8. (1R,3S,5R)-N-(6-bromo-3-(cyanomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (9): to a solution of compound 8 (45 mg, 0.10 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) at 0°C, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, and the residue was washed with ether and dried under vacuum to give compound 9 (30 mg, 86.58% yield) as a yellow solid, which was used immediately in the next step. LC/MS (ESI) m/z: 336 (M+H)+.

Step 9. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl) acetyl)-N-(6-bromo-3-(cyanomethyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (11): to a mixture of compound 9 (30 mg , 0.089 mmol) and compound 10 (28 mg, 0.089 mmol) in DMF (1.5 mL) were added DIPEA (58 mg, 0.45 mmol) followed by addition of HATU (68 mg, 0.18 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with 10% aqueous LiCl and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 100:1 to 50:1) to give compound 11 (38 mg, 67.56% yield) as a dark green solid. LC/MS (ESI) m/z: 628 (M+H) ⁺ .

Step 10. (1R,3S,5R)-N-(3-((2H-Tetrazol-5-yl)methyl)-6-bromopyridin-2-yl)-2-(2-(3-acetyl-5- (2methylnirimidin-5-yl)-1H-nirazolo[3,4-c]niridin-1-yl)acetyl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (397): in a sealed tube compound 11 (34 mg, 0.054 mmol), TBAF (0.1 ml, 1 M in THF) and azidotrimethylsilane (1 ml) were loaded and the reaction mixture was stirred at 85°C overnight. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to give compound 397 (5 mg, 27.5% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 9.33 (s, 2H), 9.26 (d, J=1.2 Hz, 1H), 8.60 (d, J=1.2 Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 6.23 (d, J=17.2Hz, 1H), 5.74 (d, J=16.8Hz, 1H), 4.44 ( dd, J=9.6, 4.8 Hz, 1H), 4.05 (d, J=15.6 Hz, 2H), 3.53-3.50 (m, 1H), 2.68 (d, J=5.6 Hz, 6H), 2.16-1.96 (m , 2H), 1.28 (s, 3H), 1.10–1.05 (m, 1H), 1.05–1.00 (m, 1H). LC/MS (ESI) m/z: 671 (M+H) ⁺ .

Scheme 108. Synthesis of (1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4c]pyridin-1-yl)acetyl) -N-(6-bromo-3-(3-morpholinopropyl)pyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (400)

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400

Step 1. (E)-Ethyl 3-(6-bromo-2-fluoropyridin-3-yl)acrylate (2): Ethyl 2-( triphenylphosphoranylidene)acetate (937.9 mg, 2.70 mmol) at 0°C and the reaction mixture was stirred at 50°C overnight. The mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to give compound 2 (523 mg, 78.4% yield) as a white solid. LC/MS (ESI) m/z: 274 (M+H)+.

Step 2 Ethyl 3-(6-bromo-2-fluoropyridin-3-yl)propanoate (3): PtO ₂ (53 mg) was added to a solution of compound 2 (523 mg, 1.92 mmol) in EtOAc (6 mL), and the mixture was degassed under N ₂ three times and stirred under ballooned H ₂ at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated under reduced pressure to give compound 3 (500 mg, 94.7% yield) as a white solid. LC/MS (ESI) m/z: 276 (M+H) ⁺ .

Stage 3. Ethyl 3-(6-bromo-2-(tert-butylamino)pyridin-3-yl)propanoate (4): to a mixture of compound 3 (500 mg, 1.82 mmol) and 2-methylpropan-2-amine (664 mg, 9.09 mmol) in DMSO (5 mL) was added DIPEA (704 mg, 5.45 mmol) and the reaction mixture was stirred at 75°C in a sealed tube for 48 h. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 1:0 to 100:1) to give compound 4 (104 mg, 17.4% yield) as a clear oil. LC/MS (ESI) m/z: 329 (M+H) ⁺ .

Step 4. 3-(6-Bromo-2-(tert-butylamino)pyridin-3-yl)propan-1-ol (5): to a solution of compound 4 (104 mg, 0.32 mmol) in anhydrous THF (3 mL) a 1 M solution of LiBH ₄ THF (0.64 ml, 0.64 mmol) was added at 0°C under N ₂ atmosphere, and the reaction mixture was stirred at 40°C for 2 h. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give compound 5 (70 mg, 76.5% yield) as a yellow oil which was used in the next reaction without further purification. LC/MS (ESI) m/z: 287 (M+H) ⁺ .

Step 5. 3-(6-Bromo-2-(tert-butylamino)pyridin-3-yl)propylmethanesulfonate (6): TEA (0.07 ml, 0.48 mmol) followed by the addition of a solution of MsCl (41.5 mg, 0.36 mmol) in DCM (0.5 ml) at 0°C under N ₂ atmosphere. The reaction mixture was stirred at 0° C. for 1 hour. The mixture was poured into ice water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 6 (85 mg, 97.2% yield) as a yellow oil which was used immediately in the next step without further purification. LC/MS (ESI) m/z: 365 (M+H) ⁺ .

Stage 6. 6-Bromo-N-(tert-butyl)-3-(3-morpholinopropyl)pyridine-2-amine (7): to a mixture of compound 6 (85 mg, 0.24 mmol) and 2-methylpropan-2-amine (0.1 ml, 1.21 mmol) in MeCN (2 ml) was added DIPEA (0.12 ml, 0.72 mmol) followed by NaI (26.4 mg, 0.24 mmol) and the reaction mixture was stirred at 50°C overnight. The mixture was poured into ice water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give compound 7 (75 mg, crude) as a yellow oil which was used immediately in the next reaction without further purification. LC/MS (ESI) m/z: 329 (M+H) ⁺ .

Step 7 6-Bromo-3-(3-morpholinopropyl)pyridine-2-amine (8): A solution of compound 7 (75 mg, 0.24 mmol) in TFA (2 ml) was stirred at 70°C for 30 min. The mixture was evaporated under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ . The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 1:1 to 0:1) to give compound 8 (44 mg, 61.3% yield) as a light brown solid. LC/MS (ESI) m/z: 300 (M+H) ⁺ .

Step 8. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-(3-morpholinopropyl)pyridin-2-yl)carbamoyl)-5methyl-2-azabicyclo[3.1.0]hexane- 2-carboxylate (10): to a mixture of compound 8 (44 mg, 0.15 mmol) and compound 9 (35.5 mg, 0.147 mmol) in anhydrous DCM (3 mL) was added pyridine (0.06 mL, 0.735 mmol) from

- 402 041794 followed by the addition of POC13 (0.02 ml, 0.162 mmol) at 0°C and the reaction mixture was stirred at room temperature for 30 min. The mixture was poured into ice water and extracted with DCM twice. The organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate = 1:1 to 0:1) to give compound 10 (27 mg, 34.6% yield) as a light yellow solid. LC/MS (ESI) m/z: 523 (M+H)+.

Step 9. (1R,3S,5R)-tert-Butyl 3-((6-bromo-3-(3-morpholinopropyl)pyridin-2-yl)carbamoyl)-5methyl-2-azabicyclo[3.1.0]hexane- 2-carboxylate (11): Solution 4n. HCl/dioxane (2 mL) was added to compound 10 (27 mg, 0.05 mmol) at 0°C under N ₂ and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness to give compound 11 (20 mg, yield 100%) as a brown solid, which was used immediately in the next step without further purification. LC/MS (ESI) m/z: 423 (M+H) ⁺ .

Step 10. (1 R,3S,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1-yl) acetyl)-N-(6-bromo-3-(3-morpholinopropyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (400): to a mixture of compound 11 (20 mg , 0.052 mmol) and compound 12 (17.7 mg, 0.057 mmol) in DMF (2 mL) was added HATU (29.6 mg, 0.078 mmol) followed by the addition of DIPEA (0.04 mL, 0.156 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into ice water and extracted with EtOAc twice. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 400 (7 mg, 18.9% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.35 (s, 2H), 9.31 (d, J=1.2 Hz, 1H), 8.62 (d, J=1.2 Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 6.07 (d, J=17.4Hz, 1H), 5.72 (d, J=17.2Hz, 1H), 4.40 (dd , J=9.2, 5.4 Hz, 1H), 3.61 (dd, J=5.5, 2.3 Hz, 1H), 3.40-3.37 (m, 4H), 2.69 (d, J=3.8 Hz, 6H), 2.60-2.52 ( m, 2H), 2.41-2.33 (m, 2H), 2.03 (d, J=12.5 Hz, 4H), 1.94 (t, J=7.1 Hz, 2H), 1.54-1.46 (m, 2H), 1.34 (s , 3H), 1.09 (dd, J=5.3, 2.2 Hz, 1H), 1.01 (t, J=5.4 Hz, 1H). LC/MS (ESI) m/z: 716 (M+H) ⁺ .

Scheme 109. Synthesis of (1R,3S,5S)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pirazolo[3,4c]pyridin-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-((difluoromethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (384)

Vos Vos

2 3

384

Stage 1. (1R,3S,5S)-2-tert-Butyl 3-ethyl 5-((difluoromethoxy)methyl)-2-azabicyclo[3.1.0]hexane-2,3dicarboxylate (2): to a mixture of compound 1 ( 500 mg, 1.44 mmol) and CuI (55 mg, 0.288 mmol) in anhydrous MeCN (25 ml) were added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (513 mg, 2.88 mmol) at room temperature under N ₂ , and the resulting mixture was stirred at 45° C. under N ₂ for 1 hour. The mixture was diluted with EtOAc and filtered, and the filtrate was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The residue was purified with a silica gel column (eluting with PE:EtOAc = 15:1) to give compound 2 (350 mg, 61.4% yield) as a colorless oil. LC/MS (ESI) m/z: 420 (M+Na) ⁺ .

Stage 2. (1R,3S,5S)-2-(tert-Butoxycarbonyl)-5-((difluoromethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxylic acid (3): to a solution of compound 2 (350 mg, 0.88 mmol) in MeOH (12 ml) was added 4 ml of an aqueous solution of LiOH (4 mmol, 1 M) and the mixture was stirred at room temperature for 4 h. The mixture was diluted with water (20 ml) and extracted with ether, and the aqueous layer withdrawn and acidified with aqueous HCl (1N) to pH 5. The mixture was extracted with DCM/MeOH (20 ml x 2, 15:1, v/v) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give compound 3 (240 mg, 88.9% yield) as a colorless oil. LC/MS (ESI) m/z: 330(M+Na) ⁺ .

Stage 3. (1R,3S,5S)-tert-Butyl 3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5((difluoromethoxy)methyl)-2-azabicyclo[3.1.0]hexane -2-carboxylate (4): to a solution of compound 3 (138 mg,

- 403 041794

0.45 mmol) and 6-bromo-3-methylpyridin-2-amine (85 mg, 0.45 mmol) in anhydrous DCM (10 ml) was added pyridine (178 mg, 2.25 mmol) followed by dropwise addition of POCl ₃ (77 mg, 0.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified with a silica gel column (eluting with PE:EtOAc=6:1) to give compound 4 (131 mg, 61.2% yield) as a colorless oil. LC/MS (ESI) m/z: 476/478 (M+H)+.

Step 4. (1R,3S,5S)-N-(6-Bromo-3-methylpyridin-2-yl)-5-((difluoromethoxy)methyl)-2azabicyclo[3.1.0]hexane-3-carboxamide, TFA salt (5): To a solution of compound 4 (55 mg, 0.116 mmol) in DCM (2 ml) was added TFA (1 ml) dropwise at 0°C under N ₂ atmosphere, and the mixture was stirred at room temperature for 1 h. concentrated to dryness to give compound 5 (60 mg, 95.9% yield) as a dark brown oil, which was used immediately in the next step without further purification. LC/MS (ESI) m/z: 376/378 (M+H)+.

Step 5. (1R,3S,5S)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridin-1yl)acetyl)- N-(6-bromo-3-methylpyridin-2-yl)-5-((difluoromethoxy)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (384): to a mixture of compound 5 (60 mg, 0.116 mmol ), compound 6 (36 mg, 0.116 mmol) and HATU (80 mg, 0.21 mmol) in DMF (3 mL) DIPEA (76 mg, 0.58 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hours The mixture was diluted with EtOAc and washed with 10% aqueous LiCl and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by preparative HPLC to give compound 384 (25 mg, 32.3% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 9.25-9.42 (m, 3H), 8.62 (d, J=1.1 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 6.56 (s, 1H), 6.07 (d, J=17.3 Hz, 1H), 5.76 ( d, J=17.2Hz, 1H), 4.51 (dd, J=9.4, 4.7Hz, 1H), 3.98 (dd, J=25.7, 10.9Hz, 2H), 3.85 (dd, J=5.7, 2.7Hz, 1H ), 2.70 (s, 3H), 2.69 (s, 3H), 2.53-2.60 (m, 1H), 2.25-2.32 (m, 1H), 2.04 (s, 3H), 1.31-1.37(m, 1H), 1.28 (t, J=5.6 Hz, 1H). LC/MS (ESI) m/z: 669/671 (M+H) ⁺ .

Scheme 110. Synthesis of (1R,3S,5R)-2-(2-(3-(1H-imidazole-2-carbonyl)-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl) -N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3carboxamide (389)

But

389

Step 1. 5-Bromo-1-(tert-butoxycarbonyl)-1H-indazole-3-carboxylic acid (2): to a solution of 5-bromo-1H-indazole-3-carboxylic acid (1 eq.) in THF (10 vol. ) at 0°C under a nitrogen atmosphere, DMAP (0.1 equiv.) and triethylamine (3 equiv.) were added. Boc anhydride (1 eq.) was added and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 2, which was used as is in the next step.

Stage 2. 5-(2-Methylpyrimidin-5-yl)-1H-indazole-3-carboxylic acid (3): to a solution of compound 2 (1 eq.) in 1,4-dioxane (20 vol.) and water ( 2 vol.) at 0°C in a nitrogen atmosphere was added 2-methyl-5-(4,4,5,5-404 041794 tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (1.5 eq.), potassium carbonate (3 eq.). After degassing with nitrogen, PdCl ₂ (dppf) (0.1 equiv.) was added to the reaction mixture. The reaction mixture was sealed and kept under microwave at 100° C. for 1 hour. After completion of the reaction, the reaction mixture was concentrated to give compound 3, and the resulting residue was used as is in the next step.

Stage 3. N-Methoxy-N-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-3-carboxamide (4): to a solution of compound 3 (1 eq.) in DMF (10 vol.) N,Odimethylhydroxylamine hydrochloride (1.5 equiv.), EDCI-HCl (1.5 equiv.), and DMAP (1.2 equiv.) were added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 4, and the resulting residue was used as is in the next step.

Stage 4. (5-(2-Methylpyrimidin-5-yl)-1 H-indazol-3 -yl) (1 - ((2- (trimethylsilyl) ethoxy) methyl) -1Himidazol-2-yl) methanone (5) : to a solution of compound 4 (1 equiv.) in THF (10 vol.) at -40°C in a nitrogen atmosphere was added n-BuLi (5 equiv.). The reaction mixture was stirred at -40°C for 1 h. 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (5 eq) was added to the reaction mixture and stirred at -40°C for 3 h After completion of the reaction, the reaction mixture was quenched with ice water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give compound 5.

Step 5 Methyl 2-(5-(2-methylpyrimidin-5-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Himidazole-2-carbonyl)-1H-indazol-1-yl )acetate (6): to a solution of compound 5 (1 equiv.) in DMF (10 vol.) were added potassium carbonate (1.5 equiv.) and methyl 2-bromoacetate (1.1 equiv.). The reaction mixture was stirred at 50° C. for 3 hours and then quenched with water. The resulting solid was filtered, taken up in MTBE, stirred for 30 min, filtered and dried to give compound 6.

Step 6 2-(5-(2-Methylpyrimidin-5-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2carbonyl)-III-indazol-1-yl) acetic acid (7): to a solution of compound 6 (1 equiv.) in THF/water (10 vol./2 vol.) was added LiOH (3 equiv.). The reaction mixture was stirred at room temperature for 4 hours and concentrated. Water was added to the residue and washed with ethyl acetate (3 times). The aqueous layer was acidified with 1.5N. HCl and then extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 7.

Step 7. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(5-(2-methylpyrimidin-5-yl)-3 (1-((2-(trimethylsilyl)ethoxy)methyl)-III-imidazole-2-carbonyl)-III-indazol-1-yl)acetyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (8): (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5- methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (1 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give compound 8.

Step 8. (1R,3S,5R)-2-(2-(3-(1H-imidazole-2-carbonyl)-5-(2-methylpyrimidin-5-yl)-1H-indazol-1yl) acetyl)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (389): solution of compound 8 (1 eq.) in TFA (5 vol.) was stirred at room temperature for 4 h and concentrated. The residue was purified by preparative purification to give compound 389.

1H NMR (400 MHz, CD3OD) δ 9.08 (s, 2H), 8.68 (s, 1H), 7.97 (s, 2H), 7.85 (s, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 6.01 (d, J=18.0 Hz, 1H), 5.96 (d, J=18.0 Hz, 1H), 3.75-3.69 (m, 2H), 3.61-3.59 (m, 2H), 3.80 (s, 3H), 2.13 (s, 3H), 1.45 (s, 3H), 1.21-1.28 (m, 1H), 1.11-1.10 (m, 1H).

Scheme 111. Synthesis of (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(7-methyl-5-(2methylpyrimidin-5-yl) )-3-(2-azaspiro[3.3]heptan-2-carbonyl)-1H-indazol-1-yl)acetyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (390)

- 405 041794

Stage 1. 7-Methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole-3-carbonitrile (2): to a solution of 3-iodo-7methyl-5-(2-methylpyrimidin-5-yl)- 1H-indazole (1 equiv.) in DMF (10 vol.) and water (1 vol.) Zn(CN) ₂ (1.1 equiv.) was added at room temperature. After degassing with nitrogen, Pd(dppf)Cl ₂ (0.1 equiv.) and Pd ₂ (dba) ₃ (0.1 equiv.) were added, and the mixture was stirred at 90°C for 5 h. The reaction mixture was cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using hexane/EtOAc to give compound 2.

Stage 2. 7-Methyl-5-(2-methylpyrimidin-5-yl)-1H-indazole-3-carboxylic acid (3): to a solution of compound 2 (1 eq.) in dioxane (5 vol.) at 0° C was added 6n. HCl (20 vol.). The reaction mixture was stirred at 90° C. for 3 h in a sealed tube and then concentrated. 10% NaHCO ₃ was added and the resulting mixture was extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give compound 3.

Stage 3. 1 -(tert-Butoxycarbonyl)-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazole-3-carboxylic acid (4): to a solution of compound 3 (1 eq.) in dioxane (10 vol.) and water (3 vol.) at 0°C was added 2 M NaOH (3 equiv.). Boc anhydride (1.5 eq.) was added and the mixture was stirred at room temperature for 16 h. After completion of the reaction, water was added and the resulting mixture was acidified with 1 M citric acid solution, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 4.

Step 4. tert-Butyl 7-methyl-5-(2-methylpyrimidin-5-yl)-3-(2-azaspiro[3.3]heptan-2-carbonyl)1H-indazole-1-carboxylate (5): to solution 2-azaspiro[3.3]heptane (1 equiv.), HATU (1.5 equiv.), and DIPEA (5 equiv.) were added to compound 4 (1 equiv.) in DMF (10 vol.) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 5.

Step 5. tert-Butyl 2-(7-methyl-5-(2-methylpyrimidin-5-yl)-3-(2-azaspiro[3.3]heptan-2-carbonyl)1H-indazol-1-yl)acetate ( 6): to a solution of compound 5 (1 equiv.) in 1,4-dioxane (3 vol.) at 0°C in a nitrogen atmosphere was added 4N. HCl in 1,4-dioxane (10 vol.), and the mixture was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure, and the resulting residue was used as is in the next step.

Potassium carbonate (3 eq.) and tert-butyl 2-bromoacetate (1.5 eq.) were added to a solution of the residue obtained above in DMF (10 vol.). The reaction mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the mixture was quenched with water. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH with

- 406 041794 by irradiation of compound 6.

Step 6. 2-(7-Methyl-5-(2-methylpyrimidin-5-yl)-3-(2-azaspiro[3.3]heptan-2-carbonyl)-1Hindazol-1-yl)acetic acid (7): to a solution of compound 6 (1 equiv.) in DCM (10 vol.) at 0°C was added TFA (5 vol.). The reaction mixture was stirred at 50° C. for 2 hours. The volatiles were removed under reduced pressure to give compound 7, and the resulting residue was used as is in the next step.

Step 7. (1R,3S,5R)-N-(6-Bromo-3-methylpyridin-2-yl)-5-methyl-2-(2-(7-methyl-5-(2methylpyrimidin-5-yl) -3-(2-azaspiro[3.3]heptan-2-carbonyl)-III-indazol-1-yl)acetyl)-2azabicyclo[3.1.0]hexane-3-carboxamide (390): to a solution of compound 7 (1 equiv. .) (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2azabicyclo[3.1.0 ]hexane-3-carboxamide (1.2 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give compound 390.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.41 (s, 1H), 7.57-7.54 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 5.92 (d, J= 18.0 Hz, 1H), 5.78 (d, J=18.0 Hz, 1H), 4.65-4.64 (m, 1H), 4.19-4.17 (m, 2H), 3.65-3.64 (m, 1H), 3.56-3.55 (m , 1H), 2.76 (s, 3H), 2.33 (s, 3H), 2.27-2.13 (m, 2H), 1.92-1.91 (m, 2H), 1.43-1.42 (m, 2H), 1.30 (s, 3H ), 1.29 (s, 3H), 0.97–0.91 (m, 2H).

Scheme 112. Synthesis of (1R,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-N(6-bromo-5 -fluoro-3-((methylthio)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (438)

438

Stage 1. N-(6-Bromo-5-fluoropyridin-2-yl)-1,1-dimethyl-N-sulfanimine (2): 6-bromo-5-fluoropyridine2-amine (0.97 g, 5.078 mmol, 1 eq. .) in dichloromethane (5 ml, 1.016 M, 5.155 vol.) was cooled to -60°C. N-chlorosuccinimide (0.712 g, 0.432 ml, 5.332 mmol, 1.05 eq.) in dichloromethane (10 ml) was added slowly at -60°C. The reaction mixture was stirred for 30 min, then methyl sulfide (0.947 g, 1.119 mL, 15.235 mmol, 3 equiv.) was slowly added and the reaction was stirred for 1 h. Sodium methoxide (0.329 g, 12.188 mL, 6.094 mmol, 1.2 equiv.) at -60°C, and the reaction was stirred for 1 h at -60°C, then the reaction was left to warm to room temperature. After evaporating the solvent, the crude material was purified by SiO ₂ chromatography to give N-(6-6pom5-fluoropyridin-2-yl)-S,S-dimethyl-λ ⁴ -sulfanimine (0.98 g, 3.903 mmol, 76.845% yield).

Stage 2. 6-Bromo-5-fluoro-3-((methylthio)methyl)pyridine-2-amine (3): to N-(6-bromo-5-fluoropyridin-2yl)-S,S-dimethyl-λ ⁴ -sulfanimine (0.98 g, 3.903 mmol) was added potassium tert-butoxide (4 mmol) in tert-butyl alcohol (10 ml) and the reaction was heated at reflux for 16 h. The solvent was removed and the residue was purified by chromatography on SiO ₂ to obtain 6-bromo-5-fluoro-3((methylthio)methyl)pyridine-2-amine (0.5 g, 1.99 mmol, 51% yield).

Stage 3. tert-Butyl (1R,5R)-3-((6-bromo-5-fluoro-3-((methylthio)methyl)pyridin-2-yl)carbamoyl)-5

- 407 041794 methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (4): (1R,3S,5R)-2-(tert-butoxycarbonyl)-5-methyl-2azabicyclo[3.1.0]hexane- 3-carboxylic acid (0.05 g, 0.209 mmol, 1.05 equiv.) and 6-bromo-5-fluoro-3[(methylsulfanyl)methyl]pyridine-2-amine (0.05 g, 0.199 mmol, 1 equiv.) were dissolved in dichloromethane (5 ml) and pyridine (0.079 g, 0.08 ml, 0.996 mmol, 5 equiv.) was added followed by the addition of phosphoryl chloride (0.031 g, 0.019 ml, 0.199 mmol, 1 equiv.) at 0°C. The reaction mixture was stirred for 1 h at 0° C. and water was added followed by K ₂ CO ₃ to make the reaction mixture alkaline. The organic layer was separated and the solvent was removed. The crude material was purified by SiO ₂ chromatography to give tert-butyl (1R,3S,5R)-3-({6-bromo-5-fluoro-3-[(methylsulfanyl)methyl]pyridin2-yl}carbamoyl)-5 -methyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.09 g, 0.19 mmol, 95.284% yield).

Step 4. (1R,5R)-N-(6-Bromo-5-fluoro-3-((methylthio)methyl)pyridin-2-yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (5): c tert-butyl (1R,3S,5R)-3-({6-bromo-5-fluoro-3[(methylsulfanyl)methyl]pyridin-2-yl}carbamoyl)-5-methyl-2 -azabicyclo[3.1.0]hexane-2-carboxylate (0.09 g, 0.19 mmol, 1 equiv.), was added 4n. hydrochloric acid in dioxane (5 ml), and the reaction was stirred for 1 h at room temperature. The solvent was removed and the residue was used in the next step.

Step 5. (1 R,5R)-2-(2-(3-Acetyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-N-(6-bromo5 -fluoro-3-((methylthio)methyl)pyridin-2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide (438): to (1R,3S,5R)-N solution -{6-bromo-5-fluoro-3-[(methylsulfanyl)methyl]pyridin-2-yl}-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (0.078 g, 0.19 mmol, 1 eq .) and [3-acetyl-5-(2methylpyrimidin-5-yl)indazol-1-yl]acetic acid (0.062 g, 0.199 mmol, 1.05 equiv.) in N,Ndimethylformamide (1.56 ml, 0.122 M, 20 vol. ) was added Hunig's base (0.123 g, 0.165 ml, 0.95 mmol, 5 equiv.), and the reaction mixture was cooled to 0°C. N,N,N',N'-tetramethyl-O-(benzotriazol-1yl)uronium tetrafluoroborate (0.067 g, 0.209 mmol, 1.1 equiv.) was added and the reaction was stirred for 1 h. The excess solvent was removed and the residue was purified with chromatography on SiO ₂ to give (1R,3S,5R)-2-{2-[3-acetyl-5-(2-methylpyrimidin-5-yl)indazol-1-yl]acetyl}-N-{6- bromine-5-fluoro-3[(methylsulfanyl)methyl]pyridin-2-yl}-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide 438 (0.05 g, 0.064 mmol, 33.729% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.97-1.08 (m, 2H), 1.34 (s, 3H), 1.77 (s, 3H), 2.06 (m, 1H), 2.56 (m, 1H), 2.66 (s, 3H), 2.70 (s, 3H), 3.60 (m, 1H), 4.00-4.80 (m, 2H), 4.40 (m, 1H), 5.59 (m, 1H), 5.92 (m, 1H), 7.85-7.96 (m, 3H), 8.45 (s, 1H), 9.05 (s, 2H), 10.35 (s, 1H).

Scheme 113. Synthesis of (S)-1-(5-(3-acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl) 5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)-24-carboxy3,12,21,26-tetraoxo -5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontanoic acid (233)

233-S2

233-S4

Vg

233-S5

- 408 041794

- 409 041794

The above scheme and the following detailed description depict one non-limiting method for synthesizing compounds with a fatty acid at the R ³² position via amide bond formation using the HATU coupling reagent. One skilled in the art will appreciate that the A-ring shown above may be replaced with other A-rings to provide additional compounds of the present invention. One of skill in the art will also appreciate that the fatty acid in R ³² shown above can be replaced with other fatty acids.

Stage 1. Methyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate (233-S2): to a solution of 1-(5-bromo-1Nindazol-3-yl)ethan-1-one (1 equiv.) in DMF (10 vol.) were added potassium carbonate (2.5 equiv.) and methyl bromoacetate (1.1 equiv.). The reaction mixture was stirred at room temperature for 3 hours and quenched with water. The resulting solid was filtered, taken up in MTBE, stirred for 30 min, filtered and dried to give compound 233-S2.

Step 2. Methyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1yl)acetate (233-S3): 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.5 eq.), potassium acetate (3 eq.) and PdCl ₂ (dppf) (0.1 eq.). The reaction mixture was stirred at 90° C. for 12 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM and the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using hexane/EtOAc to give compound 233-S3.

Step 3. Methyl 2-(3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-5-yl)-1Nindazol-1-yl)acetate (233-S4): to compound solution 233-S3 (1.2 equiv.) in 1,4-dioxane (10 vol.) at 0°C under nitrogen atmosphere was added tert-butyl ((5-bromopyrimidin-2-yl)methyl)carbamate (1 equiv.), acetate potassium (3 equiv.) and PdCl ₂ (dppf (0.1 equiv.). The reaction mixture was stirred at 90°C for 12 h and concentrated. The residue was purified using silica gel column chromatography using hexane/EtOAc to obtain compound 233-S4 .

Step 4 2-(3-Acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-5-yl)-1H-indazol-1yl)acetic acid (233-S5): to compound solution 233-S4 (1 eq.) in THF/MeOH/water (2:1:1) was added

- 410 041794

LiOH (1.5 equiv.). The reaction mixture was stirred at room temperature for 12 hours and concentrated. Water was added to the residue and the solution was washed with ethyl acetate (3 times). The aqueous layer was acidified with 1.5N. HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous

Na ₂ SO ₄ , filtered and concentrated to give compound 233-S5.

Stage 5. tert-Butyl ((5-(3-acetyl-1-(2-((1 R,3S,5R)-3-((6-6pom-3 -methylpyridin-2-yl)carbamoyl)-5methyl -2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)methyl)carbamate (6): to a solution of compound 233-S5 (1 eq.) in DMF (10 vol.) at 0°C in a nitrogen atmosphere was added (1R,3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-methyl-2-azabicyclo[ 3.1.0]hexane-3-carboxamide (1 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 233-S6.

Step 6. (9H-fluoren-9-yl)methyl(2-(2-(2-(((5-(3-acetyl- 1-(2-((1R,3S,5R)-3 -(( 6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5yl)pyrimidin-2-yl) methyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate (233-S7): to a solution of compound 233-S6 (1 eq.) in 1,4-dioxane (2 vol.) at 0°C in a nitrogen atmosphere was added 4n. HCl in 1,4-dioxane (10 vol.), and the reaction was stirred at room temperature for 3 hours, the Reaction mixture was concentrated and dissolved in DMF (10 vol.). 1-(9H-Fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadecano-12oic acid (1.2 eq.), EDCI-HCl (1.5 eq.), HOBt (1.2 eq. ) and DIPEA (5 equiv.) were added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 233-S7.

Step 7. (9H-Fluoren-9-yl)methyl( 1 -(5 -(3 -acetyl-1-(2-((1 R,3S,5R)-3-((6-6pom-3 -methylpyridine -2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)3,12-dioxo- 5,8,14,17-tetraoxa-2,11-diazanodecan-19-yl)carbamate (233-S8): a solution of compound 233S7 (1 eq) in 20% piperidine in DMF (20 vol) was stirred at room temperature within 16 hours the Reaction mixture was concentrated and dissolved in DMF (10 vol.). 1-(9H-fluoren-9-yl)-3-oxo-2,7,10trioxa-4-azadodecano-12-oic acid (1.2 eq.), EDCI-HCl (1.5 eq.), HOBt (1.2 eq. ) and DIPEA (5 equiv.) were added at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 233-S8.

Step 8. Methyl (S)-1 -(5-(3-acetyl-1-(2-((1 R,3S,5R)-3-((6-6pom-3-methylpyridin-2-yl)carbamoyl )-5methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)-24-((tert-butoxycarbonyl)amino)-3, 12,21-trioxo-5,8,14,17-tetraoxa-2,11,20-triazapentacosan-25-oate (233-S9): solution of compound 233-S8 (1 eq.) in 20% piperidine in DMF ( 20 vol.) was stirred at room temperature for 16 hours, the Reaction mixture was concentrated and dissolved in DMF (10 vol.) at 0°C. (S)4-((tert-Butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (6 eq.), EDCI-HCl (6 eq.), HOBt (1.2 eq.) and DIPEA (7.5 eq.) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 233-S9.

Step 9. (9H-fluoren-9-yl)methyl(2-(2-(2-(((5-(3-acetyl- 1-(2-((1R,3S,5R)-3 -(( 6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5yl)pyrimidin-2-yl) methyl)amino)-2-oxoethoxy)ethoxy)ethyl)carbamate (233-S7): to a solution of compound 233-S9 (1 eq.) in 1,4-dioxane (2 vol.) at 0°C in a nitrogen atmosphere was added 4n. HCl in 1,4-dioxane (10 vol.), and the reaction was stirred at room temperature for 3 hours, the Reaction mixture was concentrated and dissolved in DMF (10 vol.) at 0°C. 18-Methoxy-18-oxooctadecanoic acid (1.2 eq.), EDCI-HCl (1.5 eq.), HOBt (1.2 eq.) and DIPEA (5 eq.) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 233-S10.

Step 10 (S)-1-(5-(3-Acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)- 5methyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-indazol-5-yl)pyrimidin-2-yl)-24-carboxy3,12,21,26-tetraoxo-5 ,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontanoic acid (233): to a solution of compound 233-S10 (1 equiv.) in THF/water (8:2 ) was added LiOH (4 equiv.). The reaction mixture was stirred at room temperature for 4 hours and then quenched with 1 M citric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 233.

1H NMR (400 MHz, CD3OD) δ 9.10 (s, 1H), 8.07-8.05 (m, 1H), 7.99 (s, 1H), 7.83-7.81(m, 1H), 7.65-7.56 (m, 1H), 7.52-7.45 (m, 1H), 7.42-7.35 (m, 1H), 5.83 (d, J=17.2 Hz, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.37-5.35 (m, 1H) , 4.78-4.77 (m, 1H), 4.60-4.48 (m, 1H), 4.38-4.25 (m, 1H), 4.15-4.11 (m, 2H), 4.00-3.89 (m, 1H), 3.82-3.75 ( m, 1H), 3.73-3.71 (m, 1H), 3.67-3.53 (m, 4H), 3.52-3.48 (m, 2H), 3.01-2.95 (m, 4H), 2.88 (s, 3H), 2.82- 2.78 (m, 1H), 2.65-2.62 (m, 2H), 2.35-2.20 (m, 4H), 2.15-2.13 (m, 1H), 2.11-2.09 (m, 1H), 2.00-1.96 (m, 1H ), 1.94 (s, 3H), 1.70-1.58 (m, 3H), 1.50-1.48 (m, 4H), 1.40 (s, 3H), 1.39-1.24 (m, 23H), 0.93-0.92 (m, 2H ), 0.90–0.87 (m, 3H), 0.85–0.81 (m, 1H).

Methyl (S)-1-(5-(3-acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5- methyl-2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methyl-III-indazol-5-yl)pyrimidin-2-yl)-24(methoxycarbonyl)-3,12,21, 26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetetracontan-43-oate:

¹ H NMR (400 MHz, CD3OD) δ 9.08 (s, 2H), 8.44 (s, 1H), 7.56-7.55 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 5.95 (d, J =18.0 Hz, 1H), 5.87 (d, J=18.0 Hz, 1H), 4.75-4.74 (m, 1H), 4.55-4.54 (m, 1H), 4.34-4.33 (m, 2H), 4.19 (s, 2H), 3.95 (s, 2H), 3.85-3.43 (m, 25H), 2.82-2.79 (m, 2H), 2.32-1.85 (m, 15H), 1.55-1.53 (m, 4H), 1.42 (s, 3H), 1.28-1.19 (m, 28H), 1.11-0.98 (m, 2H).

(S)-1-(5-(3-Acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl -2azαbicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-7-methyl-1H-indazol-5-yl)pyrimidin-2-yl)-24-carboxy3,12,21,26-tetraoxo- 5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetetracontanoic acid:

1H NMR (400 MHz, CD3OD) δ 9.08 (s, 2H), 8.45 (s, 1H), 7.57-7.55 (m, 2H), 7.39 (d, J=7.2 Hz, 1H), 5.97 (d, J= 18.0 Hz, 1H), 5.87 (d, J=18.0 Hz, 1H), 4.75 (m, 2H), 4.57-4.55 (m, 1H), 4.32-4.31 (m, 1H), 4.17 (s, 2H), 3.98 (s, 2H), 3.82-3.41 (m, 13H), 2.81-2.80 (m, 2H), 2.75-2.73 (m, 4H), 2.41-1.99 (m, 10H), 1.61-1.60 (m, 4H ), 1.42 (s, 3H), 1.35-1.31 (m, 29H), 1.11-1.10 (m, 2H).

Methyl (S)-1-(5-(3-acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5- methyl-2azαbicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrimidin-2-yl)-24(methoxycarbonyl)-3, 12,21,26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetetracontan-43-oat:

1H NMR (400 MHz, CD3OD) δ 9.41 (s, 2H), 9.23 (s, 1H), 8.72 (s, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.39 (d, J=7.2 Hz , 1H), 5.97 (d, J=18.0 Hz, 1H), 5.85 (d, J=18.0 Hz, 1H), 4.77-4.75 (m, 2H), 4.56-4.55 (m, 1H), 4.354.34 ( m, 1H), 4.13 (s, 2H), 3.98 (s, 2H), 3.82-3.41 (m, 25H), 2.71 (s, 3H), 2.33-2.22 (m, 7H), 2.15 (s, 3H) , 2.132.11 (m, 2H), 1.51-1.49 (m, 4H), 1.26-1.23 (m, 26H), 1.11-1.10 (m, 2H).

(S)-1-(5-(3-Acetyl-1-(2-((1R,3S,5R)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-5-methyl -2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-n-pyrazolo[3,4-c]pyridin-5-yl)pyrimidin-2-yl)-24carboxy-3,12,21, 26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontanoic acid:

1H NMR (400 MHz, CD3OD) δ 9.44 (s, 2H), 9.26 (s, 1H), 8.74 (s, 1H), 7.56 (d, J=7.2 Hz, 1H), 7.41 (d, J=7.2 Hz , 1H), 6.00 (d, J=18.0 Hz, 1H), 5.85 (d, J=18.0 Hz, 1H), 4.85 (s, 2H), 4.55-4.54 (m, 1H), 4.31-4.30 (m, 1H), 4.18 (s, 2H), 3.98 (s, 2H), 3.82-3.21 (m, 18H), 2.74 (s, 3H), 2.73-2.72 (m, 1H), 2.33-2.12 (m, 10H) , 2.021.98 (m, 1H), 1.61-1.60 (m, 8H), 1.42-1.28 (m, 22H), 1.11-1.10 (m, 1H), 0.98-0.97 (m, 1H).

Scheme 114 yl)acetyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24(methoxycarbonyl)-3,12,21, 26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontan-43-oate (391) & (S)-1 -((1 R,3S,5R)-2-( 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-3 ((6-bromo-3-methylpyridin-2-yl) carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24-carboxy-3,12,21,26tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontan- 43-oic acid (392)

- 412 041794

The above scheme and the following detailed description depict one non-limiting method for the synthesis of compounds with a fatty acid at position R ³⁰¹ by amide bond formation using HATU. One skilled in the art will appreciate that the A-ring shown above may be replaced with other A-rings to provide additional compounds of the present invention.

Step 1. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)N-( 6-bromo-3-methylpyridin-2-yl)-5-((1,3-dioxoisoindolin-2-yl)methyl)-2-azabicyclo[3.1.0]hexane-3carboxamide (2): to solution (1R, 3S,5R)-N-(6-bromo-3-methylpyridin-2-yl)-5-((1,3-dioxoisoindolin-2yl)methyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (1.2 eq.) in DMF (10 vol.) at 0°C in a nitrogen atmosphere was added 2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl )acetic acid (1 eq.), HATU (1.5 eq.) and DIPEA (5 eq.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography using DCM/MeOH to give compound 2.

Step 2. (1R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)5-( aminomethyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide (3): to a solution of compound 2 (1 equiv.) in MeOH (10 vol .) at -30°C was added a saturated solution of ammonia in methanol (50 vol.). The reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by preparative purification to give compound 3.

Step 3 Methyl (S)-1-((1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1H-indazol1-yl )acetyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24(methoxycarbonyl)-3,12,21,26 -tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontan-43-oate (391): to a solution of compound 3 (1 equiv.) in DMF (10 vol.) at 0°C (S)-22(methoxycarbonyl)-3,20,25,34-tetraoxo-2,29,32,38,41-pentaoxa-21,26,35-triazatritetracontan-43-oic acid (1.1 equiv .), HATU (1.5 equiv.) and DIPEA (5 equiv.). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water. The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give compound 391:

1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.42 (s, 1H), 7.54-7.51 (m, 2H), 7.39 (d, J=7.2 Hz, 1H), 5.97

- 413 041794 (d, J=18.0 Hz, 1H), 5.85 (d, J=18.0 Hz, 1H), 4.63-4.62 (m, 1H), 4.44-4.43 (m, 1H), 4.08-4.01 (m, 4H), 3.89-3.45 (m, 17H), 3.31-3.29 (m, 4H), 2.85 (s, 3H), 2.83 (s, 3H), 2.56-2.55 (m, 3H), 2.32-2.12 (m, 8H), 2.55-2.53 (m,4H),

1.32-1.21 (m, 33H), 1.11-1.10 (m, 2H).

Step 4. (S)-1 -((1 R,3S,5R)-2-(2-(3-Acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1 H-indazol- 1 yl)acetyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24-carboxy3,12,21,26- tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetracontanoic acid (392): CsOH was added to a solution of compound 391 (1 eq.) in THF/water (8:2) (2 eq.). The reaction mixture was stirred at room temperature for 2 h and then quenched with 1 M citric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative purification to give compound 392:

¹ H NMR (400 MHz, CD3OD) δ 9.03 (s, 2H), 8.45 (s, 1H), 7.57-7.56 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 5.99 (d, J =17.0 Hz, 1H), 5.85 (d, J=17.0 Hz, 1H), 4.65-4.63 (m, 3H), 4.12-4.00 (m, 4H), 3.81-3.53 (m, 13H), 2.81 (s, 3H), 2.79 (s, 3H), 2.56-2.55 (m, 3H), 2.32-2.29 (m, 6H), 2.12 (s, 3H), 1.61-1.59 (m, 4H), 1.42-1.39 (m, 33H),

0.89-0.85 (m, 2H).

Methyl (S)-1-((1R,3S,5R)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine- 1 yl)acetyl)-3-((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24 (methoxycarbonyl)-3,12,21 ,26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25-tetraazatritetetracontan-43-oate:

1H NMR (400 MHz, CD3OD) δ 9.36 (s, 2H), 9.25 (s, 1H), 8.71 (s, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.43 (d, J=7.2 Hz , 1H), 6.00 (d, J=18.0 Hz, 1H), 5.82 (d, J=18.0 Hz, 1H), 4.65-4.64 (m, 1H), 4.45-4.44 (m, 1H), 4.124.11 ( m, 4H), 3.85-3.41 (m, 19H), 2.85 (s, 3H), 2.82 (s, 3H), 2.55-2.54 (m, 2H), 2.32-2.22 (m, 6H), 2.12 (s, 3H), 1.61-1.59 (m, 5H), 1.29-1.27 (m, 31H), 1.11-0.98 (m, 2H).

Scheme 115: (4S,7S,10S,13S,16S,19S,22S)-22-acetamido-4-((((1R,3S,5R)-2-(2-(3-acetyl-7-methyl- 5-(2methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-3 -((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0]hexane-5 -yl)methyl)carbamoyl)-10,16-bis(2-carboxyethyl)-7,19-bis(4-hydroxybenzyl)6,9.12,15,18,21-hexaoxo-13-(4-palmitamidobutyl)-5 ,8,11,14,17,20-hexaazapentacosanedioic acid (443)

Step 1: Loading 2-chlorotrityl chloride: A solution of 2-chlorotrityl chloride (1 eq.) in DCM (10 vol.) was allowed to swell in a closed syringe filter for 15 minutes and then filtered. A mixture of FmocGluOAll (1.5 eq.) in DCM (10 vol.) and DIPEA (4 eq.) was added to the resin. The resulting mixture was shaken for 16 hours and filtered. The resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 minutes.

Capping: capping solution (DCM, MeOH and DIPEA; 17:2:1) was added to the above resin and the mixture was shaken for 1 hour at room temperature. The capping solution was removed with nitrogen and the resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 min to give Compound 2.

Step 2: Fmoc deprotection: Resin (2) was treated with 20% piperidine in DMF (5 vol) and shaken for 15 minutes. The piperidine solution was removed with nitrogen and the process was repeated again. The resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 minutes.

Manual binding of amino acids: A mixture of FmocTyr(OtBu)OH (3 eq.), DMF (10 vol.), HATU (3 eq.) and DIPEA (5 eq.) was added to the above resin and shaken for 6 hours at room temperature. temperature. The reaction mixture was purged with nitrogen and the resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 minutes. This process was repeated throughout the Fmoc deprotection and the amino acid was bound (FmocGlu(OtBu)OH, FmocLys(ivDde)OH, FmocGlu(OtBu)OH, FmocTyr(OtBu)OH and Ac-Glu(OtBu)-OH) to give the compound 3.

Step 3: Deprotection ivDde: The resin was treated with 5% hydrazine in DMF (5 vol) and shaken for 15 minutes. The hydrazine solution was purged with nitrogen and the process was repeated again. The resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 minutes.

Binding with palmitic acid: A mixture of palmitic acid (3 eq.), DMF (10 vol.), HATU (3 eq.) and DIPEA (5 eq.) was added to the above resin and shaken for 6 hours at room temperature. The reaction mixture was purged with nitrogen and the resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 min to give compound 4.

Step 4: Alloc deprotection: Tetrakis (0.5 eq) and phenylsilane (20 eq) were added to a solution of compound 4 resin in DCM (10 vol) and the mixture was shaken for 15 min and degassed with nitrogen. The reaction mixture was purged with nitrogen and the process was repeated again. The resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 minutes.

API binding: to a mixture of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)-5- (aminomethyl)-H-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3carboxamide (3 eq.) was added DMF (10 vol.), DIPC (3 eq.) and HOBt (3 eq.), and the resin was shaken for 6 hours at room temperature. The reaction mixture was purged with nitrogen and the resin was washed again with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 min to give Compound 5.

Step 5 Resin Cleavage: The resin (compound 5) was treated with an absorbent solution (TFA:TIPS:H ₂ O; 9.5:0.25:0.25, 10 vol.) and shaken for 4 hours. The absorbent solution was filtered and the resin was washed with TFA (2 vol.) and concentrated. The crude product was purified by preparative purification to give compound 443.

¹ H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 2H), 10.31 (s, 1H), 9.21-9.20 (m, 1H), 9.00 (s, 2H), 8.12-8.00 (m, 4H) , 7.98-7.96 (m, 2H), 7.56-7.55 (m, 2H), 7.42-7.41 (m, 2H), 7.00-6.98 (m, 3H), 6.55-6.54 (m, 3H), 6.00 (d, J=18.0 Hz, 1H), 5.65 (d, J=18.0 Hz, 1H), 4.44-4.43 (m, 2H), 4.21-4.20 (m, 4H), 3.63-3.62 (m, 1H), 3.00-2.98 (m, 4H), 2.81-2.80 (m, 10H), 2.32-2.31 (m, 10H), 1.98-1.97 (m, 10H), 1.56-1.55 (m, 12H), 1.21-1.10 (m, 37H) , 1.11–1.10 (m, 1H), 0.98–0.97 (m, 1H).

Scheme 116 -5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexane -5-yl)-3-oxo6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66, 69,72,75-tetracosaoxa-2-azaheptaheptacontan77-yl)carbamoyl)-10,16-bis(2-carboxyethyl)-7,19-bis(4-hydroxybenzyl)-6,9,12,15,18,21 -hexaoxo-13(4-palmitamidobutyl)-5,8,11,14,17,20-hexaazapentacosanedioic acid (535)

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Step 1: Coupling of perfluorophenyl 2,2,2-trifluoroacetate: DMF (10 vol.), pyridine (5 eq.) and perfluorophenyl 2,2,2-trifluoroacetate (1.2 eq.) were added to a mixture of compound 1 (1 eq.) , and the resin was shaken for 16 hours at room temperature. The reaction mixture was purged with nitrogen and the resin was washed with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 min to give Compound 2.

Step 2 API coupling: mixture of (1R,3S,5R)-2-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin-5-yl)-1Hindazol-1-yl)acetyl)- 5 - (7 7-amino-3 -oxo6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63, 66,69,72,75-tetracosaoxa-2azaheptaheptacontyl)-N-(6-bromo-3-methylpyridin-2-yl)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride (1.2 eq.), DMF (10 vol.) and DIPEA (5 eq.) were added to the above resin (compound 2), and the resin was shaken for 16 h at room temperature. The reaction mixture was purged with nitrogen and the resin was washed with DMF (5 times), DCM (5 times) and DMF (5 times). The resulting resin was dried for 15 min to give Compound 3.

Step 3 Resin Cleavage: The resin (compound 3) was treated with an absorbent solution (TFA:TIPS:H ₂ O; 9.5:0.25:0.25, 10 vol) and shaken for 4 hours. The absorbent solution was filtered off and the resin was washed with TFA (2 vol.) and concentrated. The crude product was purified by preparative purification to give compound 535.

Example 9 Non-limiting examples of the compounds of the present invention.

In table. 6, 7 and 8 show exemplary factor D inhibitors with characterization data. The analysis of example 10 was used to determine the IC ₅₀ compounds. Other standard factor D inhibition assays are also available. Three *** are used to denote compounds with an IC ₅₀ of less than 1 micromol; two ** denote compounds with an IC ₅₀ between 1 µmol and 10 µmol, and one * denotes compounds with an IC 50 greater than 10 µmol.

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Table 6

Non-limiting examples of compounds of the present invention

Compound No. Structure Name 1C ₅ about RT min (Method A, B, C or D) MS (M+1) 1 ALLv, „N ₁₀ U / l o \u003d\ S D. *** 12.55 (D) 580 (M-1) 2 Br pcs/ N 0 <Ύ Jl 0=4k+% (lS,3aS,6aR)-2(2-(3-acetyl-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridine2- yl)octahydrocyclopenta[c]pyr roll-1carboxamide ** 3.52(B) 602 3 Br N=/ dL^AJ N 0 ' <Ύ I °= (ls,4s)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-N(6-bromo-3methylpyridin2-yl)-2azabicyclo[2.2. 2]octane-3carboxamide *** 3.07(B) 616 4 O .. /N=\ / o / Λ nJT jl 0=4 < -A (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5(piperidin-1ylmethyl)-2azabicyclo[ 3.1. 0]hexane-3carboxamide *** 3.66(B) 685 5 Br / N=\ <njp ^N 0 / n ₄ jl jl (3S)-5-(6azaspiro[2.5]ox tan-6-ylmethyl)2-(2-(3-acetyl5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo- 3-methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.82(B) 711

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6 R Br N=/ (3S)-2-(2-(3acetyl-5-(2- *** 3.57(B) 657 ^N ^Z NN\ ⁰⁼ \ ΗΝ— Ο Ό Q νχ ιχ methylpyrimidi n-5-yl)-1 IIindazol-1yl)acetyl)-5(azetidin-1ylmethyl)-M-(6bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide 7 b,__ N- N \ ⁰ \ ΐ 0 =0 o/g U'Br IX (2S,4R)-1- ((2S,4R)-1 -(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-4fluoropyrrolidium n-2-carbonyl)- N-(6- brompyridin2-yl)-4fluoropyrrolidium n-2carboxamide ** 1.68(A) 695 8 B, Ό ΗΝ- Λ Ib ₉ H ₁₀ U *** 13.19 (C) 570 '0 N\ Ο^\ ο IX Ν ^Χ 9 10 AND & N\ 0^ \ Ν— / N ΝΝ\ Ο=\ 4 N-/ N\ _-ΗΝ— ΌQ ΗΝ0 C ΗΝ- 0 '0 Q Br P χχ N Br I νχ N Br Ν=( ΐΧ N (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5((dimethylamino )methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lS,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-I(6-bromo-3methylpyridin2-yl) -5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5((hexahydrocyc lopenta[c]pyrr ol-2(1H)yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** ** *** 1.17(B) 2.35 (V) 0.36(B) 645 645 711

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12 0 l- bchk O=\C (3S)-5-(3azabicyclo[3.1.1]heptan-3ylmethyl)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo -3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.63 (V) 697 13 r ., N' ³ / ^Br 0 / ^0 ^N d jl Ατι oA k <^k X Ν \ (3S)-5-(2azaspiro[3.3]heptan-2ylmethyl)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo- 3-methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.58(B) 697 14 Br V °A 2=0 N-^Ss <Ύ JI Ar, o=\ L Λ \N (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-Zisopropylpyridin-2-yl)-5methyl -2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.06 (A) 630 15 Br ¢^0 _Z N.___ TjT/ °<A\ h l Ν \ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.71 (A) 605 16 ^B/ 'ch ^ΗΝ ^ ^Ν C>\>\7 k ⁰ ν'Ύ Jl °A ^A (2S,4R)-1-(2-(3 acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(cuban-1ylmethyl)-4fluoropyrrolidine n-2carboxamide ** 10.52(D) 541 17 O __HN^ \=/ ^N 0 F ' ^=0 ^ν Ά jl o^ to XN \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M((E)-2-fluoro-3phenylbut-2 -en1 -yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.08 (A) 581

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18 Br bh^ A 0 <Ύ L oA Y Ax (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-L(6bromopyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 12.76 (C) 605 (M+2) 19 Br nA ^N ^? 0 | A\ N~^Ax ^N CX Jl oA C Ax XN \ (2S,4R)-1 -(2-(3acetyl-7((dimethylamino)methyl)-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-b(6bromopyridin2-yl)-4fluoropyrrolidine n- 2carboxamide *** 2.31 (B) 637 20 Br N=( Vyr^ 0 ^O/ < Ύ Ί ^(ΐΡϊ oA C A (2S,4R)-1 -(2-(3acetyl-7(fluoromethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-LG(6bromopyridin2-yl)-4fluoropyrrolidium n-2carboxamide *** 3.29 (V) 612 21 Br FM r>J ^N AJ A ΥΥ Ν-χ^ϊΧ n/T jl jYJ oA CA XN (2S,4R)-1-(2-(3 acetyl-7-((5methylpyrimidi n-2-yl)methyl)5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridine2- yl)-4fluoropyrrolidium n-2carboxamide *** 3.18(B) 686 22 /— NH o . ^N ^/ 0 / Νχ/^ <τ 1 oA A Ax XN (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5(piperazin-1ylmethyl)-2azabicyclo[ 3.1. 0]hexane-3carboxamide *** 3.77(B) 686 23 Br ^'OchL^ J O ( 1. CN Z° A N=^ (2S,4R)-1-(2-(3 acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(cyanomethyl)pyridin-2-yl) -4fluoropyrrolidium n-2carboxamide *** 1.50 (A) 619

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24 / /—N Ο θ' kA AU O=X to -A\N (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-((4methylpiperazine n-1- yl)methyl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.70(B) 700 25 Br ^N 4 ⁷ Pnc k °ν ° Al < Ύ Ί o=\ 1 A methyl 3-acetyl-(2-((2S,4R)-2((6bromopyridin2yl)carbamoyl)4fluoropyrrolidi n-1-yl)-2oxoethyl)-5-(2methylpyrimidi n-5-yl)-1Nindazol-7carboxylate *** 1.94 (A) 638 26 /2 N=/ ^Γ Aj ⁿ 4J> ^N O'N^4> N JT Ί AAP? °< ^A (38)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5(aminomethyl)N-(6-6poM-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide ** 2.49 (V) 617 27 Br 4aA ^f N 0 / N-0 °AQ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-5-fluoro3- *** 2.01 (A) 634 ίΛ N=^ methylpyridin2-yl)-5-methyl2- azabicyclo[3.1. 0]hexane-3carboxamide 28 V-\ HN^ F αΗΊη^. /AZ ^N JJ AAl °< A (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(3-chloro-2fluorobenzyl)-5methyl-2azabicyclo[ 3.1. 0]hexane-3carboxamide *** 11.61 (C) 590 29 AV ⁰ Br cd ^O= \ ⁴ A (lS,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((allyloxy)methyl)-M-(3(( allyloxy)methyl)-6bromopyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.28 (A) 714

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thirty Br V'' N0 X <ΎΊ o=\C (lR,3S,5R)-2-(2(3-acetyl-7(fluoromethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide 3.69 (V) 620 31 Br ^O/ ^F PT J °< CA (lR,3S,5R)-2-(2(3-acetyl-7(fluoromethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.48 (V) 634 32 °A' 0 ^=0/°\ <ΎΊ o=\ C -A X N \ (3S)-2-(2-(3acetyl-7(methoxymethyl) -5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-5(methoxymethyl)-2azabicyclo[3.1. *** 3.47 (V) 662 0]hexane-3carboxamide 33 ^F \/ ^0CF3 »bа^ N 0 <Ύ JJ A ^A (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-I(2-fluoro-3(trifluoromethox and)phenyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 13.96 (C) 625 34 A£ O (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M((8)-3-fluoro-4methylpent-3ene -2-yl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 10.92(D) 547 35 < NN^CF, - N 0 ^N AP An 0=XC -A XN \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-M-(1(2,2,2trifluoroethyl) 1H-pyrazol-3yl)-2azabicyclo[3.1. *** 10.92(D) 595

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0]hexane-3carboxamide 36 N^ ³ N 0 ⁿ ' Ύ Ί A CHA (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-M-(6(trifluoromethyl)pyridine-2- yl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 12.55 (D) 592 37 OCF ₃ %Ύ Ί Aft a 'Ά (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-M-(6(trifluoromethox and)pyridin-2yl )-2azabicyclo[3.1. 0]hexane-3carboxamide *** 14.96 (C) 608 38 39 40 41 O F. /=\ /=\ ^Cl (E ^Fo <Ύ Ί LA F. )=( /=\ ^Cl £><Ύ J An 0=\ CA P ph 0 ^Fo FT Ί AA 0=\ C x N Br N=( ^f -qJ ⁿ AJ O CO ₂ H ^N ^4, ν, Ύ Ί x (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidin-5-yl)-1Nindazol-1yl)acetyl)-X(2'-chloro-2-fluoro[1, δ-biphenyl]3-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(2'-chloro-2-fluoro [1,G-biphenyl]3-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidin-5-yl)-1Nindazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxylic acid 3-acetyl-1-(2((2S,4R)-2-((6bromopyridin2yl)carbamoyl)4fluoropyrrolidi n-1-yl)-2oxoethyl)-5-(2methylpyrimidi n-5-yl) -1Nindazole-7carboxylic acid *** *** * *** 15.94 (C) 12.84 (D) 1.31 (A) 652 636 (M-1) 434 624

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42 ypf (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5((methylamino)m ethyl)- 2azabicyclo[3.1. 0]hexane-3carboxamide *** 4.42 (V) 631 43 o =/ NH / ^Br / N=\ N 0 ^N -^4s ^N Λ JL o=\ C A. XN ^- (lS,3S,5S)-5(acetamidomethyl l)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-2azabicyclo[3.1 . 0]hexane-3carboxamide ** 3.00(B) 645 44 oh~ (lR,3S,5R)-5(acetamidomethyl l)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-2azabicyclo[3.1 . 0]hexane-3carboxamide *** 3.08 (V) 645 45 —O Vnh o ° A —\ NH N=\ bl ⁰ A OCX^n O^\ N methyl ((2S)-1((((3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3((6bromopyridin2yl)carbamoyl)2azabicyclo[3.1 0]hexan-5yl)methyl)amino)-3-methyl-1oxobutan-2yl)carbamate *** 3.32(B) 760 46 Vg N=(\___ MI—3—F (E <Ύ 71 O=\C X N (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-5fluoropyridin-2yl)-5- methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.77 (B) 620 47 Br ^N PCx ° N^\ (lR,3S,5R)-2-(2(3-acetyl-7ethyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- methyl2azabicyclo[3.1. *** 3.59 (V) 630

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0]hexane-3carboxamide 48 —о ₀ Ν b Br Up to <Ύ Zl °< methyl ((2S)-1((((3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3((3-bromo-6(methoxymethyl ) pyridin-2yl) carbamoyl) 2- azabicyclo[3.1. 0]hexan-5yl)methyl)amino)-3-methyl-1oxobutan-2yl)carbamate * 3.20 (V) 804 49 N b br C° N-^4. n.Ύ Ί O=\ to (3S)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X(3-bromo-6(methoxymethyl)pyridin-2-yl)5(methoxymethyl) -2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.07 (V) 662 50 51 52 Br >bch5^ N 0 / N-^4, ^Ν νΧΧ^ A / П o^XC -A XN \ N- F ( ^N= \ LdtChu NO' ^O ul O=\ C XN bh^ ν'Ύ Ί XN ^ 5-(3-acetyl-1 (2-((lR,3S,5R)3-((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl )-7methyl-1Nindazol-5-yl)2- methyl pyrimidium and 1-oxide (3S)-2-(2-(3acetyl-7-methyl5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X(6-bromo-3methylpyridin2-yl)-5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X((R)-l- ((R)-2,2dichlorocyclopropyl)ethyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** *** 3.15 (V) 2.08 (V) 11.25 (D) 632 659 584

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53 Br TnA <ΎΊ 0=4 C \ Ν (lR,3S,5R)-2-(2- (3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyrazin-2yl)-5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide 11.10 (С) 604 54 Br Ν 0 (^ ⁰ ν Ύ Ί 0=4 C χ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-5methylpyrazin2-yl)-5- methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 14.12 (C) 615 (M-2) 55 Br 0 / Λ° N^4s <Ύ Ί 0=4 C νη ₂ 1-(2((lR,3S,5R)-3((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl)-5(2methylpyrimidi n- 5-yl)-1Nindazole-3carboxamide *** 8.30(C) 601 (M-2) 56 Br /° ^ν ' ύ ί 0=4 C νη ₂ ν 1-(2((lR,2S,5S)-2((6-bromo-3methylpyridin2yl)carbamoyl)3azabicyclo[3.1.0]hexan-3-yl)2-oxoethyl)-5(2methylpyrimidi n-5-yl) -1Nindazole-3carboxamide *** 8.30 (D) 591 (M+2) 57 Br ^£ Vw ⁴ 0 <4 ν. Ύ Ί ⁰ νη ₂ 1-(2- ((lR,3S,5R)-3((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl)-7methyl-5-(2methylpyrimidi n-5 -yl)-1Nindazole-3carboxamide *** 8.84(C) 619 (M+2) 58 Br b<$ <Ύ Ί 0=4 C << νη ₂ ν 1-(2((lR,3S,5R)-3((6bromopyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl)-7methyl-5-(2methylpyrimidi n-5 -yl) -1H- *** 12.45 (C) 605 (M+2)

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indazole-3 carboxamide 59 Br N \u003d f Yyrp o / ν'Ύ 1 o \u003d\ C ⁴ N OH (2S,4R)-1 -(2-(3acetyl-5-(2hydroxypyrim idin-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-4fluoropyrrolidium n-2carboxamide 7.92(D) 597 60 % L o (Ό W 0=/ \ < / ^N (lR,2S,5S)-3-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3azabicyclo[3.1. 0]hexane-2carboxylic acid 1.10(A) 420 61 Br nA °Yw Dl N=^ methyl 2-(2((2S,4R)-1 -(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-4fluoropyrrolidium n-2carboxamido)6bromopyridin3-yl)acetate *** 1.50 (A) 651 62 Br \yL0 A b < Ach ^on T 0 o N'\ ^ο γΑ3 An N=^ Acetic acid *** 1.27 (A) 638 63 D _ν α N 'b ' CO ₂ H ⁰ ν'Ύ JL O \u003d \ C 3-acetyl-1-(2((3S)-3-((6bromo-3methylpyridin2yl)carbamoyl)- 5- ((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexan-2-yl)2-oxoethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-7carboxylic acid 2.07 (V) 689 64 Br «DchD^ '^N t) / ^0 ⁿ CCl^ .oj i7 °h ate 5-(3-acetyl-1 (2-((lR,3S,5R)3-((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl )-1Nindazol-5-yl)2- *** 3.06 (V) 618

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methylpyrimidi Η 1-oxide 65 OH / ^Br ν/Τ ί °< ^Α (lR,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5(hydroxymethyl) -2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.46 (V) 618 66 Br N=/ 0' ^=0 ν' Ύ Ί AP Ο=\ C (2S,4R)-1 -(2-(3acetyl-7-methyl5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-4-fluoro-4(fluoromethyl)pyrolidine-2carboxamide *** 2.88 (B) 640 67 ^Br u-p Ν 0 ^0 ^ν Ά 1 ο=\ <<Α X Ν \ (lR,3S,5R)-5-(2azaspiro[3.3]heptan-2ylmethyl)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-N( 6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.78 (V) 697

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68 N' ³ / ΗΝ- Br P (lS,3S,5S)-5-(2azaspiro[3.3]heptan-2ylmethyl)-2-(2(3-acetyl-5-(2- *** 2.71 (B) 697 Ν ^Ν \ Ο=\ % =0 Ο γχ N methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide 69 Ο ^Ν Ο ⁰ \ ΗΝ— "0 0 Br P Γχ Ν (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((4methylpiperazin-1-yl)methyl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.56 (V) 714 70 ,Ν„ Ν \\ 0=/ Υ Ό Ύ Br (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((allyl(methyl)a mino)methyl)-M( s((allyloxy)methyl yl)-6bromopyridin2-yl)-2- *** 1.35(A) 727 71 72 73 N\ ηο-\ b N\ ηο-\ ,Ν Ν \\ ΗΝ- Ο=0 Ο ΗΝ- =0 Ο Br Ν=/ Λτ γχ N Br τ ΥΧ Ν ^N^N^Br and Y% azabicyclo[3.1. 0]hexane-3carboxamide (1R,2S,5S)-N(6-bromo-3methylpyridin2-yl)-3-(2-(3-(1hydroxyethyl)5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3azabicyclo[3.1. 0]hexane-2carboxamide (1R,3S,5R)-N(6-bromo-3methylpyridin2-yl)-2-(2-(3-(1hydroxyethyl)5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(sbromisoquinoli n-1-yl)- 5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide ** ** *** 1.33 (A) 1.52 (A) 2.04 (A) 592 604 638

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74 N ^Br ί Μ >:V>4 ^N Μ ^==0/ ^F ν.Ύ Ί 0=4 4 (lR,3S,5R)-2-(2(3-acetyl-7(fluoromethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X(6-bromo-3methylpyridin2-yl)-5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.19(B) 677 75 /- nJ ^'N 0 ' ^=O/ ^{f N} d 0=4 C -^k X Ν (lS,3S,5S)-2-(2(3-acetyl-7(fluoromethyl)-5(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)- 5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.28 (B) 677 76 Br N=/ <>4^47 o / % 2X Ί °4 44 (2S,4R)-1 -(2-(3acetyl-7(fluoromethyl)-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-4-fluoro-4(fluoromethyl)pyr *** 3.22 (V) 658

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rolidine-2carboxamide 77 Br N ⁼ / N C) ' ⁰ (lS,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-7(trifluoromethyl) -1H-indazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2- azabicyclo[3.1. 0]hexane-3carboxamide * 3.66 (V) 670 78 % 0 * Ъh% Ν 0 ⁷ <r ji JlCi o=\ C (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((4- acetylpiperazine n-1-yl)methyl)N-(6-6poM-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.69(B) 728 79 % ZN 0 N% ^f / / ^N 0 'o ' 0 n JT Ί C <0 \ N (lS,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((4acetylpiperazin-1-yl)methyl)N-( 6-6poM-3methylpyridin2-yl)-2azabicyclo[3.1. ** 3.74(B) 728 0]hexane-3carboxamide 80 JX- N--04, ⁿ JX 1 (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(3,3dimethylbutyl)5-methyl-2azabicyclo[3.1 . 0]hexane-3carboxamide *** 11.05(D) 531 81 Va ^hn ^\ 0 J4 ^ ^0CF 3 N 0 ^0 N-04 νΎ Ί o=\ C kk (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-M-(2(trifluoromethox and)ethyl)- 2azabicyclo[3.1. 0]hexane-3carboxamide *** 10.79(D) 559 82 o— kw^J N 0 ^N --04 ⁿ 'Ύ 1 o=\ C (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6methoxypyridi n-2-yl)-5methyl-2azabicyclo [3.1. 0]hexane-3carboxamide *** 11.79(D) 554

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83 OH F, / ^N 4 % 0 ^0 ν'Ύ JL 0=% C x N (2S,4R)-1-(2-(3 acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-4φτορ-Ν-(6hydroxypyride in-2yl)pyrrolidine2-carboxamide ** 6.71(C) 518 84 Br B M γ%/ ^ν %7 ^==0 vC% p 7 Η-θ o=\ H. D, .Zj ⁴ NO (2S, 4R)-1 -(2-(3acetyl-5-(2((1Ddioxidothietan -3- yl)oxy)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-b(6-bromo-3methylpyridin2-yl)-4fluoropyrrolidium n-2carboxamide *** 8.16(C) 698 (M-2) 86 88 89 90 >b4 ^N 5^ N 0 Br ^0^ ^N d JL o=\ C -tP Z~ NH O Br 4χΡ N^x0 ^N 0( JL o=\ 4 % N--^ / ^Br bch5^ N 0 ' ) νΛ A ^/τΡϊ o=\ 4 % Br , N=/ 0 / ^0>Λ Ν^Χ ^h y\ (lR,3S,5R)-2-(2(3-acetyl-7(methoxymethyl)-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-LG(3-bromo-6(methoxymethyl)pyridin-2-yl)5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-LG(6-bromo-3methylpyridine2- yl)-5(piperazin-1ylmethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-5-(2azaspiro[3.3]heptan-2ylmethyl)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol- 1yl)acetyl)-LG(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lS,3S,5S)-2-(2(3-acetyl-7cyclopropyl-5(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-LG(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. * *** *** *** 3.24 (V) 2.03 (V) 2.55(B) 3.81 (B) 676 700 711 642

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O]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3((dimethylamino )methyl)pyridin -2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide (lR,2S,5S)-3((lR,2S,5S)-3(2-(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl )-3azabicyclo[3.1.0]hexane-2carbonyl)-N-(6bromo-3methylpyridin2-yl)-3azabicyclo[3.1. 0]hexane-2carboxamide (lR,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((allyloxy)methyl)-M -(6-bromo3vinylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5((methylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-((2fluorocyclopent1-en-1carboxamido)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide

645

743

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96 ^'ί // V' ο ο (lR,3S,5R)-5(acetamidomethyl l)-2-(2-(3acetyl-7-methyl5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.96 (V) 673 97 °=Η _Br ΝΗ / ^ίχΡ ^0 ⁿ 0l JX °< CHA (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((2fluorobenzamido)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.52 (V) 753 98 0 , ^Br Ο / Λ <Ύ Ί X (lR,3S,5S)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( methoxymethyl)-2azabicyclo[3.1. *** 3.26 (V) 646 0]hexane-3carboxamide 99 “4 λ—ΝΗ ρ ο >Α l C^hn-A/ ^Άν ο Γι "TO / < Α^ N methyl ((S)-l((((lR,3S,5R)-2(2-(3-acetyl-7methyl-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3((6-bromo-3methylpyridin2yl)carbamoyl)2azabicyclo[3.1. 0]hexan-5yl)methyl)amino)-3-methyl-1oxobutan-2yl)carbamate *** 3.36(B) 788 100 Ν— , ^Br Έτ0 '^Ν ^/ 0 / Ν--Α4 <Ύ Ί Ο=\ < X (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( (dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.55(B) 659

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101 V ⁰ ' Rr NH , ^Br '^l/ 0 ' JL °% (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5(methylsulfone midomethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.47 (V) 709 102 o^ ^CF3 NH / ^Br >0>4^0 ^N^0 / ^N d0i ο=χ CA ^x N (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((3,3,3trifluoropropane amido)methyl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.45 (V) 741 103 Br N=/ 'bh H 4 N^A< Ύ ί / (ACA ,N. ^{x X} (lR,3S,5R)-2-(2(3-acetyl-5-(2((dimethylamino)methyl)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2azabicyclo[3.1. *** 1.28 (A) 645 0]hexane-3carboxamide 104 Br ^0 ⁿ COl (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-X(6-bromo-5-fluoro3methylpyridine2 -yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.76 (A) 621 105 _n / ^0H Ά. <Ύ 1 °< (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6hydroxypyride in-2-yl)-5methyl-2azabicyclo [3.1. 0]hexane-3carboxamide *** 8.61(D) 540 106 o /Ai /=< /Chg V u O (lR,3S,5R)-2-(2(3-acetyl-5-(2hydroxypyrim idin-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo[ 3.1. 0]hexane-3carboxamide *** 8.16(C) 603 (M-1)

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107 Br Ν O / ^0 vCX^ p Г II 7 pS=O oA C Л-J ⁴ N 0 (lR,3S,5R)-2-(2(3-acetyl-5-(2((1,1- Dioxidothietane -3- yl)oxy)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 9.30(C) 706 (M-2) 108 Br Ν O ^0 vj P Am O=\ C / ^X NO (lR,3S,5R)-2-(2(3-acetyl-5-(2methoxypyrimidin-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 12.23(D) 606 (M+2) 109 Br M O ^Mo a Λ ° ^x ^N^OH (lR,3S,5R)-2-(2(3-acetyl-5-(2hydroxypyrim idin-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 9.82(D) 588 (M-2) 110 Br N 0 N^^, 'Wxz. ,0 μ H ? r~s=o ⁰⁼ X (lR,3S,5R)-2-(2(3-acetyl-5-(2((1,1- Dioxidothietane -3- yl)oxy)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-M(6bromopyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 10.49 (C) 692 (M-2) 111 A S/wiH Λ J yrs OM ^x s / ^N (lR,2S,5S)-3-(2(3-acetyl-7methyl-5-(2methylpyrimidin-5-yl)-1Nindazol-1yl)acetyl)-3azabicyclo[3.1. 0]hexane-2carboxylic acid 1.23 (A) 434 112 A , ^Br N^+r <o Ατι oa ~ Λ ^x N \ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3-cyclopropylpyridin-2-yl)-5 ((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.37(B) 671

- 436 041794

from , ^Br PjT'kJ* '% t) / Pi ^Ν Οί j ο=\ to A X Ν \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- (((2fluoroethyl)amino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.21 (V) 677 114 0 Λ yk ° ν'Ύ Ί ο=\ to Ρ X Ν (lR,3S,5S)-2-(2(3-acetyl-7(methoxymethyl)-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5(methoxymethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.36(B) 676 115 116 117 118 kk ⁰ 1 -Νχ J Μ7 HO-/ ^ • J-d ^Η Di Τ ϊ •0 ^τ M? ⁰ λ X Ν=\ F, /~\ Ν Ν Br ϊ ° Ρ Ύ. w Μ% ^{0 0} \ 4. Ν--/ / ^Br W ^{3 ν} χΑ> ^N d jl o=\ k <=k XN \ (1R,2S,5S)-N(6-bromo-3methylpyridin2-yl)-3-(2-(3-(1hydroxyethyl)7-methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl )-3azabicyclo[3.1. 0]hexane-2carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-4fluoropyridin- 2yl)-5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (2S,4R)-1-(2-(3 acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3-(2(dimethylamino ) -2oxoethyl)pyride in-2-yl)-4fluoropyrrolidium n-2carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl) acetyl)-\(6-bromo-3methylpyridin2-yl)-5((diethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide ** *** *** *** 1.47 (A) 2.31 (A) 1.33 (A) 3.76(B) 604 620 665 687

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119 /S—V Br (lR,3S,5R)-2-(2- *** 2.82 (V) 711 120 121 122 i/G / N\ ° \ >/] / ^N \ O=\ 1Ж N\ O=\ ' ^Ν ~Λ >/T h 0= HN- 0 =0 O HN- 0 '° u HN- 0 γ u N: V 0 / A ⁰ OCX \ T Br N=/ Ό. NN Br ^N= L XX N OH Br 7 XX N = 1 (3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-N(6-bromo-3methylpyridin2-yl)-5(((3aR,6aS)opent hexahydrocycle [c]pyrro l- 2(1H)yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2(methylamino)pyrimidin-5-yl)1H-indazol-1yl)acetyl)-M(6-bromo -3-methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2hydroxypyrim idin-5-yl)-7methyl-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide (lS,3S,5S)-2-(2(3-acetyl-7(fluoromethyl)-5(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo- 3-methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** *** 1.77 (A) 1.52 (A) 2.06 (A) 617 617 633 123 \ / N—/ N\ ⁰ \ _^ ^N " Ό Q b Br XX N= (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-Zvinylpyridin2-yl)-5-(( hex5-en-1yl(methyl)amino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.47 (A) 725 124 Έ ,N. NΛ 0=/ Br HM /V0 / CN /A Vjn (lR,3S,5R)-2-(2(3-acetyl-7cyano-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.94 (A) 629

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125 126 127 128 Br N=( '^N Ό ' n.Ύ Ί ⁰ \ 1 '^/^co ₂ h J KO o =/ ^X < / ^N r° bl^ 4 0 ^Z NA kΎ Ί oK <<4 z . KZ n ^A. to Ύ Ί O=\ 4 Z\ (lR,3S,5R)-2-(2(3-acetyl-5-(2(dimethylamino)pyrimidin-5yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo [3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxylic acid (lR,3S,5R)-5-(2oxa-6azaspiro[3.3]heptan-6ylmethyl)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl )-M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5(((3aR,6aS)hexahydrocycle openta[c]pyrro l-2(1H)yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** * *** *** 2.13 (A) 1.42 (A) 2.35 (V) 2.90 (V) 631 448 713 725 129 , „ A KZ ^0 ^N Ox k Ύ JL o=\ C <K (lR,3S,5R)-5-(2azaspiro[3.4]oxtan-2-ylmethyl)2-(2-(3-ac ethyl7-methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl) acetyl)-M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.78 (V) 725 130 Br \ ^N= ( '^Ν£> / NV4 n. Ύ Ί JiiCt °A f ςχ (lR,3S,5R)-2-(2- (3-acetyl-4fluoro-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2- *** 3.41 (V) 620

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azabicyclo[3.1. 0]hexane-3carboxamide 131 V\ / 4 ^N \ 0 V Br °^N.XL ^N d jl o=\ C X X (lR,5R)-2-(2-(3acetyl-7cyclopropyl-5(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.66 (V) 642 132 ^Cx"° 0^4 (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( (ethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.31 (B) 659 133 Br wi O^ X ^{3 n} >ax ⁴ N^\ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-7(trifluoromethyl) -1H-indazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2- *** 3.72 (V) 670

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azabicyclo[3.1. 0]hexane-3carboxamide 134 O (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(3((allyloxy)methyl)-6bromopyridin2-yl) -5-vinyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.15 (A) 670 135 /< Y ' II ^x o (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-chloro-3((dimethylamino)methyl)pyridine - 2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.12(A) 601 136 ..Er'^;; Q FROM (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3((dimethylamino)methyl) pyridin -2-yl) -5-methyl2- *** 1.24 (A) 659

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azabicyclo[3.1. 0]hexane-3carboxamide 137 GU Η x/ to /C1 > A ¥ ¥ G o AyaA Αθ \l J / M7 ° \ 'AΝ N \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-chloro-3((dimethylamino)methyl) pyridin -2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.21 (A) 615 138 A n x/ k aal > A ¥ ¥ 1 o /I/ A° A Yay ^ O l_// \ ^0 (A 'An N% (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(morpholinomethyl)pyridin-2yl) -5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.21 (A) 687 139 140 141 142 n x/ k AL\/ ^C| > A ¥ ¥ L o A^L r° A N'A O \\ II \ ° \ ' An N=\ 1 ^Br Aph ϊ ⁰ / ⁰ 1 _Z N. J ko ^H0 \ ^X An V\ Br CO y° /XX _ο =Ανχ X P * k° ^N V4 nA Ί aAPi oA CA X n (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-chloro-3(morpholinomethyl)pyridin-2yl) -5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (1R,3S,5R)-N(6-bromo-3methylpyridin2-yl)-2-(2-(3-(1hydroxyethyl)7-methyl-5-(2methylpyrimidi n-5-yl)- 1Nindazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,2S,5S)-3-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6- bromo-3methylpyridin2-yl)-3azabicyclo[3.1. 0]hexane-2carboxamide (lR,3S,5R)-5-(2azaspiro[3.4]oxtan-2-ylmethyl)2-(2-(3-acetyl5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** *** *** *** 1.19(A) 1.63 (A) 1.46 (A) 2.49 (V) 643 618 589 711

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143 N- D ^G Ζ ^Ν =\ A ⁷ b ' ^Ο nA ° \lO nA (lR,3S,5R)-2-(2(3-acetyl-7cyano-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-L(6-bromo-3methylpyridin2-yl)-5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.59 (V) 670 144 I (lS,3S,5S)-2-(2(3-acetyl-7cyano-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( (dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide ** 2.65 (V) 670 145 Br LaaH A ⁷ o / Nχ^ Ύ A /TP ⁰ nh ₂ ^f Y 1-(2- ((lR,3S,5R)-3((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl)-4fluoro-5-(2methylpyrimidi n-5 -yl) -1H- *** 2.40 (V) 621 indazole-3carboxamide 146 Br W ³ A, CF ₂ H ° nA nJT Ί oA Y Αχ (lR,3S,5R)-2-(2(3-acetyl-7(difluoromethyl)5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.72 (V) 652 147 - ^Br %% AF χΝχ J m °a N^\ (lR,3S,5R)-2-(2(3-acetyl-7fluoro-5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2- azabicyclo[3.1. 0]hexane-3carboxamide *** 1.92 (A) 620 148 Br ^N Ό ⁷ ^==0 AJ /AAn 0 oA ΛΑ / ^x NN 1 (lR,3S,5R)-2-(2(3-acetyl-5-(2(2- (dimethylamino) -2- oxoethyl)pyrim idin-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-methyl2- *** 1.66 (A) 673

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azabicyclo[3.1. 0]hexane-3carboxamide 149 Ρ ^vg 1 ⁿ ' Ύ Ί O=\ -A XN \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5(azetidin-1ylmethyl)-M-(6bromo-3methylpyridine2 -yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.34 (V) 671 150 F _Lf P _z ^Br Al ΝΆ4 ^N d jl °< (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((3,3difluoroazetidin -1-yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.46 (V) 707 151 X ^H «C YhA 0 / ⁿ AJ Ί DCHP 0=4 C XN (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5((cyclopropyl mino)methyl)-2- *** 3.82 (V) 657 azabicyclo[3.1. 0]hexane-3carboxamide 152 w D /0 vl A o=\C<< (lR,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(methoxymethyl)pyridin-2-yl )5(methoxymethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 3.33 (V) 662 153 -O D-NH _n 0 V-D \ NH / ^Br ' / N \u003d \ NdtCha ( L ⁰ / ° <Ύ Ί °A CHA methyl ((S)-l((((lR,3S,5R)-2(2-(3-acetyl-5(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-3((6-bromo-3(methoxymethyl)pyridin-2yl)carbamoyl)2azabicyclo[3.1. 0]hexan-5yl)methyl)amino)-3-methyl-1oxobutan-2yl)carbamate *** 2.95 (V) 804

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154 155 156 /°A N G/ V _G y Ν _γ ν DchD o Ζ^οΑ ^N JI JI °< JA N— / ^Br AA N-/4 N Jf 1 JilCi °A ^F ^A N- / ^Br / N=\ C > / ^N Ά Ί ATTA A ^F JA (lR,3S,5S)-2-(2(3-acetyl-7allyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((allyloxy)methyl)-M-(6 -bromo3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-4fluoro-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lS,3S,5S)-2-(2(3-acetyl-4fluoro-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** *** * 3.71 (B) 2.33 (V) 2.51 (B) 698 663 663 157 / p .. j N-/4 <Ύ Ί An oA A ^x N \ (lR,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-(( 2(dimethylamino)ethoxy)methyl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.08 (A) 688 158 °A NH / ^Br ί>Γ0 N 0 ^Z N-/k < Ύ to ΑΥΐ o=\ / A (lR,3S,5R)-2-(2- (3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-((2,2difluorocyclope ntan-1carboxamido)m ethyl) -2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.87 (A) 762

- 445 041794

159 % 7 o (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-(( 2,2difluorocyclopentane-1carboxamido)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.79 (A) 748 160 £F ₃ NH , ^Br %% Nvk <T JL o=% C <% XN \ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- (((2,2,2trifluoroethyl)am ino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.70 (A) 712 161 I NH / ^Br %% N^A % Ύ Ί An 0=% C <% x ^N ^ (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((benzylamino)methyl)-XG-(6bromo- 3methylpyridin2-yl)-2azabicyclo[3.1. *** 1.36(A) 720

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0]hexane-3carboxamide 162 /Br Ar 0 / ρ j AACt o=\ C X N (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( cyanomethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.65 (A) 640 163 F , ^Br ЪлС nAx ⁿ A JL Ατι o=4 C x N (lR,3S,5S)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5( fluoromethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.77 (A) 633 164 4.4- p° <O Ατι 0=4 C XN (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((3hydroxyazetide in-1-yl)methyl)2azabicyclo[3.1. *** 1.05 (A) 686 0]hexane-3carboxamide 165 O ArF /=\ ^x °Ai y/ A, (lR,3S,5R)-5(acetamidomethyl l)-2-(2-(3acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(methoxymethyl) pyridin-2-yl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.36(A) 688 166 ΥΊ ^Gz (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(methoxymethyl)pyridin-2-yl )5- ((dimethylamino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.02 (A) 674 167 Br Awp Ν O / 1 .L ^ ^N x pa ppp oAlp (lR,3S,5R)-2-(2(3-acetyl-7((dimethylamino)methyl)-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2 -yl)-5-methyl2- *** 1.27 (A) 658

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azabicyclo[3.1. 0]hexane-3carboxamide 168 / ^CF 3 °=< Br NH / ^Br AP ^°i <Ύ P oA CA ^X N (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- ((2,2,2trifluoroacetam ido)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.89 (A) 726 169 ⁴ o N 0 Br Yo Pl P cA CA (lR,3S,5R)-2-(2- (3-acetyl-7(methoxymethyl) -5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(methoxymethyl)pyridin-2-yl)5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.01 (A) 675 170 i .. NH / ^br AX N^x PT Ί J^T> oA. ^CAxN (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X(6-bromo-3methylpyridin2-yl)-5- (((2fluorobenzyl)amino)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.35(A) 738 171 O pR^JT ⁴ % JA °CT >/ XA ⁴ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-Zvinylpyridin2-yl)-5-(( but-3en-1ylsulfonamide o)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.85 (A) 748 172 Br bA ^0 ^ν ΎΥ ATX x A (lR,2S,5S)-3-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-5-fluoro3methylpyridine2 -yl)-3azabicyclo[3.1. 0]hexane-2carboxamide *** 1.55 (A) 607

- 448 041794

173 ΝΗ, Br (lR,3S,5S)-2-(2- * 3.02 (V) 645 \__. ΗΝ '^< N ^Z t < °Ι Ν^χΑ ι/Λ °^\ - N=< 0 ΪΧ N (3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M3(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. O]hexane-3,5 dicarboxamide 174 N W Al yCX °^\ N If Br ^N N^^ (lR,3S,5S)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5- cyano2azabicyclo[3.1. 0]hexane-3carboxamide * 3.35 (V) 627 175 176 177 178 fA ΗΝ- ^Ν 0 yQ °^\ A Ν-/ Μ / Ν Ν 0 / ^ν ΆΧ ο^\ ί bh ϊ 0 \° A <Y\ 0=/ ^χ r L o \ ^Q - ^N x yrs 0= / ^x (z Br P Al N Br ^N N^^ H N Br p X % H N- .N- .Br XI, 'jA^ (2S,4S)-1 -(2-(3acetyl-7-methyl5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-4(trifluoromethyl)pyrrolidin-2carboxamide (lR,3S,5R)-2-(2(3-acetyl- 7methyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((bis(2fluoroethyl)amino)methyl)-M-(6bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3-(( 3,3difluoroazetidine -1yl)methyl)pyride in-2-yl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-5-fluoro3methylpyridine2- yl)-5-methyl2azabicyclo[3.1. *** *** *** *** 3.36(B) 2.48 (V) 1.83 (A) 1.87 (A) 658 723 693 620

- 449 041794

0]hexane-3carboxamide 179 Br O ⁷ OH F ^N CT I O^=\ < XN (lR,3S,5R)-2-(2(3-acetyl-7-(2fluoro-1hydroxyethyl)5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.70(B) 604 180 Br N=/ Ar (E' (^° < Ύ Ί ΑΆα A (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrazolo[1,5а]pyrimidin-6yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5 -methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.04 (A) 641 181 Br W* A=o N^N ⁿ ' Ύ Ί Atm O=XCA XN (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4b]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2- 1.70 (A) 603 azabicyclo[3.1. 0]hexane-3carboxamide 182 Br \ HN - b - F (D ⁷ N -*N ν'Ύ 1 A (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4b]pyridin-1yl)acetyl)-M(6-bromo-5-fluoro3methylpyridine2 -yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.79 (A) 621 183 Br K ^N= ^ 0 ⁷ A° A. ⁿ ' Ύ Ί ΑΐίΊ °=X CHA (lR,2S,5S)-3-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4b]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-3azabicyclo[3.1. 0]hexane-2carboxamide *** 1.47 (A) 589 184 Br '^N 0 ⁷ S N^4s o jn ji ^no=\ X XL XN^· (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[4,3b]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. ** 1.55 (A) 603

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185 Br 0]hexane-3carboxamide (lR,3S,5R)-2-(2- ** 1.64 (A) 621 0 ^N= \ HN-d F 0 / X viX^ A O. (3-Acetyl-5-(2methylpyrimidin-5-yl)-1Hpyrazolo[4,3b]pyridin-1yl)acetyl)-N(6-bromo-5-fluoro3methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide 187 0= m A? // '—z | (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3(difluoromethyl)4methylpyridin2-yl)- 5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.04 (A) 652 188 0- \ ⁰ NS^' // /L I 0 ' \ Br Λ <П \ ¥> N^X (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-Zvinylpyridin2-yl)-5-(( (Nmethylbut-3-en1yl)sulfones with do)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.01 (A) 761 189 Vi ύΫυΧ f χΎ JL o=\C X N \ (lR,3S,5S)-2-(2(3-acetyl-7(but-3-en-1-yl)5-(2- methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5((allyloxy)methyl)-M-(6-bromo3- methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.36 (A) 711 190 Br xx °^ _N> X x TX o=\ CX (lR,3S,5R)-2-(2(3-acetyl-7-(1fluoroethyl)-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. *** 2.05 (A) 647

- 451 041794

0]hexane-3carboxamide 191 Br C7 Cha Lul \_/>0 I (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-7(oxetan-3-yl)1H-indazol-1yl)acetyl)-M(6-bromo -3-methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide 192 o Eu ^Λ 04 OT (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3(morpholinometh yl)pyridin-2yl)-5-methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.10(A) 688 193 Br AG0 A o ⁷ ° \ ^A) CH ₃ (lR,3S,5R)-2-(2(3-acetyl-5-(2methoxypyrimidin-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.84 (A) 619 194 Br A o ⁷ 0 ^N OCX Ν ⁰ \ ^n^nh ₂ (lR,3S,5R)-2-(2(3-acetyl-5-(2aminopyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.49 (A) 604 195 Br >bhA 0 ⁷ ^00 ⁿ CXX ⁰ \ ^n^nh ₂ (lR,3S,5R)-2-(2(3-acetyl-5-(2aminopyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-5-fluoro3 - methylpyridin2-yl)-5-methyl2- azabicyclo[3.1. 0]hexane-3carboxamide *** 1.58 (A) 622 196 OCF ₃ Α Ό ⁷ ^00 <Ύ A ATT °A ^A (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-5methyl-M-(3methyl-6- (trifluoromethox and) pyridin-2yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.04 (A) 608

-452041794

197 N^O ⁿ a i ⁰ Br A^O ,N__ A °4'^A' ^N /l νΆ, (lR,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-X(6-bromo-3methylpyridin2-yl)-5(oxazol- 5-yl)2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.55 (A) 655 198 Br aA A ^ν Άϊ ⁰ X aA)ch ₃ (lR,3S,5R)-2-(2(3-acetyl-5-(2methoxypyrimidin-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-X(6-bromo-5-fluoro3 - methylpyridin2-yl)-5-methyl2- azabicyclo[3.1. 0]hexane-3carboxamide *** 1.92 (A) 637 199 Br /° ΑΓΧ Α Αΐ oA < nh ₂ n 1-(2((lR,3S,5R)-3((6-bromo-5fluoro-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl)-5(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4- *** 1.39(A) 623

- 453 041794

c]pyridine-3carboxamide 200 Br N% ¢^0 yCL, ₀₌ %A% 5-(3-acetyl-1 (2-((lR,3S,5R)3-((6-bromo-3methylpyridin2yl)carbamoyl)5-methyl-2azabicyclo[3.1.0]hexan-2-yl)2-oxoethyl )-1Hpyrazolo[3,4c]pyridin-5yl)-2- methylpyrimidine n 1-oxide *** 2.97(B) 619 201 - ^N x V \ >AM % b Br f ° N^x^, AXA Aft (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-(( 4cyclopropyl1H-1,2,3triazol-1yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.65 (A) 709 202 203 204 u _S A N % ^όΙ \ N—'k brQ b Br ^==0 N^x^, % Ύ Ί A%T o=% C <% XN _Z N. % V AM % 0 Br ^=0 ⁿ J jl 0=% % x N %QA ' An nA (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-5-(( 4(trimethylsilyl) -1Н-1,2,3- triazol-1yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide (lR,3S,5R)-5((1H-1,2,3triazol-1yl)methyl)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Nindazol-1yl)acetyl) -M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide (1R,3S,5R)-N(3-(2-oxa-6azaspiro[3.3]heptan-6ylmethyl)-6bromopyridin2-yl)-2-(2-(3acetyl-5-(2methylpyrimidine) -5-yl)-1Nindazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** *** *** 1.99 (A) 1.41 (A) 1.16(A) 741 669 699

- 454 041794

205 Br N=( >V>j ⁿ jj ^N 0 ' x (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-4(6-bromo-3methylpyridine2 -yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.78 (A) 617 206 U . /N=\ <Ph M 1° =/|C| 0=4 < -A X N (lS,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-4(6-bromo-3methylpyridin2-yl )-5(((3aR,6aS)hexahydrocycle openta[c]pyrro l-2(1H)yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.15(B) 712 207 V .. N ^- ^ , ^Br / N=\ <Ηχ ^Ν Λχ N ^? 0' /° ⁿ CXa ATI XN (lS,3S,5S)-5((2azaspiro[3.4]ox tan-2yl)methyl)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridine -1yl)acetyl)-M(6-bromo-3methylpyridin2-yl)-2azabicyclo[3.1. 0]hexane-3carboxamide *** 2.16(B) 712 208 Br N=/ 0 / ν'Ύ i r° 0=4 C /--J ^x NO (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2(oxetan-3yloxy)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-4(6-bromo-3methylpyridine2 -yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 9.30(D) 676 (M+2) 209 Br N=/ ^N 0 ⁷ xtS 0=4 JI \ N (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-5 -fluoro3- methylpyridin2-yl)-5-methyl- *** 1.86 (A) 635

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2- azabicyclo[3.1. 0]hexane-3carboxamide 210 Br o' s ^ν Ά J Ν Ο=\ X Ν (lR,3S,5R)-2-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[4,3b]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridine2 -yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide * 1.80 (A) 617 211 Br Ν=( CN 0 ζο У ^υ νη ₂ l-(2-((2S,4R)-2((6bromopyridin2yl)carbamoyl)4fluoropyrrolidi n-1-yl)-2oxoethyl)-5(pyridin-3-yl)1Н-pyrazole-3carboxamide *** 0.97 (A) 516 212 Br Ν=Χ vatA/ ^λ % _Ν 0 ' 0 ^υ νη ₂ (1R,3S,5R)-N(6-bromo-3methylpyridin2-yl)-2-(2-(3carbamoyl-5(furan-2-yl)1H-pyrazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.56 (A) 527 213 ЪchС /AJi Η ₂ Ν ^^-=0 οΡ ^Br (1R,3S,5R)-N(6-bromo-3methylpyridin2-yl)-2-(2-(5carbamoyl-3(furan-2-yl)1H-pyrazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide ** 1.67 (A) 527 214 Br Ν=( V\J ^N A/ Co nA ^N p ⁰ nh ₂ (1R,3S,5R)-N(6-bromo-3methylpyridin2-yl)-2-(2-(3carbamoyl-5(thiophen-2-yl)1H-pyrazol-1yl)acetyl)-5methyl-2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.65 (A) 543 215 Br N=( ^f ,a ⁿ AJ C _N о CcY ,N Ax И Ν _χ JX ^N 0=( nh ₂ l-(2-((2S,4R)-2((6bromopyridin2yl)carbamoyl)4fluoropyrrolidi n-1-yl)-2oxoethyl)-5-(2methylpyrimidi n-5-yl)-1Hpyrazol-3carboxamide * 1.15(A) 531

- 456 041794

216 Br N=( F 0 0. Nn HA H ₂ NVN l-(2-((2S,4R)-2((6bromopyridin2yl)carbamoyl)4fluoropyrrolidi n-1-yl)-2oxoethyl)-3-(2methylpyrimidi n-5-yl)-1Нpyrazol-5carboxamide ** 1.04 (A) 531 217 Br F o ' °^Xn OaC K/ ^CF 3 'Xj A n^ ⁿ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-7(trifluoromethyl)-2H-indazol-2yl)acetyl)-M(6-bromo-3methylpyridine2- yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide * 3.62 (V) 670 218 F rF ^F F \_ HN—(Λ <T /-0 N=( 0 Br An ° \ X \ N (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5-((3,3difluoroazetidin -1-yl)methyl)-2azabicyclo[3.1. 0]hexane-3carboxamide 219 Br x° OCX ΑΛΑιΑ ^o= x 4^=/ (lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrazolo[1,5a]pyrimidin-6yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo- 3-methylpyridin2-yl)-5-methyl2azabicyclo[3.1. 0]hexane-3carboxamide *** 1.94 (A) 642 231 CN / ^Br ^'N ^Z C>' CXT nn (lS,3S,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5(cyanomethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide 2.45(B) 628 232 CN / ^Br / N=\ (lS,3R,5S)-2-(2(3-acetyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridin2-yl )-5(cyanomethyl)-2azabicyclo[3.1. 0]hexane-3carboxamide 2.34(B) 628

- 457 041794

233 Br δΜ νώ, \N\ (lR,2S,5S)-3-(2(3-acetyl-7methyl-5-(2methylpyrimidi n-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M(6-bromo-3methylpyridine2 -yl)-3azabicyclo[3.1. 0]hexane-2carboxamide 1.58 (A) 603

Table 7

Additional non-limiting examples of compounds of the present invention

Compound No. Structure Name 1C ₅₀ (star points) RT min (A, B, C or D) MS (M+1) 234 F m-4 Vg / /R Aw X vOL oP ζ. A\N (lS,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5-((3,3difluoroazetidin-1 yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide 235 F ^Br / N=( Aa (lS,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(fluoromethyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 3.06 (V) 621 237 Br MM AX ^F ν'TX JM ΐ oA CM x N (lR,3S,5R)-2-(2-(3acetyl-7-(1,2difluoroethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin- 2-yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 3.12 (V) 666 238 Br Axi OoM _F ⁰ nA Pl X O=\ C Ν N (lR,3S,5R)-2-(2-(3acetyl-7-(2-fluoro-1hydroxyethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-( 6bromo-3methylpyridin-2-yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.70 (V) 664

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239 CN , ^Br / N=< 0 ' ATX oAAfA ^X N (lS,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-X-(6bromo-3methylpyridin-2-yl )5-(cyanomethyl)-2azabicyclo [3.1.0 ]hexane-3-carboxamide ** 2.45 (V) 628 240 CN , ^Br N 0 ' ATX o/avA x N^ (lS,3R,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-1H-(6bromo-3- methylpyridin-2-yl)5-(cyanomethyl)-2azabicyclo [3.1.0 ]hexane-3-carboxamide ** 2.34 (V) 628 241 ^z= / Xa A ² A< o (lR,2S,5S)-3-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-X-(6bromo-3 - methylpyridin-2-yl)3- azabicyclo[3.1.0]hexane-2-carboxamide *** 1.58 (A) 603 245 A , AX ATX A Ai oA X A X N^ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-X-(6bromo-3methylpyridin-2-yl )5-(((3aR,6aS)hexahydrocyclopent a[c]pyrrol-2(1H)yl)methyl)-2azabicyclo [3.1.0]hexano-3-carboxamide *** 2.44 (V) 712 246 x. AX ⁿ OTa oA XA ^x N (lR,3S,5R)-5-(2azaspiro[3.4]octan2-ylmethyl)-2-(2-(3 acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl) acetyl)-X-(6bromo-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.49 (V) 712 247 -Ο ~ ^ώ / V A 4 o (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-X-(6bromo-3methylpyridin-2-yl )5 -((4-cycle opropyl1 Η-1,2,3-triazol-1 yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.56 (A) 710

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248 NO 4 ^0N l Atl X (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-((bis(2hydroxyethyl)amino) methyl)-M-(6-bromo-5fluoro-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.11 (V) 724 249 XBr ΌΌ N 0 ' ASL frequency response X (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine -2-yl)5-(cyanomethyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 3.04 (V) 646 250 F J^ ^F P / ^Br ΌΚ OCX KA oA C -A \ ν \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine -2-yl)5-((3,3difluoroazetidin-1 yl)methyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.07 (V) 712 251 A A (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine -2-yl)5-(fluoromethyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.88 (V) 639 252 K 0 m4 (lR,3S,5R)-5-(2azaspiro[3.4]octan2-ylmethyl)-2-(2-(3 acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl) acetyl)-M-(6bromo-5-fluoro-3methylpyridin-2-yl)2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.32 (V) 730 253 ζ , Ko vCX ApH XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine -2-yl)5-(((3aR,6aS)hexahydrocyclopent a[c]pyrrol-2(1H)yl)methyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.26 (B) 730

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254 255 256 257 Br ίχΡ* % Ji kL -°' 0=4 k Y\ XN \ pp N Ya k i / ί ογ ^F N=\ । PCF ₃ bvY ΐ ⁰ / \ ^Q V-FP 0=/ N=\ bgf OF ^X PCX Y^^Y^n 0=4 Jk X 4 5-(3-acetyl-1-(2((lR,3S,5R)-3-((6bromo-5-fluoro-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hex san- 2-yl)-2oxoethyl)-1Hpyrazolo[3,4c]pyridin-5-yl)-2methylpyrimidin-1 oxide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 N-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-((2fluoroethoxy)methyl)pyridin-2-yl)-5-methyl2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-methylM-(3-methyl-6 (trifluoromethoxy)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H- pyrazolo[3,4c]pyridin-1yl)acetyl)-CH-((8)-3fluoro-4-methylpent-Zen-2-yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 2.50 (V) 1.77 (A) 1.93 (A) 2.16 (A) 637 666 609 533 258 Br N-\ °pQ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3isobutylpyridin-2yl)- 5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 2.05 (A) 645 259 bP N 0 ρτχ o^cPTl XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4с]pyridine-1nn)aHeTnn)-N-((R)-l(( R)-2,2dichlorocyclopropyl)ethyl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 2.11 (A) 569

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(lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-N-(6bromo-3methylpyridin-2- yl)5-(fluoromethyl)-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo [ 3,4с]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-((3,3difluoroazetidin-1 yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR ,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-((bis(2hydroxyethyl)amino)methyl )-M-(6-bromo-3methylpyridin-2-yl)2azabicyclo [3.1.0]hexan-3-carboxamide

263 \|- ^Br N O ' A° jl ⁰ \ L· Ά XN = (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine- 2-yl)5- ((dimethylamino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.56 (V) 677 264 I J (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine -2-yl)5- ((dimethylamino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.33 (V) 664 265 Br 'Ά o < \ LH hr Ίη Νγ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-((3 ,4dihydroisoquinoline2(1Н)- yl)methyl)pyridin-2yl)-5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 1.46 (A) 734

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269 _a . h TU (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-7- (trifluoromethyl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-N-(6bromo-3methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.54 (V) 671 270 ci Br N- ³ / ^Br / ^N= \ 0 / ¢^0 OCX XN \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((3- hydroxyazetidin-1 yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** 1.84 (V) 674 271 Br oCh Dz n Τι °<4q (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-7- (trifluoromethyl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.68 (V) 689 272 273 274 HO .Ν / ^Br Ν 0 ' OCX x N N / ^Br bb ^{5 ν} ΆΥ o=\ X <O / Br Ox ¢^0 OCX XN (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((E)- (hydroxyimino)methyl)-2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl )-M-(6bromo-3methylpyridin-2-yl)5-cyano-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidine- 5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-(cyanomethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** *** *** 2.37 (V) 2.87 (V) 2.43 (V) 632 614 628

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275 Br (lR,3S,5R)-2-(2-(3- *** 1.96 633 o' SAL oA J Jk ^x N OCH ₃ acetyl-5-(2methoxypyrimidin5-yl)-7-methyl-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-methyl-2azabicyclo[3.1.0]hexane -3-carboxamide (A) 277 A. O (lR,3S,5R)-N-(3-(2oxa-5- azabicyclo[2.2.1]heptan-5-ylmethyl)-6bromopyridin-2-yl)2-(2-(3-acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl )acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.14 (A) 700 278 Br ^A JO N °AL _n J4°ch ₃ (lR,3S,5R)-2-(2-(3acetyl-5-(2(methoxymethyl)pyrimidin-5-yl)-1Nindazol-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.77 (A) 632 279 Br ^A N^/4 OQ ΑΑΐ o=\ / y. XN (lR,3R,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-methyl- 2azabicyclo[3.1.0]hexane-3-carboxamide * 2.23 (A) 601 280 Br , N=f Aj and N t) / ^/A N'/H νλ ί Aa A A (lS,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.22 (A) 601 281 Br , N=/ <bA N 0 ⁷ ^A nA 1 ΑΑΐ O=\ / xA ^x N (lS,3R,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-\-(6bromo-3methylpyridin-2-yl)5-methyl- 2azabicyclo[3.1.0]hexane-3-carboxamide * 2.14 (A) 601 282 η K At beam ² U o (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((S)-l,2dihydroxyethyl)-2- *** 2.77 (V) 649

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azabicyclo[3.1.0]hexan-3-carboxamide 283 A / ⁷ T^° O o^° (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((S)-2-okco-1,3dioxolan-4-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide 2.45 (V) 675 284 / / ^Bg W0 P° vOL X N \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5-ethyl-2azabicyclo [3.1.0]hex san-3-carboxamide *** 3.28 (V) 617 285 M j' 0^/ N=\ <χΡ Ρ° vOL oAaSs X N (1R,3S,58)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((8)-2,2-dimethyl1,3-dioxolan-4-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.38 (V) 689 286 / / ^VG Ν 0 ' ΝΎ Ί αΑΡϊ ο=\ C X Ν (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-I-(6bromo-3- methylpyridin-2-yl)5-ETHYL-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.22 (V) 616 287 ΗΝ θΡ VG >Αρ Ν 0 ⁷ ρ ν^Α, <Ρ Ρ 0=\ <<Α X Ν (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(2-(8- methylsulfonim do yl)ethyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** 2.56 (V) 707 288 0 οΛ Br Ν 0 ⁷ ρ° nJ Ί Απ a (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(2- (methylsulfonyl) ethyl) -2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.96 (V) 708

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289 Br AtA A ⁰ С/ N'\ An % (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-((3 ,3,5,5tetramethylmorpholine o)methyl)pyridin-2yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.91 (A) 744 290 Br ^>: ^^0 A ⁷ o / ^Ao ν-^Α ^ν ' ύ ί 0=0¾ ^χ νΑα Αο (lR,3S,5R)-2-(2-(3acetyl-5-(2-(3hydroxyoxetan-3 yl)pyrimidin-5-yl)7-methyl-1 H-indazol1-yl)acetyl)-LG- (6bromo-3methylpyridin-2-yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.15 (A) 673 291 Br - A ⁷ ο / ^N d Α ΟυΑ ^χ nA Vo (lR,3S,5R)-2-(2-(3acetyl-5-(2-(3fluoroxetan-3yl)pyrimidin-5-yl)7-methyl-1 H-indazol1-yl)acetyl)-M-( 6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.41 (A) 675 292 Br ^N ⁷ b ' nA a A aU \ > N 0 (lR,3S,5R)-N-(6bromo-3methylpyridin-2-yl)5-methyl-2-(2-(7methyl-5-(2methylpyrimidin-5yl)-3-(oxetan-3-yl)1H- indazol-1yl)acetyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.07 (A) 629 293 Br ,Α^Λα* A ⁷ o / ^N Άα a ° \ La (lR,3S,5R)-2-(2-(3acetyl-5-(2-fluoro-6methylpyridin-3-yl)1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo- 3methylpyridin-2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.09 (A) 620 294 Br A c> ⁷ ^Ao vCa y^A^N oA AA-ESCH3 ⁴ N (lR,3S,5R)-2-(2-(3acetyl-5-(2(methoxymethyl)pyrimidin-5-yl)-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3 - methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.66 (A) 633

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295 296 297 298 0 , ^{Br 0 7} _χτχ oyXl X O Br êh ^{m 5} ^ _Ν O ^{' 7} Ν^Α ν'Ύ JL οΑ IL A \ Ν (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-LG-(6bromo-3methylpyridin-2-yl )5 -(methoxymethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H- indazol-1 yl)acetyl)-LH-(6bromo-3methylpyridin-2-yl)5-(pyrrolidin-1 ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)5- ((isopropylamino)methyl)-2- azabicyclo [3.1.0]hexane-3-carboxamide methyl (((lR,3S,5R)-2(2-(3-acetyl-7methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl) acetyl)-3 -((6bromo-3methylpyridin-2yl)carbamoyl)-2azabicyclo[3.1.0]hexan-5-yl)methyl)-bprolinate *** *** *** *** 3.04 (V) 2.23 (V) 2.91 (IN) 2.92 (V) 633 685 673 743 299 0 Α' 0 _Br ί ^Ν 4 "Am Α7 '^Ν Ό ^{7 n} C1^L o^\ 4 X Ν \ (((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-3-((6bromo-3methylpyridin-2yl )carbamoyl)-2azabicyclo[3.1.0]hex-san-5-yl)methyl)-bproline *** 2.85 (V) 729 300 ^ΝΗ .Λ Ν 0 ⁷ Κ^νϊ Ο=\ 0 X Ν (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)5-((tert- butylamino)methyl)2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.16 (V) 687

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301 Br A ° < X ( A ^f N=^ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-H-(6bromo-3-((2fluoroethoxy)methyl)pyridine -2-yl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.89 (A) 664 302 Br »¥>4^0 7 A N'\ An N=^ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3-((2,2,6, 6tetramethylpiperidium n-1- yl)methyl)pyridin-2yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 303 Br 'P o ^{7 N} AX - ηΑ _Ν ⁰ \ nPX (lR,3S,5R)-2-(2-(3acetyl-5-(5methylpyrazin-2-yl)1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.91 (A) 603 304 A\ A a A 0 Br ^==0 BL L oA < A X N \ (2S,4R)-4-((lH-l, 2,3triazol-1-yl)methyl)1 -(2-(3-acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1yl) acetyl)-M-(6bromo-3methylpyridin-2-yl)4-fluoropyrrolidine2-carboxamide *** 3.03 (V) 675 305 0 .7' Ax A o ^{7 N} aB pt L LLB oA XA XN a (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl) 5(morpholinomethyl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.03 (V) 703 306 ύ' i ^N P >: GN G O ⁷ p r L oA XA XN (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl) 5-((4,4difluoropiperidin-1 yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** 2.95 (V) 737

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307 308 309 310 Zjh _m / ^Br A o / ^N JX JL AAi o=\ 1 A Br A ° < \ Ό On N=^ X 4 \ \_. H to h\-o O A Z^o Br ^N \^X ^N A -Cirz ⁰ A 7 W f^O Br ,N io ⁰ n=¥ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((tert- butylamino)methyl)2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(3-(2azabicyclo[2.2.1 ]heptan-2-ylmethyl)-6bromopyridin-2-yl)2-(2 -(3-acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5 -(1-isopropyl-1H1,2,3-triazol-4-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-5-((lHpyrazol-1-yl)methyl)2-(2-(3-acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1-yl)acetyl)-M -(6bromine-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 2.26 (V) 1.71 (A) 1.62 (A) 675 699 670 311 co (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5 -(( 3-(tert-butyl)1H-pyrazol-1yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.22 (A) 726 312 O^O_ _Z JA /A <A oZ V z ^ZI /Ό J (lR,3S,5R)-5-((lH1,2,4-triazol-1yl)methyl)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1yl)acetyl )-M-(6bromine-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.36 (A) 671

- 469 041794

313 A Λν w fO Br ,N N VN ⁰ N=X (lR,3S,5R)-5-((lH1,2,4-triazol-1yl)methyl)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo [3.4c] pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.27 (A) 672 314 ό N-^ \ bxx* > 0 k (*0 7¾ o <7 N N=^ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-(( 4-methyl-1nimidazol-1yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.12 (A) 684 315 Xm U \ Wt f^O n' ^N >x Λ--ΖΛ 0 <7 N N=X (lR,3R,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-(( 4-methyl-1nimidazol-1yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide ** 1.19 (A) 684 316 „ Λ N 0 ' C ^N d Ji 0=4 XX (lR,3S,5R)-2-(2-(3acetyl-7-ethyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5- ((dimethylamino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.17 (B) 675 319 N 0 ⁷ x° ⁿ OlX ΧΛχ x _N \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(3-fluoropropyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.05 (V) 651 320 \<Br / Η 0' OCX XxwX (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5- ((dimethylamino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.23 (V) 648

- 470 041794

321 GA ^z Ay “Π (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3 -((4 -fluoro-4methylpiperidin-1 yl)methyl)pyridine -2yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.26 (A) 718 322 -Π (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3 -((4-fluoro-4methylpiperidine- 1 yl)methyl)pyridine -2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 323 Br 'A o ( N'\ θχο A (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-(3fluoropropyl) pyridin-2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide 'J' 'J' 'J' 324 i ^Br Άφ T ° / A Г X» 0=/ ^x < / ^N nA (lR,3S,5R)-2-(2-(3acetyl-7cyclopropyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2 -yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.07 (A) 643 325 X »/ ^N^ 0 _F / ° nA ^f <Ύ X AAP^ °A (lR,3S,5R)-2-(2-(3acetyl-7-(1,2difluoroethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5- ((dimethylamino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.09 (V) 709 326 o X ^z / \ Z^-A Y / \ 0 Xm /=\ A^ y/ k\ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(2-fluoroethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.31 (V) 635

- 471 041794

327 0 o' h/sl oAvx \ Ν \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(3,3difluoropropyl)-2azabicyclo [3.1.0 ]hexane-3-carboxamide *** 3.56 (V) 667 328 04' j LA (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5 -(2,2-difluoroethyl)2- azabicyclo[3.1.0]hexane-3-carboxamide *** 3.37 (V) 653 330 331 332 333 Br y^chk ^0° ^N d l a ^N [] °4 44z4 Br V4 ^mchk Ά % ⁷ ^0° N\/4 . uTL 1 oJ\ J JL \ N . OCF ₃ *44 °^Ί /N ₄ / N VA \\ // N 0=/ A. ^X < Г N=\ v o-ch \ \__. H 4 V° v Z^o Br ,N^XV/ ⁰ (lR,3S,5R)-2-(2-(3acetyl-5-(2-((3,3difluoropiperidin-1 yl)methyl)pyrimidin - 5 -yl) -1 H-indazol-1 yl)acetyl) -M-(6bromine-3- methylpyridin-2-yl)5-methyl-2- azabicyclo [3.1.0 ]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2,4- dimethyl pyrimidine 5-yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-methylM-(3 -methyl-6(trifluoromethoxy)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl) -1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(3- isopropylisoxazol5-yl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 1.65 (A) 1.81 (A) 2.03 (A) 2.13 (A) 722 618 623 699

- 472 041794

334 >/ O' __. HN- ^k N ^Z b CQ BrN=/ Y^N A N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromopyridin-2-yl)5 -methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.91 (A) 589 335 O' QT i ⁰ BrT F^N X A N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromopyrazin-2-yl)5 -methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.71 (A) 592 336 O' Br T Y^N A N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromopyridine-2 -yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.02 (A) 603 337 0= QT A Br T Y^N A N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromopyrazine-2 -yl)5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.82 (A) 604 338 O ^; € J_Q Λ % 0 Br Str nA (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)5-((4-(tert-butyl)thiazol-2yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.40 (A) 741 339 N 0 Br A _Z N.___ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)5 -((4-ethylthiazol-2yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.99 (A) 713 o ₍ % ^N= \ 340 0: and _Z N. N Λα / CF ₃ h AA 0 / Ί An nA (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-methylM-(3-methyl-6 (trifluoromethyl)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.82 (A) 593

- 473 041794

341 'ιaA _o aC XA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5-methylM-(3 -methyl-6(trifluoromethyl)pyridin-2-yl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 1.92 (A) 607 342 ^,F NH \__ ΗΝ—ζΑ <1 nX X о Br P ^N v4 n . Ύ J 0=4 IA x (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-4(6bromo-3- methylpyridin-2-yl)5-(((3- fluoropropyl)amino)methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.62 (V) 691 344 X x Aw 'o ⁷ A naS _o ati X (lR,3S,5R)-5-(2azaspiro[3.3]heptan2-ylmethyl)-2-(2-(3 acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo [3.4с] pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.71 (V) 712 345 N- Ak N-A\NyLAA^ oW (lR,3S,5R)-2-(2-(3acetyl-7- (fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-4(6bromo-3- methylpyridin-2-yl)5-(3- (dimethylamino) prop yl) -2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.61 (B) 705 346 Y A ^Br / ^N N=( '^N O / X° XOL XN (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-5(azetidin-1ylmethyl) -4(6-bromo3-methylpyridin-2yl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.31 (B) 672 347 P A Ilr ^==0 aS AAA °=χΆ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-4(6bromo-3methylpyridin- 2-yl)5-(pyrrolidin-1 ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.29 (B) 686

- 474 041794

348 349 350 351 κι Br Ή ^ζ ο ^ζ Χ°Ι οΡ X Ν ΑΧ Ν 0 Br 1 ⁰ Ν <Α 0 νΗ D % >Α g Χ°ι ν'Ύ Ί Ατι °=\ CHA Ρ % Ή Ο ' X°r ^F ν 'Ύ 1 Am 0 \u003d% H Μ X Ν (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3 - methylpyridin-2-yl)5- ((dimethylamino)methyl)-2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-( 6bromo-3- methylpyridin-2-yl)5-((5- isopropylthiazol-2yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((3,3dimethylazetidin-1 yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7( fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-X-(6bromo-3methylpyridin-2-yl)5-(pyrrolidin-1 ylmethyl)-2azabicyclo[3.1.0]hexane -3-carboxamide *** 'fc *** *** 2.56 (V) 2.20 (A) 2.47 (V) 4.28 (B) 660 729 699 703 352 θBr / N=< Ή0' X° OlX oTPH X N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-\-(6bromo-3methylpyridine -2-yl)5-((3,3dimethylazetidin-1 yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** 4.25 (V) 700 353 Ρ , ^ά %% Ν 0 ' Ν-^χΛχ ν' τ ί Am οΑ C Μ X Ν (lR,3S,5R)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5(azetidine-1- ylmethyl)-M-(6-bromo3 -methylpyridin-2yl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 4.46 (V) 689

- 475 041794

354 NP _z ^Br / N=< 0 / ^A ^F N'-Uch, nA JL o=\ C XN \ (lR,3S,5R)-5-(2azaspiro[3.3]heptan2-ylmethyl)-2-(2-(3 acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl) acetyl)-M-(6bromo-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.26 (V) 729 355 A Yp N 0 ' nA 7 o=\ 4 A XN (lR,3S,5R)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5-((3,3dimethylazetidin-1 yl)methyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.95 (V) 717 356 Br «UchR P 0 (/=0 \ \ X ^N N-\ M ^ο γΑ ^{Ν F} > A N==^ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-((3 (trifluoromethyl)-5,6dihydro- [ 1,2,4]triazolo[4,3 a]pyrazin-7(8H)yl)methyl)pyridin-2yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 357 Br UchAT ¹ AA 1 \ /^N _X NA ' vrb C ^N /\_A CF ₃ ⁰ \ ' Pn (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3-((3(trifluoromethyl)-5 ,6dihydro- [ 1,2,4]triazolo[4,3 a]pyrazin-7(8H)yl)methyl)pyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 359 O^N Αρ N 0 ⁷ ^=0 N-Uch nA JL aa o=\ 4 A XN (lR,3S,5R)-5-((l,3,4oxadiazol-2yl)methyl)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl )acetyl)-M-(6bromo-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.87 (V) 684 360 O^N -f/chp N 0 ' A N^xA^ LJ JA^aPt O=\ < A x _N \ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((5-methyl-1,3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.98 (V) 698

-476041794

361 362 363 364 Br A 0 'ATX ₀ ΑΓχ nh ₂ n % O A Ao Br , ^N A ⁿ JLAa ⁿ 0=XA ΆΧ O ^N X Ao Br ^N 0AA ^{n 0=} \ 0 N O Br n-^aA <Ύ Ί oA XA XN \ l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl)-5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-5 -(2methylpyrimidin-5yl)-1 H-pyrazolo [3,4c]pyridine-3carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl )acetyl)-CH-(6bromo-3-(5isopropyl-1,3,4oxadiazol-2yl)pyridin-2-yl)-5methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-CH-(6bromo-3methoxypyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo -3-((3fluoroazetidin-1yl)methyl)pyridine -2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** ** *** *** 2.50 (V) 1.93 (A) 1.80 (A) 2.74 (V) 604 700 620 675 365 0 Va ^RN A } L /4 ^N \ Ν O Br Ao. N^AA, aΎ Ί °A (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- (cyanomethyl)pyridi n-2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.39 (V) 641 366 4 . ₄ - Arp A o' n-va n.Ύ Ί JA0 (lR,3S,5R)-5-(5azaspiro[2.3]hexan5-ylmethyl)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl) -M-(6bromine-3- methylpyridin-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.74 (V) 697

- 477 041794

367 Br O' ^bo Mi JL Cu y ^N N (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)2-(2-(3- (cyanomethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide * 3.05 (V) 599 368 Br t)' ^=O n/T Ί MM V N N (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)2-(2-(3-(2- cyanopropan-2-yl)5-(2- methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide * 3.74 (V) 627 369 370 371 372 X nP AM ^bo/ ^F nMk mt p An 0=4 C M \ N .4 YA ^bo bcx obu x A by / ^NH Ν=/ ^Γ «bab^ 'M 0 ' ^==0 Mb O=X 4 M N^N bb ^N bx <Ύ Ί Abi 0=\ c M XN (lR,3S,5R)-5-(5azaspiro[2.3]hexan5-ylmethyl)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl )-M-(6bromo-3methylpyridin-2-yl)2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-5-(5azaspiro[2.3]hexan5-ylmethyl)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl )-1 H-pyrazolo [3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl )-M-(6bromo-3methylpyridin-2-yl)5-(((4,5dihydrooxazol-2yl)amino)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2 -(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)5-((3-methyl-1 ,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** *** *** 2.65 (V) 2.67 (V) 2.53 (V) 3.00 (IN) 715 698 687 698

- 478 041794

373 L / N\ °\ Br (lR,3S,5R)-2-(2-(3acetyl-6-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-K-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.89 (A) 616 ^N 4 0 eleven N 374 A' NN °4 Xn \ 1 ΗΝ-ζΛ ^N \ 0 Br '0 ^cx N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-((5 -butyl1,3,4-oxadiazol-2yl)methyl)pyridin-2yl)-5-vinyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.04 (A) 741 375 >1[ / N\ ⁰ \ HO HO—C hnhQ 0 Br 0 Clol (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-(1, 2dihydroxyethyl)pyridin-2-yl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.19 (B) 649 376 Oh Oh Ή N ABOUT O=\ O Br 3 Yx N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-N-(6bromo-3- methylpyridin-2-yl)5-(2,3- dihydroxypropyl) 2- azabicyclo[3.1.0]hexane-3-carboxamide *** 2.44 (V) 663 377 / —N 0 N- ^N \ ° \ Br ^N A o -O/ ^F tS XX N (lR,3S,5R)-2-(2-(3acetyl-7- (fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(2- (dimethylamino)ethyl) -2- azabicyclo[3.1.0]hexane-3-carboxamide *** 2.42 (V) 691 378 / —N N- N\ ⁰ \ Br Ο =O/ ^F Y N (lR,3S,5R)-2-(2-(3acetyl-7- (fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(4- (dimethylamino) buti l) -2- azabicyclo[3.1.0]hexane-3-carboxamide *** 2.24 (V) 719

- 479 041794

380 381 382 383 \ ^/Ν Λ / ^{CF3 N} CX А o=\ < XN = А-l HN—M <1 N=( N 0 Br < ° /XX οΧΧχ XN = AxA N 0 ' j /χχ XlX X XV\ hn4a> XN =( N 0 Br /П _ο χ4τχ XN = (lR,3S,5R)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-(3(dimethylamino)propyl) -M-(3-methyl-6(trifluoromethyl)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5- (2methylpyrimidin-5yl)-1 H-pyrazolo [3,4c]pyridin-1yl)acetyl)-\-(6bromo-3 -(2,2-dimethyl1,3-dioxolan-4yl)pyridin-2-yl)-5methyl -2azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-propyl-2azabicyclo [3.1.0]hexano-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo [3,4c]pyridin-1yl)acetyl)-M-(6bromo-3 -(2-oxo-1,3dioxolan-4yl)pyridin-2-yl)-5methyl-2azabicyclo [3.1.0]hexan-3 - carboxamide *** *** *** *** 2.95 (V) 3.29 (V) 3.40 (V) 2.70 (V) 695 689 631 675 384 F ^F X 0 ^Br brp N 0 ' A° /XX θχ^χχ XN = (lR,3S,5S)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5- ((difluoromethoxy)methyl)-2- azabicyclo[3.1.0]hexane-3-carboxamide *** 2.86 (V) 669 385 Ο \\ Z / \ ζγ ? γ^ ^ζ O ° o /=/ χχ^ζ p 4 (lR,3R,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-isobutyl-2azabicyclo[3.1.0]hexan-3-carboxamide * 3.55 (V) 645

- 480 041794

386 Br (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LH-(6bromo-3chloropyridin-2-yl)5-methyl- 2azabicyclo[3.1.0]hexane-3-carboxamide *** 3.35 (V) 622 ft,' ABOUT' N OCI L=O ill N 387 ABOUT ϊ/Α OCX ha N (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)5-methyl-2-(2-(5-(2methylpyrimidin-5yl)-3-vinyl-1Hpyrazolo[3,4c]pyridin-1yl)acetyl)-2azabicyclo [3.1.0]hexano- 3-carboxamide *** 1.78 (A) 586 388 / 0 0= A \hn- -n4 Ϊ o A J Oy Br N=( 4/ N V\ nA^ (lR,2S,5S)-3-(2-(3acetyl-7-isopropyl5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)3- azabicyclo[3.1.0]hexane-2-carboxamide *** 2.01 (A) 633 389 390 393 about ^; u o'o< I__. HN^n ^z 0 N^/^ yU γ=Ν HN^ 1__. HN- A ⁷ 0 nOx yO b X nA Br A XX N Br nA 4J Χχ Ν Br X at Η (lR,3S,5R)-2-(2-(3(1H-imidazole-2carbonyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LH-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)5-methyl-2-(2-(7methyl-5-(2- methylpyrimidin-5yl)-3-(2- azaspiro[3.3]heptane2-carbonyl)-1Nindazol-1yl)acetyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,2S,5S)-3-(2-(3acetyl-7-methyl-5- (2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-LH-(6bromo-5-fluoro-3methylpyridin-2-yl)3- azabicyclo[3.1.0]hexan-2-carboxamide * * *** 8.79(D) 11.5 1 (D) 1.73 (A) 656 (M+2) 695 (M-2) 623

- 481 041794

394 Br nA 'bh I (° N-^^A ^CH 3 ν'Ύ JL Ο^ΆΟ XN \ (lR,3S,5R)-2-(2-(3acetyl-6-methoxy-5(2-methylpyrimidin5-yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.88 (A) 632 395 Br N=( UcLe ^N ^Z 0 / o kUuL ⁰ ™ ³ /θ4θ _Ν J Ji XN methyl 3-acetyl-1-(2((lR,3S,5R)-3-((6bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl )-5-(2methylpyrimidin-5yl)-1 H-indazole-6carboxylate *** 1.87 (A) 660 396 397 398 399 Br "υαΎ ^<N 0 < i° o AJ ^CF3 On N=^ Br V\ oA ^i: А г Ao /=N \ ^N X,zNH ν'ΥΓΥ YA X J O >A O N 0 '^Ao ζτζ oOUs XN Br ahn^ SY) ( >o /NN-^^A nA T AFT oA < A XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-H-(3((bis(3, 3,3trifluoropropyl)amine o)methyl)-6bromopyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(3((2H-tetrazol-5yl)methyl)-6bromopyridin-2-yl)2-(2-(3-acetyl-5-(2methylpyrimidin-5yl)-1H- pyrazolo[3,4с]pyridin-1yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl )-Н-(6bromo-3methylpyridin-2-yl)5 -(2-oxopropyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-6 -chloro-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3((dimethylamino)methyl)pyridin-2-yl)-5methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 2.62 (A) 2.94 (V) 2.77 (V) 2.77 (V) 810 671 645 679

- 482 041794

400 401 402 407 O HN- Ά 0 Br o=\ X XN Br N=/ V-\ HN-d b- F TC) ^o OfS noA. D to XN \ 1 ^Br - to ° ' 4 OCX J YA n°A 44 Br ^N T Ά ^? ъ / ^o ⁿ 'ύ τ /TA em C XL Ν (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3-(3morpholinopropyl) p iridin-2-yl)-5methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(6bromo-5-fluoro-3methylpyridin-2-yl)2-(2-(3-(1hydroxyethyl)-7methyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo [ 3,4c]pyridin-1yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)2-(2-(3-(1- hydroxyethyl l)-5-(2methylpyrimidin-5yl)-1 H-pyrazolo [3,4c]pyridin-1yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)2-(2-(3-cyano-7methyl-5-(2- methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hex san-3-carboxamide *** *** ** *** 2.48 (V) 1.62 (A) 1.42 (A) 11.2 1 (D) 716 636 607 601 (M+2) 408 Br v-\ ⁿ A5 ^>:: XH g X ° CI / ^N " 4X4 o \u003d\ <<4 XN (lR,3S,5R)-2-(2-(3acetyl-7-chloro-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- ((dimethylamino)methyl)pyridin-2-yl)-5methyl-2- azabicyclo[3.1.0]hex san-3-carboxamide *** 3.00 (V) 679 409 N^N A° M ^Br Ny Ν O' ^od ο Ύ O=\ <<4 x _N \ (lR,3S,5R)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 2.92 (V) 716

- 483 041794

410 BrN=/ 0' s Np χΤχ x (2S,4R)-1 -(2-(3- acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4с]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)4-fluoro-4- (fluoromethyl)pyrroli din-2-carboxamide *** 3.02 (V) 641 411 ABOUT / :.P ABOUT (lR,2S,5S)-3-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-N-(3chloro-2 -fluorobenzyl)3- azabicyclo[3.1.0]hexan-2-carboxamide *** 3.29 (V) 576 412 7=0 NV4 <Ο o=\ to x (lR,2S,5S)-3-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3chloro-2-fluorobenzyl)3- azabicyclo[3.1.0]hexan-2-carboxamide *** 3.28 (V) 561 413 °/o (lR,2S,5S)-3-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-N-(3chloro-2-fluorobenzyl)3- azabicyclo[3.1.0]hexan-2-carboxamide *** 3.41 (V) 575 415 Ύΐζ B ^p ochSJ K ^N d jl O=\ k XN (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5- ((diisopropylamino) methyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.81 (B) 715 416 pX 1 ⁰ N W 0=/ ^Xh= \---x ^X < / ^N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.70 (A) 603 417 Br K ^F - / ^N 4 0 'r/l op^XX XN (2S,4R)-1 -(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5-fluoro -3methylpyridin-2-yl)- 4-fluoro-4(fluoromethyl)pyrroli din-2-carboxamide *** 3.11 (IN) 659

- 484 041794

418 A Cz W (2S,4R)-1 -(2-(3- acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4с]pyridin-1yl)acetyl)-M-(6bromopyrazin-2-yl)4-fluoro-4- (fluoromethyl)pirroly din-2-carboxamide *** 3.13 (B) 628 419 _Λ Β4 ^Ν Ρ _ν -Ν Ν o Br |M ν D Ί AFi °A CA (2S, 4S)-4-((lH-l, 2,3triazol-1-yl)methyl)1 -(2-(3-acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl) acetyl)-M-(6bromo-3methylpyridin-2-yl)4-fluoropyrrolidine2-carboxamide *** 2.97 (V) 675 420 421 422 423 _V A / GCH ^N F —NN 0 Br ^==0 n D Ί Att °% CA rhsP N o Br \D JL Ari °AA _r h4 ^N p ^F N 0 Br f ⁰ \D J Att o=\ C <A iPn L° A N 0 'A vCX oAaCC XN^' (2S,4R)-1 -(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl)4((dimethylamino)meth yl)-4fluoropyrrolidine-2carboxamide (2S,4S)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl) 4-fluoro-4(methoxymethyl)pyrr olidin-2carboxamide (2S,4S)-l-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo- 3methylpyridin-2-yl)4-fluoro-4(fluoromethyl)pyrroli din-2-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-5 -fluoro-3methylpyridin-2-yl)5-((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide ** *** *** *** 2.16 (IN) 3.22 (V) 2.67 (IN) 3.44 (IN) 651 638 626 717

- 485 041794

424 425 426 427 N^N Λ° A ^X A' - A o ' p pt p ppp oA. XA \ A a N^NV Pp A o ⁷ p bL L Ppp oA XA \ na /A ° / ,N _X __/ O'S ⁰ Λ ^P-l ' P Np N^N Pn A o X Ac P ^— N^ P bL L yaPt oA % A \ nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridine- 2-yl)5-((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-((3methyl-1,2,4oxadiazole - 5yl)methyl)-\-(3 methyl-6(trifluoromethyl)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-( 3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-X-(6bromo-3methylpyridin-2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-H-(3chloro-2-fluorobenzyl)5- ((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** *** *** 3.54 (V) 3.66 (V) 1.78 (A) 3.62 (V) 716 688 615 671 428 N^N l° A Ya A OCI N^P, bL jl On oA X A \nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3chloropyridin-2-yl) 5-((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** 3.35 (V) 720 429 N AAO ^N Y A o ⁷ nPj, bL L On oA XA \ nA (lR,3S,5R)-2-(2-(3acetyl-7(fluoromethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-((5-methyl-1,3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.22 (V) 716

- 486 041794

430 BrN=/ Al a oA A XN (2S,4R)-1-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LH-(6bromo-3methylpyridin-2-yl)4-fluoro-4methylpyrrolidin- 2carboxamide *** 3.18 (V) 608 431 Br ^Ν θΑ „OCX nh ₂ l-(2-((lR,3S,5R)-3((6-bromo-5-fluoro-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hecsan-2-yl)- 2oxoethyl)-7-methyl-5(2-methylpyrimidin5-yl)-1Hpyrazolo[3,4с]pyridine-3carboxamide *** 1.55 (A) 636 432 433 434 435 Br ^N A >%A i ⁷ o ⁷ A CxX j C? (A Y A Br 0H ^N J A o ⁷ ^== ^{o n} Ax AT A joT oA 0 A x N ^ O^N c btk A 0 C Ac ^==0 ^- nA AT A joPt oA 0 A x N O^NA Th A AX A oA 0 A XN (2S,4R)-1-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-3methylpyridin-2 -yl)4-fluoro-4methylpyrrolidine-2carboxamide (2S,4R)-1 -(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-bG-(6bromo-3- methylpyridin-2-yl)4-fluoro-4- methylpyrrolidine-2carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3chloro-2-fluorobenzyl)5- ((5-methyl-1,3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-((5methyl-1,3,4oxadiazole -2yl)methyl)-M-(3 methyl-6- (trifluoromethyl)pyridin-2-yl)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 2.84 (V) 2.96 (V) 3.15 (IN) 3.27 (V) 623 622 671 688

- 487 041794

436 437 438 439 Br bW X SSH OPG nh ₂ n 1 ^Br 1 o ⁷ 1 ⁰ J JO o =/ nA Woe Ϊ o AJ ^N %4 n A Ί Du 0 N 1 ^N= \ WW 0 ^=O nA Ί ΑΑϊ o4 LW \ n l-(2-((lR,2S,5S)-2((6-bromo-3methylpyridin-2yl)carbamoyl)-3azabicyclo [3.1.0]hexan-3-yl)-2oxoethyl)-7-methyl-5 (2-methylpyrimidin5-yl)-1Hpyrazolo[3,4c]pyridine-3carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-pyrrolo [2.3 s ]pyridin-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-( 6bromo-5-fluoro-3((methylthio)methyl)pyridin-2-yl)-5-methyl2- azabicyclo [3.1.0]hexan-3-carboxamide (2S,4R)-1 -(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-4-fluoroM-( 6-iodopyridin-2yl)pyrrolidine-2carboxamide *** *** *** *** 1.30 (A) 1.46 (A) 2.93 (V) 604 602 628 440 F, / ^N= \ P>yAU Ν^/Λχ hA JL Α^Α^Ϊ A k _N A (2S,4R)-1 -(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-4-fluoroM-(pyridin-2yl)pyrrolidine-2carboxamide *** 1.63 (V) 502 441 4 ^N Q Wy 4J 0 ⁷ N Al nA Ί ΑΑϊ OA / W x (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-(((1-(2,2,2trifluoroethyl)-1Hpyrazol-3yl)amino)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.23 (V) 779

- 488 041794

(2S,4R)-N-(6bromopyridin-2-yl)4-fluoro-1 -(2-(5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)pyrrolide in-2-carboxamide ( 2S,4R)-N-(6bromopyridin-2-yl)1-(2-(3-ethyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1yl)acetyl)-4fluoropyrrolidine-2carboxamide (2S,4R )-1 -(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromopyridin-2-yl)4-φτορ-Νmethylpyrrolidin-2carboxamide

(lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromopyrazin-2-yl)5- ((3-methyl-1,2,4oxadiazol-5yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5 -(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-5-methylM-(3-methyl-6(trifluoromethoxy)pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide ( lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(6-(pyridin-2yloxy) pyridin-2yl)-2azabicyclo [3.1.0]hexan-3-carboxamide

- 489 041794

450 to / about (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl- M-(5-methyl-[2,2'- bipyridine]-6-yl)-2azabicyclo[3.1.0]hexan-3-carboxamide ** 2.31 (B) 601 451 .I A ν'L Ί Ap oA k X N \ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-(2-okco-2H- [1,2'bipyridine]-6'-yl)-2azabicyclo[3.1.0]hexan-3-carboxamide *** 3.00 (V) 617 452 Br ^=0 >°n °^\ Π ^Ν (lR,3S,5R)-2-(2-(3acetyl-5-(pyridin4-yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hex san-3-carboxamide *** 2.26 (V) 587 453 ώ ι—( Ύ% At I about (lR,3S,5R)-2-(2-(3acetyl-5-(5methylpyridin-2-yl)1 H-indazol-1yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 2.20 (V) 601 454 Br '^N 0 ' k° ATT Hu x N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-4- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide 3.36 (V) 603 455 Br N=/ aja Ή 0 ' ^=0 ACу A*Fi ο=χ to C\ x N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(6bromo-4 - methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.48 (V) 617 456 Br ^N X a^ar 0 ' ^=0 nA ^N A JL AA? o=\ to ^k XN (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 3.50 (V) 616

-490041794

457 458 459 460 Br A o ' ¢00 OCA °4 44 0 Voh •< \ ^HN A / O ' Α Ί o=\ X \ N 1 / ^CF3 AA J ⁰ / ⁰ 1 N / M/ 0=/ ' FA nA Y y A JL OA XA (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-M-(6bromo-5-fluoro-3methylpyridin-2-yl)5- methyl-2azabicyclo[3.1.0]hexane-3-carboxamide ((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexan-3-carbonyl)-leucine (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-5-methylChG-(3-methyl-6(trifluoromethyl) pyridin-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-(2-okco-2H- [1,2'bipyridine]-3-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** *** *** *** 2.89 (V) 2.98 (V) 1.92 (A) 3.35 (V) 619 561 605 617 461 Br N OF ^0° vCX AAxN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-(2bromo-5fluoropyridin-4-yl )5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide ** 3.48 (V) 607 462 0 ^00 yΎ A ντΐ o=\ X 0 x N ((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexane-3-carbonyl)-Ophenylalanine ** 3.50 (V) 595

- 491 041794

463 0 / ^he H HN% /=\ ν'Ύ Ί ΑηΓϊ A Α ((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3-carbonyl)-b-phenylalanine 3.48 (V) 595 464 0 aO Ν 0 ^Χ Χ° 1 ν'Ύ Π ΑΑ ο=\ C Μ ((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hexan-3-carbonyl)-oleucine ** 3.30 (V) 561 465 466 467 468 Br Ν=( >Α F Ή ο ' Χ° Ν^^χ oja jfi °%F CA F ^F Br N=( >A ⁿ aj o 7 Ho NAV ν' Ύ T Aft 4 CA Me P Po ^Me A 7- 0 ^z 7>/Aj nH yUX >J /0 and X—-Ν Ν 0 0 // y-Br MX N^AA ⁿ A1 AUC 0 N (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)5-methyl-2-(2-(5-(2methylpyrimidin-5yl)-3-(2,2,2trifluoroacetyl) -1Nindol-1 -yl)acetyl)2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-6-fluoro-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide methyl 1-(2((lR,3S,5R)-3-((6bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hecsan-2-yl)-2oxoethyl)-5- (2methylpyrimidin-5yl)-1 H-indazole-3 carboxylate (lR,3S,5R)-2((lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo [3.1.0]hex san-3-κapbonyl)-N(6-bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** 3.51 (B) 3.28 (V) 655 620

- 492 041794

469 Me W ^Me A HO-0 ο Me l-(2-((lR,3S,5R)-3- ((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2- azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxylic acid * 1.52 (A) 604 470 Br A 0 ' CCA oU/alX CF ₃ (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)5-methyl-2-(2-(5-(2methylpyrimidin-5yl)-3-(2,2,2trifluoroacetyl)-1Hpyrrolo[2,3c]pyridin-1yl)acetyl)-2azabicyclo [3.1 .0]gec san-3-carboxamide *** 2.67 (V) 656 471 N 0 Br cxx amX 0N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrrolo [2,3 c]pyridin-1yl)acetyl)-X-(6bromo- 5-Fluoro-3methylpyridin-2-yl)5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 1.95 (V) 634 472 A 0 Br Ai aaX 0 N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1H-pyrrolo[2,3c]pyridin-1yl)acetyl)-X-(6bromo -3methylpyridin-2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.88 (V) 616 473 Br A 0 F ^N 01 l max (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1H-pyrazolo[3,4c]pyridin-1yl)acetyl)-X-(6bromo- 4fluoropyridin-2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.68 (V) 621 474 Me w ^Me zN ₄ W HN -/ ' 0 N A l-(2-((lR,3S,5R)-3- ((6-bromo-3methylpyridin-2yl)carbamoyl)-5methyl-2- azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-X-ethyl- 5 (2-methylpyrimidin5 -yl)-1 H-indazole-3 carboxamide *** 1.71 (A) 631

-493 041794

481 ^z 0 _L )= ⁷ 1^° O (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-LG-(6bromo-3fluoropyridin-2-yl )5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.03 (V) 607 482 BrN% A 0 / T R SOT TG? 0=%C<% X N (lR,3S,5R)-2-(2-(3acetyl-6-fluoro-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-LH-(6bromo-3methylpyridin-2-yl)5- methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 3.34 (V) 619 483 484 485 486 Br Ν=/ 'A o / OT TP o=% C T x N 0^ N %' t Nn ^F N 0 ⁷ ^0 Ν^ζΟ % Ύ Ί Ταϊ 0=% 4 % XN ^ 0^ N % T Nm ^{f n} %S ₀ %d x N O^N N OCI )= 0 nJ A jaCt o=% С T XN (lR,3S,5R)-2-(2-(3acetyl-2-methyl-5-(2methylpyrimidin-5yl)-1H-indol-1yl)acetyl)-LG-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LH-(6bromo-5-fluoro-3methylpyridine- 2-yl)5-((5-methyl-1,3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-LG-(6bromo-5 -fluoro-3methylpyridin-2-yl)5-((5-methyl-1,3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2- (2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3chloropyridin-2-yl)5-((5-methyl-1, 3,4oxadiazol-2yl)methyl)-2azabicyclo [3.1.0]hexane-3-carboxamide *** *** *** *** 3.29 (B) 3.04 (V) 2.97 (V) 2.92 (V) 615 716 717 720

- 494 041794

487 488 492 493 Me 1 ^\ HN ^L \ ° ^Me αΠ HN—Z ^{o N Me} Me ^H z^Z L o 1 ⁰ W Cq 0 / ₄ 4, nA Ί ααΡϊ o=\ 4 XN \ Br aP 0 VoH o N^^4, nA Ί ααϊ o=\ 4 l-(2-((lR,3S,5R)-5methyl-3- (propylcarbamoyl) 2- azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-5-(2methylpyrimidine-5ηπ)-N-propyl-1Nindazole-3carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-butyl5-methyl-2azabicyclo [3.1.0]hex san- 3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4methylpyridin-2-yl)5-methyl- 2azabicyclo[3.1.0]hexan-3-carboxamide 2-((lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3- carboxamido)-6 bromisonicotinic acid ** *** *** *** 1.57 (A) 1.67 (A) 3.49 (V) 3.37 (V) 518 489 602 632 494 Br N=/ >_; Va ⁿ Aj 'o ' A n>A> nA Ί warT A JA (lR,3S,5R)-2-(2-(3acetyl-7-methoxy-5 (2-methylpyrimidin5 -yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3methylpyridin-2-yl )5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.39 (V) 632 495 0 1 / ^0H L-> HN- ⁷ o ^==° N-Uch hA JL ααϊ o=\ 4 x N \ ((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexasan-3carbonyl)glycine ** 2.88 (B) 505

- 495 041794

496 Me l-(2-((lR,3S,5R)-3- *** 1.31 461 497 XA ^Me A w ^ην Ά ' ο Αν \|Ч Me 0 A S ΝΆΑ ν'Ύ Ί An ((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-M-methyl5-(2methylpyrimidin-5yl)-1 H-indazol-3 carboxamide 3-((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3- carboxamido) propanoic acid *** (A) 2.92 (B) 519 498 1__ΗΝ— 'X 0 Χ°/ ν>Α <ο ⁰ \ Oh V he χχ 4-((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3- carboxamido)butanoic acid *** 3.09 (V) 533 501 v. / w\ ^Ν-_ ^Ν 0 Χ° Ν-Χ\ νΟ- ”””ο Vx ⁰ AJA χχ N (lR,3S,5R)-2((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5 -methyl2- azabicyclo [3.1.0]hexan-3-carbonyl)-N(3,6dimethylpyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide 502 χθ'! _χ ν 7 χχ ο=/ 1=4 A ^F At ^Cl An ha (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M- (2-(3 chloro-2fluorophenyl) propan2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.31 (A) 617 503 ^{ην -} ^Ν 0 X ν α4 <Ο O Ανη ₂ Χχ Br Vl (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4carbamoylpyridin2-yl)-5-methyl-2azabicyclo [3.1.0]gek san-3-carboxamide *** 2.80 (V) 631 ze N

- 496 041794

504 Br N 0 OBn ν'Ύ Ί O=\ X (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(4(benzyloxy)-bbromopyridin-2-yl)5 -methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 4.42 (V) 694 505 A HN—r-AA <OsVy N 0 VX 2=0xA N^A JlP o=\ X X N \ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(1,3diphenylpropan-2yl)-5 -methyl-2azabicyclo[3.1.0]hexane-3-carboxamide ** 3.87 (V) 641 506 •bx L o po J <p ⁰ P^N nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-ethyl-5methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide *** 1.42 (A) 474 507 _zn . J jQj O p^N nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylΝ-προπΗΗ-2azabicyclo [3.1.0 ]gec san-3-carboxamide *** 1.58 (A) 488 508 [^° /N. J Ap ⁰ P^N nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-N-butyl5-methyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide *** 1.77 (A) 502 509 \° zN ₄ J Ap o An nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-pentyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide *** 1.94 (A) 516 510 O ⁸ - ⁴ Ao F J Ap o F \ nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M(cyclopropylmethyl)5-methyl-2azabicyclo [3.1 .0]gec san-3-carboxamide *** 1.64 (A) 500

-497041794

511 L o 1 ⁰ / Cq ° Min Np (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-neopentyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide 1.92 (A) 516 512 CY L o 1 ⁰ J jOq ° Min Np (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-Misobutyl-5-methyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide *** 1.75 (A) 502 513 Ύ' 1 ⁰ ,N. J jfn ° Mind (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-X,5dimethyl-2azabicyclo [3.1.0]hec san-3-carboxamide *** 514 Br nM MH ) », 1 >—< \ on N 0 '—Z ^bo ⁰ a X An o=\ C XN 2-(2-((lR,3S,5R)-2-(2(3-acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexane-3carboxamido)-6bromopyridin-4yl)acetic acid *** 3.23 (V) 646 516 Br nM AA Ό \ b ( α ί Ari oh h x _N \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4propylpyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide ** 4.10 (B) 630 517 Yyb/ Μ Ό ' ⁿ PCm o<M ^X N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(2,6dimethylheptan-4yl)-5 -methyl-2azabicyclo[3.1.0]hexan-3-carboxamide *** 4.30 (V) 573

-498 041794

518 Ό— ^Η L 0 1 ⁰ W XQ ο Y~A ν4 (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3aminopropyl)-5methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide * 0.89 (A) 489 519 ; J—at Η _ ΝΗ L ο ,N. JX-Q 0 Y^Y v4 (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-(3- (methylamino)propyl)-2- azabicyclo[3.1.0]hexan-3-carboxamide ** 0.91 (A) 503 520 521 522 523 ϊ 0 1 ⁰ ,ν. ⁰ y^N Κα I 0 ι' ⁰ Ο 4¾ ° ρά ν4 ,Ν. 42 Ο y^N ϊ ο [ ⁰ JhQ ο ρ _Ν Ν=\ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3(dimethylamino)prop yl)-5- methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-propyl-2azabicyclo [3.1.0]hex san- 3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-pentyl-2azabicyclo [3.1.0]hex san- 3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-neopentyl-2azabicyclo [3.1.0]hex san- 3-carboxamide ** *** *** *** 0.93 (A) 1.48 (A) 1.86 (A) 1.81 (A) 517 474 502 502

- 499 041794

524 525 526 A L o 1 ⁰ lx jmj ° Fa nP L o lx J JQ ⁰ FA AP J ⁰ / ⁰ I ^OH lx J ^N M7 0=/ ^x < / ^N Np (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-Mbenzyl-5-methyl-2azabicyclo [3.1.0]hex san- 3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-hexyl5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7- (hydroxymethyl)-5(2-methylpyrimidin5-yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3- methylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** 1.74 (A) 2.12 (A) 1.68 (A) 522 530 632 529 1 ^{Br 0} ] .—-OAc lx J o=/ ^x < / ^N (3-acetyl-1-(2((lR,3S,5R)-3-((6bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)- 2oxoethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-7yl)methyl acetate *** 1.95 (A) 674 532 Br 0 '— ^Ao RL PAY? o=\C Ax XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4ethylpyridin-2-yl)5-methyl- 2azabicyclo[3.1.0]hexane-3-carboxamide *** 3.71 (B) 616 533 0 VoH \ HN—b 'x^^ C M k Ύ J N 0 \ \A θ ΝχΛχ ^— N D JL Ari O=\ C Ax 2-((lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexane-3carboxamido)-2phenethyl-4phenylbutanoic acid * 3.96 (V) 713

- 500 041794

534 0 /=\ ^NH 2 UL ΗΝ-ζ / >/ [UCH mu XO Br Xo N-^/p <Ύ JL dd 0 N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(4-(2amino-2-oxoethyl)-6bromopyridine- 2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 2.81 (B) 645 536 y-^o A .NJ jQj o p _N nA^ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-phenethyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide *** 1.94 (A) 550 537 541 542 543 1 0 >Ί—\ ^H A/ N'lf L o 1 ⁰ .NJ jCq o UL n=4 Br . ^N X X p \— N^yp, χΎ JL Ari o=\ Y A \ N ^ Br _t nA _>; ph h ^N O \—/ ^Yo ^X NV% ⁿ JT Ί °A ^N 0 Br /==0 n JT Ί + ip 0 N (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylK-(3-phenylpropyl)2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-4- isopropylpyridin2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- isobutylpyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LG-(6bromo-4- cyanopyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** *** *** *** 2.03 (A) 3.93 (B) 4.45 (V) 1.95 (V) 564 630 644 613

- 501 041794

544 ΗΝ ^χΝ 'Ν Va ηνΥ/ )/1 )—/ Νχ 0 Br 7° ΝΑ4- jl achX 0 N = (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-I-(6bromo-4-( 1 H-tetrazol5 -yl) pyridin-2-yl)5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 3.65 (V) 656 545 Br 1 ^N= L 'H 0 '—\ X r ^N JT JL O=\ / \ N =- (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-4-(6bromo-4- isopentylpyridin2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 4.65 (V) 658 546 547 548 549 550 /OMe V\ )/[ )—< 4 0 Br A° N-^4 ^N jx Jl l CX 0 N = Br J° X NV4 n jj Jl O=\ < \ N Br \ ^N= L ) ^; Γη ^ν m J^o \_ N Ύ J o=\ 7 <7. XN = Br N=( <P>4 M* O '—< j ⁿ Jt jl o=\ 7 X _N \ Br ^N X θ l ^f FF ^N jl jl o=\ 7 x N = (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- (methoxymethyl)pyridin-2-yl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- phenylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- phenethylpyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- butylpyridin-2-yl)5-methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4- (trifluoromethyl)pyridin-2-yl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxamide *** *** *** *** *** 3.68 (V) 4.45 (V) 4.45 (IN) 4.53 (IN) 632 664 692 644

- 502 041794

551 Me 'A' Me ζΝχ ^hn v У ° < / ⁿ Che l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-Mcyclopropyl -5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide *** 1.73 (A) 642 552 Y—\ HN^ O ^Ao ⁿ CX JI AAJ o=\ <<A XN \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3,3dimethylbutyl)-5methyl-2azabicyclo [3.1.0 ]gek san-3-carboxamide *** 553 O (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-((8)-1-phenylethyl)2- azabicyclo[3.1.0]hexan-3-carboxamide *** 554 EF \__ NH O U° ^N PCo AU. ⁴ N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-((S)-1- (trifluoromethoxy)propan-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 555 Br AyrcJ k° <> vCo / II N ⁰ X < A (lR,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(4benzyl-6bromopyridin-2-yl)5-methyl-2azabicyclo [ 3.1.0]gek san-3-carboxamide *** 556 Br nA AyzAJ c ⁰ JA A _o ^HO JJ \A Jl Ατι oA 1 A XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4-(2hydroxyphenyl)pyridine-2- yl)-5-methyl-2azabicyclo[3.1.0]hexan-3-carboxamide ***

- 503 041794

557 558 559 Br N 0 ^OBn NV4, 0=4 k XN 4¾ 7=0 n.Ύ Ί 0=4 k x N - ΐ ⁰ F 1 ⁰ _N W ⁰ \ ^==4^ ^X F^/ ^N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(4((benzyloxy)methyl)6-bromopyridin-2yl )-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-((R)-1-phenylethyl)2- azabicyclo[3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((E)-2fluoro-3-phenylbut-2en- 1-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** *** *** 2.14 (A) 581 560 4/ Z' ^{L Ζ} ~Ύ iz Г Z /7^ o (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-pyrrolo [2,3 s]pyridine-1- yl)acetyl)-M-((E)-2fluoro-3-phenylbut-2en-1-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.85 (A) 581 561 fix to H ' ^Z )/ o (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((E)-2fluoro-3- phenylbut-2en-1-yl)-5-methyl-2azabicyclo [3.1.0]hexane-3-carboxamide *** 2.23 (A) 595 562 Me /4 Me ,N HN-/ o #-% \|4 Me l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl)-5methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-Misopropyl-5 -(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide ** 1.87 (A) 644

- 504 041794

563 ^ΗΝ—, Me N-allyl-1-(2((lR,3S,5R)-3-((6bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo[3.1.0]hecsan-2-yl)-2oxoethyl) -5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide *** 1.80(A) 642 [ ⁰ ,N. Me An nk Me ⁰ I 564 l· ΗΝ—Ζ i ^c Me Ύ [ ⁰ ,N PQ X Me % A Me Br l-(2-((lR,3S,5R)-3- ((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo[3.1.0]hexan-2-yl)-2oxoethyl)-5-(2methylpyrimidin-5yl)-M-(prop-2-in -1yl)-1 H-indazole-3 carboxamide 'J' 'J' 1.73(A) 640 565 b A M 1 hb 0 7 Ox Xa, 7 (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)2-(2-(3-iodo-7methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hex san-3-carboxamide 'J' 'J' 2.15(A) 699 566 HN- Me 7 A aQ 0 X On Xa Me i l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-M - (1 cycle oppropylethyl) - 5 (2-methylpyrimidin5 -yl) -1 H-indazole-3 carboxamide *** 2.07(A) 670 567 \HN- 1 Me '7 _χ Ν _χ 7¾ 0 X ^N Xa Me f l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-Y -(2methylbut-3-yn-2-yl)5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide * 1.99(A) 668 568 j^N- Me '7 [P° _n _v 0 At On nA Me i l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-M -(2cyclopropylpropan2-yl)-5-(2methylpyrimidin-5 yl)-1 H-indazole-3 carboxamide * 2.30(A) 684

- 505 041794

570 Me Before ^Me ,N. vq HN-D H ° #T Ά l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl)-5methyl-2- azabicyclo[3.1.0]hexan-2-yl)-2oxoethyl)-M-(tert-butyl)-5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide * 2.14 (A) 658 571 Vg AtU Ch 0 < G Q Ν'\_/ SO ₂ Me °Αθ A No. D (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-3-((4- (methylsulfonyl)pi peridium-l- yl)methyl)pyridin-2yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.28 (A) 776 572 F. F С Λχ4 ^Ν w Τ 0 Vg Do dΎ D aTL 0 Ν (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(6bromo-4-(2,2,2trifluoroethyl)pyridium n-2-yl)-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide *** 573 574 575 Me YES YES ^Me F w HN-D A ° P, ⁿ \\\ A ba D-Q ° Y nA D J /Md o UT nA l-(2-((lR,3S,5R)-3((6-bromo-3methylpyridin-2yl)carbamoyl) - 5 methyl-2azabicyclo [3.1.0]hexan-2-yl)-2oxoethyl)-M -(but-3yn-2-yl)-5-(2methylpyrimidin-5yl)-1 H-indazole-3 carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidine -5yl)-1 H-indazol-1 yl)acetyl)-Mbenzyl-5-methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(2methoxybenzyl)-5 methyl-2azabicyclo [3.1.0]hex san-3-carboxamide *** *** *** 1.87 (A) 1.88 (A) 1.94 (A) 654 536 566

- 506 041794

576 Αχ A A Oh wow nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3methoxybenzyl)-5methyl-2azabicyclo [3.1.0]hex san-3-carboxamide *** 1.86 (A) 566 577 Αχ A+ ΟΛ /° ° A lot of nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(4methoxybenzyl)-5 methyl-2 - azabicyclo[3.1.0]hexan-3-carboxamide *** 1.90 (A) 566 578 EF \__ NH ^N 0 N^^ ⁿ pca 0<U ^x N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-((R)-1- (trifluoromethoxy)propan-2-yl)-2azabicyclo [3.1.0]hexan-3-carboxamide 579 Va ^hn A <L >S h N 0 CF ₃ 6 ° Nx/4 <TA ΑιΓΐ oA CA XN (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-(2- (trifluoromethoxy)this l)-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 580 x/ F 7 Am 0A\ nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-((8)-1- phenylethyl) 2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.93 (A) 550 581 oA ^z x A /7 hum (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-((R)-1 - phenylethyl) 2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.92 (A) 550 582 ^oAz >7 ² . \ ²¹ L/ Tl (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-LF-(2fluorobenzyl)-5methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.87 (A) 554

- 507 041794

583 Hell l/ gu (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(3fluorobenzyl)-5methyl-2azabicyclo [3.1 .0]gec san-3-carboxamide *** 1.86 (A) 554 584 οό ^ζ > Hell A /Ά A (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(4fluorobenzyl)-5methyl-2- azabicyclo[3.1.0]hexan-3-carboxamide *** 1.88 (A) 554 585 586 587 588 pA Ad rdd P^ y l* DD ⁷ SU ⁷ C< (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(2-methylbenzyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(3-methylbenzyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(4-methylbenzyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)4,4-dimethylpentan2-yl)- 5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** *** *** ** 1.95 (A) 1.96 (A) 1.96 (A) 550 550 550

- 508 041794

589 590 591 592 4 \^\ NH A' O ¢0° N^^x y j Ί 40 °L X 0 ⁴ N \__HN—ζ F A ° ( A ^Cl C ° ⁿ CiQ oA A \ N \ '0 st J Aq ° FA nA 04 AAA / N jQa ⁰ F^N nA (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-N-((R)4,4-dimethylpentan2-yl)- 5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)-1(3-chloro-2fluorophenyl) )ethyl) - 5 methyl-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H- indazol-1 yl)acetyl)-5-methylM-(pyrimidin-2ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(pyrimidin-4ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** *** *** ** 1.37 (A) 1.32 (A) 538 538 593 4- 4°V Aq ° FA nA (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(pyrimidin-5ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.31 (A) 538 594 oAz M _f y (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(pyridin-2ylmethyl)-2azabicyclo [3.1.0]hexan-3-carboxamide *** 1.24 (A) 537

- 509 041794

595 596 597 598 599 K .Ν/ jn 0 N=0 Ά A “ 0 Ca ⁰ Y^ N N=0 A Lo ⁰ AA Ca ⁰ y^N N=0 V\ HN—ζ ΛΗ q N^A ^N d JL ί oA < A \ N YYa0a n^a ^N d jl oA XA XN (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(pyridin-3ylmethyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylChG-(pyridin-4ylmethyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylX-(pyridazin-3ylmethyl)-2azabicyclo [3.1.0]gek san-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-((S)-l-(ptolyl)ethyl )-2azabicyclo [3.1.0]hexan-3-carboxamide (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)-1(3-chlorophenyl)eti )5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide *** *** *** ** *** 1.15 (A) 1.13 (A) 1.26 (A) 537 537 538 600 Aa/v Ao θ N^A\0X01 oA X A (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-X-((8)-1(2-fluorophenyl)ethyl) 5-methyl-2azabicyclo[3.1.0]hexane-3-carboxamide *** 601 Al. hnA '' 000Q \ Cl nv4 ⁿ CX0L oA XA XN \ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-X-((K)-1(3-chloro-2fluorophenyl) )ethyl) - 5 methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide *** 602 AX L ° / 1 ⁰ A NA OsH J )s ^Ax ° ^X y^N N^ (lR,3S,5R)-N-(6bromo-3- methylpyridin-2-yl)5-methyl-2-(2-(5-(2methylpyrimidin-5yl)-3- (methylsulfonyl)1 H-pyrazolo [3,4c]pyridin-1yl)acetyl)-2azabicyclo [3.1.0]hexane-3-carboxamide 1.53 (A) 640

- 510 041794

603 co ₂ n >D < Br N o Z ^NH 2 ° nA AGU ⁰ \ < J 2-((lR,3S,5R)-2-(2-(3acetyl-7- (aminomethyl)-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methyl2- azabicyclo[3.1.0]hexan-3carboxamido)-6bromisonicotinic acid *** 1.39 (A) 660 604 Ή ,N. / jCq Ο n\ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(2cycle ohexylethyl)-5 methyl-2 - azabicyclo[3.1.0]hex san-3-carboxamide *** 2.29 (A) 556 605 Ή „N / cm ° St (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(2-(piperidin-1yl )ethyl)-2azabicyclo[3.1.0]hex san-3-carboxamide * 1.23 (A) 557 606 0^7 A ύ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylM-(2-(tetrahydro-2Hpyran -4-yl)ethyl)-2azabicyclo[3.1.0]hexan-3-carboxamide ** 1.55 (A) 558 607 [^° zN^ J CM ° St N=\ (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylN-(2morpholinoethyl)-2azabicyclo [3.1 .0]gec san-3-carboxamide ** 1.14 (A) 559 608 Ή ro CM ° St (lR,3S,5R)-2-(2-(3acetyl-7-methyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-(2cycle pentylethyl) - 5 methyl- 2- azabicyclo[3.1.0]hexan-3-carboxamide 2.14 (A) 542 609 Nyl Ή ο ^=0 Αί X Α^ΑΑ ο=\ X Μ X N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-Misopentyl-5-methyl2- azabicyclo[3.1.0]hexan-3-carboxamide

-511 041794

610 •С NN\ ⁰ \ HN- '0 ABOUT XX (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-5-methylH-((8)-3-methylbutan2-yl) -2- azabicyclo[3.1.0]hexan-3-carboxamide 611 b ΝN\ ⁰ \ HN- '0 ABOUT 7 χχ (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)- 1H-indazol-1 yl)acetyl)-H-((8)3,3-dimethylbutan-2yl)-5 -methyl-2azabicyclo[3.1.0]hexan-3-carboxamide 612 XL / ^N N-N\ ⁰ \ HN- 0 '0 about XX (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)- 1H-indazol-1 yl)acetyl)-5-methyl- M-((8)-pentan-2-yl)2- azabicyclo[3.1.0]hexan-3-carboxamide 613 TG ) Ή N- N\ ⁰ \ HN- 0'o o XX (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)- 1H-indazol-1 yl)acetyl)-N-((8)hexan-2-yl)-5methyl-2 - azabicyclo[3.1.0]hexan-3-carboxamide 614 )/T / ^N N\ ⁰ \ HN— 0=0 XX N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)heptan-2-yl)-5methyl- 2- azabicyclo[3.1.0]hexane-3-carboxamide 615 >/'[ \ Ή NN\ ⁰ \ HN— ABOUT b F XX N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)-1(4-fluorophenyl)ethyl) 5-methyl-2azabicyclo [3.1.0 ]hexane-3-carboxamide 616 b N\ ⁰ \ HN- ^s 0 O X XX N (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrimidin-5yl)-1 H-indazol-1 yl)acetyl)-M-((8)-1(2,3- d im ethyl phenyl l) these l) 5-methyl-2- azabicyclo[3.1.0]hexane-3-carboxamide 617 >/'[ \ ^N N- N\ ⁰ \ HN— About ^g 0 about Br ^Ν Η VP γ%Α (lR,3S,5R)-2-(2-(3acetyl-5-(2methylpyrazolo[1,5a]pyrimidin-6-yl)1 H-pyrazolo[3,4c]pyridin-1yl)acetyl)-M-( 6bromo-3methylpyridin-2-yl)5-methyl-2azabicyclo [3.1.0 ]hexane-3-carboxamide *** 1.94 (A) 642

- 512 041794

Table 8

Additional non-limiting examples of compounds of the present invention

Connection no.

(1k,38.5k)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5yl)-7-(2H-tetrazol-5-yl)-1H-indazol-1-yl)acetyl) -M(6-bromo-3-methylpyridin-2-yl)-5-methyl-2_______azabicyclo [3.1.0]hexane-3-carboxamide______

Vg

O (8)-1-(5-(3-acetyl-1-(2-((1K,38.5K)-3-((6-bromo-3methylpyridin-2-yl)carbamoyl)-5-methyl- 2azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1Nindazol-5-yl)pyrimidin-2-yl)-24-carboxy-

MS (M+1)

- 513 041794

(5 S,8 S)-7-(2-(3-acetyl-7-methyl-5-(2-methylpyrimidin5-yl)-1 H-indazol-1-yl)acetyl)-4-(6-bromo -3methylpyridin-2-yl)-3-phenyl-1-oxa-2,7diazaspiro [4,4 J non-2-en-8-carboxamide (88)-7-(2-(3-acetyl-7-methyl -5-(2-methylpyrimidin-5yl)-1H-indazol-1-yl)acetyl)-\-(6-bromo-3methylpyridin-2-yl)-3-cyclohexyl-1-oxa-2,7diazaspiro [4, 4] non-2-en-8-carboxamide

3,12,21,26-tetraoxo-5,8,14,17-tetraoxa-2,11,20,25tetraazatritetracontanoic acid

1K,38.5K)-2-(2-(3-acetyl-7-(but-3-en-1-yl)-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl )-M(6-bromo-3-methylpyridin-2-yl)-5-(hex-5enamidomethyl)-2-azabicyclo! 3.1.01hexane-3carboxamide (1k,3d,5k)-2-(2-(3-acetyl-5-(2-methylpyrimidin-5yl)-7-(trifluoromethyl)-III-indazol-1-yl)acetyl)- 4-(6orom-3-methylpyridin-2-yl)-5((dimethylamino)methyl)-2-azabicyclo[3.1.0]hexane-3(1k,3d,5k)-2-(2-(3-acetyl -7-cyclopropyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-4(6-bromo-3-methylpyridin-2-yl)-5((dimethylamino)methyl)-2 -azabicycloGZ. 1.0]hexane-3carboxamide carboxamide

- 514 041794

- 515 041794

- 516 041794

azabicyclo 13. 1.0]hexan-5-yl)-24-carboxy-3,12,21,26tetraoxo-5,8,14,17-tetraoxa-2,11,20,25tetraazatritetracontan-43-oic acid (8)- 1-((1k,38.5I)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-3 (( 6-bromo-3-methylpyridin-2-yl)carbamoyl)-2azabicycloG3.1.01hexan-5-yl)-24-carboxy-3,12,21,26tetraoxo-5,8,14,17-tetraoxa-2,11 ,20,25tetraazatritetetracontan-43-oic acid N-indazol-1 -yl)acetyl)-3 ((6-bromo-3-methylpyridin-2-yl)carbamoyl)-2azabicyclo13.1.01hexan-5-yl)-24-(methoxycarbonyl)3,12,21, 26-tetraox co-5,8,14,17-tetraoxa-2,11,20,25tetraazatritetetracontan-43-oat

S-methyl 1-5-3-acetyl-1-2-1R,3S,5R-3-6-bromo3-methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo! 3.1.01hexan-2-yl)-2-oxoethyl)-7-methyl1H-indazol-5-yl)pyrimidin-2-yl)-24(methoxycarbonyl)-3,12,21,26-tetraoxo-5,8, 14,17tetraoxa-2,11,20,25-tetraazatritetetracontan-43-oat

- 517 041794

- 518 041794

- 519 041794

(8)-1-(5-(3-acetyl-1-(2-((1K,38.5K)-3-((6-bromo-3methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo [3.1.0]hexan-2-yl)-2-oxoethyl)-1Hpyrazolo[3,4-c]pyridin-5-yl)pyrimidin-2-yl)-24carboxy-3,12,21,26-tetraoxo- 5,8,14,17-tetraoxa2,11,20,25-tetraazatritetracontanoic acid

ABOUT

(8)-1-((1K,38.5K)-2-(2-(3-acetyl-5-(2methylpyrimidin-5-yl)-1 H-pyrazolo[3,4-c]pyridin-1 yl )acetyl)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-2-azabicyclo[3.1.0]hexan-5-yl)-24carboxy-3,12,21,26-tetraoxo-5, 8,14,17-tetraoxa2,11,20,25-tetraazatritetracontan-43-oic acid (Structure shown below) (4S,7S, 1OS, 13S, 16S, 198,228)-22-acetamido-4(((( 1K,38.5K)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-3 ((6-bromo- 3-methylpyridin-2-yl)carbamoyl)-2azabicyclo[3.1.0]hexan-5-yl)methyl)carbamoyl)10,16-bis(2-carboxyethyl)-7,19-bis(4hydroxybenzyl)-6.9 ,12,15,18,21-hexaoxo-13-(4palmitamidobutyl)-5,8,11,14,17,20hexaazapentacosanedioic acid

- 520 041794

Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-5-(2-methylpyrimidin-5-yl)-bG________propyl-1 H-indazole-3-carboxamide________

Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-LH-butyl-5-(2-methylpyrimidin-5-yl)____________1 H-indazole-3-carboxamide ____________

Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-5-(2-methylpyrimidin-5-yl)-L-pentyl-1 H-indazole-3-carboxamide

- 521 041794

Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-M-(cyclopropylmethyl)-5-(2methylpyrimidin-5-yl)-1H-indazole-3-carboxamide

Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-M-(cyclobutylmethyl)-5-(2methylpyrimidin-5-yl)-1H-indazole-3-carboxamide Me

Br

Me

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2- oxoethyl)-5-(2-methylpyrimidin-5-yl)-Neopentyl-1 H-indazole-3-carboxamide

- 522 041794

Me

Br

Me

N-(2-aminoethyl)-1 -(2-(( 1R,3 S,5R)-3-((6-6poM-3 methylpyridin-2-yl)carbamoyl)-5-methyl-2azabicyclo[3.1, 0]hexan-2-yl)-2-oxoethyl)-5-(2methylpyrimidin-5-yl)-1H-indazole-3-carboxamide

Me

Br

Me l-(2-((lR,3S,5R)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2 -oxoethyl)-CH-(2-(methylamino)ethyl)-5-(2methylpyrimidin-5-yl)-1H-indazole-3-carboxamide Me

Br

Me l-(2-((lR,3S,5R)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.0]hexan-2yl)-2 -oxoethyl)-CH-(2-(dimethylamino)ethyl)-5-(2methylpyrimidin-5-yl)-1H-indazole-3-carboxamide

- 523 041794

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl (carbamoyl)-5-methyl-2-azabicyclo 3.1.0 hexan-2yl)-2-oxoethyl) -5-(2-methylpyrimidin-5-yl)-M-(2,2,2trifluoroethyl)-1 H-indazole-3-carboxamide (1k, 38.5k)-2-(2-(3-acetyl-7 -methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-Mheptyl-5-methyl-2-azabicyclo13.1.01hexane-3carboxamide (1k,38.5k)-2-(2 -(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5methyl-M-octyl-2-azabicyclo13.1.01hexane-3carboxamide

11k, 38.5K)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5methyl-M-nonyl-2- azabicyclo13.1.01hexane-3carboxamide

1-(2-((1K,38.5K)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicycloG3. 1.01hexan-2yl)-2-oxoethyl) -7-cyano-5-(2-methylpyrimidin-5-yl)1 H-indazol-3-carboxamide

1-(2-((1k,38.5k)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo13.1.01hexan-2yl)-2-oxoethyl)- M-isobutyl-5-(2-methylpyrimidin-5yl)-1 H-indazole-3-carboxamide

- 524 041794

(1K,38.5K)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-Mdecyl-5-methyl-2 -azabicyclo[3.1.0]hexane-3__________________carboxamide__________________ (Structure shown below) (4S,7S, 1OS, 13S, 16S, 198.228)-22-acetamido-4-(( 1 ((1K,38.5K)-2 -(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1 H-indazol-1 -yl)acetyl)-3 ((6-bromo-3-methylpyridin-2-yl) carbamoyl)-2azabicyclo[3.1.0]hexan-5-yl)-3-oxo6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51, 54,57,60.6 3,66,69,72,75-tetracosaoxa-2-azaheptageptacontan-77yl)carbamoyl)-10,16-bis(2-carboxyethyl)-7,19-bis(4hydroxybenzyl)-6, 9,12,15,18,21 -hexaoxo-13-(4palmitamidobutyl)-5,8,11,14,17,20_________hexaazapentacosanedioic acid_________

(1K,38.5K)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1 H-indazol-1-yl)acetyl)-5methyl-M-(4 -phenylbutyl)-2-azabicyclo[3.1.0]hexane-3carboxamide

- 525 041794

(1kD8.5k)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl)acetyl)-5methyl-H-(6-phenylhexyl) -2-azabicyclo 3 L.0 hexane3-carboxamide (1K,38.5K)-2-(2-(3-acetyl-7-methyl-5-(2methylpyrimidin-5-yl)-1H-indazol-1-yl )acetyl)-5methyl-M-(5-phenylpentyl)-2-azabicyclo[3.1.01hexane3-carboxamide

1-(2-((1K,38.5k)-3-((6-bromo-3-methylpyridin-2yl)carbamoyl)-5-methyl-2-azabicyclo[3.1.01hexan-2yl)-2-oxoethyl) -M-(sec-butyl)-5-(2methylpyrimidin-5-yl)-1 H-indazole-3-carboxamide

Example 10 Human Factor D Assay.

Human factor D (purified from human serum, Complement Technology, Inc.) at a final concentration of 80 nM is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1 M NaCl, pH 7.5. Synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent) are added to a final concentration of 100 μM each. Absorption at 405

- 526 041794 nm (A ₄₀₅ ) recorded at 30 second intervals for 30 minutes using a microplate spectrophotometer. IC ₅₀ values are calculated by non-linear regression of complement factor D reaction rates as a function of test compound concentration.

Example 11 Hemolysis Assay

The hemolysis assay has been previously described by G. Ruiz-Gomez, et al., J. Med. Chem. (2009) 52: 6042-6052. Before analysis, the optimal concentration of normal human serum (NHS) necessary to achieve 100% lysis of rabbit erythrocytes (RE) is determined by titration. In this assay, NHS (Complement Technology) is diluted in GVB ⁰ buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement Technology) plus 10 mM Mg-EGTA and incubated with test compound at various concentrations for 15 min at 37°C. RE (Complement Technology) freshly suspended in GVB ⁰ plus 10 mM Mg-EGTA was added to a final concentration of 1 x 10 ⁸ cells/ml and the reactions were incubated for 30 min at 37°C. Positive control reactions (100% lysis) consist of GVB ⁰ plus 10 mM Mg-EGTA with NHS and RE but no test compound; negative control reactions (0% lysis) consist of GVB ⁰ plus 10 mM Mg-EGTA with RE only. Samples are centrifuged at 2000 g for 3 min and supernatants are collected. Absorbance at 405 nm (A405) was recorded using a microplate spectrophotometer. IC ₅₀ values are calculated by non-linear regression from percent hemolysis as a function of test compound concentration.

This description has been made with reference to embodiments of the invention. However, one skilled in the art will appreciate that various modifications and changes may be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the description is to be considered in an illustrative and not a limiting sense, and all such modifications are intended to be included within the scope of the invention.

Claims (35)

CLAIM 1. Compound formula or a pharmaceutically acceptable salt thereof; R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are independently selected from halo and C ₁ -C ₆ alkyl; C5 selected from: L represents L3 is -C(O)-; R ⁵ is hydrogen or C ₁ -C ₆ alkyl; R ⁶ is selected from halogen, -CHO, -C(O)NH2, -C2-C6 alkanoyl, -C(O)NH(CH3), -C(O)OR ⁹ and CrC ₆ alkyl; R ⁸ and R ⁸ are hydrogen; R ⁹ is selected from hydrogen and C ₁ -C ₆ alkyl; X ¹¹ is N or CR ¹¹ ; X ¹² is CR ¹² ; X ¹³ is N or CR ¹³ ; - 527 041794 X ¹⁴ is CR ¹⁴ ; where one of R ¹² and R ¹³ is R ³² and the other is R ³¹ ; and where in the absence of R ¹³ , R ¹² represents R ³² ; R ³¹ is independently selected from hydrogen, halogen, -COOH, C ₁ -C ₆ -alkoxy and -C(O)OR ⁹ , R ³² is selected from 5-7 membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S and 8-10 membered bicyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (mono- and di-C1- C ₆ alkylamino)C ₀ -C ₂ -alkyl, -C ₀ -C ₆ -alkyl-(4-6-membered heterocycle containing at least one heteroatom selected from N, O or S) and C ₁ -C ₆ -haloalkoxy; or R ³² selected from R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -C ₀ -C ₄ -alkyl (mono - and di-C ₁ -C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) and C ₁ -C ₆ -haloalkyl. 2. The connection according to claim 1, where B is selected from: 3. The connection according to claim 1, where B is selected from: 4. A compound according to any one of claims 1 to 3, wherein R ³² is selected from: 5. A compound according to any one of claims 1 to 3, wherein R ³² is 6. A compound according to any one of claims 1 to 3, wherein R ³² is 7. A compound according to any one of claims 1 to 3, wherein R ³² is a 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S and optionally substituted with 1 or 2 substituents selected from halogen, hydroxyl, amino, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, (mono- and di-C1-C ₆ alkylamino) C ₀ -C ₂ -alkyl, -C ₀ -C ₆ -alkyl-( 4-6-membered heterocycle containing at least one heteroatom selected from N, O or S) and C1-C ₆ -haloalkoxy. 8. A compound according to claim 7 wherein the optional substituents are selected from halogen, hydroxyl and C1-C6 alkyl. 9. A compound according to any one of claims 1 to 8, wherein C5 is 10. A compound according to any one of claims 1 to 8, wherein C5 is 11. A compound according to any one of claims 1 to 10, wherein R ¹⁴ is hydrogen. 12. A compound according to any one of claims 1 to 10, wherein R ¹⁴ is methyl. 13. A compound according to any one of claims 1 to 12, wherein R ¹¹ is hydrogen. 14. A compound according to any one of claims 1 to 13, wherein R ³¹ is hydrogen. 15. Connection selected from: - 528 041794 or a pharmaceutically acceptable salt thereof. 16. A compound of formula or a pharmaceutically acceptable salt thereof. 17. A compound of formula or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition for the treatment of a disorder mediated by complement factor D, comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. A method of treating a disorder mediated by complement factor D, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the subject is a human. 21. The method of claim 19 or 20, wherein the disorder is selected from acute respiratory distress syndrome, age-related macular degeneration (AMD), arthritis, asthma, Alzheimer's disease dementia, amyotrophic lateral sclerosis, antibody-mediated transplant rejection, anti-neutrophil cytoplasmic antibody-associated vasculitis , antiphospholipid syndrome, atypical or typical hemolytic uremic syndrome, cardiovascular disease, cold agglutination syndrome, chronic obstructive pulmonary disease (COPD), cirrhosis, Crohn's disease, CS-glomerulopathy, C3-glomerulonephritis, diabetic retinopathy, dense sediment disease, dermatomyositis, dermatitis, acquired epidermoly bullosa - 529 041794 for, fatty liver, focal segmental glomerulosclerosis, geographic retinal atrophy, glomerulonephritis, graft versus host disease, Guillain-Barré syndrome, hemolytic anemia, suppurative hidradenitis, IgA nephropathy, ischemia-reperfusion injury, liver failure, inflammation of the liver, lupus nephritis, membranoproliferative glomerulonephritis, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, optomyelitis, non-alcoholic steatohepatitis (NASH), ophthalmic disease, pancreatitis, paroxysmal nocturnal hemoglobinuria, pemphigoid, pemphigus vulgaris, preeclampsia, reduced glomerular filtration rate, renovascular disease , retinal degeneration, retinal detachment, rheumatoid arthritis, scleroderma, Shiga toxin-associated sepsis E. coli hemolytic uremic syndrome, spinal cord injury, sickle cell anemia, craniocerebral trauma and ulcerative colitis. 22. The method of claim 21 wherein the disorder is age-related macular degeneration (AMD). 23. The method of claim 21, wherein the disorder is retinal degeneration, ophthalmic disease, multiple sclerosis, arthritis, COPD, cardiovascular disease, atypical or typical hemolytic uremic syndrome, or respiratory disease, or rheumatoid arthritis. 24. The method of claim 21 wherein the disorder is IgA nephropathy. 25. The method of claim 21 wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH). 26. The method of claim 21 wherein the disorder is geographic retinal atrophy. 27. The method of claim 21 wherein the disorder is lupus nephritis. 28. The method of claim 21 wherein the disorder is sickle cell anemia. 29. The method of claim 21 wherein the disorder is myasthenia gravis. 30. The method of claim 21 wherein the disorder is C3 glomerulopathy. 31. The method of claim 21 wherein the disorder is O3 glomerulonephritis or hard sediment disease. 32. The method of claim 21 wherein the disorder is a decrease in glomerular filtration rate. 33. The method of claim 21 wherein the disorder is a renovascular disorder. 34. The method of claim 21, wherein the disorder is opticomyelitis. 35. The use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a complement factor D mediated disorder in a subject. 36. Use according to claim 35, where the subject is a human. NaBH ₄ , LiCI ^“^^OH BzCI,Et ₃ NV O k EtOH,THF, N _THF ^r 1 Vos ή— ιζ Vos ' 1 Rm. pace. room pace. 16h 16h Stage 1 Stage 2 syun ₂ 1 λΎ _ _and -------- '4 \ OBz NH ₃ /MeOH '7 \___/OH Et ₂ Zn toluene * N 0°С to-5°С, N Room pace. _at 6 o'clock ^{Sun 48 4} Stage 3 ^{Stage 4} /n ^r 2A 4d FA ^dcm H-A 4 7 Sun O room. pace. Vos O / Zch Stage 6 FIG. 1 x ^x F ||A m-CPBA T jT t-BuNH ₂ ^ CHCI ₃ ^{Br DCE} 1 ⁰ 2 Rxn#1: 2.4 g out of 2.5 g 1 Fig. 2 ~\___ _/ OBz N Sun PDC DMF room pace. 16h Stage 5 Ax/ ^F ΙΑ N Br t °3 - 530 -